Modulators of G-Protein Coupled Receptors
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt) that modulate (e.g., agonize or partially agonize or antagonize) glucagon-like peptide-1 receptor (“GLP-1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP-1R and/or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, modulation results in enhancement of (e.g., increases) existing levels (e.g., normal or below normal levels) of GLP-1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) □-arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Q is O or S;
R* is as defined in (i), (ii), or (iii), below:
(i)
wherein:
L 1 is selected from the group consisting of:
C 1-10 alkylene optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo; C 1-4 alkoxy; —OH; phenyl; and NR′R″; and
wherein m1 is 0, 1, 2, 3, or 4;
X 1 is selected from the group consisting of: C(═O); C(═S); S(O) 1-2 ; C(═O)N(R′)*; C(═S)N(R′)*; S(O) 1-2 N(R′)*; N(R′)C(═O)*; N(R′)C(═S)*; and N(R′)S(O) 1-2 *, wherein * represents the point of attachment to L;
R X1 and R X2 are each defined according to (AA) or (AB):
(AA)
R X1 and R X2 are each independently selected from the group consisting of:
—H, —F;
C 1-8 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with from 1-3 R a ; and
C 3-8 cycloalkyl which is optionally substituted with from 1-3 R 1 ;
(AB)
R X1 and R X2 taken together with the carbon atom to which each is attached form a saturated or partially unsaturated ring having from 3-10 ring atoms, wherein from 0-2 ring atoms are heteroatoms each independently selected from the group consisting of: O, N, N(H), N(R c ), and S(O) 0-2 , wherein the ring is optionally substituted at one or more ring carbon atoms with from 1-3 R b ;
X 2 is a bond; and
R Z is selected from the group consisting of:
H;
C 1-6 alkyl optionally substituted with from 1-6 R a ;
—R ZA ; and
-L ZA -R ZA ;
L ZA is C 1-6 alkylene optionally substituted with from 1-3 independently selected R a ; and
R ZA is R e ;
(ii)
wherein:
L 5 is C 1-10 alkylene optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo; C 1-4 alkoxy; —OH; phenyl; and NR′R″;
X 5 is selected from the group consisting of: a bond; C(═O); C(═S); S(O) 1-2 ; C(═O)N(R′)*;
C(═S)N(R′)*; and S(O) 1-2 N(R′)*, wherein * represents the point of attachment to L 5 ;
R X3 and R X4 are each defined according to (BA) or (BB):
(BA)
R X3 and R X4 are each independently selected from the group consisting of:
—H, —F;
C 1-8 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with from 1-3 R a ; and
C 3-6 cycloalkyl which is optionally substituted with from 1-3 R b ;
(BB)
R X3 and R X4 taken together with the carbon atom to which each is attached form a saturated or partially unsaturated ring having from 3-10 ring atoms, wherein from 0-2 ring atoms are heteroatoms each independently selected from the group consisting of: O, N, N(H), N(R c ), and S(O) 0-2 , wherein the ring is optionally substituted at one or more ring carbon atoms with from 1-3 R b ; and
R Z5 is selected from the group consisting of: —R ZE ; -L ZE -R ZE ; and C 1-6 alkyl optionally substituted with from 1-6 R a ;
L ZE is C 1-6 alkylene optionally substituted with from 1-3 independently selected R a ; and
R ZE is R e ;
(iii)
L 7 is C 1-10 alkylene optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo; C 1-4 alkoxy; —OH; phenyl; and NR′R″; and
R Z7 is -L ZG -R ZG ;
