Therapeutic uses of GLP1r agonists

Abstract

To provide methods of using glucagon-like peptide 1 receptor (GLP1R) agonists.SOLUTION: Provided is a method of lowering glycated hemoglobin levels in a subject, the method comprising administering to a subject in need thereof from 0.1 to 5.0 mg / kg or from 10 to 500 mg daily of a glucagon-like peptide 1 receptor (GLP1R) agonist.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Generally disclosed herein is a method of using glucagon-like peptide 1 receptor (GLP1R) agonist. In certain embodiments, the present disclosure provides a method of treating type II diabetes, comprising administering a GLP1R agonist according to a specific dosage regimen. In certain other embodiments, the present disclosure provides a method of treating obesity, comprising administering a GLP1R agonist according to a specific dosage regimen. In certain other embodiments, the present disclosure provides a method of lowering glycated hemoglobin (e.g., lowering HbA1c), comprising administering a GLP1R agonist according to a specific dosage regimen. Also disclosed herein are compositions containing GLP1R agonists and their manufacture, for example, for use as pharmaceuticals. [Background technology]

[0002] Type II diabetes mellitus (type II diabetes) is a chronic metabolic disease characterized by many symptoms, including but not limited to elevated blood glucose levels, insulin resistance, impaired insulin secretion, and hyperglycemia. Symptoms associated with type II diabetes tend to develop gradually and progressively, worsening and increasing in number as the disease progresses. If unsuccessfully treated, type II diabetes can eventually lead to heart disease, stroke, blindness (due to diabetic retinopathy), kidney failure, and poor blood flow to the extremities (resulting in the need to amputate limbs, such as feet and toes, because they no longer receive adequate blood flow). Type II diabetes and its associated diseases, such as obesity, are major public health problems worldwide.

[0003] The causes of type II diabetes are multifactorial in nature. However, obesity, coupled with lack of physical activity, is a major contributing factor. Genetic factors may also increase the chances of developing type II diabetes. Treatment regimens vary. In many cases, type II diabetes is managed by keeping body weight normal, exercising regularly, and eating properly. However, such measures are often insufficient because they involve lifestyle changes that patients may resist compliance with. Therefore, antidiabetic medications such as metformin are often prescribed. However, metformin therapy often does not affect disease progression in a clinically meaningful way.

[0004] A variety of second-line antidiabetic drugs are also used. Glucagon-like peptide 1 (GLP1) analogs and glucagon-like peptide 1 receptor (GLP1R) agonists are a class of therapy that have shown particular promise in the treatment of diabetes. Non-peptide GLP1R agonists have also been discovered, such as those disclosed in U.S. Pat. No. 7,727,983 and U.S. Pat. No. 8,383,644. Protein-based therapy is generally administered by intravenous injection, which causes some inconvenience and discomfort to the patient. Several protein-based therapeutics have been developed for oral administration. In some instances, oral administration may be a more desirable alternative. Also, some compounds in this class may be amenable to oral administration, although effective regimens for oral delivery are still under development.

[0005] Thus, there is a continuing need to develop effective dosing regimens for the oral delivery of GLP1R agonists. Summary of the Invention

[0006] The present disclosure generally provides a method for treating type II diabetes and related conditions, such as elevated glycated hemoglobin levels, obesity, and lack of glycemic control.It has been surprisingly discovered that certain GLP1R agonists, when administered in vivo, exhibit non-linear dose-dependent activity, where increasing doses show decreasing efficacy after reaching a maximum efficacy point.Therefore, it has been discovered that in some respects, the efficacy of compounds can be improved by using lower doses than expected.This also has the additional benefit of reducing the possibility of side effects in certain subjects.

[0007] In a first aspect, the present invention provides a method of reducing glycated hemoglobin levels in a subject, the method comprising administering to a subject in need thereof 0.1-5.0 mg / kg or 10-500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0008] In a second aspect, the present invention provides a method of treating type II diabetes, the method comprising administering to a subject in need thereof 0.1-5.0 mg / kg or 10-500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0009] In a third aspect, the present invention provides a method of reducing body weight, the method comprising administering to a subject in need thereof between 0.1-5.0 mg / kg or 10-500 mg per day of a glucagon-like peptide 1 receptor (GLP1R) agonist. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0010] In a fourth aspect, the present invention provides a method of treating obesity, the method comprising administering to a subject in need thereof 0.1-5.0 mg / kg or 10-500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0011] In a fifth aspect, the present invention provides a method of improving glycemic control, the method comprising administering 0.1-5.0 mg / kg or 10-500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist to a subject in need thereof. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0012] In a sixth aspect, the present invention provides a glucagon-like peptide 1 receptor (GLP1R) agonist for use in reducing elevated glycated hemoglobin levels in a subject, wherein the GLP1R agonist is administered to the subject in an amount of 0.1 to 5.0 mg / kg or 10 mg to 500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0013] In a seventh aspect, the present invention provides a glucagon-like peptide 1 receptor (GLP1R) agonist for use in treating type II diabetes, wherein the GLP1R agonist is administered to a subject in an amount of 0.1 to 5.0 mg / kg or 10 mg to 500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0014] In an eighth aspect, the present invention provides a glucagon-like peptide 1 receptor (GLP1R) agonist for use in treating obesity, wherein the GLP1R agonist is administered to a subject in an amount of 0.1-5.0 mg / kg or 10-500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0015] In a ninth aspect, the present invention provides a glucagon-like peptide 1 receptor (GLP1R) agonist for use in reducing body weight, wherein the GLP1R agonist is administered to a subject in an amount of 0.1-5.0 mg / kg or 10-500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0016] In a tenth aspect, the present invention provides a glucagon-like peptide 1 receptor (GLP1R) agonist for use in improving glycemic control, wherein the GLP1R agonist is administered to a subject in an amount of 0.1-5.0 mg / kg or 10-500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0017] In an eleventh aspect, the present invention provides the use of a glucagon-like peptide 1 receptor (GLP1R) agonist in the manufacture of a medicament for reducing high levels of glycated hemoglobin in a subject, wherein the medicament is prepared to be administered to the subject in an amount of 0.1 to 5.0 mg / kg or 10 to 500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0018] In a twelfth aspect, the present invention provides the use of a glucagon-like peptide 1 receptor (GLP1R) agonist in the manufacture of a medicament for treating type II diabetes, the medicament being prepared to be administered to a subject in an amount of 0.1-5.0 mg / kg or 10-500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutical acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0019] In a thirteenth aspect, the present invention provides the use of a glucagon-like peptide 1 receptor (GLP1R) agonist in the manufacture of a medicament for treating obesity, wherein the medicament is prepared to be administered to a subject in an amount of 0.1 to 5.0 mg / kg or 10 mg to 500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0020] In a fourteenth aspect, the present invention provides the use of a glucagon-like peptide 1 receptor (GLP1R) agonist in the manufacture of a medicament for reducing elevated body weight, the medicament being prepared for administration to a subject in an amount of 0.1-5.0 mg / kg or 10-500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0021] In a fifteenth aspect, the present invention provides the use of a glucagon-like peptide 1 receptor (GLP1R) agonist in the manufacture of a medicament for improving glycemic control, wherein the medicament is prepared to be administered to a subject in an amount of 0.1-5.0 mg / kg or 10-500 mg / day. In some embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some other embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In one embodiment, the GLP1R agonist is administered orally.

[0022] Other aspects and embodiments are described in the preceding drawings, detailed description, and claims. [Brief description of the drawings]

[0023] [Figure 1] Data points represent change from baseline at week 12 in completer HbA1c (%) by treatment group and dose (mg / kg) (placebo = X, 150 mg once daily (QPM) = ·). [Diagram 2] Data points represent change from baseline at week 12 in completer HbA1c (%) by treatment group and dose (mg / kg) (placebo = X, 150 mg twice daily (BID) = ·). [Diagram 3]Data points represent change from baseline at week 12 in completer fasting plasma glucose (mg / dL) by dose (mg / kg) by treatment group (placebo = X, 150 mg once daily (QPM) = ·). [Figure 4] Data points represent change from baseline at week 12 in completer fasting plasma glucose (mg / dL) by dose (mg / kg) by treatment group (placebo = X, 150 mg twice daily (BID) = ·). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The following description lists various aspects and embodiments of the invention disclosed herein. Specific embodiments are not intended to define the scope of the invention. Rather, the embodiments provide non-limiting examples of various compositions and methods that fall within the scope of the claimed invention. This description should be read from the perspective of a person skilled in the art. Therefore, it does not necessarily include information that is known to a person skilled in the art.

[0025] definition The following terms and phrases have the meanings set forth below unless otherwise specified herein. This disclosure may use other terms and phrases not expressly defined herein. Such other terms and phrases shall have the meanings they would have in the context of this disclosure to one of ordinary skill in the art. In some instances, a term or phrase may be defined in the singular or plural. In such cases, it is understood that any term in the singular form can include its plural counterpart, and vice versa, unless expressly indicated to the contrary.

[0026] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise (e.g., reference to "a substituent" includes a single substituent, as well as two or more substituents, etc.).

[0027] As used herein, "for example," "for instance," "such as," or "including" are meant to introduce examples that further clarify a more general subject matter. Unless otherwise expressly indicated, such examples are provided merely as an aid to understanding the embodiments illustrated in this disclosure and are not meant to be limiting in any manner. Additionally, these phrases do not imply any kind of preference for the disclosed embodiments.

