Heterocyclic GLP-1 agonists
This disclosure relates to GLP-1 agonists of Formula (I): including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.
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;
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;
T 1 is C(═O) OH;
T 2 is
L 1 is CH 2 ;
L 2 is a bond;
Ring A is selected from the group consisting of:
and
wherein n1 is 0, 1, or 2; W 1 is CR Y1 or N; and W 2 is CR Y2 or N;
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 and R Y2 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):
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 phenyl;
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 . The compound of claim 1 , wherein:
i) X 1 and X 6 are CH; or
ii) X 1 is N; and X 6 is CH; or
iii) X 1 is CH; and X 6 is N.
3 . The compound of claim 1 , wherein the stereocenter in
of T 2 has (S)-configuration.
4 . The compound of claim 1 , wherein Ring A is
5 . The compound of claim 4 , wherein W 1 is N; and W 2 is CR Y2 .
6 . The compound of claim 5 , wherein R Y2 is hydrogen.
7 . The compound of claim 4 , wherein n1 is 0 or 1.
8 . The compound of claim 4 , wherein W 1 is N; and W 2 is N.
9 . The compound of claim 1 , wherein Ring A is
10 . The compound of claim 1 , wherein Ring B is
11 . The compound of claim 1 , wherein Ring B is
12 . The compound of claim 1 , wherein B 1 is —O-; and B 2 is —O-.
13 . The compound of claim 1 , wherein R aa is H or (C 1 -C 3 )alkyl; R ab is H;
and R ac is H.
14 . The compound of claim 1 , wherein B 3 , B 4 , and B 5 are independently CH or CR a .
15 . The compound of claim 1 , wherein Ring B is selected from the group consisting of:
16 . The compound of claim 1 , wherein b is 0, 1, or 2.
17 . The compound of claim 1 , wherein each occurrence of R b is independently selected from the group consisting of—F, -Cl,—CH 3 ,—CF 3 , and CN.
18 . The compound of claim 1 , wherein the compound is of Formula IB:
or a pharmaceutically acceptable salt thereof, or
the compound is of Formula IC:
or a pharmaceutically acceptable salt thereof; or
the compound is of Formula ID:
or a pharmaceutically acceptable salt thereof; or
the compound is of Formula IE:
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising a compound claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
20 . 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 claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
21 . The method of claim 20 , wherein the compound, or the pharmaceutically acceptable salt or solvate thereof, is administered orally.
22 . A method for modulating insulin levels or glucose levels in a patient in need of such modulating, the method comprising administering to the patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof.
23 . 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 of claim 1 .
24 . The method of claim 23 , 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.
25 . The method of claim 23 , 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.
26 . The method of claim 23 , 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.
27 . A method for treating obesity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or the pharmaceutically acceptable salt or solvate thereof.