L ZG is C 1-6 alkylene optionally substituted with from 1-3 independently selected R a ;
R ZG is R e ;
each of R 1 and R 2 is independently selected from the group consisting of H and C 1-3 alkyl;
a1 is 0, 1, 2, 3, or 4;
R 2 ′ is
wherein:
R 3 is —C(O)OH, —C(O)OR 4a , —CH(C(O)OH) 2 , or a carboxylic acid isostere;
a is 0, 1, 2, 3, 4, or 5; a2 is 0 or 1;
each of R 3a and R 3b is independently H or C 1-3 alkyl; and
R 4a is —(C 0-3 alkylene)-R e or C 1-6 alkyl optionally substituted with from 1-6 R a
—N(R 4 )—W has Formula WD:
*GT(Xaa3)(Xaa4)SD(Xaa7)SI(Xaa10)LD(Xaa13)(Xaa14)A(Xaa16)(Xaa17)(Xaa18)F(Xaa20)(Xaa2l)(Xaa22)L(Xaa24)(Xaa25)GGPSSGAPPPS(Xaa37)-R 6 (SEQ ID NO: 4), wherein:
Xaa3 is F, F*, F†, or F‡;
Xaa4 is T, A or V;
Xaa7 is Y, or K*;
Xaa10 is Y, L*, or Aib;
Xaa13 is K, Orn, or R;
Xaa14 is Q, I, or K*;
Xaa16 is A, or Q;
Xaa17 is Aib, or K*;
Xaa18 is A, or E;
Xaa20 is V or I;
Xaa21 is N, Q, K*, or dE;
Xaa22 is W or Y;
Xaa24 is I or L;
Xaa25 is A or E;
Xaa37 is K* or absent;
R 6 is —NH 2 or —OH;
wherein —N(R 4 )—W is attached to the remainder of Formula (I) by the amino group of N-terminal amino acid *G;
each occurrence of R a is independently selected from the group consisting of: halo; —OH; —N(R f )(R′); C 1-4 alkoxy; C 1-4 haloalkoxy; —OC(═O)(C 1-6 alkyl); —C(═O)O(C 1-6 alkyl); —C(═O)OH, —C(═O)N(R′)(R′″), —S(O) 1-2 (C 1-6 alkyl); and cyano;
each occurrence of R b is independently selected from the group consisting of: C 1-6 alkyl optionally substituted with from 1-6 R a ; C 2-6 alkenyl; C 2-6 alkynyl; —OH; oxo; -halo; —N(R f )(R′); C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)(C 1-4 alkyl); —C(═O)O(C 1-6 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O) 1-2 N(R′)(R″); —S(O) 1-2 (C 1-6 alkyl); —SF 5 ; —NO 2 ; and cyano;
each occurrence of R c is independently selected from the group consisting of: C 1-6 alkyl; C 1-6 haloalkyl; —C(═O)(C 1-6 alkyl); —C(═O)O(C 1-6 alkyl); —C(═O)N(R′)(R″); and —S(O) 1-2 (C 1-6 alkyl);
each occurrence of R d is independently selected from the group consisting of: —R e , —(C 1-3 alkylene)-R e , —O—(C 0-3 alkylene)-R e , —C(═O)(C 0-3 alkylene)-R e , and —C(═O)(C 0-3 alkylene)O—R e ;
each occurrence of R e is independently selected from the group consisting of:
(i) C 3-10 cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1-4 independently selected R b ;
(ii) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are each independently selected from the group consisting of N, N(H), N(R c ), O, and S(O) 0-2 , wherein the heterocyclyl is optionally substituted with from 1-4 independently selected R b at one or more ring carbon atoms;
(iii) C 6-10 aryl, wherein the aryl is optionally substituted with from 1-5 independently selected R b ; and
(iv) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(H), N(R c ), 0, and S(O) 0-2 , wherein the heteroaryl is optionally substituted with from 1-3 independently selected R b at one or more ring carbon atoms;
each occurrence of R f is independently selected from the group consisting of: H; C 1-4 alkyl; C 3-6 cycloalkyl; —C(═O)(C 1-6 alkyl); —C(═O)O(C 1-6 alkyl); and —S(O) 1-2 (C 1-6 alkyl); and
each occurrence of R′ and R″ is independently selected from the group consisting of: H and C 1-6 alkyl.
2 . The compound of claim 1 , wherein —N(R 4 )—W is:
GT(Xaa3)(Xaa4)SD(K*)SI(Xaa10)LD(Xaa13)(Xaa14)A(Xaa16)(Xaa17)(Xaa18)F(Xaa 20)(Xaa21)(Xaa22)L(Xaa24)(Xaa25)GGPSSGAPPPS(Xaa37)-R 6 (Formula WD-1; SEQ ID NO: 5).
