US2023295154A1PendingUtilityA1
Heterocyclic glp-1 agonists
Est. expiryApr 29, 2040(~13.8 yrs left)· nominal 20-yr term from priority
C07D 401/12C07D 409/06C07D 405/06C07D 401/06C07D 405/14C07D 471/04A61P 3/10A61K 31/496A61K 31/4545A61K 31/437A61K 31/538A61K 45/06
61
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
This disclosure relates to GLP-1 agonists of Formula (I): including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein: indicates an optional single or double bond, as allowed by valence; each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently selected from the group consisting of C, CH, and N, provided that at least two and no more than four of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are N; T 1 is C(=O)OH or a carboxylic acid bioisostere; T 2 is a (C 1 -C 6 )alkyl optionally substituted with (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl, wherein each of the (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 R x ; each R x is independently selected from the group consisting of OH, SH, CN, NO 2 , halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cycloalkyl, amino, (C 1 -C 6 )alkylamino, and di(C 1 -C 6 )alkylamino; L 1 is a bond or (C 1 -C 3 )alkylene which is optionally substituted with 1-3 R L ; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; each R L is independently selected from the group consisting of: halogen, (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl; or a pair of R L on the same or on adjacent carbon atoms, taken together with the atom(s) to which each is attached, forms a (C 3 -C 6 )cycloalkyl ring; Ring A is selected from the group consisting of: phenylene optionally substituted with 1-4 R Y ; 5- to 6-membered heteroarylene optionally substituted with 1-3 R Y ; partially unsaturated monocyclic (C 5 -C 8 )cycloalkylene optionally substituted with 1-4 R Y ; partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with 1-4 R Y ; wherein n1 is 0, 1, or 2; W 1 is CR Y1 or N; and W 2 is CR Y2 or N; and wherein W 3 is C, CR Y3 , or N, L 3 is (C 1 -C 3 )alkylene, and each is independently a single bond or a double bond, as allowed by valence; wherein mm represents the point of attachment to L 2 , and nn represents the point of attachment to Ring B; and each occurrence of R Y is independently selected from the group consisting of halogen, cyano, -OH, oxo, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; R Y1, R Y2 , and RY 3 are each independently selected from the group consisting of hydrogen, halogen, cyano, -OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or when W 1 is CR Y1 and W 2 is CR Y2 , the R Y1 and R Y2 groups taken together can form (C 1 -C 4 )alkylene, wherein one of the CH 2 units of the (C 1 -C 4 )alkylene is optionally replaced by a heteroatom selected from the group consisting of O, S, NH, and N(C 1-3 )alkyl; Ring B is selected from the group consisting of (B-I) and (B-II):
and
wherein rr represents the point of attachment to Ring A; and ss represents the point of attachment to Ring C; B 1 and B 2 are independently selected from the group consisting of: -O-, -NR N -, and -C(R 1 ) 2 -; B 6 is N or CR aa ; each R 1 is independently selected from the group consisting of: hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and halogen; R N is selected from the group consisting of: hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, C(=O)(C 1 -C 6 )alkyl, S(O) 2 (C 1 -C 6 )alkyl, and C(=O)O(C 1 -C 6 )alkyl; B 3 , B 4 , and B 5 are independently selected from the group consisting of CH, CR a , and N; each R a is independently selected from the group consisting of: halogen, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkyl(3- to 5-membered heterocycloalkyl), -C(O)NR 2 R 3 , and (C 1 -C 6 )fluoroalkyl; each R 2 and R 3 is independently selected from the group consisting of H and (C 1 -C 6 )alkyl; R aa , R ab , and R ac are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl; Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 10 )bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; each R b is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 3 -C 6 )cycloalkyl, and CN; and b is an integer selected from 0-3.
