GLP-1 receptor agonists and uses thereof

Patent metadata

Field	Value
Publication number	US-10669259-B2
Application number	US-201816220184-A
Country	US
Kind code	B2
Filing date	Dec 14, 2018
Priority date	Dec 16, 2016
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-, 5-aza-, 7-aza- and 4,7-diaza-benzimidazoles as GLP-1R agonists, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

First claim

It is claimed:

1. A method of treating a disease or disorder comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein
each R 1 is independently halogen, —CN, —C 1-3 alkyl, or —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl is substituted with 0 to 3 F atoms;
m is 0, 1, 2, or 3;
each R 2 is independently F, Cl, or —CN;
p is 0, 1 or 2;
each R 3 is independently F, —OH, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, or —C 3-4 cycloalkyl, or 2 R 3 s may together cyclize to form —C 3-4 spirocycloalkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1 —OH;
q is 0, 1, or 2;
Y is CH or N;
R 4 is —C 1-3 alkyl, —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 , wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 , and

wherein said alkylene and cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 ;
R 5 is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 1 oxo (═O),
0 to 1 —CN,
0 to 2 F atoms, and
0 to 2 substituents independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O ;

R 6 is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 halogens,
0 to 1 substituent selected from —OR O and —N(R N ) 2 , and
0 to 2 —C 1-3 alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms, and
0 to 1 —OR O ;

each R O is independently H, or —C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
each R N is independently H, or —C 1-3 alkyl;
Z 1 is CH or N;
Z 2 and Z 3 are each independently —CR Z or N, provided that when Z 1 or Z 3 is N, Z 2 is —CR Z ; and

each R Z is independently H, F, Cl, or —CH 3 ; and
wherein the disease or disorder is selected from the group consisting of T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity, eating disorders, weight gain from use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, NASH with fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, Polycystic Ovary Syndrome, and addiction.

2. The method of claim 1 , wherein the compound is a compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein
m is 0 or 1;
R 2 is F;
p is 0, or 1; and
q is 0 or 1.

3. The method of claim 1 , wherein the compound is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein
m is 0 or 1;
R 2 is F;
p is 0, or 1;
R 3 is —C 1-2 alkyl, wherein C 1-2 alkyl may be substituted as valency allows with 0 to 3 F atoms; and
q is 0 or 1.

4. The method of claim 1 , wherein each R 1 is independently F, Cl, —CN, —CH 3 , or —CF 3 .

5. The method of claim 1 , wherein
R 4 is —CH 2 —R 5 , wherein R 5 is the 4- to 5-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 F atoms, and
0 to 1 substituent selected from —OCH 3 and —CH 2 OCH 3 .

6. The method of claim 1 , wherein the heterocycloalkyl of R 5 is a monovalent radical of

wherein the heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 1 oxo (O═),
0 to 1 —CN,
0 to 2 F atoms, and
0 to 2 substituents independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be independently substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O .

7. The method of claim 1 , wherein
R 4 is —CH 2 —R 6 , wherein R 6 is the 5-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substitutents as valency allows independently selected from:
0 to 2 halogens, wherein the halogen is independently selected from F and Cl,
0 to 1 —OCH 3 , and
0 to 1 —CH 3 , —CH 2 CH 3 , —CF 3 , or —CH 2 CH 2 OCH 3 .

8. The method of claim 1 , wherein said heteroaryl of R 6 is a monovalent radical of

and wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 halogens,
0 to 1 substituent selected from —OR O and —N(R N ) 2 , and
0 to 2 —C 1-3 alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms, and
0 to 1 —OR O .

9. A method for treating disease or disorder comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound, wherein the compound is

or a pharmaceutically acceptable salt thereof, and wherein the disease or disorder is selected from the group consisting of T2DM, pre-diabetes, malnutrition-rel

Assignees

• Pfizer

Inventors

• Aspnes Gary Erik
• Bagley Scott W
• Curto John M
• Dowling Matthew S
• Edmonds David
• Flanagan Mark E
• Futatsugi Kentaro
• Griffith David A
• Huard Kim
• Ingle Gajendra
• Jiao Wenhua
• Limberakis Chris
• Mathiowetz Alan M
• Piotrowski David W
• Ruggeri Roger B

Classifications

• A61P19/06

  Antigout agents, e.g. antihyperuricemic or uricosuric agents · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title