US2017066751A1PendingUtilityA1
Difluorolactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated diseases and conditions
Est. expiryJul 19, 2032(~6 yrs left)· nominal 20-yr term from priority
Inventors:Stephen Douglas BarrettFred Lawrence CiskeJoseph Michael ColomboGregory William EndresBradlee David GermainAndriy KomilovJames Bernard KramerAdam UziebloKirk M. Maxey
A61P 43/00A61P 25/02A61P 27/02A61P 27/06A61P 29/02A61P 27/00A61P 25/00A61P 19/10A61P 19/08A61P 17/00A61P 17/14A61P 19/00C07D 207/26A61L 27/12A61L 24/0015A61L 24/02A61K 31/4025A61K 9/0053C07D 409/06A61L 2430/02A61L 27/54C07D 207/273A61L 27/3608A61L 24/0042A61L 2300/412A61L 27/58A61L 27/365A61K 31/4015A61L 2300/604A61K 9/0019
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Claims
Abstract
Disclosed herein are compounds of formula (I) and therapeutic methods of treatment with compounds of formula (I), wherein L 1 , L 2 , L 4 , R 1 , R 4 , R 5 , R 6 , and s are as defined in the specification. Compounds of formula (I) are EP4 agonists useful in the treatment of glaucoma, neuropathic pain, and related disorders.
Claims
exact text as granted — not AI-modified1 - 20 . (canceled)
21 . A compound of formula
wherein:
B is
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) (CH 2 ) n -G 2 -(CH 2 ) p , —(CH 2 ) n —C≡C-G 2 -, or —(CH 2 ) n —C(R 13 )═C(R 13 )-G 2 -, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2, or 3, and n+p=1, 2, 3, 4, 5, or 6;
G 2 is
R 10 is H, C 1 -C 4 alkyl, or aryl;
R 13 , at each occurrence, is independently H or C 1 -C 4 alkyl;
R 4 and R 5 are each independently H or C 1 -C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl;
R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy;
L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; and
R 7 is C 3 -C g cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
22 . The compound of claim 21 , wherein:
L 1 is n-hexylene, (CH 2 ) n -G 2 -(CH 2 ) p , —(CH 2 ) n —C≡C-G 2 -, or —(CH 2 ) n —C(R 13 )═C(R 13 )-G 2 -; G 2 is
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
R 6 is phenyl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 7 is phenyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
23 . The compound of claim 22 wherein:
L 1 is —(CH 2 ) 3 -G 2 -;
R 4 is methyl;
R 5 is hydrogen;
R 6 is C 3 -C 10 alkynyl or L 3 -R 7 ;
L 3 is C 1 -C 6 alkylene; and
R 7 is phenyl.
24 . The compound of claim 22 wherein:
L 1 is (CH 2 ) 3 -G 2 -;
R 4 is hydrogen;
R 5 is methyl;
R 6 is C 3 -C 10 alkynyl or L 3 -R 7 ;
L 3 is C 1 -C 6 alkylene; and
R 7 is phenyl.
25 . A compound of formula
wherein:
L i is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n -G 2 -(CH 2 ) p , —(CH 2 ) n —C≡C-G 2 -, or —(CH 2 ) n —C(R 13 )═C(R 13 )-G 2 -, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2, or 3, and n+p=1, 2, 3, 4, 5, or 6;
G 2 is
R 1 is CO 2 R 10 ;
R 10 is H, C 1 -C 4 alkyl, or aryl; and
R 13 , at each occurrence, is independently H or C 1 -C 4 alkyl.
26 . The compound of claim 25 wherein:
L 1 is n-hexylene, —(CH 2 ) n -G 2 -(CH 2 ) p , —(CH 2 ) n —C≡C-G 2 -, or —(CH 2 ) n —C(R 13 )═C(R 13 )-G 2 -;
G 2 is
and
the oxygen protecting group is 1-ethoxyethyl or tert-butyldimethylsilyl.
27 . The compound of claim 26 wherein
L 1 is —(CH 2 ) 3 -G 2 -.
28 . The compound of claim 25 of formula
29 . A method of preparing the compound of claim 28 comprising reacting a compound of formula
with a compound of formula LG-L 1 -R 1 , wherein LG is a leaving group and L 1 and R 1 are as defined in claim 28 .
30 . The method of claim 29 wherein:
L 1 is n-hexylene, —(CH 2 ) n -G 2 -(CH 2 ) p , —(CH 2 ) n —C≡C-G 2 -, or —(CH 2 ) n —C(R 13 )═C(R 13 )-G 2 -;
G 2 is
and
the oxygen protecting group is 1-ethoxyethyl or tert-butyldimethylsilyl.
31 . The method of claim 30 wherein:
L 1 is —(CH 2 ) 3 -G 2 -; and
the oxygen protecting group is tert-butyldimethylsilyl.
32 . The method of claim 29 comprising reacting the compound of formula
with the compound of formula LG-L 1 -R 1 and sodium hydride.
33 . The method of claim 29 , wherein LG is iodo, bromo, chloro, trifluoromethanesulfonyl, methanesulfonyl, toluenesulfonyl, or 4-nitrobenzenesulfonyl.
34 . The method of claim 33 , wherein LG is bromo.
35 . The method of claim 32 , wherein LG is iodo, bromo, chloro, trifluoromethanesulfonyl, methanesulfonyl, toluenesulfonyl, or 4-nitrobenzenesulfonyl.
36 . The method of claim 35 , wherein LG is bromo.
37 . A compound of formula 15
wherein:
B is
R 4 and R 5 are each independently H or C 1 -C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -0 5 cycloalkyl;
R 6 is aryl, heteroaryl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and C 1 -C 3 alkyleneC 1 -C 3 alkoxy;
L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; and
R 7 is C 3 -C g cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and C 1 -C 3 alkyleneC 1 -C 3 alkoxy.
38 . The compound of claim 37 wherein:
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
R 6 is phenyl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and C 1 -C 3 alkyleneC 1 -C 3 alkoxy; and
R 7 is phenyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and C 1 -C 3 alkyleneC 1 -C 3 alkoxy.
39 . The compound of claim 38 wherein:
R 4 is methyl;
R 5 is hydrogen;
R 6 is C 3 -C 10 alkynyl or L 3 -R 7 ;
L 3 is C 1 -C 6 alkylene; and
R 7 is phenyl.
40 . The compound of claim 39 wherein:
R 4 is hydrogen;
R 5 is methyl;
R 6 is C 3 -C 10 alkynyl or L 3 -R 7 ;
L 3 is C 1 -C 6 alkylene; and
R 7 is phenyl.Join the waitlist — get patent alerts
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