IP Library › Granted Patent US 11,098,040

Granted Patent B2

US 11,098,040 · App. 16/287,805 · Granted Aug 24, 2021

Compounds and methods of use

Inventors: Chun Jiang (Hillsborough, CA); Ruihong Chen (Burlingame, CA); Anjali Pandey (Fremont, CA); Biswajit Kalita (Bangalore, IN); Athisayamani Jeyaraj Duraiswamy (Bangalore, IN)

Assignee: Ferro Therapeutics, Inc.

C07D471/04 A61P35/00 C07D217/04 C07D217/14 C07D217/26 C07D495/04 A61K45/06 A61K47/40

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Quick Facts

Patent No.: US 11,098,040
App. No.: 16/287,805
Granted: Aug 24, 2021
Kind: B2

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Abstract

This present disclosure relates to compounds with ferroptosis inducing activity, a method of treating a subject with cancer with the compounds, and combination treatments with a second therapeutic agent.

Claims (154)

1. A compound of formula (I):

or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein:

ring A is C 4 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

X is NR 5 , O, or S;

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —CN, —OH, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —S(O)R 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —NO 2 , —OR 8 , —C 1 -C 6 alkyl-OH, —C 1 -C 6 alkyl-OR 8 , or —Si(R 15 ) 3 ;

R 2 is —C(O)R 9 ;

each R 3 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 12 ) 3 , —SF 5 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)R 8 , —C(O)R 6 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl of R 3 is independently optionally substituted with one to three R 10 ;

each R 4 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 15 ) 3 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —OC(O)R 8 , —C(O)R 6 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl of R 4 is independently optionally substituted with one to three R 10 ;

R 5 is hydrogen or C 1 -C 6 alkyl;

each R 6 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl; wherein each R 6 is optionally independently further substituted with one to three R 11 ;

each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 6 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, or two R 7 together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocyclyl, wherein each R 7 or ring formed thereby is optionally independently further substituted with one to three R 11 ;

each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each R 8 is optionally independently further substituted with one to three R 11 ;

R 9 is C 2 alkynyl optionally substituted with one —CH 3 ;

each R 10 is independently halo, —CN, —OR 12 , —NO 2 , —N(R 12 ) 2 , —S(O)R 13 , —S(O) 2 R 13 , —S(O)N(R 12 ) 2 , —S(O) 2 N(R 12 ) 2 , —Si(R 12 ) 3 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —OC(O)R 12 , —OC(O)OR 12 , —OC(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —OC(O)CHR 12 N(R 12 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 10 is optionally independently substituted with one to three R 11 ;

each R 11 is independently halo, —CN, —OR 12 , —NO 2 , —N(R 12 ) 2 , —S(O)R 13 , —S(O) 2 R 13 , —S(O)N(R 12 ) 2 , —S(O) 2 N(R 12 ) 2 , —Si(R 12 ) 3 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —OC(O)R 12 , —OC(O)OR 12 , —OC(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —OC(O)CHR 12 N(R 12 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R 12 is independently hydrogen, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl;

each R 13 is independently C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl; and

each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, and heteroarylC 2 -C 6 alkenyl-.

2. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, represented by formula (II):

3. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, represented by formula (III):

4. The compound of claim 1 , wherein ring A is C 4 -C 10 cycloalkyl.

5. The compound of claim 1 , wherein ring A is heterocyclyl.

6. The compound of claim 1 , wherein ring A is aryl.

7. The compound of claim 1 , wherein ring A is heteroaryl.

8. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —CN, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —OH, —OR 8 , —C 1 -C 6 alkyl-OH, or —C 1 -C 6 alkyl-OR 8 .

9. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —NH 2 , —NHR 8 , —N(R 8 ) 2 , —OH, —OR 8 , —C 1 -C 6 alkyl-OH, or —C 1 -C 6 alkyl-OR 8 .

10. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.

11. The compound of claim 1 , or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, represented by formula (IV):

12. The compound of claim 1 , wherein each R 4 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 15 ) 3 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —OC(O)R 8 , —C(O)R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl of R 4 is independently optionally substituted with one to three R 10 .

13. The compound of claim 1 , wherein each R 4 is independently halo, —CN, —OH, —OR 8 , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl of R 4 is independently optionally substituted with one to three R 10 .