3 . The compound of claim 1 , wherein —N(R 4 )—W is:
GT(Xaa3)(Xaa4)SD(Xaa7)SI(Xaa10)LD(Xaa13)(K*)A(Xaa16)(Xaa17)(Xaa18)F(Xaa20)(Xaa21)(Xaa22)L(Xaa24)(Xaa25)GGPSSGAPPPS(Xaa37)-R 6 (Formula WD-2; SEQ ID NO: 6);
4 . The compound of claim 1 , wherein —N(R 4 )—W is:
GT(Xaa3)(Xaa4)SD(Xaa7)SI(Xaa10)LD(Xaa13)(Xaa14)A(Xaa16)(K*)(Xaa18)F(Xaa20)(Xaa21)(Xaa22)L(Xaa24)(Xaa25)GGPSSGAPPPS(Xaa37)-R 6 (Formula WD-3; SEQ ID NO: 7);
5 . The compound of claim 1 , wherein —N(R 4 )—W is:
GT(Xaa3)(Xaa4)SD(Xaa7)SI(Xaa10)LD(Xaa13)(Xaa14)A(Xaa16)(Xaa17)(Xaa18)F(Xaa20)(K*)(Xaa22)L(Xaa24)(Xaa25)GGPSSGAPPPS(Xaa37)-R 6 (Formula WD-4; SEQ ID NO: 8); and
6 . The compound of claim 1 , wherein —N(R 4 )—W is:
GT(Xaa3)(Xaa4)SD(Xaa7)SI(Xaa10)LD(Xaa13)(Xaa14)A(Xaa16)(Xaa17)(Xaa18)F(Xaa20)(Xaa21)(Xaa22)L(Xaa24)(Xaa25)GGPSSGAPPPS(K*)—R 6 (Formula WD-5; SEQ ID NO: 9).
7 . The compound of any one of claims 1-6 , wherein, Xaa3 is F.
8 . The compound of any one of claims 1-6 , wherein Xaa3 is F*, F†, or F‡.
9 . The compound of any one of claims 1-8 , wherein Xaa4 is T.
10 . The compound of any one of claims 1-8 , wherein Xaa4 is V.
11 . The compound of any one of claims 1 and 3-10 , wherein Xaa7 is Y.
12 . The compound of any one of claims 1 and 3-10 , wherein Xaa7 is K*.
13 . The compound of any one of claims 1-12 , wherein Xaa13 is K.
14 . The compound of any one of claims 1-12 , wherein, Xaa13 is R.
15 . The compound of any one of claims 1, 2 and 4-14 , wherein Xaa14 is I.
16 . The compound of any one of claims 1, 2 and 4-14 , wherein, Xaa14 is Q.
17 . The compound of any one of claims 1, 2 and 4-14 , wherein Xaa14 is K*.
18 . The compound of any one of claims 1-17 , wherein Xaa16 is Q.
19 . The compound of any one of claims 1-17 , wherein Xaa16 is A.
20 . The compound of any one of claims 1-3 and 5-19 , wherein Xaa17 is K*.
21 . The compound of any one of claims 1-3 and 5-19 , wherein Xaa17 is Aib.
22 . The compound of any one of claims 1-21 , wherein Xaa18 is A.
23 . The compound of any one of claims 1-21 , wherein Xaa18 is E.
24 . The compound of any one of claims 1-23 , wherein Xaa20 is V.
25 . The compound of any one of claims 1-4 and 6-24 , wherein Xaa21 is Q.
26 . The compound of any one of claims 1-4 and 6-24 , wherein Xaa21 is N.
27 . The compound of any one of claims 1-4 and 6-24 , wherein Xaa21 is K*.
28 . The compound of any one of claims 1-4 and 6-24 , wherein Xaa21 is dE.
29 . The compound of any one of claims 1-28 , wherein Xaa22 is W.
30 . The compound of any one of claims 1-28 , wherein Xaa22 is L.
31 . The compound of any one of claims 1-30 , wherein Xaa24 is I.
32 . The compound of any one of claims 1-30 , wherein Xaa24 is L.
33 . The compound of any one of claims 1-32 , wherein Xaa25 is A.
34 . The compound of any one of claims 1-32 , wherein Xaa25 is E.
35 . The compound of any one of claims 1-5 and 7-34 , wherein. Xaa37 is absent.
