GLP-1 receptor modulators
Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as products containing such compounds, and methods of their use and synthesis. Such compounds have the structure of Formula (I) below: (I) or pharmaceutically acceptable salts thereof, wherein A, J, W 1 , Y, Z, R 1 , R 2 , R 3 and R 4 are as defined herein.
1. A compound having the structure of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
J is null or has the structure:
each of X 1A , X 1B , X 1C , X 1D , X 1E , X 1F and X 1G is C, CH or N;
X 1H is O or S;
X 1J is CH 2 or NH;
R 1 is H, alkyl or alkoxy;
Y is —C(O)—, —CH 2 —, —C(O)—CH 2 —, —CH 2 —C(O)—, —C(O)—(CR a R b ) n —N(R c )—C(O)—(CR a R b ) n —, —C(O)—(CR a R b ) n —N(R d ) w here R d may form a fused ring with J or with a fused J-R 4 —W 1 ring system, —C(O)—(CR a R b ) n —N(R c )—C(O)—(CR a R b ) n —N(R c )—S(O) k —(CR a R b ) n —, —C(O)—(CR a R b ) n —N(R c )—C(O)—(CR a R b )—N(R d )— where R d may form a fused ring with J or with a fused J-R 4 —W 1 ring system, or —C(O)—(CR a R b ) n —N(R c )—S(O) k —(CR a R b )—;
Z is —(CR a R b ) n —C(O)—R 7 ;
R 7 is —OR 30 , —NR 31 R 32 , —NH(CR a R b ) n —C(O)—R 7 , —NHSO 2 R 7 or —(CO)—NH—SO 2 —R 7 , or R 31 ;
each R 30 is independently H or alkyl;
each R 31 and R 32 is independently H or C 1 -C 6 alkyl optionally substituted with one or more R 33 , or taken together with the N atom to which they are attached can form a 3- to 7-membered heterocyclic ring;
each R 33 is independently halo, hydroxyl, alkoxy, perhaloalkyl, perhaloalkoxy, carboxyl, —C(O)O—R 30 , —OR 30 , —N(R 30 ) 2 or heterocyclyl;
each R 4 is independently H, alkyl, alkoxy, or alkyl substituted with one or more R 43 , halogen, perhaloalkyl, perhaloalkoxy, —CN, —OR 40 or —NR 41 R 42 ;
each R 41 and R 42 is independently H, alkyl, —(CH 2 ) n —C(O)O—R 40 , —C(O)—R 40 , aryl, heteroaryl; or R 41 and R 42 , taken together with the N atom to which they are attached, can form a 3- to 7-membered heterocyclic ring;
each R 43 is independently H, halo, hydroxyl, —NR 41 R 42 , or alkoxy;
W 1 is —(CR a R b ) il -L 1 —(CR a R b ) j1 —R 60 or R 4 ; or W 1 and R 4 taken together comprise a 5- or 6-membered carbocyclic or heterocyclic ring fused with the ring to which W 1 and R 4 are attached and optionally having one, two or three heteroatoms where each such heteroatom is independently selected from O, N, and S, and where any ring atom of such heterocyclic ring may be optionally substituted with one or more —L 1 —R 13 or R 13 ; or W 1 is a 5- or 6-membered heterocyclic ring fused with a phenyl ring and having one, two or three heteroatoms where each such heteroatom is independently selected from O, N, and S, and where any ring atom of such fused heterocyclic ring and phenyl ring moiety may be optionally substituted with one or more R 14 ;
L 1 is —O—, —C(O)—, —OC(O)—, —C(O)O—, —NR 10 —, —C(O)NR 10 —, —N(R 10 )—(CH 2 ) n —C(O)—,—N(R 10 )—C(O)—N(R 10 )—,—N(R 10 )—S(O) 2 —, —S(O) 2 —NR 10 )—, or —N(S(O) 2 —(CH 2 ) n —R 60 ) 2 ;
R 60 is R 13 , —O—(CH 2 ) n —R 13 , or R 10 ;
each R 10 , R 11 and R 12 is independently H or alkyl;
R 13 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a fused bicycle or tricycle of any two or three of such ring moieties, or R 13 and R 10 taken together with the N atom to which they are attached form a heterocyclic ring, where any ring atom of R 13 may be optionally substituted with one or more R 14 or R 15 ;
each R 14 is independently H, alkyl, halo, hydroxy, cyano, alkoxy, perhaloalkyl, and perhaloalkoxy, —OR 10 ,—(CH 2 ) n —C(O)OR 10 , —SR 10 , —SO—R 10 , —S(O) 2 —R 10 ), —(CH 2 ) n —NR 11 R 12 , —NH—C(O)—(CH 2 ) n —R 12 , —N(R 11 )—C(O)—(CH 2 ) n —R 12 , or —NH(CH 2 ) n —R 12 ;
R 15 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a fused bicycle of any two of such ring moieties, where any ring atom of R 15 may be optionally substituted with one or more R 14 ,
each R 40 is independently H or alkyl;
each R a and R b is independently H, hydroxy, alkyl, or aralkyl optionally substituted with hydroxyl; or both R a and R b attached to the same carbon are, taken together, oxo, or cycloalkyl;
each R c and R d is independently H, hydroxy, alkyl, —S(O) k —R 7 or —C(O)—R 7 ;
A is cycloalkyl;
R 2 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a fused bicycle of any two of such ring moieties, where any ring atom of R 2 may be optionally substituted with one or more R 3 , each R 3 is independently H, alkyl, or perhaloalkyl;
each k is 2;
each n is independently 0, 1, 2, 3 or 4; and
each i 1 and j 1 is independently 0, 1, 2, 3 or 4.
2. The compound of claim 1 , wherein the compound has a structure of Formula (II):
3. The compound of claim 2 , wherein the compound has a structure of Formula (III):
4. The compound of claim 1 , wherein the compound has a structure of Formula (IV):
5. The compound of claim 3 , wherein the compound has a structure of Formula (V):
6. The compound of claim 5 , wherein the compound has a structure of Formula (VI):
7. The compound of claim 2 , wherein the compound has a structure of Formula (VII):
8. The compound of claim 7 , wherein the compound has a structure of Formula (VIII):
9. The compound of claim 8 , wherein the compound has a structure of Formula (IX):
10. The compound of claim 2 , wherein the compound has the structure of Formula (X):
11. The compound of claim 10 , wherein the compound has the structure of Formula (XI):
12. The compound of claim 11 , wherein the compound has the structure of Formula (XII):
13. The compound of claim 1 , wherein the compound is selected from any one of the following compounds or any pharmaceutically acceptable salt thereof:
Structure
Cpd. No.
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14. A pharmaceutical composition comprising a compound of claim 1 together with at least one pharmaceutically acceptable carrier, diluent or excipient.
15. A method of modulating a glucagon-like peptide 1 receptor comprising contacting the receptor with an effective amount of a compound of claim 1 .
16. A method for treating a malcondition in a patient for which modulation of a glucagon-like peptide 1 receptor is medically indicated, comprising administering an effective amount of a compound of claim 1 , to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient.
17. The method of claim 16 wherein the malcondition is type I diabetes, type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety or metabolic disorder.
18. The method of claim 16 wherein the malcondition is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).