Granted Patent B2

US 12,421,252 · App. 17/756,221 · Granted Sep 23, 2025

Inventors: Jianguo Chen (Shanghai, CN); Weixing Zhang (Shanghai, CN); Zhisen Zhang (Shanghai, CN); Wei Zhu (Shanghai, CN)

Assignee: Hoffmann-La Roche Inc.

C07D519/00C07D491/107C07D491/147

Abstract

Claims (102)

1. A compound of formula (I),

wherein:

R 1 is

wherein

R 4 is C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, halogen, nitro or cyano;

R 4a is C 1-6 alkyl; or C 3-7 cycloalkyl;

R 5 , R 5a and R 5b are independently selected from H and deuterium; and

R 6 is H or halogen;

R 2 is C 1-6 alkyl;

R 3 is unsubstituted or substituted heterocyclyl; and

Y and A are independently selected from CH and N;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein:

R 1 is

wherein

R 4 is cyano;

R 4a is C 1-6 alkyl;

R 5 is H or deuterium; and

R 6 is H or halogen;

R 2 is C 1-6 alkyl;

R 3 is 2,6-diazaspiro[3.3]heptanyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; amino (C 1-6 alkyl) azetidinyl; amino (C 1 -6alkyl) pyrrolidinyl; amino (C 1-6 alkoxy) pyrrolidinyl; amino (hydroxy) pyrrolidinyl; aminoazetidinyl; C 1-6 alkyl-2,6-diazaspiro[3.3]heptanyl; halopyrrolidinylamino or piperazinyl; and

Y and A are independently selected from CH and N, provided that Y and A are not N simultaneously;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (Ia),

wherein

R 1 is

wherein

R 4 is cyano;

R 4a is C 1-6 alkyl;

R 5 is H or deuterium; and

R 6 is H or halogen;

R 2 is C 1-6 alkyl;

R 3 is 2,6-diazaspiro[3.3]heptanyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; 5-oxa-2,8-diazaspiro[3.5]nonanyl; amino (C 1-6 alkyl) azetidinyl; amino(C 1-6 alkyl) pyrrolidinyl; amino(C 1-6 alkoxy) pyrrolidinyl; amino (hydroxy) pyrrolidinyl; aminoazetidinyl; C 1-6 alkyl-2,6-diazaspiro[3.3]heptanyl; halopyrrolidinylamino; or piperazinyl; and

Y and A are independently selected from CH and N, provided that Y and A are not N simultaneously;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

wherein

R 4 is cyano;

R 5 is H or deuterium; and

R 6 is H or halogen.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H or fluoro.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Y is CH, and A is N; or Y is N, and A is CH.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 3 is amino (C 1-6 alkyl) azetidinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; or amino (C 1-6 alkoxy) pyrrolidinyl.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 3-amino-3-methyl-azetidin-1-yl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl; or 3-amino-4-methoxy-pyrrolidin-1-yl.

9. The compound of claim 3 , wherein

R 1 is

wherein

R 4 is cyano;

R 5 is deuterium;

R 2 is C 1-6 alkyl;

R 3 is amino (C 1-6 alkyl) azetidinyl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazinyl; or amino (C 1-6 alkoxy) pyrrolidinyl; and

Y is CH, and A is N; or Y is N, and A is CH;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein

R 2 is methyl; and

R 3 is 3-amino-3-methyl-azetidin-1-yl; 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl; or 3-amino-4-methoxy-pyrrolidin-1-yl;

or a pharmaceutically acceptable salt thereof.

11. A compound selected from:

4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

3-fluoro-4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

3-fluoro-4-[(2S,6R)-2-[[6-[[(3S,4R)-4-fluoropyrrolidin-3-yl]amino]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

3-fluoro-4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2S,6R)-2-[[6-[(3S)-3-amino-3-methyl-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

3-fluoro-4-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl)methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2R,6S)-2-methyl-6-[[6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2S,6R)-2-[[6-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

4-[(2S,6R)-2-[[6-(2,6-diazaspiro[3.3]heptan-2-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-1-methyl-1,8-naphthyridin-2-one;

5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

2-deuterio-5-[(2R,6S)-2-methyl-6-[[6-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]morpholin-4-yl]quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[6-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a, 5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

2-deuterio-5-[(2R,6S)-2-methyl-6-[(6-piperazin-1-ylspiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl)methyl]morpholin-4-yl]quinoline-8-carbonitrile;

4-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

5-[(2S,6R)-2-[[3-(3-aminoazetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

3-fluoro-4-[(2R,6S)-2-methyl-6-[[3-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

5-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2S,6R)-2-[[6-(3-amino-3-methyl-azetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]pyrazolo[1,5-a]pyridine-7-carbonitrile;

5-[(2S,6R)-2-[[6-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[1H-furo[3,4-c]pyridine-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3-[(4aR,7aR)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[3-[(3R,4R)-3-amino-4-methoxy-pyrrolidin-1-yl]spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile;

5-[(2S,6R)-2-[[6-(3-aminoazetidin-1-yl)spiro[1H-furo[3,4-c]pyridine-3,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-2-deuterio-quinoline-8-carbonitrile; and

4-[(2S,6R)-2-[[3-(3-amino-3-methyl-azetidin-1-yl)spiro[5H-furo[3,4-b]pyridine-7,3′-azetidine]-1′-yl]methyl]-6-methyl-morpholin-4-yl]-3-fluoro-pyrazolo[1,5-a]pyridine-7-carbonitrile;

or a pharmaceutically acceptable salt thereof.

12. A process for the preparation of a compound of claim 1 , the process comprising the following step:

the reaction of compound of formula (VII),

and

amine HR 3 (VIII) via Buchwald-Hartwig amination, wherein

X is halogen; and

R 1 , R 2 , R 3 , Y and A are defined as in claim 1 ,

to produce the compound of claim 1 .

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

14. A compound of formula (I), or pharmaceutically acceptable salt thereof, manufactured according to the process of claim 12 .

15. A method for the treatment of systemic lupus erythematosus or lupus nephritis in a human mammal in need thereof, which method comprises administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the human mammal.

16. A pharmaceutical composition comprising a compound of claim 11 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

17. A method for the treatment of systemic lupus erythematosus or lupus nephritis in a human mammal in need thereof, which method comprises administering a therapeutically effective amount of a compound of claim 11 , or a pharmaceutically acceptable salt thereof, to the human mammal.

Assignments (5)

Continuity (1)

References Cited (53)