36 . The compound of any one of claims 1-5 and 7-34 , wherein Xaa37 is K*.
37 . The compound of any one of claims 1 and 3-5 , wherein Xaa4 is T; Xaa7 is Y; and Xaa13 is K.
38 . The compound of claim 37 , wherein Xaa 20 is V.
39 . The compound of claim 37 or 38 , wherein Xaa22 is W.
40 . The compound of any one of claims 37-39 , wherein Xaa25 is A.
41 . The compound of any one of claims 37-40 , wherein Xaa37 is absent; optionally wherein R 6 is NH 2 .
42 . The compound of any one of claims 1 and 3-5 , wherein Xaa4 is T; Xaa7 is Y; Xaa13 is K; and Xaa 20 is V.
43 . The compound of any one of claims 1 and 3-5 , wherein Xaa4 is T; Xaa7 is Y; Xaa13 is K; Xaa 20 is V; and Xaa22 is W.
44 . The compound of any one of claims 1 and 3-5 , wherein Xaa4 is T; Xaa7 is Y; Xaa13 is K; Xaa 20 is V; Xaa22 is W; and Xaa25 is A.
45 . The compound of any one of claims 1 and 3-5 , wherein Xaa4 is T; Xaa7 is Y; Xaa13 is K; Xaa 20 is V; Xaa22 is W; Xaa25 is A; and Xaa37 is absent; optionally wherein R 6 is NH 2 .
46 . The compound of any one of claims 37-45 , wherein Xaa14 is I.
47 . The compound of any one of claims 37-46 , wherein Xaa21 is Q.
48 . The compound of any one of claims 37-47 , wherein Xaa24 is I.
49 . The compound of any one of claims 37-48 , wherein Xaa3 is F, Xaa16 is Q, and Xaa18 is A.
50 . The compound of any one of claims 37-49 , wherein, Xaa17 is K*.
51 . The compound of any one of claims 1-36 , wherein R 6 is —NH 2 .
52 . The compound of any one of claims 1-36 , wherein R 6 is —OH.
53 . The compound of claim 1 , wherein —N(R 4 )—W is selected from the groups consisting of:
SEQ
CT
ID
SEQ.
NO:
ID
Sequence
10
A
GTFTSDYSI(Aib)LDKIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
12
B
GTFTSDYSI(Aib)LD R IAQK*AFVQWLIAGGPSSGAPPPS-NH 2
13
C
GT F* TSDYSI(Aib)LDRIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
14
D
GT F † TSDYSI(Aib)LDRIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
15
E
GT F ‡ TSDYSI(Aib)LDRIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
16
I
GTFTSDYSI Y LDKIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
17
J
GTFTSDYSI(Aib)LDKIAQK*AFVQWL L AGGPSSGAPPPS-NH 2
18
K
GTFTSDYSI(Aib)LDKIAQK* E FVQWLIAGGPSSGAPPPS-NH 2
19
L
GTFTSDYSI(Aib)LDK Q AQK*AFVQWLIAGGPSSGAPPPS-NH 2
20
M
GTFTSDYSI Y LDK Q AA(Aib) E FV N WL L AGGPSSGAPPPS K* -NH 2
21
N
GTFTSDYSI(Aib)LDKIA A K*AFVQWLIAGGPSSGAPPPSK*-NH 2
22
O
GTFTSDYSI Y LDK Q A A K* E FV N WL L AGGPSSGAPPPS-NH 2
23
P
GTFTSDYSI(Aib)LDKIAQK*AFV N WLIAGGPSSGAPPPSNH 2
24
Q
GTF V SDYSI(Aib)LDKIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
25
R
GTF A SDYSI(Aib)LDKIAQK*AFVQWLIAGGPSSGAPPPS-NH 2
26
S
GTFTSD K* SI Y LDK Q AA(Aib) E FV N WL L AGGPSSGAPPPS-NH 2
27
T
GTFTSDYSI(Aib)LDKIAQK*AFVQWLIAGGPSSGAPPPS-OH
28
V
GT F* TSDYSI Y LDK Q AA(Aib) E FV N WL L AGGPSSGAPPPS K*- NH 2
29
W
GT F* TSD K* SI Y LDK Q AA(Aib) E FV N WL L AGGPSSGAPPPS-NH 2
30
X
GTFTSDYSI(Aib)LDKIAQK*AFVQWLIAG-NH 2
31
Y
GT F* TSDYSI(Aib)LDKIAQK*AFVQWLIAG-NH 2
32
Z
GTFTSDYSI L* LD (Orn)K* AQ (Aib)E F I(dE)Y LI E GGPSSGAPPPS-NH 2
33
AA
GT F* TSDYSI L* LD (Orn)K* AQ (Aib)E F I(dE)Y LI E GGPSSGAPPPS-NH 2
34
AB
GTFTSDYSI(Aib)LDKIAQ K* AFVQWLIAGGPSSGAPPPS-NH 2
35
AC