2 . A compound of Formula IA:
or a pharmaceutically acceptable salt or solvate thereof, wherein: indicates an optional single or double bond, as allowed by valence; each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently selected from the group consisting of C, CH, and N, provided that at least two and no more than four of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are N; T 1 is C(=O)OH or a carboxylic acid bioisostere; T 2 is a (C 1 -C 6 )alkyl optionally substituted with (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5-to 6-membered heteroaryl, wherein each of the (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with 1-4 R x ; each R x is independently selected from the group consisting of OH, SH, CN, NO 2 , halogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )cyanoalkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cycloalkyl, amino, (C 1 -C 6 )alkylamino, and di(C 1 -C 6 )alkylamino; L 1 is a bond or (C 1 -C 3 )alkylene which is optionally substituted with 1-3 R L ; L 2 is a bond, -O-, -S(O) 0-2 -, or -NH-; each R L is independently selected from the group consisting of: halogen, (C 1 -C 3 )alkyl, and (C 1 -C 3 )haloalkyl; or a pair of R L on the same or on adjacent carbon atoms, taken together with the atom(s) to which each is attached, forms a (C 3 -C 6 )cycloalkyl ring; Ring A is selected from the group consisting of: phenylene optionally substituted with 1-4 R Y ; 5- to 6-membered heteroarylene optionally substituted with 1-3 R Y ; partially unsaturated monocyclic (C 5 -C 8 )cycloalkylene optionally substituted with 1-4 R Y ; partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with 1-4 R Y ; or wherein n1 is 0, 1, or 2; W 1 is CR Y1 or N; and W 2 is CR Y2 or N; and wherein W 3 is C, CR Y3 , or N, L 3 is (C 1 -C 3 )alkylene, and each
is independently a single bond or a double bond, as allowed by valence, provided that (1) the ring containg W
3 is partially unsaturated, or (2) L 3 is (C 2 -C 3 )alkylene; wherein mm represents the point of attachment to L 2 , and nn represents the point of attachment to Ring B; and each occurrence of R Y is independently selected from the group consisting of halogen, cyano, -OH, oxo, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; R Y3 is selected from the group consisting of hydrogen, halogen, cyano, -OH, oxo, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; R Y1 and R Y2 are independently selected from the group consisting of halogen, cyano, -OH, (C 1 -C 6 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, and (C 1 -C 3 )haloalkoxy; or R Y1 and R Y2 groups taken together form (C 1 -C 4 )alkylene, wherein one of the CH 2 units of the (C 1 -C 4 )alkylene is optionally replaced by a heteroatom selected from the group consisting of O, S, NH, and N(C 1-3 )alkyl; Ring B is selected from the group consisting of (B-I) and (B-II):
and
wherein rr represents the point of attachment to Ring A; and ss represents the point of attachment to Ring C; B 1 and B 2 are independently selected from the group consisting of: -O-, -NR N -, and -C(R 1 ) 2 -; B 6 is N or CR aa ; each R 1 is independently selected from the group consisting of: hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and halogen; R N is selected from the group consisting of: hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, C(=O)(C 1 -C 6 )alkyl, S(O) 2 (C 1 -C 6 )alkyl, and C(=O)O(C 1 -C 6 )alkyl; B 3 , B 4 , and B 5 are independently selected from the group consisting of CH, CR a , and N; each R a is independently selected from the group consisting of: halogen, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkyl(C 3 -C 6 )cycloalkyl, (C 1 -C 3 )alkyl(3- to 5-membered heterocycloalkyl), -C(O)NR 2 R 3 , and (C 1 -C 6 )fluoroalkyl; each R 2 and R 3 is independently selected from the group consisting of H and (C 1 -C 6 )alkyl; R aa , R ab , and R ac are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl; Ring C is selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, (C 3 -C 6 )cycloalkyl, (C 5 -C 10 )bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl; each R b is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, (C 3 -C 6 )cycloalkyl, and CN; and b is an integer selected from 0-3.
3 . The compound of claims 1 or 2 , wherein X 8 is C; and X 5 is C.
4 . The compound of any one of claims 1-3 , wherein X 3 is C.
5 . The compound of any one of claims 1-4 , wherein X 2 is N.
6 . The compound of any one of claims 1-5 , wherein X 4 is N.
7 . The compound of any one of claims 1-6 , wherein X 2 is N; X 3 is C; and X 4 is N.
8 . The compound of any one of claims 1-7 , wherein X 7 is CH.
9 . The compound of any one of claims 1-8 , wherein X 8 , X 5 , and X 3 are C; X 2 and X 4 are N; X 7 is CH; and X 1 and X 6 are independently CH or N.
10 . The compound of claim 9 , wherein X 1 and X 6 are CH.
11 . The compound of claim 9 , wherein X 1 is N; and X 6 is CH.
12 . The compound of claim 9 , wherein X 1 is CH; and X 6 is N.
13 . The compound of any one of claims 1-12 , wherein T 1 is C(=O)OH.
14 . The compound of any one of claims 1-13 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl.
