Tricyclic heterocycles as BET protein inhibitors

Patent metadata

Field	Value
Publication number	US-9527864-B2
Application number	US-201514852958-A
Country	US
Kind code	B2
Filing date	Sep 14, 2015
Priority date	Sep 15, 2014
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The present disclosure relates to tricyclic heterocycles of Formula I, which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is a group of Formula Cy 1 -A or Cy 1 -B:

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and C 1-4 alkyl; or R 2 and R 4 are combined to form a bridging —CH 2 — or —CH 2 CH 2 — group;
R 5 is —C(═O)R 5a , —C(═O)OR 5a , —C(═O)NR 5a R 5b , —S(═O) 2 R 5a , or —S(═O)2NR 5a R 5b ;
R 5a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;
R 5b is H or C 1-4 alkyl;
R 6 is H or methyl;
R 7 is H, C 1-4 alkyl, —C(═O)R 7a , —C(═O)OR 7a , —C(═O)NR 7a R 7b , —S(═O) 2 R 7a , or —S(═O) 2 NR 7a R 7b ;
R 7a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;
R 7b is H or C 1-4 alkyl;
R 8 is H or methyl;
Cy 2 is pyridin-2-yl or pyridin-3-yl, each of which is optionally substituted by F or Cl, wherein said F and Cl are meta or para to the pyridine nitrogen;
R 9 is H, F, or CH 2 OH; and
R 10 is H, —C(═O)NHCH 3 , —C(═O)NHCH 2 CH 3 , —C(═O)NHCH 2 CH 2 CH 3 , or —C(═O)NHCH(CH 3 ) 2 ;
provided:

i) when R 5a is methyl, ethyl or i-propyl, then one of R 2 , R 3 , and R 4 is other than H;
ii) when R 7a is methyl, ethyl, i-propyl, —CF3, or methoxymethyl, then one of R 2 , R 3 , and R 4 is other than H; and
iii) when R 7 and R 8 are both methyl, then one of R 2 , R 3 , and R 4 is other than H.

2. A compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is a group of Formula Cy 1 -A or Cy 1 -B:

R 1 , R 2 , R 3 , and R 4 are each independently selected from H and C 1-4 alkyl;
or R 2 and R 4 are combined to form a bridging —CH 2 — or —CH 2 CH 2 — group;
R 5 is —C(═O)R 5a , —C(═O)OR 5a , —C(═O)NR 5a R 5b , —S(═O) 2 R 5a , or —S(═O) 2 NR 5a R 5b ;
R 5a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;
R 5b is H or C 1-4 alkyl;
R 6 is H or methyl;
R 7 is H, C 1-4 alkyl, —C(═O)R 7a , —C(═O)OR 7a , —C(═O)NR 7a R 7b , —S(═O) 2 R 7a , or —S(═O) 2 NR 7a R 7b ;
R 7a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;
R 7b is H or C 1-4 alkyl; and
R 8 is H or methyl;
provided:

i) when R 5a is methyl, ethyl or i-propyl, then one of R 2 , R 3 , and R 4 is other than H;
ii) when R 7a is methyl, ethyl, i-propyl, —CF3, or methoxymethyl, then one of R 2 , R 3 , and R 4 is other than H; and
iii) when R 7 and R 8 are both methyl, then one of R 2 , R 3 , and R 4 is other than H.

3. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is a group of Formula Cy 1 -A;
R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;
or R 2 and R 4 are combined to form a bridging —CH 2 — group;
R 5 is —C(═O)R 5a , —C(═O)OR 5a , —C(═O)NR 5a R 5b , —S(═O) 2 R 5a , or —S(═O) 2 NR 5a R 5b ;
R 5a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;
R 5b is H or methyl;
provided when R 5a is methyl, ethyl or i-propyl, then one of R 2 , R 3 , and R 4 is other than H.

4. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is a group of Formula Cy 1 -A;
R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;
or R 2 and R 4 are combined to form a bridging —CH 2 — group;
R 5 is —C(═O)R 5a ; and
R 5a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(═O)R 5a .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxyethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxymethyl, cyclopropyl, or cyclobutyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5a is n-propyl, t-butyl, methoxymethyl, cyclopropyl, or cyclobutyl.

12. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is a group of Formula Cy 1 -B;
R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;
or R 2 and R 4 are combined to form a bridging —CH 2 — group;
R 6 is H or methyl;
R 7 is H, C 1-4 alkyl, —C(═O)R 7a , —C(═O)OR 7a , —C(═O)NR 7a R 7b , —S(═O) 2 R 7a , or —S(═O) 2 NR 7a R 7b ;
R 7a is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-4 alkyl-;
R 7b is H or methyl; and
R 8 is H or methyl;
provided: when R 7a is methyl, ethyl, i-propyl, —CF 3 , or methoxymethyl, then one of R 1 , R 2 , R 3 , and R 4 is other than H; and when R 7 and R 8 are both methyl, then one of R 1 , R 2 , R 3 , and R 4 is other than H.

13. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is a group of Formula Cy 1 -B;
R 1 , R 2 , R 3 , and R 4 are each independently selected from H and methyl;
or R 2 and R 4 are combined to form a bridging —CH 2 — group;
R 6 is H or methyl;
R 7 is —

Assignees

• Incyte Corp

Inventors

• Combs Andrew P
• Sparks Richard B

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title