Granted Patent B2

US 12,649,745 · App. 18/062,892 · Granted Jun 9, 2026

Inventors: Angélica Beurier (Courtavon, FR); Luke Green (Basel, CH); Christian Kramer (Lörrach, DE); Dmitry Mazunin (Grenzach-Wyhlen, DE); Emmanuel Pinard (Linsdorf, FR); Hasane Ratni (Habsheim, FR)

Assignee: Hoffmann-La Roche Inc.

C07D487/04C07D471/04

Abstract

Claims (110)

1 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of

i) H,

ii) C 1-6 -alkyl,

iii) C 3-8 -cycloalkyl,

iv) C 3-8 -cycloalkylalkyl,

v) C 1-6 -alkoxy,

vi) C 1-6 -alkoxy-C 1-6 -alkyl,

vii) heterocycloalkyl,

viii) heterocycloalkylalkyl,

ix) substituted C 3-8 -cycloalkyl,

x) substituted C 3-8 -cycloalkylalkyl,

xi) substituted heterocycloalkyl,

xii) substituted heterocycloalkylalkyl,

xiii) halo-C 1-6 -alkyl, and

xiv) hydroxy-C 1-6 -alkyl,

wherein substituted C 3-8 -cycloalkyl or substituted heterocycloalkyl are substituted with one or more substituents selected from the group consisting of H, C 1-6 -alkyl, halogen, hydroxy, and C 1-6 -carbonyl;

R 2 is selected from the group consisting of

i) H,

ii) halogen,

iii) halo-C 1-6 -alkyl,

iv) C 1-6 -alkyl, and

v) cyano,

wherein at least one of R 1 and R 2 is other than H;

R 3 is selected from the group consisting of

i) H, and

ii) halogen; and

n is 0 or 1.

2 . A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.

3 . A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cl.

4 . A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of

i) H, and

ii) cyano.

5 . A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of

i) H,

ii) C 1-6 -alkyl,

iii) C 3-8 -cycloalkyl,

iv) C 3-8 -cycloalkylalkyl,

v) C 1-6 -alkoxy,

vi) C 1-6 -alkoxy-C 1-6 -alkyl,

vii) heterocycloalkyl,

viii) heterocycloalkylalkyl,

ix) substituted C 3-8 -cycloalkyl,

x) substituted C 3-8 -cycloalkylalkyl,

xi) substituted heterocycloalkyl,

xii) substituted heterocycloalkylalkyl,

xiii) halo-C 1-6 -alkyl, and

xiv) hydroxy-C 1-6 -alkyl,

wherein substituted C 3-8 -cycloalkyl or substituted heterocycloalkyl are substituted with one or more substituents selected from the group consisting of H, C 1-6 -alkyl, halogen, hydroxy, and C 1-6 -carbonyl; and

wherein heterocycloalkyl is a 4-6 atom ring system comprising one heteroatom selected from N and O.

6 . A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is Cl, R 2 is H or cyano, and R 1 is selected from the group consisting of

i) H,

ii) C 1-6 -alkyl,

iii) C 3-8 -cycloalkyl,

iv) C 3-8 -cycloalkylalkyl,

v) C 1-6 -alkoxy,

vi) C 1-6 -alkoxy-C 1-6 -alkyl,

vii) heterocycloalkyl,

viii) heterocycloalkylalkyl,

ix) substituted C 3-8 -cycloalkyl,

x) substituted C 3-8 -cycloalkylalkyl,

xi) substituted heterocycloalkyl,

xii) substituted heterocycloalkylalkyl,

xiii) halo-C 1-6 -alkyl, and

xiv) hydroxy-C 1-6 -alkyl,

wherein substituted C 3-8 -cycloalkyl or substituted heterocycloalkyl are substituted with one or more substituents selected from the group consisting of H, C 1-6 -alkyl, halogen, hydroxy, and C 1-6 -carbonyl;

wherein heterocycloalkyl is a 4-6 atom ring system comprising one heteroatom selected from N and O;

wherein at least one of R 1 and R 2 is other than H; and

n is 0 or 1.

7 . A compound according to claim 1 , selected from the group consisting of

2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(oxetan-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;

2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(3-methyloxetan-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;

(S)-6-chloro-2-((6-(3-methyloxetan-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(6,6-difluorospiro[3.3]heptan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;

2-((5-chloro-2,3-dihydro-1H-inden-2-yl)amino)-6-(3,3-difluorocyclobutyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one;

(S)-6-chloro-2-((6-(3,3-difluoro-1-methylcyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(6,6-difluorospiro[3.3]heptan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(3,3-difluorocyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((5-oxo-6-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((5-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S,S) and (S,R)-6-chloro-2-((5-oxo-6-(tetrahydrofuran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-isopropyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-cyclopropyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(oxetan-3-ylmethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(1-methylcyclopropyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(oxetan-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(oxetan-3-yl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(cyclopropylmethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-((1r,3S)-3-hydroxycyclobutyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(2-methoxyethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(2-hydroxy-2-methylpropyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(2-fluoroethyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-((1-hydroxycyclopropyl)methyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-2-((6-(1-acetylpiperidin-4-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(1,3-difluoropropan-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-((3-methyloxetan-3-yl)methyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((5-oxo-6-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-isopropyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-(cyclopropylmethyl)-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S,S) and (S,R) 6-chloro-2-((5-oxo-6-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-ethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

(S)-6-chloro-2-((5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile; and

(S)-6-chloro-2-((5-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)-2,3-dihydro-1H-indene-4-carbonitrile;

or a pharmaceutically acceptable salt thereof.

8 . A process to prepare a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, the process comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III) to provide a compound of formula (I), wherein R 1 , R 2 , R 3 , and n are as defined in claim 1 :

9 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

Assignments (2)

Priority Claims (1)

Continuity (2)

References Cited (15)