Imide and acylurea derivatives as modulators of the glucocorticoid receptor

Patent metadata

Field	Value
Publication number	US-2016185776-A1
Application number	US-201414911485-A
Country	US
Kind code	A1
Filing date	Aug 21, 2014
Priority date	Aug 22, 2013
Publication date	Jun 30, 2016
Grant date	—

Abstract

Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF- K B activity, including metabolic and inflammatory and immune diseases or disorders, having the structure of formula (I): an enantiomer, diastereomer, or tautomer thereof, or a pharmaceutically-acceptable salt thereof, in which the variables are as defined in the specification.

First claim

What is claimed is:

1 . A compound according to formula I,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:
X is selected from N and CR 1 ;
R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 are the same or different and at each occurrence are independently selected from hydrogen, halogen, C 1-8 alkyl, substituted C 1-8 alkyl, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, C 2-8 substituted alkynyl, nitro, cyano, dialkylaminoalkoxy, alkoxyalkyloxyalkyloxy, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3-7 cycloalkynyl, heterocyclo, aryl, and heteroaryl, wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl are each substituted with zero to three halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —OR 12 , ═O, —NR 12 R 13 , —C(═O)R 12 , —C(═O)OR 12 , —C(═O)NR 12 R 13 , —OC(═O)NR 12 , R 13 , —NR 12 C(O)NR 12 R 13 , —OC(═O)R 12 , —NR 12 C(═O)R 13 , —NR 12 C(O)OR 13 , —NR 12 C(S)OR 13 , —S(O) p R 14 , —NR 12 SO 2 R 14 , SO 2 NR 12 R 13 , C 3-7 cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered heteroaryl optionally substituted with C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
R 4 is C(O)R 11 ;
R 9 and R 10 are the same or different and at each occurrence are independently C 1-6 alkyl; or
R 9 and R 10 are taken together with the atom to which they are attached to form a C 3-7 cycloalkyl, C 3-7 cycloalkenyl, or heterocyclo group;
R 11 at each occurrence is independently selected from C 1-6 alkyl, —OR 15 , —NR 15 R 16 , C 3-7 cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered heteroaryl optionally substituted with C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
R 12 and R 13 are the same or different and at each occurrence are independently selected from (i) hydrogen, C 1-8 alkyl, substituted C 1-8 alkyl, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R 12 is taken together with R 13 to form a heteroaryl or heterocyclo ring each optionally substituted with OH, oxo, C 1-4 alkoxy, C 1-4 alkyl, halogen, and C 1-4 haloalkyl;
R 14 at each occurrence is independently selected from C 1-8 alkyl, substituted C 1-8 alkyl, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, aryl, heteroaryl, and heterocyclo;
R 15 and R 16 are the same or different and at each occurrence are independently selected from (i) hydrogen, C 1-8 alkyl, substituted C 1-8 alkyl, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R 15 is taken together with R 16 to form a heteroaryl or heterocyclo ring; p is 0, 1 and 2; and
provided the following compounds are excluded:

2 . The compound as defined in claim 1 , having formula II,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:
R 1 , R 2 , and R 3 are the same or different and at each occurrence are independently selected from halogen, C 1-8 alkyl, cyano, C 3-7 cycloalkyl, 3- to 10-membered heterocyclo, 5- to 10-membered aryl, and 5- to 10-membered heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclo, aryl, and heteroaryl are each substituted with zero to three substituents independently selected from halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —OR 12 , —NR 12 R 13 , —C(═O)R 12 , —C(═O)OR 12 , —C(═O)NR 12 R 13 , —OC(═O)NR 12 , R 13 , —NR 12 C(O)NR 12 R 13 , —OC(═O)R 12 , —NR 12 C(═O)R 13 , —NR 12 C(O)OR 13 , —NR 12 C(S)OR 13 , —S(O) p R 14 , —NR 12 SO 2 R 14 , SO 2 NR 12 R 13 , C 3-7 cycloalkyl, 3- to 6-membered heterocyclo, phenyl, and 5- to 6-membered heteroaryl optionally substituted with C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
R 5 , R 6 , R 7 , and R 8 are the same or different and at each occurrence are independently selected from hydrogen, halogen, and C 1-6 alkyl;
R 11 at each occurrence is independently selected from C 1-6 alkyl, —NR 15 R 16 , C 3-7 cycloalkyl, and 3- to 6-membered heterocycle;
R 12 and R 13 are the same or different and at each occurrence are independently selected from (i) hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclo; or (ii) where possible, R 12 is taken together with R 13 to form a 5- to 6-membered heteroaryl or 4- to 6-membered heterocyclo ring optionally substituted with OH, oxo, C 1-4 alkoxy, C 1-4 alkyl, halogen, and C 1-4 haloalkyl;
R 14 at each occurrence is independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycle; and
R 15 , and R 16 are the same or different and at each occurrence are independently selected from (i) hydrogen, C 1-8 alkyl, substituted C 1-8 alkyl, C 2-8 alkenyl, substituted C 2-8 alkenyl, C 2-8 alkynyl, substituted C 2-8 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R 15 is taken together with R 16 to form a heteroaryl or heterocyclo ring.

3 . The compound as defined in claim 2 having the following formula III,

or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:
R 1 is independently selected from 5- to 10-membered aryl and 5- to 10-membered heteroaryl, wherein said aryl and heteroaryl group are each substituted with zero to three substituents independently selected from halogen, C 1-6 hydroxyalkyl, —OR 12 , —NR 12 R 13 , —C(═O)R 12 , —C(═O)OR 12 , —C(═O)NR 12 , R 13 , —NR 12 C(═O)R 13 , —S(O) 2 R 14 , —NR 12 SO 2 R 14 , phenyl, and 5- to 6-membered heteroaryl optionally substituted with C 1-3 alkyl;
R 5 is independently selected from is hydrogen and halogen;
R 9 and R 10 are C 1-3 alkyl;
R 12 and R 13 are the same or different and at each occurrence are independently selected from (i) hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and 5- to 6-membered heterocyclo; or (ii) where possible, R 12 is taken together with R 13 to form a 4- to 6-membered heterocyclo ring optionally substituted with C 1-3 alkyl and oxo; and
R 14 at each occurrence is independently C 1-6 alkyl.

4 . The compound as defined in claim 3 , or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt thereof, wherein:
R 11 at each occurrence is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, and —NR 15 R 16 ; and R 15 , and R 16 are the same or different and at each occurrence are independently selected from (i) hydrogen, C 1-8 alkyl, substituted C 1-8 alkyl wherein the substituent is selected from OH and aryl optionally substitute with C 1-4 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, aryl, heteroaryl, and heterocyclo; or (ii) where possible, R 15 is taken together with R 16 to form a heteroaryl or heterocyclo ring.

5 . A compound as defined in claim 4 , or an enantiomer, diastereomer, tautomer, or a phar

Assignees

• Bristol Myers Squibb Co

Inventors

• Weinstein David S
• Gong Hua
• Yang Michael G
• Xiao Zili

Classifications

• A61P5/44

  Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title