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:
Ring A is C 6-10 aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, each of which is optionally substituted with from 1-5 substituents each independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy;
R 1 , R 2 and R 3 are each independently selected from the group consisting of H and C 1-6 alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of halo, —OH, and C 1-6 alkoxy;
L 1 is selected from the group consisting of: —C(═O)—, —CH 2 —, —CH(C 1-6 alkyl)-, and —S(═O) 2 ;
Ring B is selected from the group consisting of:
wherein bb represents point of attachment to L 1 ;
R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: H, halo, and C 1-6 alkyl;
L 3 is a bond or C 1-3 alkylene;
L 4 is a bond or C 1-5 alkylene;
R 8a and R 8b are independently selected from the group consisting of: H and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halo and C 3-15 cycloalkyl; or
R 8a and R 8b taken together with the carbon atom to which each is attached forms a C 3-15 cycloalkyl ring which is optionally substituted with from 1-3 independently selected C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with from 1-6 independently selected R f ,
R 9 is selected from the group consisting of: C(═O)OH, C(═O)(OC 1-6 alkyl), C(═O)NR 9a R 9b , (IX-1), (IX-2), (IX-3), and (IX-4):
R 9a is H or C 1-6 alkyl;
R 9b is H, C 1-6 alkyl, C(═O)(C 1-6 alkyl), S(O) 0-2 (C 1-6 alkyl), or cyano;
R 9c , R 9d , R 9e , R 9f , and R 9g are each independently selected from the group consisting of: H; C 1-6 alkyl optionally substituted with from 1-6 independently selected halo and C 1-6 alkoxy; and C(═O)(C 1-6 alkyl);
Ring C is selected from the group consisting of 3-12 membered heterocyclyl; C 3-10 cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted with from 1-3 R Ca ;
each R Ca is independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and NR c R d ;
or a pair of R Ca on the same or different ring atoms, taken together with the ring atom(s) to which each is attached, forms a carbocyclic ring including from 3-8 ring atoms;
L 2 is selected from the group consisting of:
wherein aa represents the point of attachment to Q;
n1 is an integer from 1-3;
L 2A is a bond or C 1-10 alkylene;
R La is selected from the group consisting of H, C 1-6 alkyl, and C(═O)(C 1-6 alkyl);
each of R Lb and R Lc is independently selected from the group consisting of: H and C 1-6 alkyl;
Q is selected from the group consisting of: C 1-10 alkyl; C 3-15 cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 aryl, each of which is optionally substituted with from 1-6 independently selected R Q ;
each R Q is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) OH or oxo;
(d) —NR c R d ,
(e) —C(═O)NR c R d or —S(O) 2 NR c R d ,
(f) —S(═O) 0-2 R e ;
(g) C 1-6 alkyl optionally substituted with from 1-6 independently selected R f ,
(h) C 1-6 alkoxy optionally substituted with from 1-6 independently selected R f ;
(i) 3-12 membered heterocyclyl optionally substituted with from 1-6 independently selected R g ;
(j) C 6-10 aryl optionally substituted with from 1-6 independently selected R g ;
(k) 5-10 membered heteroaryl optionally substituted with from 1-6 independently selected R g ;
(l) C 3-8 cycloalkyl optionally substituted with from 1-6 independently selected R g ;
(m) —P(═O)R a R b , and
(n) —(CR h R h ) q1 —S(O) 2 -L e -R e , wherein q1 is 1, 2, or 3;
R a and R b are independently selected from the group consisting of C 1-6 alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of C 1-6 alkoxy, C 3-6 cycloalkyl, and halo; C 3-6 cycloalkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of C 1-3 alkyl and halo; and C 6-10 aryl optionally substituted with from 1-3 independently selected C 1-3 alkyl; or
R a and R b taken together with the phosphorous atom to which each is attached forms a ring including from 5-8 ring atoms, wherein from 0-2 ring atoms (in addition to the phosphorous attached to R a and R b ) are heteroatoms each independently selected from the group consisting of: O, S, and N, wherein the ring is optionally substituted with from 1-3 independently selected C 1-6 alkyl;
each R c and R d are independently selected from the group consisting of: H, C 1-6 alkyl, C 3-6 cycloalkyl, C(═O)(C 1-6 alkyl), C(═O)(C 3-6 cycloalkyl), C(═O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl), and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 alkyl, C(═O)(C 1-6 alkyl), C(═O)(C 3-6 cycloalkyl), C(═O)O(C 1-6 alkyl), S(O) 1-2 (C 1-6 alkyl), and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted with from 1-6 substituents independently selected from the group consisting of: —OH, halo, and C 1-6 alkoxy;