[0028] As used herein, "administer" or "administration" refers to introducing a compound or composition into a subject. This term is not limited to any particular delivery mode, and can include, for example, subcutaneous delivery, intravenous delivery, intramuscular delivery, intracisternal delivery, delivery by injection technique, transdermal delivery, oral delivery, nasal delivery, and rectal delivery. Furthermore, depending on the mode of delivery, administration can be performed by various individuals, including, for example, a medical professional (e.g., a doctor, a nurse, etc.), a pharmacist, or a subject (e.g., self-administration).

[0029] As used herein, "treating" or "treatment" can refer to one or more of: slowing the progression of the disease, disorder or condition; controlling the disease, disorder or condition; alleviating one or more characteristic symptoms of the disease, disorder or condition; or, depending on the nature of the disease, disorder or condition and its characteristic symptoms, delaying the recurrence of the disease, disorder or condition or its characteristic symptoms.

[0030] As used herein, a "subject" refers to any mammal, including, but not limited to, humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, and primates, such as chimpanzees, gorillas, and rhesus monkeys. In some embodiments, a "subject" is a human. In some such embodiments, a "subject" is a human exhibiting one or more conditions characteristic of a disease, disorder, or condition. The term "subject" does not require having a particular status with respect to a hospital, clinic, or research facility (e.g., as an admitted patient, a study participant, etc.).

[0031] As used herein, the term "pharmaceutical composition" is used to indicate a composition which can be administered to a mammalian host, for example, orally, topically, parenterally, by inhalation spray, or rectally, in a unit dosage formulation containing conventional non-toxic carriers, diluents, adjuvants, vehicles and the like; as used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intracisternal injection, or infusion techniques.

[0032] As used herein, the term "pharmaceutical acceptable salts" generally refers to salts of compounds prepared by reacting free bases with suitable organic or inorganic acids, or by reacting acids with suitable organic or inorganic bases. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, Lactobionic acid, lauric acid, malic acid, maleic acid, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate, palmitate, pantothenic acid, phosphate / diphosphate, polygalacturonic acid, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, trimethylammonium, and valerate. When an acidic substituent (e.g., -COOH) is present, ammonium, morpholinium, sodium, potassium, barium, calcium salts, and the like, can be formed for use as dosage forms. When a basic group is present, such as an amino group or a basic heteroaryl radical such as pyridyl, acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate, etc. In certain embodiments, the GLP1R agonist is a hydrochloride salt.In other embodiments, the GLP1R agonist is a tris(hydroxymethyl)aminomethane salt.

[0033] As used herein, the term "mass equivalent" when used in reference to a pharma- ceutically acceptable salt of a compound refers to the equivalent mass of the salt form of the compound required to provide the same molar amount of the compound, for example, the phrase "the mass equivalent of 100 mg of 3-(dimethylamino)propionic acid, or its hydrochloride, in the second part of the phrase, refers to the amount of 3-(dimethylamino)propionic acid hydrochloride required to provide the same molar amount of 3-(dimethylamino)propionic acid as 100 mg of 3-(dimethylamino)propionic acid. Here, the molecular weight of 3-(dimethylamino)propionic acid is 117.15 g / mol, and the molecular weight of 3-(dimethylamino)propionic acid hydrochloride is 153.61 g / mol. Thus, the mass equivalent amount of 3-(dimethylamino)propionic acid hydrochloride to 100 mg of 3-(dimethylamino)propionic acid is 131.12 mg. The same analysis applies when using units such as mg / kg.

[0034] As used herein, the unit term "mg / kg" refers to the mass of compound (measured in mg) administered to a subject per the mass of the subject (measured in kg), e.g., "administering 1.0 mg / kg daily to a subject" refers to administering 170 mg daily to a subject having a mass of 170 kg.

[0035] As used herein, "mixing," "mixed," and "mixture" refer broadly to a combination of two or more compositions. The two or more compositions need not be in the same physical state. Thus, a solid can be "mixed" with a liquid to form a slurry, liquid suspension, or solution. Furthermore, these terms do not require homogeneity or uniformity of the composition. Such a "mixture" can be homogeneous or heterogeneous, uniform or heterogeneous. Furthermore, these terms do not require the use of any particular equipment, such as an industrial mixer, to perform the mixing.

[0036] As used herein, "optionally" means that the event described below may or may not occur. In some embodiments, the optional event does not occur. In some other embodiments, the optional event occurs one or more times.

[0037] As used herein, "comprise" or "comprises" or "including" or "comprising" refers to an open group, meaning that the group can include additional members in addition to those explicitly listed. For example, the phrase "comprises A" means that A must be present, but other members can also be present. The terms "comprise," "have," and "consist of" and their grammatical variations have the same meaning. In contrast, "consist of" or "consist of" or "consist of" refers to a group that is closed.

[0038] As used herein, "or" should be given its broadest reasonable interpretation and should not be limited to any one or the other structure, and thus the phrase "comprising A or B" means that A is present and B is not present, or B is present but A is not present, or both A and B are present. Further, for example, A may include a plurality of members, e.g., A 1 and A 2 When you define a class that can have one or more members of that class, then one or more members of that class can exist at the same time.

[0039] As used herein, the term "glucagon-like peptide 1 receptor agonist" or "GLP1R agonist" refers to a compound that functions as an agonist or partial agonist of the glucagon-like peptide 1 receptor at a given in vivo or in vitro concentration, but may exhibit a secondary (weaker) antagonist of the glucagon-like peptide 1 receptor at certain other concentrations. In some cases, a GLP1R agonist or agonist may be referred to as "protein-based" or "non-protein". As used herein, the term "peptide-based" refers to a compound that includes one or more chains of six or more α-amino acids linked by amide bonds, and the one or more chains of amino acids constitute at least 40% by mass of the compound. As used in this context herein, the term "non-peptide" or "non-protein" refers to a compound that has 40% or less of its mass composed of one or more chains of six or more α-amino acids connected by amide bonds. In some embodiments, the non-protein GLP1R agonist has a molecular weight of 2000 Da or less, or a molecular weight of 1500 Da or less, or a molecular weight of 1200 Da or less.

[0040] Other terms not included in this subsection are defined elsewhere in this specification. Dosing regimens for GLP1R agonists

[0041] In one or more of the foregoing aspects, the present invention provides a method of administering a non-protein GLP1R agonist of a GLP1R agonist to a subject in need thereof. Generally, such methods include administering 0.1-3.0 mg / kg or 10-500 mg daily of a GLP1R agonist to a subject in need thereof. In some aspects and embodiments, the GLP1R agonist is a GLP1R agonist. Any suitable GLP1R agonist or agonist can be used. Suitable non-limiting examples include the compounds listed in U.S. Pat. No. 7,727,983 (e.g., Example 86) and U.S. Pat. No. 8,383,644 (e.g., Example 179).

[0042] In some embodiments of any of the foregoing embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. In some further such embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid. In some other such embodiments, the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2). In some other such embodiments, the GLP1R agonist is any combination of the above.

[0043] In some embodiments of any of the foregoing embodiments, the GLP1R agonist is a mass equivalent of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-propionic acid, a pharma- ceutically acceptable salt thereof, or any combination thereof. In some such embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid. In some other such embodiments, the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid. The agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1). In some other such embodiments, the GLP1R agonist is (S)-3-(4'-cyano- biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid tris(hydroxymethyl)aminomethane salts (1:1). In some other such embodiments, the GLP1R agonist is any combination of the above.

[0044] The administration may be carried out by any suitable delivery means, including but not limited to subcutaneous delivery, intravenous delivery, intramuscular delivery, intracisternal delivery, delivery by injection technique, transdermal delivery, oral delivery, nasal delivery, and rectal delivery.In some embodiments of any of the above-mentioned embodiments, the administration comprises orally administering the GLP1R agonist.Suitable oral dosage forms are described in more detail below.

[0045] The disclosed methods may be performed on any suitable subject, including humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, and primates, such as chimpanzees, gorillas, and rhesus monkeys. In some embodiments of any of the foregoing embodiments, the subject is a human. In the methods disclosed herein, the subject is a subject in need of administration of a GLP1R agonist. The nature of the need depends on the treatment goal. In some embodiments of any of the foregoing embodiments, the subject exhibits high levels of glycated hemoglobin in its blood, e.g., high levels of HbA1c in its blood. In some such embodiments, the administration of the GLP1R agonist is performed to reduce the subject's amount of HbA1c. In some other embodiments of any of the foregoing embodiments, the subject exhibits one or more symptoms consistent with type II diabetes. In some such embodiments, the administration of the GLP1R agonist is performed to treat type II diabetes or type I diabetes (including treating one or more symptoms associated therewith). In some other embodiments of any of the foregoing embodiments, the subject has weight gain, or in some cases, obesity. In some such embodiments, the administration of the GLP1R agonist is performed to reduce weight, treat obesity (including treating one or more symptoms associated therewith), or delay gastric emptying. In some other embodiments of any of the above embodiments, the subject exhibits one or more symptoms consistent with poor glycemic control. In some such embodiments, the administration of the GLP1R agonist is performed to improve glycemic control (including treating one or more symptoms associated therewith).

