IP Library › Granted Patent US 11,559,538
Granted Patent B2
US 11,559,538 · App. 17/082,102 · Granted Jan 24, 2023

Substituted 1,2-oxaborolan-2-ols as PDE4 inhibitors

Inventors: Joseph Walter Strohbach (Wentzville, MO); Tsutomu Akama (Tokyo, JP); David Clive Blakemore (East Lyme, CT); Robert Toms Jacobs (Wake Forest, NC); Peter Jones (Sharon, MA); David Christopher Limburg (Salem, CT); Martins Sunday Oderinde (Ewing, NJ); Matthew Alexander Perry (Uncasville, CT); Jacob John Plattner (Bend, OR); Rubben Federico Torella (Cambridge, MA); Yasheen Zhou (Moraga, CA); Thean Yeow Yeoh (Salem, CT)
Assignee: Pfizer Inc.
A61K31/69A61K31/519C07F5/025C07B2200/13
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Quick Facts
Patent No.
US 11,559,538
App. No.
17/082,102
Granted
Jan 24, 2023
Kind
B2
Abstract

The present invention relates to boron containing compounds of Formula (IA): that inhibit phosphodiesterase 4 (PDE4). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating diseases, conditions, or disorders ameliorated by inhibition of PDE4.

Claims (57)

1. A compound of Formula (IA):

or a pharmaceutically acceptable salt thereof,

wherein:

A 1 is —O— or —S—;

A 2 is —O— or —S—;

R 1 is H, D, halogen, CN, NO 2 , (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-NR A R B , (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-SH, (C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, (C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, (C 1 -C 6 ) alkylene-aryl, (C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)(C 1 -C 6 ) alkyl, C(O)NR A R B , C(O)OH, C(O)O(C 1 -C 6 ) alkyl, NR A R B , OH, O(C 1 -C 6 ) alkyl, d 1-13 -O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) haloalkyl, O(C 1 -C 6 ) alkylene-C(O)OH, O(C 1 -C 6 ) alkylene-NR A R B , O(C 1 -C 6 ) alkylene-OH, O(C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) alkylene-aryl, O(C 2 -C 6 ) alkenyl, O(C 2 -C 6 ) alkynyl, O(C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, O(C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, O(C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, O(C 3 -C 8 ) cycloalkyl, O(4-7 membered) heterocyclyl, Oaryl, O(5-6 membered) heteroaryl, SH, S(C 1 -C 6 ) alkyl, S(C 1 -C 6 ) haloalkyl, S(C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, S(C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, S(C 1 -C 6 ) alkylene-aryl, S(C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, S(C 2 -C 6 ) alkenyl, S(C 2 -C 6 ) alkynyl, S(C 3 -C 8 ) cycloalkyl, S(4-7 membered) heterocyclyl, Saryl, S(5-6 membered) heteroaryl, (C 3 -C 8 ) cycloalkyl, (4-7 membered) heterocyclyl, aryl, or (5-6 membered) heteroaryl, wherein the (4-7 membered) heterocyclyl contains at least one heteroatom independently selected from the group consisting of N, O, and S;

R 2 is H, D, halogen, CN, NO 2 , (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-NR A R B , (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-SH, (C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, (C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, (C 1 -C 6 ) alkylene-aryl, (C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)(C 1 -C 6 ) alkyl, C(O)NR A R B , C(O)OH, C(O)O(C 1 -C 6 ) alkyl, NR A R B , OH, O(C 1 -C 6 ) alkyl, d 1-13 -O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) haloalkyl, O(C 1 -C 6 ) alkylene-C(O)OH, O(C 1 -C 6 ) alkylene-NR A R B , O(C 1 -C 6 ) alkylene-OH, O(C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) alkylene-aryl, O(C 2 -C 6 ) alkenyl, O(C 2 -C 6 ) alkynyl, O(C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, O(C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, O(C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, O(C 3 -C 8 ) cycloalkyl, O(4-7 membered) heterocyclyl, Oaryl, O(5-6 membered) heteroaryl, SH, S(C 1 -C 6 ) alkyl, S(C 1 -C 6 ) haloalkyl, S(C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, S(C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, S(C 1 -C 6 ) alkylene-aryl, S(C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, S(C 2 -C 6 ) alkenyl, S(C 2 -C 6 ) alkynyl, S(C 3 -C 8 ) cycloalkyl, S(4-7 membered) heterocyclyl, Saryl, S(5-6 membered) heteroaryl, (C 3 -C 8 ) cycloalkyl, (4-7 membered) heterocyclyl, aryl, or (5-6 membered) heteroaryl, wherein the (4-7 membered) heterocyclyl contains at least one heteroatom independently selected from the group consisting of N, O, and S;

R 3 is H, D, (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-OH, or (C 3 -C 8 ) cycloalkyl;

R 4 is H, D, (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-OH, or (C 3 -C 8 ) cycloalkyl;