GTFTSDYSI(Aib)LDKIAQ K* AFVQWLIAGGPSSGAPPPS-NH 2
36
AG
GTFTSDYSI Y LDK K* AA(Aib) E FV N WL L AGGPSSGAPPPS-NH 2
37
AH
GTFTSDYSI Y LDK Q AA(Aib) E FV K* WL L AGGPSSGAPPPS-NH 2
54 . The compound of claim 1 , wherein —N(R 4 )—W has formula WE:
-GTFTSDYSI(Aib)LDKIAQK*AFVQWLIAGGPSSGAPPPS-NH 2 (SEQ ID NO: 10).
55 . The compound of claim 1 , wherein —N(R 4 )—W:
GT(Xaa3)TSDYSI(Aib)LDKIAQK*AFVQWLIAG-NH 2 (SEQ ID NO: 11),
wherein Xaa3 is F or F*
56 . The compound of any one of claims 1-55 , wherein R* is (i)
57 . The compound of any one of claims 1-56 , wherein R X1 and R X2 are each defined according to (AA) or (AB):
(AA)
R X1 and R X2 are each independently selected from the group consisting of:
—F;
C 1-8 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with from 1-3 R a ; and
C 3-6 cycloalkyl which is optionally substituted with from 1-3 R b ; or
(AB)
R X1 and R X2 taken together with the carbon atom to which each is attached form a saturated or partially unsaturated ring having from 3-10 ring atoms, wherein from 0-2 ring atoms are heteroatoms each independently selected from the group consisting of: O, N, N(H), N(R c ), and S(O) 0-2 , wherein the ring is optionally substituted at one or more ring carbon atoms with from 1-3 R b .
58 . The compound of any one of claims 1-57 , wherein R X1 and R X2 are each independently selected from the group consisting of:
—F;
C 1-8 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with from 1-3 R a ; and
C 3-6 cycloalkyl which is optionally substituted with from 1-3 R b .
59 . The compound of any one of claims 1-58 , wherein R X1 and R X2 are the same.
60 . The compound of any one of claims 1-58 , wherein R X1 and R X2 are different.
61 . The compound of any one of claims 1-60 , wherein R X1 and R X2 are independently selected C 1-8 alkyl, which is optionally substituted with from 1-3 R a .
62 . The compound of any one of claims 1-61 , wherein R X1 and R X2 are independently selected unsubstituted C 1-6 alkyl.
63 . The compound of any one of claims 1-62 , wherein R X1 and R X2 are independently selected unsubstituted C 1-3 alkyl.
64 . The compound of any one of claims 1 - 59 and 61 - 64 , wherein R X1 and R X2 are both methyl.
65 . The compound of any one of claims 1-59 and 61-64 , wherein R X1 and R X2 are both ethyl.
66 . The compound of any one of claims 1-59 , wherein R X1 and R X2 are both —F.
67 . The compound of any one of claims 1-57 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form a saturated or partially unsaturated ring having from 3-10 ring atoms, wherein from 0-2 ring atoms are heteroatoms each independently selected from the group consisting of: O, N, N(H), N(R c ), and S(O) 0-2 , wherein the ring is optionally substituted at one or more ring carbon atoms with from 1-3 R b .
68 . The compound of any one of claims 1-57 and 67 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form a C 3-8 cycloalkyl ring which is optionally substituted with from 1-3 R b .
69 . The compound of any one of claims 1-57 and 67-68 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form a C 3-6 cycloalkyl ring which is optionally substituted with from 1-3 independently selected C 1-3 alkyl.
