IP Library › Granted Patent US 11,352,328

Granted Patent B2

US 11,352,328 · App. 16/309,858 · Granted Jun 7, 2022

Heterocyclic compounds for the treatment of arenavirus

Inventors: Michael Plewe (San Diego, CA); Eric Brown (Santee, CA); Vidyasagar Gantla (San Diego, CA); Gregory Henkel (Carlsbad, CA); Kenneth McCormack (Oceanside, CA); Nadzeda V. Sokolova (San Diego, CA); Young-Jun Shin (San Diego, CA)

Assignee: Arisan Therapeutics Inc.

C07D235/06 A61K31/416 A61K31/4184 A61K31/4192 A61K31/423 A61K31/437 A61K31/439 A61K31/4439 A61K31/454 A61K31/4985 A61K31/5025 A61K31/519 A61K31/52 A61K31/53 A61K31/5377 A61K31/7056 A61K31/713 A61K31/7105 A61K45/06 A61P31/14 C07D235/20 C07D249/18 C07D413/00 C07D471/04 C07D471/08 C07D473/00

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Quick Facts

Patent No.: US 11,352,328
App. No.: 16/309,858
Granted: Jun 7, 2022
Kind: B2

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Abstract

The invention relates to compounds of structural formula I wherein A, D, and E are independently N or C—R 3 , G, H, and J are independently N or C, K is N or C—H, L is N, N—R 3 or C—R 3 , and A, D, E, G, H, J, K, and L together cannot have more than 4 N, R 1 is selected from (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, and 5-indolyl, wherein each of the said (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl is substituted with at least one R 4a group, and wherein said (C 2 to C 9 ) heteroaryl is C-attached, and R 2 is selected from the group consisting of

Claims (140)

1. A compound of Structural Formula I

wherein:

G and H are C;

J and L are N;

K is C—H;

A, D, and E are independently C—R 3 ;

R 1 is selected from (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl is substituted with at least one R 4a group, and wherein said (C 2 to C 9 ) heteroaryl is C-attached;

with the proviso that R 1 is not selected from the group consisting of substituted 3-carbamoyl-2-phenyl-1-benzofuran-5-yl, substituted 1,3,4-oxadiazolyl, substituted 1,3,4-triazolyl, substituted 1,3,4-thiadiazolyl, substituted oxazoyl, substituted thiazoyl, substituted 1H-pyrazol-4- yl, substituted 1H-pyrazol-5-yl, optionally substituted 1-phenyl-1H-imidazol-5-yl, 4-{[(2-aminoethyl) amino]methyl}phenyl, (2-amino-1,3-benzoxazol)-5-yl; (2-amino-1,3-benzoxazol)-4-yl, 2-chloropyridyl-3-yl, 2-methylpyridinyl-4-yl, 2-fluoropyridyl-4-yl, 6-aminopyridyl-3-yl, 6-methoxypyridyl-3-yl, pyridyl-4-yl-N-oxide, 3,4-difluorphenyl, and substituted 1H-pyrrol-3-yl;

R 2 is selected from the group consisting of

each of the R 3 is independently selected from hydrogen, halogen, cyano, OH, CF 3 , (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, —C(O)R 5 , —C(O)NR 6a R 6b , —NR 6a R 6b , —S(O) m R 5 , —S(O) m NR 6a R 6b , —NR 6a S(O) m R 5 , —(CH 2 ) n C(O)OR 5 , —(CH 2 ) n C(O)NR 6a R 6b , —OC(O)R 5 , —NR 6a C(O)R 5 , and —NR 6c C(O)NR 5a R 5b , wherein

each of the said (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 7 group;

R 4a is independently selected from halogen, cyano, OH, CF 3 , (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, —C(O)R 5 , —NR 6a R 6b , —NR 6a S(O) m R 5 , —OC(O)R 5 , —NR 6a C(O)R 5 , and —NR 6c C(O)NR 6a R 6b , wherein