14. The compound of claim 1 , wherein p is 0.

15. The compound of claim 1 , wherein q is 0.

16. The compound of claim 1 , wherein p is 1, 2, or 3.

17. The compound of claim 1 , wherein q is 2 or 3.

18. A pharmaceutical composition comprising a compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable carrier.

19. A compound of formula (V):

or an enantiomer or pharmaceutically acceptable salt thereof, wherein:

X is N, O, or S;

A is a 4- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 1 is H, C 1 —C 6 alkyl, —C 1 —C 6 alkylhalo, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —SO 2 R 8 , —SOR 8 , NO 2 , —OR 8 , —C 1 —C 6 alkyl—OR 12 , or —Si(R 15 ) 3 ;

R 2 is —C(O)R 9 ;

R 3 is H, halo, —C(O)OR 10 , —C(O)N(R 11 ) 2 , —OC(O)R 10 , —C 0 —C 6 alkylC 3 —C 8 cycloalkyl, —C 0 -C 6 alkylheterocyclyl, —N(R 11 ) 2 , —SO 2 R 8 , —SOR 8 , —NO 2 , or —Si(R 15 ) 3 ;

R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12, —C 1—C 6 alkyl-OR 12 , —C 1 —C 6 alkyl—NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

p is 0, 1, 2, or 3;

each R 6 is independently C 1 —C 6 alkyl, C 3 —C 6 alkyl, C 2 —C 6 alkynyl, C 2 —C 6 alkynyl,

C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1—C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, (R 11 ) 2 NC 1 —C 6 alkyl—, or (R 11 ) 2 NC 2 —C 6 alkenyl-;

each R 7 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O—C 1 —C 6 alkyl-, or R 12 O(O)C—C 1 —C 6 alkyl-, or two R 7 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is optionally substituted with OH, halo, C 1 —C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N-, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 8 is independently C 1 —C 6 alkyl, C 3 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2—C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, (R 11 ) 2 NC 1 —C 6 alkyl-, or (R 11 ) 2 N-;

R 9 is C 2 alkynyl;

R 10 is C 1 —C 6 alkyl, C 2 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 13 (NH 2 )CH-, R 14 C 0 —C 6 alkyl-, or (R 15 ) 3 SiC 0 —C 6 alkyl-;

each R 11 is independently H, C 1 —C 6 alkyl, C 2 C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1—C 6 aliphatic-, R 12 O—C 1 —C 6 alkyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O(O)C—C 1 —C 6 alkyl—, R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl—, (R 15 ) 3 SiC 0 —C 6 alkyl-, or an N-protecting group, or two R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has optionally 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is optionally substituted with OH, halo, C 1 C 6 alkyl, C 1 —C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with OH, halo, —NH 2 , or C 1 —C 6 alkyl, or when containing 2 or more N atoms is optionally substituted with an N- protecting group;

each R 12 is independently H or C 1 —C 6 alkyl;

each R 13 is independently H, C 1 —C 6 alkyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, or an N protecting group;

R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R 15 is independently C 1 —C 6 alkyl, C 2 —C 6 alkenyl, aryl, heteroaryl, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, or heteroarylC 2 —C 6 alkenyl-;

wherein each C 1 —C 6 alkyl, —C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently optionally substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 —C 6 alkyl, C 1 —C 6 alkyl—O—, R 12 O—C 1 —C 6 alkyl(O)C—, and R 12 O(O)C—.

20. The compound of claim 19 , having the structure formula (Va):

or an enantiomer or pharmaceutically acceptable salt thereof,

wherein:

X is N, O, or S;

R 1 is C 1 —C 6 alkyl, —C 1 —C 6 alkylhalo, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —SO 2 R 8 , —SOR 8 , NO 2 , —OR 8 , —C 1 —C 6 alkyl—OR 12 , or —Si(R 15 ) 3 ;

R 2 is —C(O)R 9 ;

R 3 is —C(O)OR 10 , —C(O)N(R 11 ) 2 , —OC(O)R 10 , —C 0 —C 6 alkylC 3 —C 8 cycloalkyl, —C 0 —C 6 alkylheterocyclyl, —N(R 11 ) 2 , —SO 2 R 8 , —SOR 8 , —NO 2 , or —Si(R 15 ) 3 ;