[0046] As described above, the method includes administering 0.1-5.0 mg / kg of a GLP1R agonist daily. These amounts can be administered in any suitable regimen throughout the day. In some embodiments, administering includes administering the GLP1R agonist one or more times per day, such as once per day, twice per day, three times per day, etc. In some further such embodiments, administering includes administering the GLP1R agonist twice per day. Administration can be with or without food. In some embodiments where administering includes administering the GLP1R agonist one or more times per day, at least one of the one or more times is with food. In some such embodiments, administering includes administering the GLP1R agonist twice per day with food. In some embodiments, two or more daily doses include equal amounts of the GLP1R agonist. In other embodiments, the method comprises administering 0.1-5.0 mg / kg of a GLP1R agonist every other day, or every third day, or every fourth day, or every fifth day, or every sixth day.

[0047] The duration of the method disclosed herein can be carried out for any suitable period depending on the goal of treatment.Since type II diabetes or type I diabetes and its related disorders are chronic conditions, administration can be carried out indefinitely, such as for several years or more, in some embodiments.In some embodiments of any of the above-mentioned embodiments, administering comprises administering GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0048] In some embodiments of any of the above aspects and embodiments, the GLP1R agonist may be co-administered with one or more other antidiabetic drugs in combination with the GLP1R agonist. In this context, the terms "co-administration" and "combined with" do not necessarily mean that the diabetic drug is administered on the same schedule as the GLP1R agonist, after all, in some cases these drugs may only be administered once a day or once a week, so in this context, the terms "co-administration" and "combined with" mean that the drug is administered such that the one or more diabetic drugs have a non-zero blood concentration in the subject when the GLP1R agonist is administered. In some embodiments, the GLP1R agonist and one or more antidiabetic drugs are formulated into the same dosage form, such as a tablet or capsule for oral administration.

[0049] Any suitable antidiabetic agent can be used. For example, in some embodiments, the one or more antidiabetic agents are insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), and the like. In some such embodiments, the one or more antidiabetic agents are selected from the group consisting of: alpha-glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators. In some such embodiments, the one or more antidiabetic agents is metformin.

[0050] In embodiments where metformin is administered in combination with a GLP1R agonist, the co-administration includes oral co-administration of 1 mg to 30 mg of metformin per day to the subject, or oral co-administration of 1 mg to 2,500 mg of metformin per day to the subject. This co-administration can be performed at any suitable dose. In some embodiments, the co-administration includes co-administration of metformin one or more times per day, such as once per day, twice per day, three times per day, four times per day, etc. In some such embodiments, the co-administration includes co-administration of metformin twice per day. In some further such embodiments, the co-administration includes co-administration of metformin twice per day with food. In some embodiments, the two or more daily doses contain equal amounts of metformin.

[0051] As noted above, in certain aspects and embodiments, administering a GLP1R agonist comprises administering 0.1-5.0 mg / kg / day to a subject in need thereof.

[0052] In some further embodiments of any of the foregoing aspects and embodiments, administering the GLP1R agonist comprises administering 0.1 to 2 mass equivalents of the GLP1R agonist (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a pharma- ceutically acceptable salt thereof, or any combination thereof. 0.5 mg / kg / day, or 0.1-2.0 mg / kg / day, or 0.1-1.7 mg / kg / day, or 0.1-1.5 mg / kg / day, or 0.3-3.0 mg / kg / day, or 0.3-2.5 mg / kg / day, or 0.3-2.0 mg / kg / day, or 0.3-1.7 mg / kg / day, or 0.3-1.5 mg / kg / day, or 0.5-3.0 mg / kg / day, or 0.5-2.5 mg / kg / day, or 0.5-2.0 mg / kg / day, or 0.5-1.7 mg / kg / day, or 0.5-1.5 mg / kg / day to a subject in need thereof. In other embodiments, these ranges of GLP1R agonist are administered every other day, or every third day, or every fourth day, or every fifth day, or every sixth day.

[0053] In some other such embodiments, the GLP1R agonist is administered in a manner similar to that described above, where the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutical acceptable salt thereof, or any combination thereof. The method includes administering to a human subject in need thereof 10-200 mg / day, or 10-175 mg / day, or 10-150 mg / day, or 10-125 mg / day, or 10-100 mg / day, or 20-200 mg / day, or 20-175 mg / day, or 20-150 mg / day, or 20-125 mg / day, or 20-100 mg / day, or 30-200 mg / day, or 30-175 mg / day, or 30-150 mg / day, or 30-125 mg / day, or 30-100 mg / day of a GLP1R agonist. In other embodiments, these amounts of a GLP1R agonist are administered every other day, or every third day, or every fourth day, or every fifth day, or every sixth day.

[0054] In some further embodiments of any of the aforementioned aspects and embodiments, the mass equivalent of the GLP1R agonist (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a pharma- ceutically acceptable salt thereof, or any combination thereof, is administered at a dose of 1.0 to 5.0 mg / kg / day, or 1.1 to 4.9 mg / kg / day, or 1.2 to 4.8 mg / kg / day. g / day, or 1.3-4.7 mg / kg / day, or 1.4 mg-4.6 mg / kg / day, or 1.5-4.5 mg / kg / day, or 2.0-4.5 mg / kg / day, or 2.1-4.5 mg / kg / day, or 2.2-4.5 mg / kg / day, or 2.3-4.5 mg / kg / day, or 2.8-4.5 mg / kg / day, or 2.8-4.1 mg / kg / day, or 2.8-4.0 mg / kg / day to a subject in need thereof. In other embodiments, the GLP1R agonist in these ranges is administered every other day, or every third day, or every fourth day, or every fifth day, or every sixth day.

[0055] In some other embodiments where the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutical acceptable salt thereof, or any combination thereof, administering the GLP1R agonist This includes administering to a human subject in need thereof 25-450 mg per day, or 50-425 mg per day, or 50-400 mg per day, or 200-400 mg daily, or 250-450 mg per day, or 250-350 mg per day, or 50-350 mg per day, or 50-300 mg per day, or 100-300 mg per day. In other embodiments, these amounts of GLP1R agonist are administered every other day, or every third day, or every fourth day, or every fifth day, or every sixth day.

[0056] As noted above, in certain aspects and embodiments, administering metformin comprises co-administering 1-30 mg / kg per day to a subject in need thereof. In some further embodiments of any of the foregoing aspects and embodiments, co-administering metformin comprises administering 1-25 mg / kg per day, or 1-20 mg / kg per day, or 1-18 mg / kg per day, or 1-16 mg / kg per day, or 3-25 mg / kg per day, or 3-20 mg / kg per day, or 3-18 mg / kg per day, or 3-16 mg / kg per day, or 5-25 mg / kg per day, or 5-20 mg / kg per day, or 5-18 mg / kg per day, or 5-16 mg / kg per day of metformin to a subject in need thereof. In some other such embodiments, metformin co-administration comprises co-administering to a human subject in need thereof 100-1500 mg / day, or 100-1400 mg / day, or 100-1300 mg / day, or 100-1200 mg / day, or 200-1500 mg / day, or 200-1400 mg / day, or 200-1300 mg / day, or 200-1200 mg / day, or 300-1500 mg / day, or 300-1400 mg / day, or 300-1300 mg / day, or 300-1200 mg / day. Use for lowering glycated hemoglobin

[0057] The above method is described as a general method. In some embodiments of any of the above aspects and embodiments, the method is a method of reducing the glycosylated hemoglobin level in a subject. In some further such embodiments, reducing the glycosylated hemoglobin amount (level) comprises reducing the HbA1c amount in a subject. For example, in some embodiments, reducing the glycosylated hemoglobin level comprises reducing the HbA1c level in a subject by at least 0.3% absolute amount, at least 0.5% absolute amount, at least 0.7% absolute amount, at least 0.9% absolute amount, or at least 1.0% absolute amount, where HbA1c level is measured as a percentage according to the National Glycohemoglobin Standardization Program (NGSP) protocol.

[0058] In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a GLP1R agonist for use in reducing elevated glycated hemoglobin levels in a subject according to any of the above embodiments.In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a use of a GLP1R agonist in the manufacture of a medicament for reducing elevated levels of glycated hemoglobin in a subject, wherein the medicament is prepared to be administered to the subject according to any of the methods described above. Use for the treatment of type II diabetes

[0059] The above methods are described as general methods. In some embodiments of any of the above aspects and embodiments, the method is a method of treating type II diabetes.

[0060] In some other embodiments of any of the above aspects and embodiments, the disclosure provides a GLP1R agonist for use in treating type II diabetes according to any of the above embodiments. In some other embodiments of any of the above aspects and embodiments, the disclosure provides a use of a GLP1R agonist in the manufacture of a medicament for treating type II diabetes, wherein the medicament is prepared for administration to a subject according to any of the above methods. Use for the treatment of obesity, weight loss, or delayed gastric emptying

[0061] The above methods are described as general methods. In some embodiments of any of the above aspects and embodiments, the method is a method for treating obesity, or a method for reducing weight or body mass, or a method for delaying gastric emptying.

[0062] In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a GLP1R agonist for use in treating obesity or reducing body weight or body mass, or delaying gastric emptying according to any of the above embodiments.In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a GLP1R agonist in the manufacture of a medicament for treating obesity or reducing body weight or body mass, or delaying gastric emptying, which is prepared to be administered to a subject according to any of the above methods. Use for improving glycemic control

[0063] The above methods are described as general methods. In some embodiments of any of the aforementioned aspects and embodiments, the method is a method for improving glycemic control.