R 4b is selected from the group consisting of

isopropoxy, cyclopropoxy, tert-butoxy, cyclopropylmethoxy, (2-hydroxypropan)-2-yl, (1-hydroxycyclopropan)-1-yl, (1-hydroxycyclobutan)-1-yl, difluoromethoxy, methoxyethoxy, difluoromethyl, cyclopropyl, acetyl, n-propyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, cyclobutyloxy, cyclopentyloxy, (1-hydroxycyclopentan)-1-yl, hydroxyethoxy, ethoxyethoxy, isopropoxyethoxy, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, cyclobutyl, cyclopentyl, propanoyl, isobutanoyl, sec-butanoyl, tert-butanoyl, cyclopropanoyl, cyclobutanoyl, and cyclopentanoyl;

each of the R 5 is independently selected from hydrogen, (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 7 group;

each of the R 6a , R 6b , and R 6c are independently selected from hydrogen, (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl,

or R 6a and R 6b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyl ring, wherein

said 4 to 8 membered cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said 4 to 8 membered cycloheteroalkyl ring is optionally substituted with at least one R 7 group;

R 7 is independently selected from hydrogen, halogen, OH, CF 3 , (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, cyano, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl, —C(O)R 8 , —C(O)NR 9a R 9b , —NR 9a R 9b , —NR 9a S(O) m R 8 , —(CH 2 ) n C(O)OR 8 , —(CH 2 ) n C(O)N(R 9a R 9b ), —OC(O)R 8 , —NR 9a C(O)R 8 , and —NR 9a C(O)N(R 9a R 9b ), wherein

each of the said (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, is optionally substituted with at least one R 10 group;

each of the R 8 is independently selected from hydrogen, (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

each of the R 9a , R 9b , and R 9c are independently selected from hydrogen, (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, (C 2 to C 9 ) heteroaryl,

or R 9a and R 9b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyl ring, wherein

said 4 to 8 membered cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said 4 to 8 membered cycloheteroalkyl ring is optionally substituted;

R 10 is independently selected from hydrogen, halogen, cyano, OH, CF 3 , (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, wherein

m is 0, 1, or 2;

n is 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1 , wherein R 4b is isopropoxy.

3. The compound of claim 1 , wherein:

A, D, and E are independently C—R 3 and R 3 is H, CH 3 , —CN, CF 3 , —C(O)OC 2 H 5 , —OCH 3 , —COOH, —C(O)NH 2 , and halogen.

4. The compound of claim 2 , wherein:

A, D, and E are independently C—R 3 and R 3 is H, CH 3 , —CN, CF 3 , —C(O)OC 2 H 5 , —OCH 3 , —COON, —C(O)NH 2 , and halogen.

5. The compound of claim 1 , wherein:

D is C—R 3 and R 3 is CH 3 .

6. The compound of claim 5 , wherein:

A and E are CH, and D is C CH 3 .

7. A compound selected from the group consisting of

8. The compound of claim 7 , wherein the compound is selected from the group consisting of

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound, selected from:

and a pharmaceutically acceptable carrier, diluent, or vehicle.

10. The pharmaceutical composition of claim 9 comprising a therapeutically effective amount of a compound, selected from:

and a pharmaceutically acceptable carrier, diluent, or vehicle.

11. The pharmaceutical composition of claim 10 comprising a therapeutically effective amount of a compound of claim 10 with a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, T-705 (favipiravir), Triazavirin, small interfering RNAs (siRNAs), vaccines, and immunomodulators.

12. A method of relieving arenavirus infection comprising administration of a therapeutically effective amount of a compound of Structural Formula 1

wherein:

G and H are C;

J and L are N;

K is C—H;

A, D, and E are independently C—R 3 ;

R 1 is selected from (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl is substituted with at least one R 4a group, and wherein said (C 2 to C 9 ) heteroaryl is C-attached;

R 2 is selected from the group consisting of

R 4b is selected from the group consisting of

or R 6a and R 6b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyl ring, wherein

said 4 to 8 membered cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said 4 to 8 membered cycloheteroalkyl ring is optionally substituted with at least one R 7 group;

each of the said (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, is optionally substituted with at least one R 10 group;

or R 9a and R 9b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyl ring, wherein

said 4 to 8 membered cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said 4 to 8 membered cycloheteroalkyl ring is optionally substituted;

m is 0, 1, or 2;

n is 1, 2, 3, 4, 5, or 6.

13. The method of claim 12 , wherein R 4b is isopropoxy.

14. The method of claim 12 , wherein:

A, D, and E are independently C—R 3 and R 3 is H, CH 3 , —CN, CF 3 , —C(O)OC 2 H 5 , —OCH 3 , —COOH, —C(O)NH 2 , and halogen.

15. The method of claim 13 , wherein:

A, D, and E are independently C—R 3 and R 3 is H, CH 3 , —CN, CF 3 , —C(O)OC 2 H 5 , —OCH 3 , —COOH, —C(O)NH 2 , arid halogen.

