IP Library › Granted Patent US 12,473,296
Granted Patent B2
US 12,473,296 · App. 17/639,169 · Granted Nov 18, 2025

Perk inhibiting compounds

Inventors: Mark J. Mulvihill (New York, NY); An-Hu Li (New York, NY); Matthew David Surman (Albany, NY)
Assignee: HiberCell, Inc.
C07D487/10C07D213/82C07D241/26C07D401/12C07D405/12C07D417/12
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Quick Facts
Patent No.
US 12,473,296
App. No.
17/639,169
Granted
Nov 18, 2025
Kind
B2
Abstract

Provided herein are compounds, compositions, and methods useful for inhibiting PERK and for treating related conditions, diseases, and disorders. PERK-inhibiting compounds of Formula (I) having the following structure: are described herein. Also described herein are pharmaceutical compositions containing a compound of Formula (I) in one or more pharmaceutically acceptable carriers, diluents, or excipients, as well as methods for inhibiting a PERK enzyme in a patient or treating cancer in a patient.

Claims (120)

1 . A compound of the formula (I):

wherein:

Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents;

Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents;

Y is C(R 3a )(R 3b )C 0-6 alkyl, NR 3a , —O—, C(O), CF 2 , CNOR 3bb , or a direct bond to Ar 1 ;

R 3a is H, alkyl, or cycloalkyl;

R 3b is H, alkyl, OR 3c , or NR 3d R 3e ;

R 3bb is H or alkyl;

R 4 is H, alkyl, or OH;

X is CR 7 or N;

R 1 is one or more independent H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl, C 0-6 alkyl-O—C 1-12 alkyl, C 0-6 alkyl-OH, C 0-6 alkyl-O—C 3-12 cycloalkyl, or C 0-6 alkyl-O—C 3-12 heterocycloalkyl, optionally substituted by one or more independent G 1 substituents;

R 2 is one or more independent H, deuterium, halo, CN, NO 2 , alkyl, C 0-6 alkylcycloalkyl, C 0-6 alkyl-O—C 1-12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 3-12 cycloalkyl, optionally substituted by one or more independent G 2 substituents;

R 3c , R 3d and R 3e are each independently H, alkyl, or cycloalkyl, optionally substituted by one or more independent G 3 substituents;

R 5 is H, CH 3 , NHR 9 , or OR 9 ;

R 6 is selected from the group consisting of:

R 7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;

R 8a and R 8b are each independently H, C 1-12 alkyl, C 0-12 alkyl-C 3-12 cycloalkyl, or C 0-12 alkyl-C 3-12 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; or

R 8a and R 8b taken together with the nitrogen to which they are attached form 5-10 membered heterocyclyl;

R 9 is H, alkyl, cycloalkyl, or heterocycloalkyl;

G 1 , G 2 , G 3 , or G 4 are each independently H, deuterium, halo, CN, NO 2 , C 1-12 alkyl, C 0-12 alkyl-C 3-12 cycloalkyl, C 0-12 alkyl-C 3-12 heterocycloalkyl, OR 10 , NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)NR 10 R 11 , OC(O)R 10 , OC(O)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(O)R 10 , N(R 12 )C(O)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(O) n R 10 , S(O) n OR 10 , S(O) n NR 10 R 11 , N(R 12 )S(O) n R 10 , N(R 12 )S(O) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 of the formula (Ia):

wherein:

Y is CR 3a R 3b ;

R 3a is H or alkyl;

R 3b is OR 3c or NR 3d R 3e ;

R 1 is one or more independent H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O—C 1-12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 3-12 cycloalkyl, optionally substituted by one or more independent G 1 substituents;

R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkylcycloalkyl, C 0-6 alkyl-O—C 1-12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 3-12 cycloalkyl, optionally substituted by one or more independent G 2 substituents;

R 3c , R 3d and R 3e are each independently H or alkyl, optionally substituted by one or more independent G 3 substituents;

X is CR 7 or N;

R 6 is selected from the group consisting of:

R 7 is H, CN, or alkyl, optionally substituted by one or more independent deuterium or halo;

R 8a and R 8b are each independently H, C1-12alkyl, C 0-12 alkylC 3-12 cycloalkyl, or C 0-12 alkylC 3-12 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents;