70 . The compound of any one of claims 1-57 and 67-69 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form a cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, or cyclohexyl ring.
71 . The compound of any one of claims 1-57 and 67 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form a saturated or partially unsaturated ring having from 4-10 ring atoms, wherein from 1-2 ring atoms are heteroatoms each independently selected from the group consisting of: O, N, N(H), N(R c ), and S(O) 0-2 , wherein the ring is optionally substituted at one or more ring carbon atoms with from 1-3 R b .
72 . The compound of any one of claims 1-57, 67 and 71 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form a saturated ring having from 4-6 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of: O, N, N(H), N(R c ), and S(O) 0-2 , wherein the ring is optionally substituted at one or more ring carbon atoms with from 1-3 R b .
73 . The compound of any one of claims 1-57, 67 and 71-72 , wherein R X1 and R X2 taken together with the carbon atom to which each is attached form
each of which is optionally substituted with from 1-2 independently selected C 1-3 alkyl.
74 . The compound of any one of claims 1-73 , wherein X 2 is a bond.
75 . The compound of any one of claims 1-74 , wherein R Z is —R ZA .
76 . The compound of any one of claims 1-75 , wherein R Z is selected from the group consisting of:
(iii) C 6-10 aryl, wherein the aryl is optionally substituted with from 1-5 independently selected R b ; and
(iv) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(H), N(R c ), O, and S(O) 0-2 , wherein the heteroaryl is optionally substituted with from 1-3 independently selected R b at one or more ring carbon atoms.
77 . The compound of any one of claims 1-76 , wherein R Z is C 6-10 aryl, wherein the aryl is optionally substituted with from 1-5 independently selected R b .
78 . The compound of any one of claims 1-77 , wherein R Z is phenyl which is optionally substituted with from 1-3 independently selected R b .
79 . The compound of any one of claims 1-78 , wherein R Z is selected from the group consisting of:
80 . The compound of any one of claims 1-79 , wherein R Z is
81 . The compound of any one of claims 1-76 , wherein R Z is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(H), N(R c ), O, and S(O) 0-2 , wherein the heteroaryl is optionally substituted with from 1-3 independently selected R b at one or more ring carbon atoms.
82 . The compound of any one of claims 1-76 and 81 , wherein R Z is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(H), N(R c ), O, and S, wherein the heteroaryl is optionally substituted with from 1-3 independently selected R b at one or more ring carbon atoms.
83 . The compound of any one of claims 1-76 and 81-82 , wherein R Z is monocyclic heteroaryl including 6 ring atoms, wherein from 1-2 ring atoms are ring nitrogen atoms, wherein the heteroaryl is optionally substituted with from 1-3 independently selected R b at one or more ring carbon atoms.
84 . The compound of any one of claims 1-76 and 81-83 , wherein R Z is selected from the group consisting of:
each optionally substituted with R b .
85 . The compound of any one of claims 1-76 and 81 , wherein R Z is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are each independently selected from the group consisting of N, N(H), N(R c ), O, and S, wherein the heteroaryl is optionally substituted with from 1-2 independently selected R b at one or more ring carbon atoms.
86 . The compound of any one of claims 1-76, 81 and 85 , wherein R Z is selected from the group consisting of:
87 . The compound of any one of claims 1-86 , wherein each R b present in R Z is independently selected from the group consisting of: C 1-3 alkyl optionally substituted with from 1-3 independently selected halo; —F; —Cl; —N(R f )(R′); C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)OH; —C(═O)N(R′)(R″); and cyano.
88 . The compound of any one of claims 1-80 and 87 , wherein R Z is selected from the group consisting of:
wherein each R b present in R Z is independently selected from the group consisting of: C 1-3 alkyl optionally substituted with from 1-3 independently selected halo; —F; —Cl; —N(R f )(R′); C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)OH; —C(═O)N(R′)(R″); and cyano.
89 . The compound of any one of claims 1-80 and 87-88 , wherein R Z is
wherein each R b present in R Z is independently selected from the group consisting of: C 1-3 alkyl optionally substituted with from 1-3 independently selected halo; —F; —Cl; —N(R f )(R′); C 1-4 alkoxy; C 1-4 haloalkoxy; —C(═O)OH; —C(═O)N(R′)(R″); and cyano.
