Granted Patent B2

US 12,252,490 · App. 17/265,883 · Granted Mar 18, 2025

Inventors: David J. Guerin (Natick, MA); Justin A. Caravella (Cambridge, MA); Hongbin Li (Madison, CT); Steven Mischke (Waltham, MA); David J. Richard (Littleton, MA); Shawn E. R. Schiller (Haverhill, MA); Tatiana Shelekhin (Ridgefield, CT)

Assignee: Valo Health, Inc.

C07D487/04C07D471/04C07D519/00

Abstract

Claims (186)

1. A compound of Formula (I):

or pharmaceutically acceptable form thereof, wherein:

X is selected from N or C(R′);

R′ is selected from hydrogen, deuterium, and CH 3 ;

Y is C(R);

R is selected from hydrogen, NH 2 , and C1-C4 alkyl groups;

R 1 is selected from Rx, hydrogen, C1-C5 linear and C3-C5 branched alkyl groups, wherein the alkyl groups are optionally substituted with one or more Rx;

each Rx is selected from halogen or —OH;

R 2 is selected from hydrogen and halogen;

R 3 , R 4 , and R 4′ are each independently selected from hydrogen and C1-C4 alkyl;

R 5 is a 6- to 8-membered heterocyclic ring;

R 6 is selected from hydrogen, deuterium, halogen, C1-C4 alkyl, and —CN; and

n is 0, 1, or 2.

2. The compound of claim 1 , wherein:

X is C(R′);

R′ is selected from hydrogen and deuterium;

R is NH 2 ;

R 1 , R 2 , R 3 , R 4 , and R 4′ are hydrogen;

R 5 is a 6-membered heterocyclic ring; and

n is 0.

3. The compound of claim 1 , wherein:

X is C(R′);

R′ is selected from hydrogen and deuterium;

R is hydrogen;

R 1 is C1-C3 linear alkyl, optionally substituted with one to three Rx;

R 2 and R 3 are hydrogen;

R 4 and R 4′ are independently selected from hydrogen and CH 3 ;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen, deuterium, and halogen; and

n is 0, 1, or 2.

4. The compound of claim 1 , wherein:

X is C(R′), wherein R′ is hydrogen;

R is hydrogen;

R 1 is methyl or ethyl, optionally substituted with one to three Rx;

R 2 and R 3 are hydrogen;

R 4 and R 4′ are independently selected from hydrogen and CH 3 ;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen and halogen; and

n is 0, 1, or 2.

5. The compound of claim 1 , wherein:

X is C(R′);

R′ is selected from hydrogen and deuterium;

R is hydrogen;

R 1 is C3-C4 branched alkyl optionally substituted with one to three Rx;

R 2 and R 3 are hydrogen;

R 4 and R 4′ are independently selected from hydrogen and CH 3 ;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen, deuterium, and halogen; and

n is 0, 1, or 2.

6. The compound of claim 1 , wherein:

X is C(R′), wherein R′ is hydrogen;

R is hydrogen;

R 1 is C3-C4 branched alkyl, optionally substituted with one to three Rx;

R 2 and R 3 are hydrogen;

R 4 and R 4′ are hydrogen;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen and halogen; and

n is 0, 1, or 2.

7. The compound of claim 1 , wherein:

X is C(R′), wherein R′ is hydrogen;

R is hydrogen;

R 1 is hydrogen;

R 2 is halogen;

R 3 is hydrogen;

R 4 and R 4′ are hydrogen;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen and halogen; and

n is 0, 1, or 2.

8. The compound of claim 1 , wherein:

X is C(R′), wherein R′ is hydrogen;

R is hydrogen;

R 1 is selected from hydrogen, and C1-C3 linear alkyl optionally substituted with one to three Rx;

R 2 is halogen;

R 3 is hydrogen;

R 4 and R 4′ are hydrogen;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen and halogen; and

n is 0, 1, or 2.