15 . The compound of any one of claims 1-14 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with (C 3 -C 6 )cycloalkyl or 3- to 6-membered heterocycloalkyl.
16 . The compound of any one of claims 1-15 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with 3- to 6-membered heterocycloalkyl.
17 . The compound of any one of claims 1-16 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with 4- to 6-membered heterocycloalkyl.
18 . The compound of any one of claims 1-17 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with oxetanyl.
19 . The compound of any one of claims 1-18 , wherein T 2 is
.
20 . The compound of claim 19 , wherein the stereocenter in
has (S)-configuration.
21 . The compound of any one of claims 1-20 , wherein L 2 is a bond.
22 . The compound of any one of claims 1-21 , wherein L 1 is CH 2 .
23 . The compound of any one of claims 1-22 , wherein L 1 is CH 2 ; and L 2 is a bond.
24 . The compound of any one of claims 1 or 3-23 , wherein Ring A is
.
25 . The compound of claim 24 , wherein W 1 is N.
26 . The compound of claims 24 or 25 , wherein W 2 is CR Y2 .
27 . The compound of claim 26 , wherein R Y2 is hydrogen.
28 . The compound of any one of claims 24-25 , wherein W 2 is N.
29 . The compound of any one of claims 24-28 , wherein n1 is 0.
30 . The compound of any one of claims 24-28 , wherein n1 is 1.
31 . The compound of any one of claims 1 , 3-27 , or 29 , wherein Ring A is
.
32 . The compound of any one of claims 1 , 3-27 , or 30 , wherein Ring A is
.
33 . The compound of any one of claims 1 , 3-25 , or 28-29 , wherein Ring A is
.
34 . The compound of any one of claims 1-23 , wherein Ring A is selected from the group consisting of:
phenylene optionally substituted with 1-4 R Y ; and 5- to 6-membered heteroarylene optionally substituted with 1-3 R Y .
35 . The compound of any one of claims 1-23 or 34 , wherein Ring A is selected from the group consisting of:
phenylene optionally substituted with 1-4 R Y ; and
6-membered heteroarylene optionally substituted with 1-3 R Y ; and
mm is para or meta to nn.
36 . The compound of any one of claims 1-23 or 34-35 , wherein Ring A is phenylene optionally substituted with 1-2 R Y ; and mm is para or meta to nn.
37 . The compound of any one of claims 1-23 or 34-36 , wherein Ring A is 1,4-phenylene which is optionally substituted with 1-2 R Y .
38 . The compound of any one of claims 1-23 or 34-37 , wherein Ring A is:
.
39 . The compound of any one of claims 1-23 , wherein Ring A is selected from the group consisting of:
partially unsaturated monocyclic (C 5 -C 8 )cycloalkylene optionally substituted with 1-4 R Y ; and partially unsaturated monocyclic 5- to 8-membered heterocycloalkylene optionally substituted with 1-4 R Y .
40 . The compound of claim 39 , wherein Ring A is selected from the group consisting of:
partially unsaturated monocyclic C 6 cycloalkylene optionally substituted with 1-4 R Y ; and partially unsaturated monocyclic 6-membered heterocycloalkylene optionally substituted with 1-4 R Y ; and mm is para to nn.
41 . The compound of any one of claims 1-20 , wherein L 1 is CH 2 ; L 2 is a bond; and Ring A is
or
.
42 . The compound of claim 41 , wherein Ring A is
.
43 . The compound of claim 41 , wherein Ring A is
; and R Y is (C 1 -C 3 )alkyl.
44 . The compound of claim 41 , wherein Ring A is
.
45 . The compound of any one of claims 1-20 , wherein L 1 is CH 2 ; L 2 is a bond; and Ring A is selected from the group consisting of:
phenylene optionally substituted with 1-4 R Y ; and
6-membered heteroarylene optionally substituted with 1-3 R Y ; and
mm is para or meta to nn.
46 . The compound of claim 45 , wherein Ring A is phenylene optionally substituted with 1-2 R Y ; and mm is para or meta to nn.
47 . The compound of claim 46 , wherein Ring A is
or .
48 . The compound of any one of claims 1-47 , wherein Ring B is
.
49 . The compound of any one of claims 1-47 , wherein Ring B is
.
50 . The compound of any one of claims 1-49 , wherein B 1 is -O-.
51 . The compound of any one of claims 1-49 , wherein B 1 is -C(R 1 ) 2 -.
