Carbazole derivatives

Patent metadata

Field	Value
Publication number	US-11053197-B2
Application number	US-202016859103-A
Country	US
Kind code	B2
Filing date	Apr 27, 2020
Priority date	Oct 24, 2014
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

Disclosed are compounds of Formula (I):

or a salt thereof, wherein Q, R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6a , R 6c , R 7a , R 7b , R 7c , and R 7d are defined herein. Also disclosed are methods of using such compounds as inhibitors of Bruton's tyrosine kinase (Btk), and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

First claim

The invention claimed is:

1. A compound of Formula (I)

or a salt thereof, wherein:
the two dotted lines represent either two single or two double bonds; and R 1b and R 2b are present only if said two dotted lines are two single bonds;

R 1a is H, —CN, —CF 3 , —CH 3 , —CR 8a R 8b OH, —CR 8a R 8b CR 8a R 8b OH, —CH(OH)CH 2 OH, NHR 9 , —C(O)NR 10a R 10b , —C(O)(morpholinyl), —C(O)(piperazinyl), or C(O)(methyl piperazinyl);
R 1b , when present, is H or —CH 3 , provided that if R 1a is H then R 1b is also H; R 2a is H, F, or Cl, provided that if R 1a is other than H then R 2a is H;
R 2b , when present, is the same as R 2a ;
R 3 is H, F, or Cl;
R 7b is —C(O)CH═CH 2 ;
R 7c is —C(O)CH═CH 2 or —C(O)C≡CR 12 ;
R 8a is H or —CH 3 ;
R 8b is H or —CH 3 ;
R 9 is C 1-4 alkyl;
R 10a and R 10b are independently H or —CH 3 ; and
R 12 is H, C 1-4 alkyl, or cyclopropyl.

2. The compound according to claim 1 or a salt thereof, wherein:
R 1a is H, —CF 3 , —CH 3 , —CR 8a R 8b OH, —CR 8a R 8b CR 8a R 8b OH, —NHR 9 , —C(O)NR 10a R 10b , —C(O)(piperazinyl), or —C(O)(methyl piperazinyl);
R 1b is H;
R 2a is H or F, provided that if R 1a is other than H then R 2a is H;
R 2b , when present, is the same as R 2a ;
R 3 is F or Cl;
R 7b is —C(O)CH═CH 2 ;
R 7c is —C(O)CH═CH 2 or —C(O)C≡CR 12 ;
R 8a is H or —CH 3 ;
R 8b is H or —CH 3 ;
R 10a and R 10b are independently H or —CH 3 ; and
R 12 is H, C 1-4 alkyl, or cyclopropyl.

3. The compound according to claim 1 or a salt thereof, wherein R 3 is F.

4. The compound according to claim 1 or a salt thereof, having the structure of Formula (Ia):

5. The compound according to claim 1 or a salt thereof, having the structure of Formula (Ib):

6. The compound according to claim 1 or a salt thereof, wherein Q is:

7. The compound according to claim 1 or a salt thereof, wherein said compound is:

8. The compound according to claim 1 or a salt thereof, wherein said compound is:

9. The compound according to claim 5 or a salt thereof, wherein Q is:

10. The compound according to claim 1 or a salt thereof, wherein said compound is:

11. The compound according to claim 1 or a salt thereof, wherein Q is:

12. The compound according to claim 1 or a salt thereof, wherein said compound is:

13. The compound according to claim 1 or a salt thereof, wherein said compound is:

14. The compound according to claim 1 or a salt thereof, wherein Q is:

15. The compound according to claim 1 or a salt thereof, wherein said compound is:

16. The compound according to claim 1 or a salt thereof, wherein the compound is selected from:
4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (96);
(RS)-4-(1-acryloylpiperidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (97);
4-(1-acryloylpiperidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide, single enantiomers (98 and 99);
4-(1-acryloylpyrrolidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (112);
4-(1-acryloylpyrrolidin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (113 and 114);
cis-4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoro-9H-carbazole-1-carboxamide (115);
cis-4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoro-9H-carbazole-1-carboxamide (116 and 117);
cis-4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoro-9H-carbazole-1-carboxamide (119-121);
cis-4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5 (1H)-yl)-3-fluoro-9H-carbazole-1-carboxamide (123);
cis-4-(1-acryloylhexahydropyrrolo[3,4-b]pyrrol-5 (1H)-yl)-3-fluoro-9H-carbazole-1-carboxamide (124 and 125);
4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-9H-carbazole-1-carboxamide (126);
4-((4aS, 7aS)-1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-9H-carbazole-1-carboxamide and 4-((4aR,7aR)-1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-chloro-9H-carbazole-1-carboxamide (127 and 128);
4-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (134);
5-(1-acryloylpyrrolidin-3-yl)-6-fluoro-2,3,4,9-tetrahy dro-1H-carbazole-8-carboxamide (135);
4-(1-(but-2-ynoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-3-fluoro-9H-carbazole-1-carboxamide (137);
4-(1-acryloyl-1,4,5,6-tetrahydropyridin-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (138);
4-(7-(but-2-ynoyl)-2,7-diazaspiro[4.4] nonan-2-yl)-3-fluoro-9H-carbazole-1-carboxamide (139);
4-(7-acryloyl-2,7-diazaspiro [4.4]nonan-2-yl)-3-fluoro-9H-carbazole-1-carboxamide (140);
4-(1-acryloyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-3-fluoro-9H-carbazole-1-carboxamide (141);
4-(1-(but-2-ynoyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-3-fluoro-9H-carbazole-1-carboxamide (142);
4-(6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (143);
4-(6-(but-2-ynoyl)-3,6-diazabicyclo[3.2.0] heptan-3-yl)-3-fluoro-9H-carbazole-1-carboxamide (144);
4-(7-acryloyloctahydro-2,7-naphthyridin-2(1H)-yl)-3-fluoro-9H-carbazole-1-carboxamide (145);
4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b] pyridin-6-yl)-3-chloro-9H-carbazole-1-carboxamide (146);
4-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-3-fluoro-7-(trifluoromethyl)-9H-carbazole-1-carboxamide (160);
4-(1-acryloylpiperidin-3-yl)-3-fluoro-7-(trifluoromethyl)-9H-carbazole-1-carboxamide (161 and 162);
4-(1-acryloyl-1-azaspiro[4.4]nonan-7-yl)-3-fluoro-7-(trifluoromethyl)-9H-carbazole-1-carboxamide (171);
4-(1-acryloyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-chloro-3-fluoro-9H-carbazole-1-carboxamide (182);
4-(1-(but-2-ynoyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-chloro-3-fluoro-9H-carbazole-1-carboxamide (183);
5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-fluoro-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (184);
4-(7-(but-2-ynoyl)octahydro-2,7-naphthyridin-2(1H)-yl)-3-fluoro-9H-carbazole-1-carboxamide (190);
4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-9H-carbazole-1-carboxamide (191);
4-(1-(but-2-ynoyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-9H-carbazole-1-carboxamide (192); and
4-((1S,4S)-2-acryloyl-2-azabicyclo

Assignees

• Bristol Myers Squibb Co

Inventors

• Ahmad Saleem
• Batt Douglas G
• Liu Qingjie
• Macor John E
• Tino Joseph A
• Hunter Scott
• Nair Satheesh Kesavan
• Maishal Tarun Kumar

Classifications

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D209/88 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title