G 1 , G 2 , G 3 , or G 4 are each independently H, deuterium, halo, CN, NO 2 , C 1-12 alkyl, C 0-12 alkylC 3-12 cycloalkyl, C 0-12 alkylC 3-12 heterocycloalkyl, OR 10 , NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)NR 10 R 11 , OC(O)R 10 , OC(O)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(O)R 10 , N(R 12 )C(O)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(═O) n R 10 ,S(O) n OR 10 , S(O) n NR 10 R 11 , N(R 12 )S(O) n R 10 , N(R 12 )S(O) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 of the formula (Ib):

wherein:

X is CH or N;

R 1 is one or more independent H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O—C 1-12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 3-12 cycloalkyl, optionally substituted by one or more independent G 1 substituents;

R 2 is one or more independent H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O—C 1-12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 3-12 cycloalkyl, optionally substituted by one or more independent G 2 substituents;

R 3a is H or alkyl;

R 3b is OR 3c or NR 3d R 3e ;

R 3c , R 3d and R 3e are each independently H or alkyl, optionally substituted by one or more independent G 3 substituents;

R 6 is selected from the group consisting of:

R 8a and R 8b are each independently H, C 1-12 alkyl, C 3-12 cycloalkyl, or C 3-12 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents;

G 1 , G 2 , G 3 , or G 4 are each independently H, deuterium, halo, CN, NO 2 , C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, OR 10 , NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)NR 10 R 11 , OC(O)R 10 , OC(O)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(O)R 10 , N(R 12 )C(O)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(O) n R 10 , S(O) n OR 10 , S(O) n NR 10 R 11 , N(R 12 )S(O) n R 10 , N(R 12 )S(O) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 of the formula (Ic):

wherein:

X is CH or N;

R 1 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 1-12 alkyl, optionally substituted by one or more independent G 1 substituents;

R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 1-12 alkyl, optionally substituted by one or more independent G 2 substituents;

R 3b is OR 3c ;

R 3c is H or alkyl, optionally substituted by one or more independent G 3 substituents;

R 6 is selected from the group consisting of:

R 8a and R 8b are each independently H, C 1-12 alkyl, C 0-12 alkylC 3-12 cycloalkyl, or C 0-12 alkylC 3-12 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents;

G 1 , G 2 , G 3 , or G 4 are each independently H, deuterium, halo, CN, NO 2 , C 1-12 alkyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, OR 10 , NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)NR 10 R 11 , OC(O)R 10 , OC(O)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(O)R 10 , N(R 12 )C(O)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(O) n R 10 , S(O) n OR 10 , S(O) n NR 10 R 11 , N(R 12 )S(O) n R 10 , N(R 12 )S(O) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 of the formula (Id):

wherein:

X is CH or N;

R 1 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 1-12 alkyl, optionally substituted by one or more independent H, deuterium, or halo;

R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O—C 1-12 alkyl, optionally substituted by one or more independent H, deuterium or halo;

the C(O)NR 8a R 8b moiety in Formula (1d) is selected from the group consisting of:

R 10 , R 11 , or R 12 are each independently selected from H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 ;

n is 0, 1, or 2;

or a pharmaceutically acceptable salt thereof.

6 . The compound of any one of claim 1 , wherein X is CH.

7 . The compound of any one of claim 1 , wherein R 1 is H, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, CF 3 , fluoro, or chloro.

8 . The compound of claim 1 , wherein R 2 is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoro, chloro, CF 3 or OCF 3 .

9 . The compound of claim 1 , wherein R 8a and R 8b are each independently H, C 1-6 alkyl, C 0-6 alkylC 3-8 cycloalkyl, or C 0-6 alkylC 3-6 heterocycloalkyl.

10 . The compound of claim 1 , wherein R 8a and R 8b are each independently H, C 1-3 alkyl, C 0-3 alkylC 3-6 cycloalkyl, or C 0-3 alkylC 3-6 heterocycloalkyl.

11 . The compound of claim 1 , wherein R 8a and R 8b are each independently H, C 1-3 alkyl, C 3-6 cycloalkyl, or C 3-6 heterocycloalkyl.

12 . The compound of claim 1 , wherein G 1 , G 2 , G 3 , or G 4 are each independently H, deuterium, halo, CN, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, OR 10 , NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)NR 10 R 11 , OC(O)R 10 , OC(O)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(O)R 10 , N(R 12 )C(O)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(O) n R 10 , S(O) n OR 10 , S(O) n NR 10 R 11 , N(R 12 )S(O) n R 10 ,N(R 12 )S(O) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 .