52 . The compound of any one of claims 1-49 or 51 , wherein B 1 is -CH 2 -.
53 . The compound of any one of claims 1-52 , wherein B 2 is -O-.
54 . The compound of any one of claims 1-52 , wherein B 2 is -C(R 1 ) 2 -.
55 . The compound of any one of claims 1-52 or 54 , wherein B 2 is -CH 2 -.
56 . The compound of any one of claims 1-52 , wherein B 2 is -NR N -.
57 . The compound of any one of claims 1-52 or 56 , wherein B 2 is -NH-.
58 . The compound of any one of claims 1-49 , wherein B 1 is -O-; and B 2 is -O-.
59 . The compound of any one of claims 1-49 , wherein B 1 is -O-; and B 2 is -NR N -.
60 . The compound of any one of claims 1-49 or 59 , wherein B 1 is -O-; and B 2 is -NH-.
61 . The compound of any one of claims 1-49 , wherein B 1 is -O-; and B 2 is -C(R 1 ) 2 -.
62 . The compound of any one of claims 1-49 or 61 , wherein B 1 is -O-; and B 2 is -CH 2 -.
63 . The compound of any one of claims 1-49 , wherein B 1 is -C(R 1 ) 2 -; and B 2 is -O-.
64 . The compound of any one of claims 1-49 or 63 , wherein B 1 is -CH 2 -; and B 2 is -O-.
65 . The compound of any one of claims 1-48 , wherein Ring B is
.
66 . The compound of claim 65 , wherein B 1 is -C(R 1 ) 2 -.
67 . The compound of claims 65 or 66 , wherein B 2 is -C(R 1 ) 2 -.
68 . The compound of any one of claims 1-64 , wherein R aa is H.
69 . The compound of any one of claims 1-64 , wherein R aa is (C 1 -C 6 )alkyl.
70 . The compound of any one of claims 1-64 or 69 , wherein R aa is methyl.
71 . The compound of any one of claims 1-70 , wherein R ab is H.
72 . The compound of any one of claims 1-71 , wherein R ac is H.
73 . The compound of any one of claims 1-64 , wherein R aa is H; R ab is H; and R ac is H.
74 . The compound of any one of claims 1-64 , wherein R aa is (C 1 -C 3 )alkyl; R ab is H; and R ac is H.
75 . The compound of any one of claims 1-74 , wherein B 3 , B 4 , and B 5 are independently CH or CR a .
76 . The compound of any one of claims 1-75 , wherein B 3 , B 4 , and B 5 are CH.
77 . The compound of any one of claims 1-49 , wherein B 6 is CR aa ; B 1 is -O-; B 2 is -O-; and B 3 , B 4 , and B 5 are independently CH or CR a .
78 . The compound of any one of claims 1-49 , wherein B 6 is CR aa ; B 1 is -O-; B 2 is -NH-; and B 3 , B 4 , and B 5 are independently CH or CR a .
79 . The compound of any one of claims 1-49 , wherein B 6 is CR aa ; B 1 is -O-; B 2 is -CH 2 -; and B 3 , B 4 , and B 5 are independently CH or CR a .
80 . The compound of any one of claims 1-49 , wherein B 6 is CR aa ; B 1 is -CH 2 -; B 2 is -O-; and B 3 , B 4 , and B 5 are independently CH or CR a .
81 . The compound of any one of claims 77-80 , wherein B 3 , B 4 , and B 5 are CH.
82 . The compound of any one of claims 1-49 , wherein B 6 is CR aa ; B 1 and B 2 are -O-; and B 3 , B 4 , and B 5 are CH.
83 . The compound of any one of claims 1-49 , wherein B 6 is CR aa ; one of B 1 and B 2 is -O-; the other one of B 1 and B 2 is -CH 2 - or -NH-; and B 3 , B 4 , and B 5 are CH.
84 . The compound of any one of claims 77-83 , wherein R aa is H; R ab is H; and R ac is H.
85 . The compound of any one of claims 77-83 , wherein R aa is (C 1 -C 3 )alkyl; R ab is H; and R ac is H.
86 . The compound of any one of claims 1-48 , wherein Ring B is
wherein: B 3 , B 4 , and B 5 are each CH; B 1 and B 2 are each -O-; R ac and R ab are each H; and R aa is H or (C 1 -C 3 )alkyl.