[0064] In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a GLP1R agonist for use in improving glycemic control according to any of the above embodiments. In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a use of a GLP1R agonist in the manufacture of a medicament for improving glycemic control, wherein the medicament is prepared to be administered to a subject according to any of the above methods. Use to lower fasting blood sugar levels

[0065] The above method is described as a general method.In some embodiments of any of the above aspects and embodiments, the method is a method for reducing fasting plasma glucose (FPG), for example, in a subject in need thereof, for example, in a subject with elevated FPG.

[0066] In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a GLP1R agonist for use in reducing FPG according to any of the above embodiments. In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a use of a GLP1R agonist in the manufacture of a medicament for reducing FPG, wherein the medicament is prepared for administration to a subject according to any of the above procedures. Use to reduce systolic blood pressure

[0067] The above method is described as a general method.In some embodiments of any of the above aspects and embodiments, the method is a method for reducing systolic blood pressure, for example, in a subject in need thereof (for example, a subject with elevated systolic blood pressure).

[0068] In some other embodiments of any of the above aspects and embodiments, the present disclosure provides a GLP1R agonist for use in reducing systolic blood pressure according to any of the above embodiments. In some other embodiments of any of the above aspects and embodiments, the present invention provides the use of a GLP1R agonist in the manufacture of a medicament for reducing systolic blood pressure, wherein the medicament is prepared to be administered to a subject according to any of the above methods. Dosage forms of pharmaceutical compositions

[0069] The GLP1R agonist can be formulated into any suitable pharmaceutical composition. As used herein, the term "pharmaceutical composition" refers to a composition (e.g., granulated powder or liquid) that contains a pharma- ceutically active ingredient (e.g., a GLP1R agonist) and a pharma- ceutically acceptable carrier. As used herein, the term "pharmaceutical acceptable" refers to a substance that is not generally biologically undesirable in the amount administered. In some embodiments, the GLP1R agonist is included in a separate pharmaceutical composition from any co-administered antidiabetic agent (e.g., metformin), each of which also includes a pharma- ceutically acceptable carrier. In other embodiments, the GLP1R agonist is included in the same pharmaceutical composition as one or more co-administered antidiabetic agents (e.g., metformin), which also includes a pharma- ceutically acceptable carrier.

[0070] The pharmaceutical compositions described herein can be packaged in a form for oral administration as a separate unit (i.e., dosage form), such as capsule, tablet, sachet, etc. Preparation of solid compositions in a form intended for oral administration is within the capabilities of a person skilled in the art, including the selection of pharma- ceutically acceptable additional ingredients from the groups listed above to provide a pharma- ceutically elegant and palatable preparation. Such pharmaceutical compositions can be prepared by methods known in the pharmaceutical formulation art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. (Mack Publishing Company, Easton, PA, 1990)). Embodiment

[0071] In addition to, or in further illustration of, the various aspects and embodiments described above, the present disclosure provides methods, uses and the like as described in the following embodiments.

[0072] (First embodiment) A method for reducing glycated hemoglobin levels in a subject, the method comprising administering to a subject in need thereof between 0.1 to 5.0 mg / kg or 10 to 500 mg of a glucagon-like peptide 1 receptor (GLP1R) agonist per day.

[0073] (Second embodiment) The method of embodiment 1, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0074] (Embodiment 3) The method of embodiment 2, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0075] (Embodiment 4) The method of embodiment 2, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0076] (Fifth embodiment) The GLP1R agonist is a mixture of (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 3. The method of embodiment 2, wherein the compound is a combination of 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0077] (Embodiment 6) The method of embodiment 1, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0078] (Embodiment 7) The method of embodiment 6, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0079] (Embodiment 8) The method of embodiment 6, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0080] (9th embodiment) The GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 7. The method of embodiment 6, wherein the aryl ester is in combination with 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0081] (10th embodiment) The method of any one of embodiments 1 to 9, wherein the administering comprises orally administering the GLP1R agonist.

[0082] (11th embodiment) The method of any one of embodiments 1 to 10, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0083] (12th embodiment) The method of any one of embodiments 1 to 11, wherein the subject is a human.

[0084] (13th embodiment) The method of any one of embodiments 1 to 12, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0085] (14th embodiment) The method of embodiment 13, wherein at least one of the one or more doses is administered with food.

[0086] (15th embodiment) The method of embodiment 13, wherein the administering comprises administering the GLP1R agonist twice daily.

[0087] (16th embodiment) The method of embodiment 15, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0088] (17th embodiment) The method of any one of embodiments 1 to 16, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0089] (18th embodiment) The method of any one of embodiments 1 to 17, further comprising co-administering to the subject one or more antidiabetic agents in combination with said GLP1R agonist.

[0090] (19th embodiment) The one or more antidiabetic drugs are insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), α-glutamate, ... 19. The method of embodiment 18, wherein the therapeutic agent is selected from the group consisting of glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0091] (20th embodiment) The method of embodiment 19, wherein the one or more antidiabetic drugs is metformin.

[0092] (21st embodiment) The method of embodiment 20, wherein the co-administration comprises orally co-administering 1 to 30 mg / kg of metformin per day to the subject.

[0093] (22nd embodiment) The method of embodiment 21, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, or four times per day.

[0094] (23rd embodiment) The method of embodiment 22, wherein the co-administration comprises co-administering metformin twice daily.

[0095] (24th embodiment) The method of embodiment 23, wherein the co-administration comprises co-administering metformin twice daily with food.

[0096] (25th embodiment) The method of any one of embodiments 1 to 24, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1 to 2.5 mg / kg / day, or 0.1 to 2.0 mg / kg / day, or 0.1 to 1.7 mg / kg / day, or 0.1 to 1.5 mg / kg / day, or 0.3 to 3.0 mg / kg / day, or 0.3 to 2.5 mg / kg / day, or 0.3 to 2.0 mg / kg / day, or 0.3 to 1.7 mg / kg / day, or 0.3 to 1.5 mg / kg / day, or 0.5 to 3.0 mg / kg / day, or 0.5 to 2.5 mg / kg / day, or 0.5 to 2.0 mg / kg / day, or 0.5 to 1.7 mg / kg / day, or 0.5 to 1.5 mg / kg / day.

[0097] (26th embodiment) The method of any one of embodiments 1 to 25, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10 to 200 mg / day, or 10 to 175 mg / day, or 10 to 150 mg / day, or 10 to 125 mg / day, or 10 to 100 mg / day, or 20 to 200 mg / day, or 20 to 175 mg / day, or 20 to 150 mg / day, or 20 to 125 mg / day, or 20 to 100 mg / day, or 30 to 200 mg / day, or 30 to 175 mg / day, or 30 to 150 mg / day, or 30 to 125 mg / day, or 30 to 100 mg / day of the GLP1R agonist.

[0098] (27th embodiment) The method of any one of embodiments 1-26, wherein the co-administering metformin comprises co-administering 1-25 mg / kg / day, or 1-20 mg / kg / day, or 1-18 mg / kg / day, or 1-16 mg / kg / day, or 3-25 mg / kg / day, or 3-20 mg / kg / day, or 3-18 mg / kg / day, or 3-16 mg / kg / day, or 5-25 mg / kg / day, or 5-20 mg / kg / day, or 5-18 mg / kg / day, or 5-16 mg / kg / day of metformin to a subject in need thereof.

[0099] (28th embodiment) The method of any one of embodiments 1 to 27, wherein the co-administration of metformin comprises co-administering 100 to 1500 mg / day, or 100 to 1400 mg / day, or 100 to 1300 mg / day, or 100 to 1200 mg / day, or 200 to 1500 mg / day, or 200 to 1400 mg / day, or 200 to 1300 mg / day, or 200 to 1200 mg / day, or 300 to 1500 mg / day, or 300 to 1400 mg / day, or 300 to 1300 mg / day, or 300 to 1200 mg / day of metformin to a human subject in need thereof.

[0100] (29th embodiment) The method of any one of embodiments 1 to 28, wherein reducing glycated hemoglobin levels comprises reducing HbA1c levels in the subject.

[0101] (Thirtieth embodiment) The method of embodiment 29, wherein reducing the glycated hemoglobin level comprises reducing the HbA1c level in the subject by at least 0.3% absolute amount, at least 0.5% absolute amount, at least 0.7% absolute amount, at least 0.9% absolute amount, or at least 1.0% absolute amount, wherein the HbA1c level is measured as a percentage according to the National Glycohemoglobin Standardization Program (NGSP) protocol.

[0102] (Thirty-first embodiment) A method for treating type II diabetes, comprising administering 0.1 to 5.0 mg / kg or 10 to 500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist to a subject in need thereof.

[0103] (32nd embodiment) The method of embodiment 31, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0104] (33rd embodiment) The method of embodiment 32, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0105] (34th embodiment) The method of embodiment 32, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0106] (35th embodiment) The GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 33. The method of embodiment 32, wherein the aryl ester is 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0107] (36th embodiment) The method of embodiment 31, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0108] (37th embodiment) The method of embodiment 36, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0109] (38th embodiment) The method of embodiment 36, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0110] (39th embodiment) The GLP1R agonist is selected from the group consisting of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 37. The method of embodiment 36, wherein the aryl ester is in combination with 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0111] (40th embodiment) The method of any one of embodiments 31 to 39, wherein the administering comprises orally administering the GLP1R agonist.

[0112] (41st embodiment) The method of any one of embodiments 31 to 40, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0113] (42nd embodiment) The method of any one of embodiments 31 to 41, wherein the subject is a human.