90 . The compound of any one of claims 1-89 , wherein L 1 is C 1-10 alkylene optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo; C 1-4 alkoxy; —OH; phenyl; and NR′R″.
91 . The compound of any one of claims 1-90 , wherein L 1 is unsubstituted C 1-10 alkylene.
92 . The compound of any one of claims 1-91 , wherein L 1 is unsubstituted C 1-6 alkylene.
93 . The compound of any one of claims 1-92 , wherein L 1 is unsubstituted C 2-4 alkylene.
94 . The compound of any one of claims 1-93 , wherein L 1 is unsubstituted C 3 alkylene.
95 . The compound of any one of claims 1-94 , wherein L 1 is —CH 2 CH 2 CH 2 —.
96 . The compound of any one of claims 1-93 , wherein L 1 is —CH 2 CH 2 —.
97 . The compound of any one of claims 1-96 , wherein X 1 is selected from the group consisting of: C(═O)N(R′)*; C(═S)N(R′)*; and S(O) 1-2 N(R′)*, wherein * represents the point of attachment to L 1 .
98 . The compound of any one of claims 1-97 , wherein X 1 is C(═O)N(R′)*.
99 . The compound of any one of claim 1 or 56-98 , wherein X 1 is C(═O)N(H)*.
100 . The compound of any one of claims 1-97 , wherein X 1 is C(═S)N(R′)*.
101 . The compound of any one of claims 1-97 and 100 , wherein X 1 is C(═S)N(H)*.
102 . The compound of any one of claims 1-99 , wherein L 1 is unsubstituted C 2-4 alkylene; and X 1 is C(═O)N(R′)*.
103 . The compound of any one of claims 1-99 and 102 , wherein L 1 is —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —; and X 1 is C(═O)N(H)*.
104 . The compound of any one of claims 1-97 and 100-101 , wherein L 1 is unsubstituted C 2-4 alkylene; and X 1 is C(═S)N(R′)*.
105 . The compound of any one of claims 1-97, 100-101, and 104 , wherein L 1 is —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —; and X 1 is C(═S)N(H)*.
106 . The compound of any one of claims 1-105 , wherein Q is O.
107 . The compound of any one of claims 1-106 , wherein R 1 is —H.
108 . The compound of any one of claims 1-107 , wherein a1 is 0.
109 . The compound of any one of claims 1-107 , wherein a1 is 1, 2, or 3.
110 . The compound of any one of claims 1-109 , wherein R 2 is —H.
111 . The compound of any one of claims 1-109 , wherein R 2 is C 1-3 alkyl, optionally methyl.
112 . The compound of any one of claims 1-111 , wherein a2 is 1.
113 . The compound of any one of claims 1-112 , wherein R 3a and R 3b are both H.
114 . The compound of any one of claims 1-111 , wherein a2 is 0.
115 . The compound of any one of claims 1-114 , wherein a is 1.
116 . The compound of any one of claims 1-114 , wherein a is 0.
117 . The compound of any one of claims 1-116 , wherein R 2 ′ is —CH 2 CH 2 R 3 .
118 . The compound of any one of claims 1-116 , wherein R 2 ′ is —CH 2 R 3 .
119 . The compound of any one of claims 1-116 , wherein R 2 ′ is —R 3 .
120 . The compound of any one of claims 1-119 , wherein R 3 is —C(O)OH.
121 . The compound of any one of claims 1-119 , wherein R 3 is —CH(C(O)OH) 2 .
122 . The compound of any one of claims 1-119 , wherein R 3 is a carboxylic acid biosisostere.
123 . The compound of any one of claim 1-119 and 122 , wherein R 3 is tetrazolyl.
124 . The compound of any one of claims 1-107 , wherein a1 is 0; R 1 and R 2 are each H; and R 2 ′ is —CH 2 CH 2 R 3 , wherein R 3 is —C(O)OH.
125 . The compound of any one of claims 1-124 , wherein K* is a lysyl residue that is optionally substituted with from 1-2 modifying groups; optionally 1-2 groups independently selected from the group consisting of an acyl group, a PEG group; and combinations thereof.
