Hydroxy formamide derivatives and their use

Patent metadata

Field	Value
Publication number	US-10450288-B2
Application number	US-201515110776-A
Country	US
Kind code	B2
Filing date	Jan 9, 2015
Priority date	Jan 10, 2014
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

Disclosed are compounds having the formula:

wherein R1, R2 and R3 are as defined herein, and methods of making and using the same, including use as inhibitors of BMP1, TLL1 and/or TLL2 and in treatment of diseases associated with BMP1, TLL1 and/or TLL2 activity.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt thereof,
wherein:
R1 is selected from the group consisting of H, (C 1 -C 4 ) straight chain alkyl, and (C 1 -C 4 ) straight chain alkyl substituted with a hydroxy group;
R2 is selected from H, (C 1 -C 11 )alkyl, (C 1 -C 3 )alkyl-(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkyl-phenyl, (C 1 -C 3 )alkyl-naphthyl and (C 1 -C 3 )alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (C 1 -C 11 )alkyl, cycloalkyl, phenyl, naphthyl and heterocyclyl are optionally substituted with 1-2 groups independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo, and cyano; and
R3 is selected from:
a) phenyl, optionally substituted with 1-3 groups independently selected from:

(C 1 -C 6 )alkyl, optionally substituted with 1-3 groups independently selected from: fluoro; —CO 2 H; —P(O)R f R g ; NR a R b wherein R a is selected from H and (C 1 -C 4 )alkyl and R b is selected from (C 1 -C 4 )alkyl substituted with —CO 2 H or —P(O)R f R g , and —C(O)NR a R b wherein R a and R b are independently selected from H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, —CO 2 H, —C(O)O(C 1 -C 4 )alkyl and —P(O)R f R g ;
cyclopropyl, optionally substituted with 1 —CO 2 H;
—C(O)NR a R b wherein R a and R b are independently selected from H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, —CO 2 H, —C(O)O(C 1 -C 4 )alkyl, —P(O)R f R g , NR c R d and N + R c R d R e ;
(C 1 -C 6 )alkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, —CO 2 H, (C 3 -C 6 )cycloalkyl, —C(O)NH 2 and pyrrolidinyl;
(C 3 -C 6 )cycloalkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, and —CO 2 H;
—NR a R b wherein R a and R b are independently selected from H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with 1-3 groups independently selected from oxo and —CO 2 H;
—SR a wherein R a is selected from H and (C 1 -C 4 )alkyl;
—CO 2 H; —C(NOH)NH 2 , cyano; —C(O)O(C 1 -C 4 )alkyl; —C(O)CO 2 H; —P(O)R f R g ; —OP(O)R f R g ; halo; hydroxy; nitro; —NHSO 2 (C 1 -C 2 )alkyl; —SO 3 H; —SO 2 (C 1 -C 2 )alkyl; —SO 2 NR c R d ; —SO 2 NHC(O)(C 1 -C 2 )alkyl; and —B(OH) 2 ;
and
b) heteroaryl, optionally substituted with 1-2 groups independently selected from: (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, oxo, —CO 2 H, —P(O)R f R g , and —OP(O)R f R g ;
wherein in each occurrence: R c , R d and R e are independently selected from H and (C 1 -C 2 )alkyl; and
R f and R g are independently selected from hydroxy, (C 1 -C 2 )alkyl and (C 1 -C 2 )alkoxy.

2. The compound or salt thereof according to claim 1 , wherein the compound of Formula (I):
R1 is selected from the group consisting of H, (C 1 -C 4 ) straight chain alkyl, and (C 1 -C 4 ) straight chain alkyl substituted with a hydroxy group;
R2 is selected from H, (C 1 -C 11 )alkyl, (C 1 -C 3 )alkyl-(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkyl-phenyl, and (C 1 -C 3 )alkyl-heterocyclyl, wherein heterocyclyl is a monocyclic ring having 5-6 ring atoms wherein 1-2 of the ring atoms are selected from nitrogen, oxygen and sulfur, and wherein said (C 1 -C 11 )alkyl, cycloalkyl, phenyl, and heterocyclyl are optionally substituted with 1-2 groups independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo, and cyano; and
R3 is selected from:
c) phenyl, optionally substituted with 1-3 groups independently selected from:

(C 1 -C 6 )alkyl, optionally substituted with 1-3 groups independently selected from: fluoro; —CO 2 H; —P(O)R f R g ; and —C(O)NR a R b wherein R a and R b are independently selected from H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, —CO 2 H, —C(O)O(C 1 -C 4 )alkyl and —P(O)R f R g ;
cyclopropyl, optionally substituted with 1 —CO 2 H;
—C(O)NR a R b wherein R a and R b are independently selected from H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with 1-3 groups independently selected from hydroxy, —CO 2 H, —C(O)O(C 1 -C 4 )alkyl, —P(O)R f R g , NR c R d and N + R c R d R e ;
(C 1 -C 6 )alkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, —CO 2 H, (C 3 -C 6 )cycloalkyl, and pyrrolidinyl;
(C 3 -C 6 )cycloalkoxy, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, and —CO 2 H;
—NR a R b wherein R a and R b are independently selected from H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with 1-3 groups independently selected from oxo and —CO 2 H;
—SR a wherein R a is selected from H and (C 1 -C 4 )alkyl;
—CO 2 H; —C(NOH)NH 2 , cyano; —C(O)O(C 1 -C 4 )alkyl; —C(O)CO 2 H; —P(O)R f R g ; —OP(O)R f R g ; halo; hydroxy; nitro; —NHSO 2 (C 1 -C 2 )alkyl; —SO 3 H; —SO 2 (C 1 -C 2 )alkyl; —SO 2 NR c R d ; —SO 2 NHC(O)(C 1 -C 2 )alkyl; and —B(OH) 2 ;
and
d) heteroaryl, optionally substituted with 1-2 groups independently selected from: (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, oxo, —CO 2 H, —P(O)R f R g , and —OP(O)R f R g ;
wherein in each occurrence: R c , R d and R e are independently selected from H and (C 1 -C 2 )alkyl; and
R f and R g are independently selected from hydroxy, (C 1 -C 2 )alkyl and (C 1 -C 2 )alkoxy.

3. The compound or salt thereof according to claim 1 , wherein the compound according to Formula (I) has the Formula (I)(a):

4. The compound or salt thereof according to claim 1 wherein the compound according to Formula (I) has the Formula (I)(b):

5. The compound or salt thereof according to claim 1 , wherein R1 is H, methyl, ethyl or —CH 2 OH.

6. The compound or salt thereof according to claim 1 , wherein R2 is H or optionally substituted n-pentyl, 2-ethylbutyl, (cyclopentyl)methyl, benzyl, 2-phenylethyl, 3-phenylpropyl, or 2-naphthylethyl.

7. The compound or salt thereof according to claim 1 , wherein R1 and R2 have (R) stereochemistry.

8. The compound or salt thereof according to claim 1 , wherein R3 is optionally substituted phenyl.

9. The compound or salt thereof according to claim 1 , wherein R3 is disubstituted phenyl wherein the substituents are ethoxy in the 3-position and —P(O)(OH) 2 , —CO 2 H, —OCH 2 CO 2 H, or C(O)NHCH(CO 2 H)(CH 2 CO 2 H) in the 4- or 5-position.

10. The compound or salt thereof according to claim 1 , wherein R3 is phenyl optionally substituted with 1-3 groups selected from: —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OCH(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCH 2 CHF 2 , —OC 2 H 4 -pyrrolidine, —OCH 2 CO 2 H, —OCH 2 C(O)NH 2 , —CO 2 H, —CH 3 , cyclopropane-1-carboxylic acid, —CH 2 CO 2 H, —C(CH 3 ) 2 CO 2 H, —CH(CH 3 )CO 2 H, —CF 2 CO 2 H, —CH 2 C(O)NHCH(CO 2 H)(CH 2 CO 2 H), —CH 2 P(O)(OH) 2 , —CH 2 N(CH 3 )(CH 2 CO 2 H), —CH 2 NHCH 2 P(O)(OH) 2 , —C(NH 2 )(NOH), cyano, nitro, hydroxy, —SO 2 NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NH(CH 3 ), —SO 2 CH 3 , —SO 2 NHC(O)C 2 H 5 , —SCH 3 , —SC 2 H 5 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —C(O)NHCH 3 , —C(O)NH(C 2 H 4 NH 2 ), —C(O)NH

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Dowdell Sarah E
• Eidam Hilary Schenck
• Elban Mark
• Fox Ryan Michael
• Hammond Marlys
• Hilfiker Mark A
• Hoang Tram H
• Kallander Lara
• Lawhorn Brian Griffin
• Manns Sharada
• Philp Joanne
• Washburn David G
• Ye Guosen

Classifications

• A61P43/00

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

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · 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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title