16. The method of claim 12 , wherein:

D is C—R 3 and R 3 is CH 3 .

17. A method of relieving arenavirus infection comprising administration of a therapeutically effective amount of a compound selected from the group consisting of

18. The method of claim 17 , wherein the compound is selected from the group consisting of

19. The method of claim 12 further comprising administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and immunomodulators.

20. The method of claim 17 further comprising administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and immunomodulators.

21. A method of alleviating arenavirus infection comprising administration of a therapeutically effective amount of a compound of Structural Formula I

wherein:

G and H are C;

J and L are N;

K is C—H;

A, D, and E are independently C—R 3 ;

R 1 is selected from (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl, wherein

each of the said (C 6 to C 10 ) aryl and (C 2 to C 9 ) heteroaryl is substituted with at least one R 4a group, and wherein said (C 2 to C 9 ) heteroaryl is C-attached;

R 2 is selected from the group consisting of

R 4b is selected from the group consisting of

or R 6a and R 6b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyl ring, wherein

said 4 to 8 membered cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said 4 to 8 membered cycloheteroalkyl ring is optionally substituted with at least one R 7 group;

each of the said (C 1 to C 6 ) alkyl, (C 1 to C 6 ) alkenyl, (C 1 to C 6 ) alkynyl, (C 1 to C 6 ) alkoxy, aryloxy, (C 3 to C 10 ) cycloalkyl, (C 5 to C 10 ) cycloalkenyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 10 ) aryl, and (C 2 to C 9 ) heteroaryl, is optionally substituted with at least one R 10 group;

or R 9a and R 9b may be taken together with the nitrogen atom to which they are attached to form a 4 to 8 membered cycloheteroalkyl ring, wherein

said 4 to 8 membered cycloheteroalkyl ring has 1 to 3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein

the said 4 to 8 membered cycloheteroalkyl ring is optionally substituted;

m is 0, 1, or 2;

n is 1, 2, 3, 4, 5, or 6.

22. The method of claim 21 , wherein R 4b is isopropoxy.

23. The method of claim 21 , wherein:

A, D, and E are independently C—R 3 and R 3 is H, CH 3 , —CN, CF 3 , —C(O)OC 2 H 5 , —OCH 3 , —COOH, —C(O)NH 2 , and halogen.

24. The method of claim 22 , wherein:

A, D, and E are independently C—R 3 and R 3 is H, CH 3 , —CN, CF 3 , —C(O)OC 2 H 5 , —OCH 3 , —COON, —C(O)NH 2 , and halogen.

25. The method of claim 21 , wherein:

D is C—R 3 and R 3 is CH 3 .

26. A method of alleviating arenavirus infection comprising administration of a therapeutically effective amount of a compound selected from the group consisting of

27. The method of claim 26 , wherein the compound is selected from the group consisting of

28. The method of claim 21 further comprising administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and immunomodulators.

29. The method of claim 26 further comprising administering a therapeutic amount of a therapeutic agent selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors, Triazavirin, small interfering RNAs (siRNAs) and microRNAs, vaccines, and immunomodulators.

Assignments (4)

LICENSE Recorded Dec 5, 2025

From: ARISAN THERAPEUTICS, INC.

To: NATIONAL INSTITUTES OF HEALTH

Reel/Frame 073852/0692 →

LICENSE Recorded Aug 25, 2025

From: ARISAN THERAPEUTICS, INC.

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 072524/0357 →

LICENSE Recorded Apr 25, 2025

From: ARISAN THERAPEUTICS, INC.

To: NATIONAL INSTITUTES OF HEALTH

Reel/Frame 071059/0344 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2019

From: MCCORMACK, KENNETH, DR; SHIN, YOUNG-JUN, DR; HENKEL, GREGORY, DR; PLEWE, MICHAEL BRUNO, DR; GANTLA, VIDYASAGAR REDDY, DR; SOKOLOVA, NADEZDA V., DR; BROWN, ERIC

To: ARISAN THERAPEUTICS INC.

Reel/Frame 048983/0733 →

Continuity (3)

Provisional Application 62361423 · Jul 12, 2016

Provisional Application 62378177 · Aug 22, 2016

Related Publication 20190308938A1 · Oct 10, 2019

Cited By (1)

US 12,419,865