[0114] (43rd embodiment) The method of any one of embodiments 31 to 42, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0115] (44th embodiment) The method of embodiment 43, wherein at least one of the one or more doses is administered with food.

[0116] (45th embodiment) The method of embodiment 43, wherein the administering comprises administering the GLP1R agonist twice daily.

[0117] (46th embodiment) The method of embodiment 45, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0118] (47th embodiment) The method of any one of embodiments 31 to 46, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0119] (48th embodiment) The method of any one of embodiments 31 to 47, further comprising co-administering to the subject one or more antidiabetic agents in combination with the GLP1R agonist.

[0120] (49th embodiment) The one or more antidiabetic drugs are selected from the group consisting of insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), alpha-glutamate, ... 49. The method of embodiment 48, wherein the therapeutic agent is selected from the group consisting of glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0121] (50th embodiment) The method of embodiment 49, wherein the one or more antidiabetic drugs is metformin.

[0122] (51st embodiment) The method of embodiment 50, wherein the co-administration comprises oral co-administration of 1 to 30 mg / kg of metformin per day to the subject.

[0123] (52nd embodiment) The method of embodiment 51, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, four times per day, etc.

[0124] (53rd embodiment) The method of embodiment 52, wherein the co-administration comprises co-administering metformin twice daily.

[0125] (54th embodiment) The method of embodiment 53, wherein the co-administration comprises co-administering metformin twice daily with food.

[0126] (55th embodiment) The method of any one of embodiments 31 to 54, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1 to 2.5 mg / kg / day, or 0.1 to 2.0 mg / kg / day, or 0.1 to 1.7 mg / kg / day, or 0.1 to 1.5 mg / kg / day, or 0.3 to 3.0 mg / kg / day, or 0.3 to 2.5 mg / kg / day, or 0.3 to 2.0 mg / kg / day, or 0.3 to 1.7 mg / kg / day, or 0.3 to 1.5 mg / kg / day, or 0.5 to 3.0 mg / kg / day, or 0.5 to 2.5 mg / kg / day, or 0.5 to 2.0 mg / kg / day, or 0.5 to 1.7 mg / kg / day, or 0.5 to 1.5 mg / kg / day of the GLP1R agonist.

[0127] (56th embodiment) The method of any one of embodiments 31 to 55, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10 to 200 mg / day, or 10 to 175 mg / day, or 10 to 150 mg / day, or 10 to 125 mg / day, or 10 to 100 mg / day, or 20 to 200 mg / day, or 20 to 175 mg / day, or 20 to 150 mg / day, or 20 to 125 mg / day, or 20 to 100 mg / day, or 30 to 200 mg / day, or 30 to 175 mg / day, or 30 to 150 mg / day, or 30 to 125 mg / day, or 30 to 100 mg / day of the GLP1R agonist.

[0128] (57th embodiment) The method of any one of embodiments 31-56, wherein co-administering metformin comprises administering to a subject in need thereof 1-25 mg / kg / day, or 1-20 mg / kg / day, or 1-18 mg / kg / day, or 1-16 mg / kg / day, or 3-25 mg / kg / day, or 3-20 mg / kg / day, or 3-18 mg / kg / day, or 3-16 mg / kg / day, or 5-25 mg / kg / day, or 5-20 mg / kg / day, or 5-18 mg / kg / day, or 5-16 mg / kg / day of metformin.

[0129] (58th embodiment) The method of any one of embodiments 31 to 57, wherein the metformin co-administration comprises administering 100 to 1500 mg / day, or 100 to 1400 mg / day, or 100 to 1300 mg / day, or 100 to 1200 mg / day, or 200 to 1500 mg / day, or 200 to 1400 mg / day, or 200 to 1300 mg / day, or 200 to 1200 mg / day, or 300 to 1500 mg / day, or 300 to 1400 mg / day, or 300 to 1300 mg / day, or 300 to 1200 mg / day of metformin to a human subject in need thereof.

[0130] (59th embodiment) A method for reducing body weight, comprising administering to a subject in need thereof between 0.1 to 3.0 mg / kg or 10 to 500 mg of a glucagon-like peptide 1 receptor (GLP1R) agonist per day.

[0131] (60th embodiment) The method of embodiment 59, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0132] (61st embodiment) The method of embodiment 60, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0133] (62nd embodiment) The method of embodiment 60, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0134] (63rd embodiment) The GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 61. The method of embodiment 60, wherein the compound is in combination with 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0135] (64th embodiment) The GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof. The method of embodiment 59, wherein the method is a combination.

[0136] (65th embodiment) The method of embodiment 64, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0137] (66th embodiment) The method of embodiment 64, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0138] (67th embodiment) The GLP1R agonist is selected from the group consisting of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 65. The method of embodiment 64, wherein the aryl ester is 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0139] (68th embodiment) The method of any one of embodiments 59 to 67, wherein the administering comprises orally administering the GLP1R agonist.

[0140] (69th embodiment) The method of any one of embodiments 59 to 68, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0141] (70th embodiment) The method of any one of embodiments 59 to 69, wherein the subject is a human.

[0142] (71st embodiment) The method of any one of embodiments 59 to 70, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0143] (72nd embodiment) The method of embodiment 71, wherein at least one of the one or more doses is administered with food.

[0144] (73rd embodiment) The method of embodiment 71, wherein the administering comprises administering the GLP1R agonist twice daily.

[0145] (74th embodiment) The method of embodiment 73, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0146] (75th embodiment) The method of any one of embodiments 59 to 74, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0147] (76th embodiment) The method of any one of embodiments 59 to 75, further comprising co-administering to the subject one or more antidiabetic agents in combination with the GLP1R agonist.

[0148] (77th embodiment) The one or more antidiabetic drugs are insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), alpha-glutamate, ... 77. The method of embodiment 76, wherein the therapeutic agent is selected from the group consisting of glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0149] (78th embodiment) The method of embodiment 77, wherein the one or more antidiabetic drugs is metformin.

[0150] (79th embodiment) The method of embodiment 78, wherein the co-administration comprises oral co-administration of 1 to 30 mg / kg of metformin per day to the subject.

[0151] (80th embodiment) The method of embodiment 79, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, four times per day, etc.

[0152] (81st embodiment) The method of embodiment 80, wherein the co-administration comprises co-administering metformin twice daily.

[0153] (82nd embodiment) The method of embodiment 81, wherein the co-administration comprises co-administering metformin twice daily with food.

[0154] (Embodiment 83) The method of any one of embodiments 59 to 82, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1 to 2.5 mg / kg / day, or 0.1 to 2.0 mg / kg / day, or 0.1 to 1.7 mg / kg / day, or 0.1 to 1.5 mg / kg / day, or 0.3 to 3.0 mg / kg / day, or 0.3 to 2.5 mg / kg / day, or 0.3 to 2.0 mg / kg / day, or 0.3 to 1.7 mg / kg / day, or 0.3 to 1.5 mg / kg / day, or 0.5 to 3.0 mg / kg / day, or 0.5 to 2.5 mg / kg / day, or 0.5 to 2.0 mg / kg / day, or 0.5 to 1.7 mg / kg / day, or 0.5 to 1.5 mg / kg / day of the GLP1R agonist.

[0155] (84th embodiment) The method of any one of embodiments 59 to 83, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10 to 200 mg / day, or 10 to 175 mg / day, or 10 to 150 mg / day, or 10 to 125 mg / day, or 10 to 100 mg / day, or 20 to 200 mg / day, or 20 to 175 mg / day, or 20 to 150 mg / day, or 20 to 125 mg / day, or 20 to 100 mg / day, or 30 to 200 mg / day, or 30 to 175 mg / day, or 30 to 150 mg / day, or 30 to 125 mg / day, or 30 to 100 mg / day of the GLP1R agonist.

[0156] (85th embodiment) The method of any one of embodiments 59-84, wherein co-administering metformin comprises administering to a subject in need thereof 1-25 mg / kg / day, or 1-20 mg / kg / day, or 1-18 mg / kg / day, or 1-16 mg / kg / day, or 3-25 mg / kg / day, or 3-20 mg / kg / day, or 3-18 mg / kg / day, or 3-16 mg / kg / day, or 5-25 mg / kg / day, or 5-20 mg / kg / day, or 5-18 mg / kg / day, or 5-16 mg / kg / day of metformin.

[0157] (86th embodiment) The method of any one of embodiments 59 to 85, wherein the metformin co-administration comprises co-administering 100 to 1500 mg / day, or 100 to 1400 mg / day, or 100 to 1300 mg / day, or 100 to 1200 mg / day, or 200 to 1500 mg / day, or 200 to 1400 mg / day, or 200 to 1300 mg / day, or 200 to 1200 mg / day, or 300 to 1500 mg / day, or 300 to 1400 mg / day, or 300 to 1300 mg / day, or 300 to 1200 mg / day of metformin to a human subject in need thereof.

[0158] (87th embodiment) A method for treating obesity, comprising administering to a subject in need thereof 0.1 to 3.0 mg / kg or 10 to 500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist.

[0159] (88th embodiment) The method of embodiment 87, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0160] (89th embodiment) The method of embodiment 88, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0161] (90th embodiment) The method of embodiment 88, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0162] (91st embodiment) The GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 89. The method of embodiment 88, wherein the compound is in combination with 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0163] (92nd embodiment) The method of embodiment 87, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0164] (93rd embodiment) The method of embodiment 92, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0165] (94th embodiment) The method of embodiment 92, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0166] (95th embodiment) The GLP1R agonist is selected from the group consisting of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 93. The method of embodiment 92, wherein the aryl ester is 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0167] (96th embodiment) The method of any one of embodiments 87 to 95, wherein the administering comprises orally administering the GLP1R agonist.