87 . The compound of any one of claims 1-48 , 50-64 , or 68-86 , wherein Ring B is (B-I); B 6 is CR aa ; and the carbon atom to which R aa and B 2 are both attached has (S)-configuration.
88 . The compound of any one of claims 1-48 , 50-64 , or 68-86 , wherein Ring B is (B-I); B 6 is CR aa ; and the carbon atom to which R aa and B 2 are both attached has (R)-configuration.
89 . The compound of any one of claims 1-48 , wherein Ring B is
wherein B 3 , B 4 , and B 5 are each CH; B 1 and B 2 are each -O-; R ac and R ab are each H; and R aa is H or (C 1 -C 3 )alkyl.
90 . The compound of any one of claims 1-47 , 49-64 , 68-85 , or 89 , wherein Ring B is (B-II); B 6 is CR aa ; and the carbon atom to which R aa and B 1 are both attached has (S)-configuration.
91 . The compound of any one of claims 1-47 , 49-64 , 68-85 , or 89 , wherein Ring B is (B-II); B 6 is CR aa ; and the carbon atom to which R aa and B 1 are both attached has (R)-configuration.
92 . The compound of any one of claims 1-47 , wherein Ring B is selected from the group consisting of:
; and .
93 . The compound of claim 92 , wherein the carbon atom marked with * has (R)-configuration.
94 . The compound of claim 92 , wherein the carbon atom marked with * has (S)-configuration.
95 . The compound of any one of claims 1-94 , wherein Ring C is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl, and 5- to 10-membered bicycloheteroaryl.
96 . The compound of any one of claims 1-95 , wherein Ring C is phenyl.
97 . The compound of any one of claims 1-96 , wherein b is 1-3.
98 . The compound of any one of claims 1-97 , wherein b is 2.
99 . The compound of any one of claims 1-97 , wherein b is 1.
100 . The compound of any one of claims 1-96 , wherein b is 0.
101 . The compound of any one of claims 1-98 , wherein Ring C is phenyl; and b is 2.
102 . The compound of any one of claims 1-98 or 101 , wherein
is
.
103 . The compound of any one of claims 1-98 or 101 , wherein
is
.
104 . The compound of any one of claims 1-97 or 99 , wherein Ring C is phenyl; and b is 1.
105 . The compound of any one of claims 1-97 , 99 or 104 , wherein
is
.
106 . The compound of any one of claims 1-97 , 99 , or 104 , wherein
is .
107 . The compound of any one of claims 1-97 , 99 or 104 , wherein
is
.
108 . The compound of any one of claims 1-96 or 100 , wherein Ring C is phenyl; and b is 0.
109 . The compound of any one of claims 1-108 , wherein each occurrence of R b is independently selected from the group consisting of: (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, and CN.
110 . The compound of claim 109 , wherein each occurrence of R b is independently selected from the group consisting of -F, -Cl, -CH 3 , -CF 3 , and CN.
111 . The compound of claims 109 or 110 , wherein each occurrence of R b is independently selected from the group consisting of -F, -Cl, and -CN.
112 . The compound of claim 1 , wherein the compound is a compound of Formula IB:
or a pharmaceutically acceptable salt thereof.
113 . The compound of claim 1 , wherein the compound is a compound of Formula IC:
or a pharmaceutically acceptable salt thereof.
114 . The compound of claim 1 , wherein the compound is a compound of Formula ID:
or a pharmaceutically acceptable salt thereof.
115 . The compound of claim 1 , wherein the compound is a compound of Formula IE:
or a pharmaceutically acceptable salt thereof.
116 . The compound of any one of claims 112-115 , wherein B 3 , B 4 , and B 5 are independently selected from the group consisting of CH and CR a .
117 . The compound of any one of claims 112-116 , wherein B 3 , B 4 , and B 5 are CH.
118 . The compound of any one of claims 112-117 , wherein R aa is H; and R ab and R ac are H.
119 . The compound of any one of claims 112-117 , wherein R aa is (C 1 -C 3 )alkyl; and R ab and R ac are H.
120 . The compound of any one of claims 112-119 , wherein X 8 , X 5 , and X 3 are C; X 2 and X 4 are N; X 7 is CH; and X 1 and X 6 are independently CH or N.
121 . The compound of claim 120 , wherein X 1 is N; and X 6 is CH.
122 . The compound of claim 120 , wherein X 1 is CH; and X 6 is CH.