R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12, —C 1 —C 6 alkyl—OR 12 , —C 1 —C 6 alkyl—NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

p is 0, 1, 2, or 3;

each R 6 is independently C 1 —C 6 alkyl, C 3 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, or (R 11 ) 2 NC 2 —C 6 alkenyl-;

each R 7 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O—C 1 —C 6 alkyl-, or R 12 O(O)C—C 1 —C 6 alkyl-, or two R 7 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is optionally substituted with OH, halo, C 1 —C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 8 is independently C 1 —C 6 alkyl, C 3 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, (R 11 ) 2 NC 1 —C 6 alkyl-, or (R 11 ) 2 N-;

R 9 is C 2 alkynyl;

each R 11 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, R 12 O—C 1 —C 6 alkyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O(O)C—C 1 —C 6 alkyl- , R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl-, (R 15 ) 3 SiC 0 —C 6 alkyl-, or an N-protecting group, or two R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has optionally 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is optionally substituted with OH, halo, C 1 —C 6 alkyl, C 1 —C 6 alkyl—O(O)C-, (R 11 ) 2 N-, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with OH, halo, —NH 2 , or C 1 —C 6 alkyl, or when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 12 is independently H or C 1 —C 6 alkyl;

R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R 15 is independently C 1 —C 6 alkyl, C 2 —C 6 alkenyl, aryl heteroaryl, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, or heteroarylC 2 —C 6 alkenyl-;

21. The compound of claim 19 , having a structure of formula (Vg):

or an enantiomer or pharmaceutically acceptable salt thereof, wherein:

X is N, O, or S;

R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12, —C 1 —C 6 alkyl-OR 12 , —C 1 —C 6 alkyl-NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

p is 0, 1, 2, or 3;

each R 7 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O—C 1 —C 6 alkyl-, or R 12 O(O)C—C 1 —C 6 alkyl-, or two R 7 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is optionally substituted with OH, halo, C 1 —C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is optionally substituted with an N-protecting group;

R 9 is C 2 alkynyl;

each R 11 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, R 12 O—C 1 —C 6 alkyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O(O)C—C 1 —C 6 alkyl- , R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl-, (R 15 ) 3 SiC 0 —C 6 alkyl-, or an N-protecting group, or two R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has optionally 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is optionally substituted with OH, halo, C 1 —C 6 alkyl, C 1 —C 6 alkyl—O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with OH, halo, —NH 2 , or C 1 —C 6 alkyl, or when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 12 is independently H or C 1 —C 6 alkyl;

R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R 15 is independently C 1 —C 6 alkyl, C 2 —C 6 alkenyl, aryl, heteroaryl, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, or heteroarylC 2 —C 6 alkenyl-;

22. The compound of claim 19 , having as structure of formula (Vi):

or an enantiomer or pharmaceutically acceptable salt thereof, wherein:

X is N, O, or S;

R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12, —C 1 —C 6 alkyl-OR 12 , —C 1 —C 6 alkyl-NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

p is 0, 1, 2, or 3;

R 6 is independently C 1 —C 6 alkyl, C 3 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, (R 11 ) 2 NC 1—C 6 alkyl-, or (R 11 ) 2 NC 2 —C 6 alkenyl-;

R 8 is independently C 1 —C 6 alkyl, C 3 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, (R 11 ) 2 NC 1 —C 6 alkyl-, or (R 11 ) 2 N—;

R 9 is C 2 alkynyl;

each R 11 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, R 12 O—C 1 —C 6 alkyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O(O)C—C 1 —C 6 alkyl- , R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl-, (R 15 ) 3 SiC 0 —C 6 alkyl-, or an N-protecting group, or two R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has optionally 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is optionally substituted with OH, halo, C 1 —C 6 alkyl, C 1 —C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with OH, halo, —NH 2 , or C 1 —C 6 alkyl, or when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 12 is independently H or C 1 —C 6 alkyl;

each R 13 is independently H, C 1 —C 6 alkyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, or an N protecting group;

R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

R 15 is independently C 1 —C 6 alkyl, C 2 —C 6 alkenyl, aryl, heteroaryl, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, or heteroarylC 2 —C 6 alkenyl-;

23. The compound of claim 19 , having a structure of formula (Vj):

or an enantiomer or pharmaceutically acceptable salt thereof, wherein:

X is N, O, or S;

R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12, —C 1 —C 6 alkyl-OR 12 , —C 1 —C 6 alkyl-NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

P is 0, 1, 2, or 3;

each R 7 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O—C 1 —C 6 alkyl-, or R 12 O(O)C—C 1 —C 6 alkyl-, or two R 7 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is optionally substituted with OH, halo, C 1 —C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is optionally substituted with an N-protecting group;