[0168] (97th embodiment) The method of embodiments 87 to 96, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0169] (98th embodiment) The method of any one of embodiments 87 to 97, wherein the subject is a human.

[0170] (99th embodiment) The method of any one of embodiments 87 to 98, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0171] (100th embodiment) The method of embodiment 99, wherein at least one of the one or more doses is administered with food.

[0172] (101st embodiment) The method of embodiment 99, wherein the administering comprises administering the GLP1R agonist twice daily.

[0173] (102nd embodiment) The method of embodiment 101, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0174] (103rd embodiment) Any one of the methods of embodiments 87 to 102, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0175] (104th embodiment) The method of any one of embodiments 87 to 103, further comprising co-administering to the subject one or more antidiabetic agents in combination with said GLP1R agonist.

[0176] (105th embodiment) The one or more antidiabetic drugs are insulin, insulin analogs (insulin Insulin glulispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose, ribavirin ... 105. The method of embodiment 104, wherein the therapeutic agent is selected from the group consisting of: glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0177] (106th embodiment) The method of embodiment 105, wherein the one or more antidiabetic drugs is metformin.

[0178] (107th embodiment) The method of embodiment 106, wherein the co-administration comprises oral co-administration of 1 to 30 mg / kg of metformin per day to the subject.

[0179] (108th embodiment) The method of embodiment 107, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, four times per day, etc.

[0180] (Embodiment 109) The method of embodiment 108, wherein the co-administration comprises co-administering metformin twice daily.

[0181] (Embodiment 110) The method of embodiment 109, wherein the co-administration comprises co-administering metformin twice daily with food.

[0182] (111th embodiment) The method of any one of embodiments 87 to 110, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1 to 2.5 mg / kg / day, or 0.1 to 2.0 mg / kg / day, or 0.1 to 1.7 mg / kg / day, or 0.1 to 1.5 mg / kg / day, or 0.3 to 3.0 mg / kg / day, or 0.3 to 2.5 mg / kg / day, or 0.3 to 2.0 mg / kg / day, or 0.3 to 1.7 mg / kg / day, or 0.3 to 1.5 mg / kg / day, or 0.5 to 3.0 mg / kg / day, or 0.5 to 2.5 mg / kg / day, or 0.5 to 2.0 mg / kg / day, or 0.5 to 1.7 mg / kg / day, or 0.5 to 1.5 mg / kg / day.

[0183] (112th embodiment) The method of any one of embodiments 87-111, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10-200 mg / day, or 10-175 mg / day, or 10-150 mg / day, or 10-125 mg / day, or 10-100 mg / day, or 20-200 mg / day, or 20-175 mg / day, or 20-150 mg / day, or 20-125 mg / day, or 20-100 mg / day, or 30-200 mg / day, or 30-175 mg / day, or 30-150 mg / day, or 30-125 mg / day, or 30-100 mg / day of the GLP1R agonist.

[0184] (113th embodiment) The method of any one of embodiments 87-112, wherein the co-administering comprises administering to a subject in need thereof 1 to 25 mg / kg / day, or 1 to 20 mg / kg / day, or 1 to 18 mg / kg / day, or 1 to 16 mg / kg / day, or 3 to 25 mg / kg / day, or 3 to 20 mg / kg / day, or 3 to 18 mg / kg / day, or 3 to 16 mg / kg / day, or 5 to 25 mg / kg / day, or 5 to 20 mg / kg / day, or 5 to 18 mg / kg / day, or 5 to 16 mg / kg / day of metformin.

[0185] (114th embodiment) The method of any one of embodiments 87-113, wherein the co-administration of metformin comprises co-administering 100-1500 mg / day, or 100-1400 mg / day, or 100-1300 mg / day, or 100-1200 mg / day, or 200-1500 mg / day, or 200-1400 mg / day, or 200-1300 mg / day, or 200-1200 mg / day, or 300-1500 mg / day, or 300-1400 mg / day, or 300-1300 mg / day, or 300-1200 mg / day of metformin to a human subject in need thereof.

[0186] (115th embodiment) A method for improving glycemic control, comprising administering to a subject in need thereof 0.1 to 3.0 mg / kg or 10 to 500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist.

[0187] (116th embodiment) The method of embodiment 115, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0188] (117th embodiment) The method of embodiment 116, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0189] (118th embodiment) The method of embodiment 116, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0190] (119th embodiment) The GLP1R agonist is selected from the group consisting of (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 117. The method of embodiment 116, wherein the compound is in combination with 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0191] (120th embodiment) The method of embodiment 115, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0192] (121st embodiment) The method of embodiment 120, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0193] (122nd embodiment) The method of embodiment 120, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0194] (123rd embodiment) The GLP1R agonist is selected from the group consisting of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 121. The method of embodiment 120, wherein the aryl ester is 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0195] (124th embodiment) The method of any one of embodiments 115 to 123, wherein the administering comprises orally administering the GLP1R agonist.

[0196] (125th embodiment) The method of embodiments 115-124, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0197] (126th embodiment) The method of any one of embodiments 115 to 125, wherein the subject is a human.

[0198] (127th embodiment) The method of any one of embodiments 115 to 126, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0199] (Embodiment 128) The method of embodiment 127, wherein at least one of the one or more doses is administered with food.

[0200] (129th embodiment) The method of embodiment 127, wherein the administering comprises administering the GLP1R agonist twice daily.

[0201] (Embodiment 130) The method of embodiment 129, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0202] (131st embodiment) Any one of the methods of embodiments 115 to 130, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0203] (132nd embodiment) The method of any one of embodiments 115 to 131, further comprising co-administering to the subject one or more antidiabetic agents in combination with said GLP1R agonist.

[0204] (133rd embodiment) The one or more antidiabetic agents are insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), alpha-glutamate, ... The method of embodiment 132, wherein the therapeutic agent is selected from the group consisting of glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0205] (134th embodiment) The method of embodiment 133, wherein the one or more antidiabetic drugs is metformin.

[0206] (135th embodiment) The method of embodiment 134, wherein the co-administration comprises oral co-administration of 1 to 30 mg / kg of metformin per day to the subject.

[0207] (136th embodiment) The method of embodiment 135, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, four times per day, etc.

[0208] (137th embodiment) The method of embodiment 136, wherein the co-administration comprises co-administering metformin twice daily.

[0209] (138th embodiment) The method of embodiment 137, wherein the co-administration comprises co-administering metformin twice daily with food.

[0210] (139th embodiment) The method of any one of embodiments 115-138, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1-2.5 mg / kg / day, or 0.1-2.0 mg / kg / day, or 0.1-1.7 mg / kg / day, or 0.1-1.5 mg / kg / day, or 0.3-3.0 mg / kg / day, or 0.3-2.5 mg / kg / day, or 0.3-2.0 mg / kg / day, or 0.3-1.7 mg / kg / day, or 0.3-1.5 mg / kg / day, or 0.5-3.0 mg / kg / day, or 0.5-2.5 mg / kg / day, or 0.5-2.0 mg / kg / day, or 0.5-1.7 mg / kg / day, or 0.5-1.5 mg / kg / day.

[0211] (140th embodiment) The method of any one of embodiments 115-139, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10-200 mg / day, or 10-175 mg / day, or 10-150 mg / day, or 10-125 mg / day, or 10-100 mg / day, or 20-200 mg / day, or 20-175 mg / day, or 20-150 mg / day, or 20-125 mg / day, or 20-100 mg / day, or 30-200 mg / day, or 30-175 mg / day, or 30-150 mg / day, or 30-125 mg / day, or 30-100 mg / day of the GLP1R agonist.

[0212] (141st embodiment) The method of any one of embodiments 115-140, wherein co-administering metformin comprises administering to a subject in need thereof 1-25 mg / kg / day, or 1-20 mg / kg / day, or 1-18 mg / kg / day, or 1-16 mg / kg / day, or 3-25 mg / kg / day, or 3-20 mg / kg / day, or 3-18 mg / kg / day, or 3-16 mg / kg / day, or 5-25 mg / kg / day, or 5-20 mg / kg / day, or 5-18 mg / kg / day, or 5-16 mg / kg / day of metformin.

[0213] (142nd embodiment) The method of any one of embodiments 115-141, wherein the co-administering metformin comprises co-administering 100-1500 mg / day, or 100-1400 mg / day, or 100-1300 mg / day, or 100-1200 mg / day, or 200-1500 mg / day, or 200-1400 mg / day, or 200-1300 mg / day, or 200-1200 mg / day, or 300-1500 mg / day, or 300-1400 mg / day, or 300-1300 mg / day, or 300-1200 mg / day of metformin to a human subject in need thereof.

[0214] (143rd embodiment) A method for lowering fasting plasma glucose (FPG), comprising administering to a subject in need thereof between 0.1 to 3.0 mg / kg or 10 to 500 mg of a glucagon-like peptide 1 receptor (GLP1R) agonist per day.