123 . The compound of claim 120 , wherein X 1 is CH; and X 6 is N.
124 . The compound of any one of claims 112-123 , wherein T 1 is C(=O)OH.
125 . The compound of any one of claims 112-124 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with 4- to 6-membered heterocycloalkyl.
126 . The compound of claim 125 , wherein T 2 is (C 1 -C 3 )alkyl which is substituted with oxetanyl.
127 . The compound of claim 126 , wherein T 2 is
.
128 . The compound of claim 127 , wherein the stereocenter of T 2 has (S)-configuration.
129 . The compound of any one of claims 112-128 , wherein L 1 is CH 2 ; L 2 is a bond; and Ring A is
or
.
130 . The compound of claim 129 , wherein Ring A is
.
131 . The compound of claim 129 , wherein Ring A is
; and R Y is (C 1 -C 3 )alkyl.
132 . The compound of claim 129 , wherein Ring A is
.
133 . The compound of any one of claims 112-128 , wherein L 1 is CH 2 ; L 2 is a bond; and Ring A is selected from the group consisting of:
phenylene optionally substituted with 1-4 R Y ; and
5- to 6-membered heteroarylene optionally substituted with 1-3 R Y .
134 . The compound of claim 133 , wherein mm is meta or para to nn.
135 . The compound of claims 133 or 134 , wherein Ring A is phenylene optionally substituted with 1-2 R Y ; and mm is meta or para to nn.
136 . The compound of claim 135 , wherein Ring A is 1,4-phenylene optionally substituted with 1-2 R Y .
137 . The compound of claim 136 , wherein Ring A is
or .
138 . The compound of any one of claims 112-137 , wherein Ring C is phenyl.
139 . The compound of any one of claims 112-138 , wherein b is 1-3.
140 . The compound of claim 139 , wherein b is 2.
141 . The compound of claim 139 , wherein b is 1.
142 . The compound of any one of claims 112-138 , wherein b is 0.
143 . The compound of any one of claims 112-139 , wherein Ring C is phenyl; and b is 2.
144 . The compound of any one of claims 112-139 or 143 , wherein
is
.
145 . The compound of any one of claims 112-139 or 143 , wherein
is
.
146 . The compound of any one of claims 112-138 , wherein Ring C is phenyl; and b is 1.
147 . The compound of any one of claims 112-138 or 146 , wherein
is
.
148 . The compound of any one of claims 112-138 or 146 , wherein
is
.
149 . The compound of any one of claims 112-138 or 146 , wherein
is
.
150 . The compound of any one of claims 112-138 , wherein Ring C is phenyl; and b is 0.
151 . The compound of any one of claims 112-149 , wherein each occurrence of R b is independently selected from the group consisting of: (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, halogen, and CN.
152 . The compound of claim 151 , wherein each occurrence of R b is independently selected from the group consisting of -F, -Cl, -CH 3 , -CF 3 , and CN.
153 . The compound of claims 151 or 152 , wherein each occurrence of R b is independently selected from the group consisting of -F, -Cl, and CN.
154 . The compound of any one of claims 112-153 , wherein the carbon atom to which R aa and Ring C are both attached has (S)-configuration.
155 . The compound of any one of claims 112-153 , wherein the carbon atom to which R aa and Ring C are both attached has (R)-configuration.
156 . The compound of any one of claims 1-155 , wherein the compound of Formula I is selected from the group consisting of the compounds in Table C1 and Table C2, or a pharmaceutically acceptable salt or solvate thereof.
157 . A pharmaceutical composition comprising a compound of any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
158 . A method of treating type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 .
159 . A method for treating type 2 diabetes mellitus in a patient, the method comprising administering to a patient identified or diagnosed as having type 2 diabetes mellitus a therapeutically effective amount of a compound of any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 .
160 . A method of treating diabetes mellitus in a patient, the method comprising:
a) determining that the patient has type 2 diabetes mellitus; and b) administering to the patient a therapeutically effective amount of a compound of any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 .
161 . The method of any one of claims 158-160 , wherein the step of determining that the patient has type 2 diabetes mellitus includes performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof.
162 . The method of claim 161 , wherein the level of HbA1c is greater than or about 6.5%.
163 . The method of any one of claims 161-162 , wherein the level of fasting plasma glucose is greater than or about 126 mg/dL.
164 . The method of any one of claims 161-162 , wherein the level of non-fasting plasma glucose is greater than or about 200 mg/dL.