R e is H, or R e is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, and 3-8 membered heterocyclyl, each of which is optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, —OH, NH 2 , NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , C 1-3 alkoxy, and C 1-3 haloalkoxy;
L e is a bond, NR c , or O;
each R f is independently selected from the group consisting of halo, —OH, NR c R d , C 1-6 alkoxy, C 1-6 haloalkoxy, and 3-12 membered heterocyclyl which is optionally substituted with from 1-4 substituents each independently selected from the group consisting of —OH, C 1-6 alkyl, and 3-12 membered heterocyclyl;
each R g is independently selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NR c R d , cyano, halo, C 3-6 cycloalkyl, and 3 to 12 membered heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl and C(═O)C 1-6 alkyl; and
each occurrence of R h is independently selected from the group consisting of: H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and halo; or
a pair of R h on the same or different carbon atom(s), taken together with the carbon atom(s) connecting them forms C 3-6 cycloalkyl or 4-8 membered heterocyclyl, each of which is optionally substituted with from 1-3 substituents each independently selected from the group consisting of: halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, —OH, C 1-3 alkoxy, and C 1-3 haloalkoxy.
2 . The compound of claim 1 , wherein Q is
wherein n1 is 0 or 1.
3 . The compound of claim 1 , wherein Q is phenyl optionally substituted with from 1-6 independently selected R Q .
4 . The compound of claim 1 , wherein the R Q para to L 2 is —P(═O)R a R b .
5 . The compound of claim 4 , wherein R a and R b are independently selected C 1-6 alkyl optionally substituted with from 1-6 substituents each independently selected from the group consisting of C 1-6 alkoxy, C 3-6 cycloalkyl, and halo.
6 . The compound of claim 1 , wherein R 1 , R 2 , and R 3 are H.
7 . The compound of claim 1 , wherein R 1 and R 2 are H; and R 3 is C 1-6 alkyl.
8 . The compound of claim 7 , wherein R 3 is methyl.
9 . The compound of claim 1 , wherein L 2 is
10 . The compound of claim 1 , wherein Ring A is
wherein R AA , R AB , and R AC are independently halo or C 1-6 alkyl.
11 . The compound of claim 1 , wherein L 1 is C(═O).
12 . The compound of claim 1 , wherein Ring B is
13 . The compound of claim 12 , wherein R 4 , R 5 , and R 6 are each H.
14 . The compound of claim 12 , wherein R 7 is H.
15 . The compound of claim 1 , wherein both of L 3 and L 4 are bonds.
16 . The compound of claim 1 , wherein R 8a and R 8b taken together with the carbon atom to which each is attached forms a C 3-5 cycloalkyl ring which is optionally substituted with from 1-2 independently selected C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with from 1-3 independently selected R f .
17 . The compound of claim 1 , wherein R 8a and R 8b taken together with the carbon atom to which each is attached forms:
18 . The compound of claim 1 , wherein R 9 is
19 . The compound of claim 1 , wherein Ring C is tetrahydropyranyl which is optionally substituted with from 1-3 independently R Ca .
20 . A compound selected from the group consisting of the compounds in Table C1 or Table C2,
TABLE C1
Compound No.
Structure
101
102
103
104
105
106
107
108
109/110
111/112
113
114
115
116
117
118
TABLE C2
Compound No.
Structure
105a
106a
107a
108a
109a
110a
single diastereomer 2
111a
single diastereomer 2
112a
single diastereomer 1
113a
single diastereomer 2
114a
single diastereomer 2
115a
single diastereomer 2
116a
single diastereomer 2
117a
single diastereomer 2
118a
single diastereomer 2
or a pharmaceutically acceptable salt or solvate thereof.
21 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
22 . 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 claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 21 , 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, 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.
23 . The method of claim 22 , wherein the disease, disorder, or condition is type 2 diabetes mellitus.
24 . The method of claim 22 , wherein the disease, disorder, or condition is obesity.