[0215] (144th embodiment) The method of embodiment 143, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0216] (145th embodiment) The method of embodiment 144, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0217] (146th embodiment) The method of embodiment 144, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0218] (147th embodiment) The GLP1R agonist is selected from the group consisting of (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 145. The method of embodiment 144, wherein the compound is in combination with 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0219] (148th embodiment) The method of embodiment 143, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0220] (149th embodiment) The method of embodiment 148, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0221] (150th embodiment) The method of embodiment 148, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0222] (151st embodiment) The GLP1R agonist is selected from the group consisting of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 149. The method of embodiment 148, wherein the aryl ester is 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0223] (152nd embodiment) The method of any one of embodiments 143 to 151, wherein the administering comprises orally administering the GLP1R agonist.

[0224] (153rd embodiment) The method of embodiments 143 to 152, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0225] (154th embodiment) The method of any one of embodiments 143 to 153, wherein the subject is a human.

[0226] (155th embodiment) The method of any one of embodiments 143 to 154, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0227] (156th embodiment) The method of embodiment 155, wherein at least one of the one or more doses is administered with food.

[0228] (157th embodiment) The method of embodiment 155, wherein the administering comprises administering the GLP1R agonist twice daily.

[0229] (158th embodiment) The method of embodiment 157, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0230] (159th embodiment) The method of any one of embodiments 143 to 158, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0231] (160th embodiment) The method of any one of embodiments 143 to 159, further comprising co-administering to the subject one or more antidiabetic agents in combination with said GLP1R agonist.

[0232] (161st embodiment) The one or more antidiabetic drugs are insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), alpha-glutamate, ... The method of embodiment 160, wherein the agent is selected from the group consisting of glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0233] (162nd embodiment) The method of embodiment 161, wherein the one or more antidiabetic drugs is metformin.

[0234] (163rd embodiment) The method of embodiment 162, wherein the co-administration comprises oral co-administration of 1 to 30 mg / kg of metformin per day to the subject.

[0235] (164th embodiment) The method of embodiment 163, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, four times per day, etc.

[0236] (165th embodiment) The method of embodiment 164, wherein the co-administration comprises co-administering metformin twice daily.

[0237] (166th embodiment) The method of embodiment 165, wherein the co-administration comprises co-administering metformin twice daily with food.

[0238] (167th embodiment) The method of any one of embodiments 143 to 166, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1 to 2.5 mg / kg / day, or 0.1 to 2.0 mg / kg / day, or 0.1 to 1.7 mg / kg / day, or 0.1 to 1.5 mg / kg / day, or 0.3 to 3.0 mg / kg / day, or 0.3 to 2.5 mg / kg / day, or 0.3 to 2.0 mg / kg / day, or 0.3 to 1.7 mg / kg / day, or 0.3 to 1.5 mg / kg / day, or 0.5 to 3.0 mg / kg / day, or 0.5 to 2.5 mg / kg / day, or 0.5 to 2.0 mg / kg / day, or 0.5 to 1.7 mg / kg / day, or 0.5 to 1.5 mg / kg / day of the GLP1R agonist.

[0239] (168th embodiment) The method of any one of embodiments 143 to 167, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10 to 200 mg / day, or 10 to 175 mg / day, or 10 to 150 mg / day, or 10 to 125 mg / day, or 10 to 100 mg / day, or 20 to 200 mg / day, or 20 to 175 mg / day, or 20 to 150 mg / day, or 20 to 125 mg / day, or 20 to 100 mg / day, or 30 to 200 mg / day, or 30 to 175 mg / day, or 30 to 150 mg / day, or 30 to 125 mg / day, or 30 to 100 mg / day of the GLP1R agonist.

[0240] (169th embodiment) The method of any one of embodiments 143-168, wherein co-administering metformin comprises administering to a subject in need thereof 1-25 mg / kg / day, or 1-20 mg / kg / day, or 1-18 mg / kg / day, or 1-16 mg / kg / day, or 3-25 mg / kg / day, or 3-20 mg / kg / day, or 3-18 mg / kg / day, or 3-16 mg / kg / day, or 5-25 mg / kg / day, or 5-20 mg / kg / day, or 5-18 mg / kg / day, or 5-16 mg / kg / day of metformin.

[0241] (170th embodiment) The method of any one of embodiments 143-169, wherein the co-administering metformin comprises co-administering 100-1500 mg / day, or 100-1400 mg / day, or 100-1300 mg / day, or 100-1200 mg / day, or 200-1500 mg / day, or 200-1400 mg / day, or 200-1300 mg / day, or 200-1200 mg / day, or 300-1500 mg / day, or 300-1400 mg / day, or 300-1300 mg / day, or 300-1200 mg / day of metformin to a human subject in need thereof.

[0242] (171st embodiment) Any one of the methods of embodiments 143 to 170, wherein reducing FPG includes reducing FPG in a subject having an FPG of at least 100 mg / dL, or at least 110 mg / dL, or at least 120 mg / dL, or at least 130 mg / dL, or at least 140 mg / dL.

[0243] (172nd embodiment) The method of any one of embodiments 143 to 171, wherein reducing FPG comprises reducing FPG in the subject by at least 10 mg / dL, or at least 20 mg / dL, or at least 30 mg / dL, or at least 40 mg / dL after daily administration over a period of 12 weeks.

[0244] (173rd embodiment) A method for lowering systolic blood pressure, comprising administering to a subject in need thereof 0.1 to 3.0 mg / kg or 10 to 500 mg / day of a glucagon-like peptide 1 receptor (GLP1R) agonist.

[0245] (174th embodiment) The method of embodiment 173, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0246] (175th embodiment) The method of embodiment 174, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid.

[0247] (176th embodiment) The method of embodiment 174, wherein the GLP1R agonist is (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0248] (177th embodiment) The GLP1R agonist is selected from the group consisting of (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid and (S 175. The method of embodiment 174, wherein said compound is in combination with 2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid hydrochloride (1:2).

[0249] (178th embodiment) The method of embodiment 173, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid, a mass equivalent of a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0250] (179th embodiment) The method of embodiment 178, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-proionic acid.

[0251] (180th embodiment) The method of embodiment 178, wherein the GLP1R agonist is (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0252] (181st embodiment) The GLP1R agonist is selected from the group consisting of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid and 179. The method of embodiment 178, wherein the aryl ester is 3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid hydrochloride (1:1).

[0253] (182nd embodiment) The method of any one of embodiments 173 to 181, wherein the administering comprises orally administering the GLP1R agonist.

[0254] (183rd embodiment) The method of embodiments 173-182, wherein the GLP1R agonist functions primarily as a GLP1R agonist at the administered dose.

[0255] (184th embodiment) The method of any one of embodiments 173 to 183, wherein the subject is a human.

[0256] (185th embodiment) The method of any one of embodiments 173 to 184, wherein the administering comprises administering the GLP1R agonist one or more times per day, such as once per day, twice per day, or three times per day.

[0257] (186th embodiment) The method of embodiment 185, wherein at least one of the one or more doses is administered with food.

[0258] (187th embodiment) The method of embodiment 185, wherein the administering comprises administering the GLP1R agonist twice daily.

[0259] (188th embodiment) The method of embodiment 187, wherein the administering comprises administering the GLP1R agonist twice daily with food.

[0260] (189th embodiment) The method of any one of embodiments 173 to 188, wherein the administering comprises administering the GLP1R agonist for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

[0261] (190th embodiment) The method of any one of embodiments 173 to 189, further comprising co-administering to the subject one or more antidiabetic agents in combination with said GLP1R agonist.

[0262] (191st embodiment) The one or more antidiabetic drugs are insulin, insulin analogs (including insulin lispro, insulin aspart, insulin glulisine, isophane insulin, insulin zinc, insulin glargine, insulin detemir), biguanides (including metformin, phenformin, buformin), thiazolidinediones (including rosiglitazone, pioglitazone, troglitazone), sulfonylureas (including tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide, glyclopyramide, and gliquidone), meglitinides (including repaglinide and nateglinide), alpha-glutamate, ... The method of embodiment 190, wherein the agent is selected from the group consisting of glucosidase inhibitors (including miglitol, acarbose, voglibose), glucagon-like peptide analogs and agonists (including exenatide, liraglutide, semaglutide, taspoglutide, lixisenatide, albuglutide, dulaglutide), gastric inhibitory peptide analogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (including vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs, sodium / glucose cotransporter 2 (SGLT2) inhibitors, and glucokinase activators.

[0263] (192nd embodiment) The method of embodiment 191, wherein the one or more antidiabetic drugs is metformin.

[0264] (193rd embodiment) The method of embodiment 192, wherein the co-administration comprises oral co-administration of 1 to 30 mg / kg of metformin per day to the subject.

[0265] (194th embodiment) The method of embodiment 193, wherein the co-administration comprises co-administering metformin one or more times per day, such as once per day, twice per day, three times per day, or four times per day.

[0266] (195th embodiment) The method of embodiment 194, wherein the co-administration comprises co-administering metformin twice daily.

[0267] (196th embodiment) The method of embodiment 195, wherein the co-administration comprises co-administering metformin twice daily with food.

[0268] (197th embodiment) The method of any one of embodiments 173 to 196, wherein administering the GLP1R agonist comprises administering to a subject in need thereof 0.1 to 2.5 mg / kg / day, or 0.1 to 2.0 mg / kg / day, or 0.1 to 1.7 mg / kg / day, or 0.1 to 1.5 mg / kg / day, or 0.3 to 3.0 mg / kg / day, or 0.3 to 2.5 mg / kg / day, or 0.3 to 2.0 mg / kg / day, or 0.3 to 1.7 mg / kg / day, or 0.3 to 1.5 mg / kg / day, or 0.5 to 3.0 mg / kg / day, or 0.5 to 2.5 mg / kg / day, or 0.5 to 2.0 mg / kg / day, or 0.5 to 1.7 mg / kg / day, or 0.5 to 1.5 mg / kg / day of the GLP1R agonist.