R 8 is independently C 1 —C 6 alkyl, C 3 —C 6 , C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, (R 11 ) 2 NC 1 —C 6 alkyl-, or (R 11 ) 2 N-;

R 9 is C 2 alkynyl;

each R 11 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, R 12 O—C 1 —C 6 alkyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O(O)C—C 1 —C 6 alkyl- , R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl-, (R 15 ) 3 SiC 0 —C 6 alkyl-, or an N-protecting group, or two R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has optionally 0, 1, or 2 additional heteroatoms selected from nitrogen oxygen, and sulfur, and the heterocyclyl is optionally substituted with OH, halo, C 1 —C 6 alkyl, C 1 —C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with OH, halo, —NH 2 , or C 1 —C 6 alkyl, or when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 12 is independently H or C 1 —C 6 alkyl;

each R 13 is independently H, C 1 —C 6 alkyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl—, adamantyl, adamantylC 1 —C 6 aliphatic-, or an N protecting group;

R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R 15 is independently C 1 —C 6 alkyl, C 2 —C 6 alkenyl, aryl, heteroaryl, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, or heteroarylC 2 —C 6 alkenyl-;

wherein each C 1 —C 6 alkyl, —C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently optionally substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 —C 6 alkyl, C 1 —C 6 alkyl-O—, R 12 O—C 1 —C 6 alkyl(O)C—, and R 12 O(O)C—.

24. The compound of claim 19 , having a structure of formula (Vn):

or an enantiomer or pharmaceutically acceptable salt thereof, wherein:

X is N, O, or S;

R 1 is C 1 —C 6 alkyl, —C 1 —C 6 alkylhalo, or —C 1 —C 6 alkyl-OR 12 ;

R 2 is —C(O)R 9 ;

R 4 is independently halo, CN, —NH 2 , —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12 , —C 1 —C 6 alkyl-OR 12 , —C 1 —C 6 alkyl-NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

p is 0, 1, 2, or 3;

R 9 is C 2 alkynyl;

R 10 is C 1 —C 6 alkyl, C 2 —C 6 alkyl, C 2 —C 6 alkenyl, C 2 —C 6 alkynyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl-, or (R 15 ) 3 SiC 0 —C 6 alkyl-;

each R 11 is independently H, C 1 —C 6 alkyl, C 2 —C 6 alkenyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 —C 6 cycloalkylC 1 —C 6 alkyl-, C 3 —C 6 cycloalkylC 3 —C 6 cycloalkylC 2 —C 6 alkenyl-, heterocyclylC 1 —C 6 alkyl-, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, R 12 O—C 1 —C 6 alkyl-, (R 11 ) 2 NC 1 —C 6 alkyl-, (R 11 ) 2 NC 2 —C 6 alkenyl-, R 12 O(O)C—C 1 —C 6 alkyl- , R 13 (NH 2 )CH—, R 14 C 0 —C 6 alkyl-, (R 15 ) 3 SiC 0 —C 6 alkyl-, or an N-protecting group, or two R 11 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has optionally 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is optionally substituted with OH, halo, C 1 —C 6 alkyl, C 1 —C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with OH, halo, —NH 2 , or C 1 —C 6 alkyl, or when containing 2 or more N atoms is optionally substituted with an N-protecting group;

each R 12 is independently H or C 1 —C 6 alkyl;

each R 13 is independently H, C 3 —C 6 alkyl, C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylC 2 —C 6 alkenyl-, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, heteroarylC 2 —C 6 alkenyl-, adamantyl, adamantylC 1 —C 6 aliphatic-, or an N protecting group;

R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R 15 is independently C 1 —C 6 alkyl, C 2 —C 6 alkenyl, aryl, heteroaryl, arylC 1 —C 6 alkyl-, arylC 2 —C 6 alkenyl-, heteroarylC 1 —C 6 alkyl-, or heteroarylC 2 —C 6 alkenyl-;

wherein each C 1 —C 6 alkyl, —C 3 —C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently optionally substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 —C 6 alkyl, C 1 —C 6 alkyl-O—, R 12 O—C 1 —C 6 alkyl(O)C—, and R 12 O(O)C—.

25. The compound of claim 19 , having a structure of formula (Vp):

or an enantiomer or pharmaceutically acceptable salt thereof, wherein:

X is N, O, or S;

R 1 is C 1 —C 6 alkyl, —C 1 —C 6 alkylhalo, or —C 1 —C 6 alkyl-OR 12 ;

R 3 is —C 0 —C 6 alkylC 3 —C 8 cycloalkyl, or —C 0 —C 6 alkylheterocyclyl;

R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 —C 8 alkyl, —OR 12, —C 1 —C 6 alkyl-OR 12 , —C 1 —C 6 alkyl-NR 12 , or —OC(O)R 12 ;

R 5 is H, C 1 —C 6 alkyl, or is absent when X is S or O;

0, 1, 2, or 3;

R 9 is C 2 alkynyl;

R 12 independently H or C 1 —C 6 alkyl;

wherein each C 0 —C 6 alkyl or —C 3 —C 8 cycloalkyl are independently optionally substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 —C 6 alkyl, C 1 —C 6 alkyl-O—, R 12 O—C 1 —C 6 alkyl(O)C—, and R 12 O(O)C—.

26. A compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, selected from:

Assignments (6)

RELEASE OF SECURITY INTEREST IN PATENT COLLATERAL Recorded Mar 5, 2025

From: BLUE OWL CAPITAL CORPORATION, AS ADMINISTRATIVE AGENT

To: BRIDGEBIO PHARMA, INC.; QED THERAPEUTICS, INC.; EIDOS THERAPEUTICS, INC.; ML BIO SOLUTIONS INC.; CALCILYTIX THERAPEUTICS INC.; ADRENAS THERAPEUTICS INC.; PHOENIX TISSUE REPAIR, INC.; NAVIRE PHARMA, INC.; VENTHERA, INC.; MOLECULAR SKIN THERAPEUTICS, INC.; CANTERO THERAPEUTICS, INC.; COA THERAPEUTICS, INC.; PORTAL THERAPEUTICS, INC.; BRIDGEBIO GENE THERAPY RESEARCH, INC.; FERRO THERAPEUTICS, INC.

Reel/Frame 070551/0095 →

SECURITY INTEREST Recorded Jan 19, 2024

From: BRIDGEBIO PHARMA, INC.; QED THERAPEUTICS, INC.; EIDOS THERAPEUTICS, INC.; THERAS, INC.; ML BIO SOLUTIONS INC.; CALCILYTIX THERAPEUTICS INC.; ADRENAS THERAPEUTICS INC.; PHOENIX TISSUE REPAIR, INC.; NAVIRE PHARMA, INC.; VENTHERA, INC.; MOLECULAR SKIN THERAPEUTICS, INC.; CANTERO THERAPEUTICS, INC.; COA THERAPEUTICS, INC.; PORTAL THERAPEUTICS, INC.; BRIDGEBIO GENE THERAPY RESEARCH, INC.; FERRO THERAPEUTICS, INC.; SUB21, INC.

To: BLUE OWL CAPITAL CORPORATION, AS ADMINISTRATIVE AGENT

Reel/Frame 066355/0126 →

SECURITY INTEREST Recorded Jan 17, 2024

From: CALCILYTIX THERAPEUTICS INC.; ADRENAS THERAPEUTICS INC.; PHOENIX TISSUE REPAIR, INC.; NAVIRE PHARMA, INC.; VENTHERA, INC.; MOLECULAR SKIN THERAPEUTICS, INC.; CANTERO THERAPEUTICS, INC.; COA THERAPEUTICS, INC.; PORTAL THERAPEUTICS, INC.; BRIDGEBIO GENE THERAPY RESEARCH, INC.; FERRO THERAPEUTICS, INC.; SUB21, INC.

To: BLUE OWL CAPITAL CORPORATION, AS ADMINISTRATIVE AGENT

Reel/Frame 066342/0154 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 30, 2019

From: KALITA, BISWAJIT; DURAISWAMY, ATHISAYAMANI JEYARAJ

To: JUBILANT BIOSYS LIMITED

Reel/Frame 049041/0034 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 30, 2019

From: JUBILANT BIOSYS LIMITED

To: FERRO THERAPEUTICS, INC

Reel/Frame 049041/0038 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 30, 2019

From: CHEN, RUIHONG; JIANG, CHUN; PANDEY, ANJALI

To: FERRO THERAPEUTICS, INC.

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Continuity (2)

Provisional Application 62636614 · Feb 28, 2018

Related Publication 20190263802A1 · Aug 29, 2019