R 5 is H, D, halogen, CN, NO 2 , (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-NR A R B , (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-SH, (C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, (C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, (C 1 -C 6 ) alkylene-aryl, (C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, C(O)(C 1 -C 6 ) alkyl, C(O)NR A R B , C(O)OH, C(O)O(C 1 -C 6 ) alkyl, NR A R B , OH, O(C 1 -C 6 ) alkyl, d 1-13 -O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) haloalkyl, O(C 1 -C 6 ) alkylene-C(O)OH, O(C 1 -C 6 ) alkylene-NR A R B , O(C 1 -C 6 ) alkylene-OH, O(C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) alkylene-aryl, O(C 2 -C 6 ) alkenyl, O(C 2 -C 6 ) alkynyl, O(C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, O(C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, O(C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, O(C 3 -C 8 ) cycloalkyl, O(4-7 membered) heterocyclyl, Oaryl, O(5-6 membered) heteroaryl, SH, S(C 1 -C 6 ) alkyl, S(C 1 -C 6 ) haloalkyl, S(C 1 -C 6 ) alkylene-(C 3 -C 8 ) cycloalkyl, S(C 1 -C 6 ) alkylene-(4-7 membered) heterocyclyl, S(C 1 -C 6 ) alkylene-aryl, S(C 1 -C 6 ) alkylene-(5-6 membered) heteroaryl, S(C 2 -C 6 ) alkenyl, S(C 2 -C 6 ) alkynyl, S(C 3 -C 8 ) cycloalkyl, S(4-7 membered) heterocyclyl, Saryl, S(5-6 membered) heteroaryl, (C 3 -C 8 ) cycloalkyl, (4-7 membered) heterocyclyl, aryl, or (5-6 membered) heteroaryl, wherein the (4-7 membered) heterocyclyl contains at least one heteroatom independently selected from the group consisting of N, O, and S;

R 6 is H, D, halogen, CN, NO 2 , (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-C(O)O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-NR C R D , (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, C(O)(C 1 -C 6 ) alkyl, C(O)NR C R D , C(O)OH, C(O)O(C 1 -C 6 ) alkyl, NR C R D , OH, O(C 1 -C 6 ) alkyl, d 1-13 -O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) haloalkyl, O(C 1 -C 6 ) alkylene-C(O)OH, O(C 1 -C 6 ) alkylene-NR C R D , O(C 1 -C 6 ) alkylene-OH, O(C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, SH, or S(C 1 -C 6 ) alkyl;

R 7 is H, D, halogen, CN, NO 2 , (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-C(O)O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-NR C R D , (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, C(O)(C 1 -C 6 ) alkyl, C(O)NR C R D , C(O)OH, C(O)O(C 1 -C 6 ) alkyl, NR C R D , OH, O(C 1 -C 6 ) alkyl, d 1-13 -O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) haloalkyl, O(C 1 -C 6 ) alkylene-C(O)OH, O(C 1 -C 6 ) alkylene-NR C R D , O(C 1 -C 6 ) alkylene-OH, O(C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, SH, or S(C 1 -C 6 ) alkyl;

R 9 is H, D, halogen, CN, NO 2 , (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-C(O)O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-NR C R D , (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, C(O)(C 1 -C 6 ) alkyl, C(O)NR C R D , C(O)OH, C(O)O(C 1 -C 6 ) alkyl, NR C R D , OH, O(C 1 -C 6 ) alkyl, d 1-13 -O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) haloalkyl, O(C 1 -C 6 ) alkylene-C(O)OH, O(C 1 -C 6 ) alkylene-NR C R D , O(C 1 -C 6 ) alkylene-OH, O(C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, SH, or S(C 1 -C 6 ) alkyl;

R 10 is D, (C 1 -C 6 ) alkyl, d 1-13 -(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-SH, or (C 1 -C 6 ) alkylene-S(C 1 -C 6 ) alkyl;

R A is H, (C 1 -C 6 ) alkyl, or C(O)(C 1 -C 6 ) alkyl;

R B is H, (C 1 -C 6 ) alkyl, or C(O)(C 1 -C 6 ) alkyl;

R C is H, (C 1 -C 6 ) alkyl, or C(O)(C 1 -C 6 ) alkyl;

R D is H, (C 1 -C 6 ) alkyl, or C(O)(C 1 -C 6 ) alkyl; and

p is 0, 1, 2, 3, 4, or 5.

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

A 1 is —O—;

A 2 is —O—;

R 1 is H, halogen, CN, or (C 1 -C 6 ) haloalkyl;

R 2 is H, halogen, CN, or (C 1 -C 6 ) haloalkyl;

R 3 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-OH, or (C 3 -C 8 ) cycloalkyl;

R 4 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-OH, or (C 3 -C 8 ) cycloalkyl;

R 5 is H, halogen, CN, or (C 1 -C 6 ) haloalkyl;

R 6 is H, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-C(O)O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) alkyl, or O(C 1 -C 6 ) alkylene-OH;

R 7 is H, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-C(O)O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) alkyl, or O(C 1 -C 6 ) alkylene-OH;

R 9 is H, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-C(O)OH, (C 1 -C 6 ) alkylene-C(O)O(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkylene-OH, (C 1 -C 6 ) alkylene-O(C 1 -C 6 ) alkyl, O(C 1 -C 6 ) alkyl, or O(C 1 -C 6 ) alkylene-OH;

R 10 is (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkylene-OH; and

p is 0 or 1.

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

A 1 is —O—;

A 2 is —O—;

R 1 is H;

R 2 is H;

R 3 is (C 1 -C 3 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-OH, or (C 3 -C 8 ) cycloalkyl;

R 4 is (C 1 -C 3 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkylene-OH, or (C 3 -C 8 ) cycloalkyl;

R 5 is H;

R 6 is H or (C 1 -C 3 ) alkyl;

R 7 is H or (C 1 -C 3 ) alkyl;

R 9 is H or (C 1 -C 3 ) alkyl;

R 10 is CH 3 ; and

p is 0, 1, or 2.

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

A 1 is —O—;

A 2 is —O—;

R 1 is H;

R 2 is H;

R 3 is (C 1 -C 3 ) alkyl;

R 4 is (C 1 -C 3 ) alkyl;

R 5 is H;

R 6 is H or (C 1 -C 3 ) alkyl;

R 7 is H or (C 1 -C 3 ) alkyl;

R 9 is H or (C 1 -C 3 ) alkyl; and

p is 0.

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →