Apelin receptor (APJ) agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-10377718-B2
Application number	US-201515023510-A
Country	US
Kind code	B2
Filing date	Jun 5, 2015
Priority date	Jun 6, 2014
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

This disclosure is directed to agonists of the apelin receptor (APJ) and uses of such agonists.

First claim

We claim:

1. A compound represented by the Formula I:

or a pharmaceutically acceptable salt, a prodrug, or a salt of a prodrug thereof, wherein
R 1 is represented by the formula:

each A is independently C 1-8 alkoxy, C 1-8 alkoxy-C 5-12 aryl, halogen, or O(CH 2 ) x CO 2 R 7 ;
R 7 and R 8
R 7 and R 8 are independently optionally substituted C 5-12 aryl, optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, hydroxyl, or H; or
R 7 and R 8 together make an optionally substituted 3-8 member ring, which may be substituted with one or more heteroatoms selected from O, N, or S;
n is 1, 2, 3, or 4;
wherein the first A is substituted ortho to the point of attachment from the depicted pyrazole;
each x is independently 1, 2, 3, or 4;
R 2 is substituted C 5-12 aryl, optionally substituted C 1-8 alkyl, optionally substituted C 2-8 alkyl-substituted C 5-12 aryl, optionally substituted C 2-8 alkyl-optionally substituted C 3-8 cycloalkyl, or optionally substituted C 3-8 cycloalkyl;
R 3 is absent;
R 4 is C 2-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, C 2-8 alkyl-C 5-12 aryl, C 1-8 alkyl-C 3-8 cycloalkyl, C 1-8 alkyl-5 to 7 membered heteroaryl, (CH 2 ) x NR 7 R 8 , or C 1-8 alkyl-substituted C 5-12 aryl where the C 5-12 aryl is substituted either meta or para from the C 1-8 alkylene linker;
R 5 is optionally substituted C 1-8 alkyl, C 5-12 aryl, C 1-8 alkyl-C 5-12 aryl, C 1-8 alkyl-C 3-8 cycloalkyl, C 1-8 alkyl-5 to 7 membered heteroaryl, C 3-8 cycloalkyl, (CH 2 ) x NR 7 R 8 , (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
or R 4 and R 5 together make a 4-8 member ring which may be substituted with one or more heteroatoms selected from O, N, or S, and may be further substituted with one or more of C 1-8 alkoxy, C 1-8 alkyl, H, isoxazolyl, or hydroxyl;
R 9 is C 1-8 alkoxy, C 1-8 alkyl, H, isoxazolyl, or hydroxyl;
each y is independently 1, 2, or 3;
and Z is ═O, where the depicted dashed line to Z is a double bond,
wherein substituted refers to substitution with one or more of C 1-8 alkyl, halogen, C 1-8 haloalkyl, C 1-8 alkoxy, hydroxyl, carbonyl, CO 2 R 9 , C 5-12 aryl, 5 to 7 membered heteroaryl, C 3-8 cycloalkyl, C 1-8 alkyl-C 5-12 aryl, C 1-8 alkyl-5 to 7 membered heteroaryl, C 1-8 alkyl-C 3-8 cycloalkyl, NO 2 , N 3 , NH 2 , N(CH 3 ) 2 , SO (1-3) H, or SH.

2. The compound of claim 1 , wherein
n is 4;
each A is independently C 1-4 alkoxy, C 1-4 alkoxy-C 5-12 aryl, or halogen;
R 2 is C 5-12 aryl, C 1-8 alkyl, or C 3-8 cycloalkyl;
R 4 is C 2-8 alkyl, C 2-8 alkyl-C 5-12 aryl, C 1-8 alkyl-C 3-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
R 9 is C 1-8 alkyl, H, or an oxazole;
each x independently is 1, 2, 3, or 4;
each y independently is 1, 2, or 3; and
Z is ═O.

3. The compound of claim 2 , wherein
n is 4;
each A is independently C 1 alkoxy, C 1 alkoxy-C 5-12 aryl, or halogen;
R 2 is C 5-12 aryl, C 4 alkyl or C 6 cycloalkyl;
R 4 is C 2-4 alkyl, C 2-8 alkyl(C 5-12 aryl), C 1-8 alkyl-C 3-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
R 8 is C 1-4 alkyl or H;
R 9 is C 1-8 alkyl, H, or an oxazole;
each x independently is 1, 2, 3, or 4;
each y independently is 1, 2, or 3; and
Z is ═O.

4. The compound of claim 3 , wherein
n is 4;
each A is independently C 1 alkoxy, C 1 alkoxy-C 5-12 aryl, or fluorine;
R 2 is C 5-12 aryl, C 4 alkyl or C 6 cycloalkyl;
R 4 is C 2-4 alkyl, C 2-4 alkyl-C 5-12 aryl, C 1-4 alkyl-C 5-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is(CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
R 8 is C 1-4 alkyl or H;
R 9 is C 1-8 alkyl, H, or an oxazole;
each x independently is 1, 2, 3, or 4; and
each y independently is 1, 2, or 3.

5. The compound of claim 4 , wherein
n is 4;
each A is independently C 1 alkoxy, C 1 alkoxy-C 5-12 aryl, or fluorine;
R 2 is C 5-12 aryl, C 4 alkyl, or C 6 cycloalkyl;
R 4 is C 2-4 alkyl, C 2-4 alkyl(C 5-12 aryl), C 1-4 alkyl-C 5-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
R 8 is H;
R 9 is C 1-8 alkyl, H, or an oxazole;
each x independently is 1, 2, 3, or 4; and
each y independently is 1, 2, or 3.

6. The compound of claim 1 , wherein
n is 2;
each A is independently C 1-4 alkoxy, or C 1-4 alkoxy-C 5-12 aryl;
R 2 is C 5-12 aryl, C 1-8 alkyl or C 3-8 cycloalkyl;
R 4 is C 2-4 alkyl, C 2-8 alkyl(C 5-12 aryl), C 1-8 alkyl-C 3-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
R 9 is C 1-8 alkyl, H, or an oxazole;
each x independently is 1, 2, 3, or 4;
each y independently is 1, 2, or 3; and
Z is ═O.

7. The compound of claim 6 , wherein
n is 2;
each A is independently C 1 alkoxy, or C 1 alkoxy-C 5-12 aryl;
R 2 is C 5-12 aryl, C 4 alkyl or C 6 cycloalkyl;
R 4 is C 2-8 alkyl, C 2-8 alkyl-C 5-12 aryl, C 1-8 alkyl-C 3-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 ) x COR 7 , (CH 2 ) x CO 2 R 7 , CHR 7 COR 9 , CHR 7 CONHCHR 8 COR 9 , or CONR 7 R 8 ;
R 6 is H;
R 8 is C 1-4 alkyl or H;
R 9 is C 1-8 alkyl, H, or an oxazole;
each x independently is 1, 2, 3, or 4;
each y independently is 1, 2, or 3; and
Z is ═O.

8. The compound of claim 7 , wherein
n is 2;
each A is independently C 1 alkoxy, or C 1 alkoxy-C 5-12 aryl;
R 2 is C 5-12 aryl, C 4 alkyl or C 6 cycloalkyl;
R 4 is C 2-4 alkyl, C 2-4 alkyl-C 5-12 aryl, C 1-4 alkyl-C 5-8 cycloalkyl, or (CH 2 ) x NR 7 R 8 ;
R 5 is (CH 2 ) x NHCOR 7 , (CH 2 ) x NHCO 2 R 7 , (CH 2 ) x CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y CO 2 R 9 , (CH 2 ) x CONR 7 (CH 2 ) y CONR 7 R 8 , (CH 2 ) x CONR 7 (CH 2 ) y R 9 , (CH 2 )

Assignees

• Res Triangle Inst
• Runyon Scott P
• Maitra Rangan
• Narayanan Sanju
• Thomas James Barnwell

Inventors

• Runyon Scott P
• Maitra Rangan
• Narayanan Sanju
• Thomas James Barnwell

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

• A61P9/12

  Antihypertensives · 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title