Bicyclic lactams and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12281101-B2
Application number	US-202117198238-A
Country	US
Kind code	B2
Filing date	Mar 10, 2021
Priority date	Jul 2, 2015
Publication date	Apr 22, 2025
Grant date	Apr 22, 2025

Abstract

The invention provides novel compounds having the general formula I:

wherein R 1 , X, Z 1 , L, n, the A ring, the B ring, and the C ring are as described herein, pharmaceutical compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of H and unsubstituted C 1 -C 4 alkyl;
the A ring is phenyl optionally substituted with:
(a) 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, cyano, phenyl, benzyl, CH 2 —(C 3 -C 6 cycloalkyl) and CH 2 CH 2 —(C 3 -C 6 cycloalkyl);
(b) 1 substituent selected from the group consisting of C 4 -C 6 heterocyclyl, C 5 -C 6 heteroaryl, CH 2 —(C 4 -C 6 heterocyclyl), CH 2 CH 2 —(C 4 -C 6 heterocyclyl), CH 2 —(C 5 -C 6 heteroaryl) and CH 2 CH 2 —(C 5 -C 6 heteroaryl); and optionally a second substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy; or
(c) two adjacent substituents which together form phenyl, C 5 -C 6 heteroaryl, C 4 -C 6 heterocyclyl or C 4 -C 6 cycloalkyl;

X is O or CH 2 ;
Z 1 is C;
n is 1; and

is selected from the group consisting of:

Y is selected from the group consisting of O, S, SO and SO 2 ;
X 1 , X 2 and X 3 are each independently N or CH, wherein 1 or 2 of X 1 , X 2 and X 3 is N;
X 4 and X 5 are each independently N or CH;
R 5a and R 5b are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, benzyl, —CH 2 (C 3 -C 6 cycloalkyl) and 5 to 6 membered heteroaryl; wherein R 5a and R 5b together with the carbon to which they are attached may form a 3 to 4 membered cycloalkyl or a 4 membered cycloalkoxy;
R 6a and R 6b are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH 2 (C 3 -C 6 cycloalkyl), and 5 to 6 membered heteroaryl; wherein R 6a and R 6b together with the carbon to which they are attached may form a 3 to 4 membered cycloalkyl or a 4 membered cycloalkoxy;
wherein, when R 5a and R 6a are each H, R 5b and R 6b may together form a 3 or 4 membered cycloalkyl;
and wherein only two of R 5a , R 5b , R 6a and R 6b may be other than H in each instance;
R 7 is selected from the group consisting of H and unsubstituted C 1 -C 4 alkyl;
R 10 is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, phenyl and benzyl; and
R 11 is selected from the group consisting of H, halogen, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

is selected from the group consisting of:

 and
R 5a and R 5b are each H or R 5a and R 6a are each H, and R 5b and R 6b together form cyclopropyl or cyclobutyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is O.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are each H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

is selected from the group consisting of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

and
R 6b is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH 2 (C 3 -C 6 cycloalkyl) and 5 to 6 membered heteroaryl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

and
R 6b is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH 2 (C 3 -C 6 cycloalkyl) and 5 to 6 membered heteroaryl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

and
Y is O; and R 6b is selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, phenyl, mono- or di-fluorophenyl, benzyl, —CH 2 (C 3 -C 6 cycloalkyl and 5 to 6 membered heteroaryl.

9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl.

10. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl.

11. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl.

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

13. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
5a-methyl-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide
(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1′,4′,5′,7′-tetrahydrospiro[cyclopropane-1,6′-indazole]-3′-carboxamide
5-(tert-butyl)-N—((S)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
N—((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxamide
(S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

Assignees

• Genentech Inc

Inventors

• Patel Snahel
• Hamilton Gregory
• Stivala Craig
• Chen Huifen
• Zhao Guiling

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D491/044

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title