9. The compound of claim 1 , wherein:

X is N;

R is hydrogen;

R 1 is selected from hydrogen, and C1-C3 linear alkyl optionally substituted with one to three Rx;

R 2 is hydrogen;

R 3 is hydrogen;

R 4 and R 4′ are selected from hydrogen and CH 3 ;

R 5 is a 6-8-membered heterocyclic ring;

R 6 is selected from hydrogen and halogen; and

n is 0, 1, or 2.

10. The compound of claim 1 , wherein R5 is a 6-8 membered heterocyclic ring with two nitrogens.

11. The compound of claim 1 , wherein each halogen is independently selected from F and Cl.

12. The compound of claim 1 , wherein the compound is chosen from:

Ex. #

Structure

Compound Name

1-1

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-1-ethyl- 1H-pyrrolo[2,3-b]pyridine-5- carboxamide

1-2

N-(4-(piperazin-1-yl)phenethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-3

1-methyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

1-4

1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

1-5

4-amino-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

1-6

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-7

N-(2,5-difluoro-4-(piperazin-1- yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-8

N-(4-(piperazin-1-yl)phenethyl)-1- (2,2,2-trifluoroethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-9

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-1-(2- hydroxy-2-methylpropyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-10

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-3-fluorophenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

2-1

(S)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

2-2

(R)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

2-3

N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

2-4

N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

3-1

3-chloro-1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

3-2

3-chloro-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

4-1

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3- carboxamide

4-2

N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide

4-3

N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide

4-4

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-5- chloro-7-ethyl-7H-pyrrolo[2,3- c]pyridazine-3-carboxamide

and;

wherein the compound is:

(a) a USP28 Inhibitor compound having an IC 50 of 0.001-10 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP28;

(b) a USP25 Inhibitor compound having an IC 50 of 0.001-10 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP25.

13. The compound of claim 12 , wherein the compound is

(c) a USP28 Inhibitor compound having an IC 50 of 0.001-2 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP28;

(d) a USP25 Inhibitor compound having an IC 50 of 0.001-2 micromolar in the Ubiquitin-Rhodamine 110 Assay for USP25.

14. The compound of claim 1 , chosen from:

Ex. #

Structure

Compound Name

1-1

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-y1)-2,5-difluorophenethyl)-1-ethyl- 1H-pyrrolo[2,3-b]pyridine-5- carboxamide

1-2

N-(4-(piperazin-1-yl)phenethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-3

1-methyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

1-4

1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

1-5

4-amino-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

1-6

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-7

N-(2,5-difluoro-4-(piperazin-1- yl)phenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-8

N-(4-(piperazin-1-yl)phenethyl)-1- (2,2,2-trifluoroethyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-9

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-yl)-2,5-difluorophenethyl)-1-(2- hydroxy-2-methylpropyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-10

N-(4-(3,8-diazabicyclo[3.2.1 ]octan- 3-yl)-3-fluorophenethyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

2-1

(S)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

2-2

(R)-N-(2-(2,5-difluoro-4-(piperazin- 1-yl)phenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

2-3

N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5-carboxamide

2-4

N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-1-ethyl-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

3-1

3-chloro-1-ethyl-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

3-2

3-chloro-N-(4-(piperazin-1- yl)phenethyl)-1H-pyrrolo[2,3- b]pyridine-5-carboxamide

4-1

N-(4-(3,8-diazabicyclo[3.2.1 ]octan- 3-yl)-2,5-difluorophenethyl)-7-ethyl- 7H-pyrrolo[2,3-c]pyridazine-3- carboxamide

4-2

N-((2R)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3-carboxamide

4-3

N-((2S)-2-(4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-2,5- difluorophenyl)propyl)-7-ethyl-7H- pyrrolo[2,3-c]pyridazine-3- carboxamide

4-4

N-(4-(3,8-diazabicyclo[3.2.1]octan- 3-y1)-2,5-difluorophenethyl)-5- chloro-7-ethyl-7H-pyrrolo[2,3- c]pyridazine-3-carboxamide

15. A composition comprising at least one compound of claim 1 , and a biologically acceptable carrier.

Assignments (6)

Continuity (2)

References Cited (87)