126 . The compound of any one of claims 1-125 , wherein K* is an L-lysyl residue that is optionally substituted with from 1-2 modifying groups optionally 1-2 groups independently selected from the group consisting of an acyl group, a PEG group; and combinations thereof.
127 . The compound of any one of claims 1-126 , wherein K* has the formula:
wherein, R K is a modifying group independently selected from the group consisting of an acyl group, a PEG group; and combinations thereof.
128 . The compound of claim 127 , wherein R K is a group of Formula (KA):
wherein:
k1 is 1, 2, 3, or 4;
k2 is 1, 2, 3, or 4;
k3 is 0, 1, 2, 3, or 4; and
k4 is an integer from 5 to 25.
129 . The compound of claim 128 , wherein k1 is 1.
130 . The compound of claim 128 or 129 , wherein k2 is 2.
131 . The compound of any one of claims 128-130 , wherein k3 is 1.
132 . The compound of any one of claims 128-131 , wherein k4 is an integer from 10 to 20.
133 . The compound of any one of claims 128-132 , wherein k4 is an integer from 15 to 20.
134 . The compound of any one of claims 128-133 , wherein k4 is 16 or 18.
135 . The compound of claim 128 , wherein k1 is 1; k2 is 2; k3 is 1; and k4 is an integer from 15 to 20.
136 . The compound of any one of claims 127-135 , wherein R K is
137 . The compound of any one of claims 127-135 , wherein R K is
138 . The compound of any one of claims 125-135 , wherein K* is an internal amino acid having the formula:
139 . The compound of any one of claims 125-135 , wherein K* is an internal amino acid having the formula:
140 . The compound of claim 1 , wherein the compound is selected from the group consisting of the compounds delineated in FIG. 1 , or a pharmaceutically acceptable salt thereof.
141 . A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1-140 and one or more pharmaceutically acceptable excipients.
142 . A method for modulating GLP-1R and/or GIPR activity, the method comprising contacting GLP-1R and/or GIPR with a compound as claimed in any one of claims 1-140 or a pharmaceutical composition as claimed in claim 141 .
143 . The method of claim 142 , wherein the modulating comprises agonizing GLP-1R and/or GIPR.
144 . The method of claim 142 or 143 , wherein the modulating comprises partially agonizing or antagonizing GLP-1R and/or GIPR.
145 . The method of any one of claims 142-144 , which is carried out in vitro.
146 . The method of any one of claims 142-144 , which is carried out in vivo.
147 . A method for modulating GLP-1R and/or GIPR induced aversion, nausea and/or vomiting, the method comprising contacting GLP-1R and/or GIPR with a compound as claimed in any one of claims 1-140 or a pharmaceutical composition as claimed in claim 141 .
148 . A method for modulating (e.g., increasing) insulin levels in a subject in need of such modulating, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-140 or a pharmaceutical composition as claimed in claim 141 .
149 . A method for modulating (e.g., decreasing) glucose levels in a subject in need of such modulating, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-140 or a pharmaceutical composition as claimed in claim 141 .
150 . A method for treating a disease, disorder, or condition, in which modulating GLP-1R and/or GIPR signaling can alter the pathology and/or symptoms and/or progression of the disease, disorder, or condition, the method comprising administering to the subject in need thereof an effective amount of a compound as claimed in any one of claims 1-140 or a pharmaceutical composition as claimed in claim 141 .
151 . The method of claim 150 , wherein the disease, disorder, or condition or disorder is diabetes.
152 . The method of claim 150 , wherein the disease, disorder, or condition or disorder is NASH.
153 . The method of claim 150 , wherein the disease, disorder, or condition or disorder is obesity.
154 . The method of claim 150 , wherein the disease, disorder, or condition or disorder is fatty liver disease.
155 . The method of claim 150 , wherein the disease, disorder, or condition or disorder is steatohepatitis.
156 . The method of any one of claims 150-155 , wherein the method further comprises identifying the subject.
157 . The method of any one of claims 148-156 , wherein the subject is a human.
158 . A method for treating a disease, disorder, or condition, in which modulating GLP-1R and/or GIPR signaling causes aversion, nausea or vomiting, the method comprising administering to the subject in need thereof an effective amount of a compound as claimed in any one of claims 1-140 or a pharmaceutical composition as claimed in claim 141 .