165 . The method of any one of claims 158-164 , further comprising obtaining a sample from the patient.
166 . The method of claim 165 , wherein the sample is a body fluid sample.
167 . The method of any one of claims 158-166 , wherein the patient is about 40 to about 70 years old and is overweight or obese.
168 . The method of any one of claims 158-167 , wherein the patient has a body mass index (BMI) greater than or about 22 kg/m 2 .
169 . The method of any one of claims 158-168 , wherein the patient has a BMI greater than or about 30 kg/m 2 .
170 . The method of any one of claims 158-169 , wherein the treatment of type 2 diabetes mellitus comprises a reduction in fasting plasma glucose levels.
171 . The method of claim 170 , wherein the fasting plasma glucose levels are reduced to about or below 100 mg/dL.
172 . The method of any one of claims 158-171 , wherein the treatment of type 2 diabetes mellitus comprises a reduction in HbA1c levels.
173 . The method of claim 172 , wherein the HbA1c levels are reduced to about or below 5.7 %.
174 . The method of any one of claims 158-173 , wherein the treatment of type 2 diabetes mellitus comprises a reduction in glucagon levels.
175 . The method of any one of claims 158-174 , wherein the treatment of type 2 diabetes mellitus comprises an increase in insulin levels.
176 . The method of any one of claims 158-175 , wherein the treatment of type 2 diabetes mellitus comprises a decrease in BMI.
177 . The method of claim 176 , wherein the BMI is decreased to about or below 25 kg/m 2 .
178 . The method of any of one of claims 158-177 , wherein the compound of any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 , is administered orally.
179 . The method of any one of claims 158-178 , further comprising administering an additional therapy or therapeutic agent to the patient.
180 . The method of claim 179 , wherein the additional therapy or therapeutic agent is selected from the group consisting of an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent to treat non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or any combinations thereof.
181 . The method of claim 180 , wherein the anti-diabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose linked transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic peptide (GIP), an insulin or insulin analogue, an alpha glucosidase inhibitor, a sodium-glucose linked transporter 1 (SGLT1) inhibitor, or any combinations thereof.
182 . The method of claim 181 , wherein the biguanide is metformin.
183 . The method of claim 180 , wherein the anti-obesity agent is selected from the group consisting of neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine/dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, a sodium-glucose cotransporter 1 (SGLT-1) inhibitor, or any combinations thereof.
184 . The method of claim 180 , wherein the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combinations thereof.
185 . The method of claim 180 , wherein the agent to treat NASH is selected from the group consisting of an FXR agonist, PF-05221304, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21) agonist, a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, or any combinations thereof.
186 . The method of any one of claims 179-185 , wherein the compound of any one of claims 1-156 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 , and the additional therapeutic agent are administered as separate dosages sequentially in any order.
187 . A method for modulating insulin levels in a patient in need of such modulating, the method comprising administering to the patient an effective amount of a compound as claimed in any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 .
188 . The method of claim 187 , wherein the modulation results in an increase of insulin levels.
189 . A method for modulating glucose levels in a patient in need of such modulating, the method comprising administering to the patient an effective amount of a compound as claimed in any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 .
190 . The method of claim 189 , wherein the modulation results in a decrease of glucose levels.
191 . A method for treating a GLP-1 associated disease, disorder, or condition, the method comprising administering to a patient in need thereof an effective amount of a compound as claimed in any one of claims 1-156 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 157 .
192 . The method of claim 191 , wherein the disease, disorder, or condition is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type 1 diabetes mellitus (Type 1b), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder/major depressive disorder, skin and connective tissue disorders, foot ulcerations, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn’s disease, short bowel syndrome, Parkinson’s, Alzheimer’s disease, impaired cognition, schizophrenia, Polycystic Ovary Syndrome (PCOS), or any combination thereof.
193 . The method of claim 192 , wherein the disease, disorder, or condition is selected from the group consisting of type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder/major depressive disorder, skin and connective tissue disorders, foot ulcerations, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson’s disease, Polycystic Ovary Syndrome (PCOS), idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.
194 . The method of claim 193 , wherein the disease, disorder, or condition includes, but is not limited to type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral adipose deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attacks, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcerations, idiopathic intracranial hypertension, Wolfram syndrome, or any combination thereof.Join the waitlist — get patent alerts
Track US2023295154A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.