13 . The compound of claim 1 , wherein G 1 , G 2 , G 3 , or G 4 are each independently H, deuterium, halo, CN, NO 2 , C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, OR 10 , NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)NR 10 R 11 , OC(O)R 10 , OC(O)OR 10 , OC(O)NR 10 R 11 , N(R 12 )C(O)R 10 ,N(R 12 )C(O)OR 10 , N(R 12 )C(O)NR 10 R 11 , S(O) n R 10 , S(O) n OR 10 , S(O) n NR 10 R 11 , N(R 12 )S(O) n R 10 , N(R 12 )S(O) n OR 10 , or N(R 12 )S(O) n NR 10 R 11 , optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO 2 .

14 . The compound of claim 1 of the formula (Ie):

wherein:

Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents;

Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents;

Y is C(R 3a )(R 3b )C 0-6 alkyl, NR 3a , —O—, C(O), CF 2 , or a direct bond to Ar 1 ;

R 3a is H or alkyl;

R 3b is OR 3d or NR 3d R 3e ;

R 4 is H or OH;

X is CR 7 or N;

R 1 is one or more independent halo, alkyl, or C 0-6 alkyl-O—C 1-12 alkyl, optionally substituted by one or more independent G 1 substituents;

R 2 is one or more independent halo, alkyl, or C 0-6 alkyl-O—C 1-12 alkyl, optionally substituted by one or more independent G 2 substituents;

R 3c , R 3d and R 3e are each independently H or alkyl;

R 5 is H, CH 3 , NH 2 , or NHCH 3 ;

R 6 is selected from the group consisting of:

R 7 is H or alkyl;

R 8a and R 8b are each independently H, C 1-12 alkyl, C 0-12 alkyl-C 3-12 cycloalkyl, or C 0-12 alkyl-C 3-12 heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; or

R 8a and R 8b taken together with the nitrogen to which they are attached form 5-10 membered heterocyclyl;

G 1 , G 2 , G 3 , or G 4 are each independently halo, OR 10 , NR 10 R 11 , C(O)R 10 ; and

R 10 or R 11 are each independently selected from H, or alkyl;

or a pharmaceutically acceptable salt thereof.

15 . The compound of claim 14 , wherein Ar 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl,

optionally substituted by one or more independent R 1 substituents.

16 . The compound of claim 14 , wherein R 1 , for each occurrence, is independently chloro, fluoro, methyl, ethyl, methoxy, or CF 3 .

17 . The compound of claim 14 , wherein Y is —C(H)(OH)—, —C(CH 3 )(OH)—, —C(H)(OCH 3 )—, —C(H)(NH 2 )—, CF 2 , C(O), CH 2 , —CH 2 CH 2 —, N(CH 3 ), —O—, or a direct bond to Ar 1 .

18 . The compound of claim 14 , wherein R 4 is H.

19 . The compound of claim 14 , wherein R 4 is OH.

20 . The compound of claim 14 , wherein Ar 2 is phenyl or pyridyl, optionally substituted by one or more independent R 2 substituents.

21 . The compound of claim 14 , wherein R 2 , for each occurrence, is independently methyl, ethyl, methoxy, fluoro, chloro, CF 3 , or OCF 3 .

22 . The compound of claim 14 , wherein X is CR 7 .

23 . The compound of claim 22 , wherein R 7 is H.

24 . The compound of claim 14 , wherein X is N.

25 . The compound of claim 14 , wherein R 5 is H, methyl, NH 2 , or NHCH 3 .

26 . A compound of claim 1 selected from the group consisting of:

of:

or a pharmaceutically acceptable salt thereof.

27 . A pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 with one or more pharmaceutically acceptable carriers, diluents, or excipients.

28 . A method of inhibiting a protein kinase R-like endoplasmic reticulum kinase (PERK) enzyme in a patient comprising administering to a patient in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 23, 2023
From: MULVIHILL, MARK J.; LI, AN-HU
To: HIBERCELL, INC.
Reel/Frame 062456/0477 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 18, 2022
From: SURMAN, MATTHEW DAVID
To: CURIA GLOBAL, INC.
Reel/Frame 060537/0545 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 18, 2022
From: CURIA GLOBAL, INC.
To: HIBERCELL, INC.
Reel/Frame 060537/0811 →
Continuity (2)
Provisional Application 62893512 · Aug 29, 2019
Related Publication 20220332722A1 · Oct 20, 2022
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