[0269] (198th embodiment) The method of any one of embodiments 173 to 197, wherein administering the GLP1R agonist comprises administering to a human subject in need thereof 10 to 200 mg / day, or 10 to 175 mg / day, or 10 to 150 mg / day, or 10 to 125 mg / day, or 10 to 100 mg / day, or 20 to 200 mg / day, or 20 to 175 mg / day, or 20 to 150 mg / day, or 20 to 125 mg / day, or 20 to 100 mg / day, or 30 to 200 mg / day, or 30 to 175 mg / day, or 30 to 150 mg / day, or 30 to 125 mg / day, or 30 to 100 mg / day of the GLP1R agonist.

[0270] (199th embodiment) The method of any one of embodiments 173-198, wherein co-administering metformin comprises administering to a subject in need thereof 1-25 mg / kg / day, or 1-20 mg / kg / day, or 1-18 mg / kg / day, or 1-16 mg / kg / day, or 3-25 mg / kg / day, or 3-20 mg / kg / day, or 3-18 mg / kg / day, or 3-16 mg / kg / day, or 5-25 mg / kg / day, or 5-20 mg / kg / day, or 5-18 mg / kg / day, or 5-16 mg / kg / day of metformin.

[0271] (200th embodiment) The method of any one of embodiments 173-199, wherein co-administering metformin comprises co-administering 100-1500 mg / day, or 100-1400 mg / day, or 100-1300 mg / day, or 100-1200 mg / day, or 200-1500 mg / day, or 200-1400 mg / day, or 200-1300 mg / day, or 200-1200 mg / day, or 300-1500 mg / day, or 300-1400 mg / day, or 300-1300 mg / day, or 300-1200 mg / day of metformin to a human subject in need thereof.

[0272] (201st embodiment) Any one of the methods of embodiments 173 to 200, wherein reducing the systolic blood pressure comprises reducing the systolic blood pressure in a subject having a systolic blood pressure of at least 130 mmHg, or at least 135 mmHg, or at least 140 mmHg, or at least 145 mmHg, or at least 150 mmHg.

[0273] (202nd embodiment) The method of any one of embodiments 173 to 201, wherein reducing systolic blood pressure comprises reducing systolic blood pressure in the subject by at least 2 mmHg, or at least 3 mmHg, or at least 4 mmHg after 12 weeks of daily administration. Working Example Tablet Dose of API-1

[0274] A tablet was prepared containing 75 mg of (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2) ("API-1"). Tablet Dose of API-2

[0275] A tablet was prepared containing 200 mg of (S)-3-(4'-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichlorobenzyloxy)-phenyl]-1-methyl-2-oxo-6-(((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid as a 1:1 tris(hydroxymethyl)aminomethane salt ("API-2"). Example 1 - Phase 2 Study of API-1

[0276] A Phase 2 clinical trial was designed as a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of API-1 after 12 weeks of treatment in human type 2 diabetic subjects receiving stable doses of metformin. Subjects were randomized to one of three treatment arms: API-1 150 mg BID, API-1 150 mg QPM, or placebo, with approximately n=52 / group.

[0277] A total of approximately 156 patients were randomized into the study, with 174 ultimately randomized. Subjects were enrolled and randomized according to a blocked fixed randomization scheme by study site. Severity of diabetes was determined by HbA1c measurements at screening (7.5%-10%) and confirmed at baseline, with HbA1c used as a stratification variable in the randomization scheme: HbA1c <8% vs. ≥8%. Randomization was to be a balanced allocation (1:1:1) between the three treatment arms. Dropouts were not to be replaced.

[0278] Statistical analyses of the top-line results included placebo-subtracted change from baseline (LSM-CFB) for HbA1c (primary endpoint) and body weight (secondary endpoint), as well as post-hoc concentration / effect analyses to assess the effect of exposure on efficacy.

[0279] The API-1 once-daily and twice-daily treatment arms demonstrated placebo-subtracted reductions from baseline in HbA1c (%) of 0.9 ± 0.2% (p < 0.001) and 0.7 ± 0.2% (p < 0.001), respectively, at 12 weeks. Although the study was not powered to demonstrate weight loss, a trend was noted at week 12 in patients who lost a mean of 0.9 kg ± 0.5 kg (p = 0.08) in the 150 mg once-daily group and 0.6 kg ± 0.5 kg in the 150 mg twice-daily group. Additionally, API-1 once-daily and twice-daily treatment arms demonstrated placebo-subtracted reductions from baseline in fasting plasma glucose (mg / dL) at week 12 of approximately 16 and 17, respectively.

[0280] Subsequent concentration / effect analysis of completers revealed that the lower dose demonstrated more pronounced effects on key efficacy endpoints including, but not limited to, HbA1c, fasting plasma glucose (FGP), and weight loss. This observation is confirmed when correlating plasma concentrations with efficacy. Patients receiving less than 1.35 mg / kg API-1 had greater efficacy with reductions from baseline in HbA1c and weight of 1.7% (p<0.01) and 3.7 kg (p<0.05), respectively, at week 12 (see Table 3 below).

[0281] Table 3. Mean change from baseline HbA1c (%) with API-1 analyzed by dose / weight (mg / kg) per visit

[0282] [Table 1]

[0283] Figure 1. Dose (mg / kg) response of HbA1c for the 150 mg QPM treatment group: In Figure 1, the data points represent the change from baseline in HbA1c (%) by dose (mg / kg) at week 12 for completers (placebo = X; 150 mg QPM = ·) by treatment group. The line through the data points between 1 and 2.2 mg / kg represents a linear fit of these data points. The slope of the line through the data points for the 150 mg QPM group indicates that the change from baseline in HbA1c increased as the dose was reduced from 2.2 mg / kg to 1.0 mg / kg.

[0284] Figure 2. Dose (mg / kg) response for HbA1c in the 150 mg twice daily (BID) group: In Figure 2, the data points represent the change from baseline in HbA1c (%) by dose (mg / kg) at week 12 for completers by treatment group (placebo = X; 150 mg twice daily (QPM) = ·). The line through the data points between 2.2 mg / kg and 4.8 mg / kg represents a linear fit of these data points. The slope of the line through the data points for the 150 mg twice daily (BID) group indicates that the change from baseline in HbA1c was nearly constant between doses of 2.2 mg / kg and 4.8 mg / kg.

[0285] Figure 3. Dose (mg / kg) response in FPG for the 150 mg QPM treatment group: In Figure 3, the data points represent the change from baseline at 12 weeks in fasting plasma glucose (FPG) by dose (mg / kg) for completers by treatment group (placebo = X; 150 mg QPM = ·). The line through the data points between 1 and 2.2 mg / kg represents a linear line fit of these data points. The slope of the line through the data points for the 150 mg QPM treatment group indicates that the change from baseline in FPG increased as the dose decreased from 2.2 mg / kg to 1.0 mg / kg.

[0286] Figure 4. Dose (mg / kg) response in the FPG 150 mg twice daily (BID) treatment group: In Figure 4, the data points represent the change from baseline at 12 weeks in fasting plasma glucose (FPG) by dose (mg / kg) for completers by treatment group (placebo = X; 150 mg BID = ·). The line through the data points between 2.2 mg / kg and 4.8 mg / kg represents a linear fit of these data points. The slope of the line through the data points in the 150 mg BID group indicates that the change from baseline in FPG (mg / dL) was approximately unchanged between doses of 2.2 mg / kg and 4.8 mg / kg. Example 2 - Phase 2 Study of API-2

[0287] The Phase 2 study was designed as a randomized, double-blind, placebo-controlled, dose-ranging, parallel-group study to evaluate the efficacy and safety of API-2 after 12 weeks of treatment in T2DM subjects (humans). The study was conducted in two parts: Part A and Part B. Parts A and B were identical except for the dose level administered. In Part A, subjects received one of two treatments orally for 12 weeks: API-2 400 mg QD (n=51) or matching placebo (n=26). In Part B, subjects received one of three treatments orally for 12 weeks: API-2 200 mg QD (n=28), API-2 800 mg QD (n=56), or matching placebo (n=26).

[0288] Table 4. Mean percent change from baseline in HbA1c in the API-2 target population (baseline 8-11%) analyzed by dose / weight (mg / kg) per visit

[0289] [Table 2]

Claims

1. A glucagon-like peptide 1 receptor (GLP1R) agonist (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2) for use in the manufacture of a medicament for the treatment of obesity, wherein the GLP1R agonist is capable of being administered at between 50 mg and 300 mg per day to a subject in need thereof.

2. Treating obesity comprises: Losing weight, or Improve glycemic control, or lowering fasting plasma glucose (FPG), or Lowering systolic blood pressure 2. The GLP1R agonist for use according to claim 1, comprising:

3. A glucagon-like peptide 1 receptor (GLP1R) agonist (S)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin)-4-yl)-phenyl]-propionic acid hydrochloride (1:2) for use in the manufacture of a medicament for reducing body weight, wherein the GLP1R agonist is capable of being administered at between 50 mg and 300 mg per day to a subject in need thereof.

4. A GLP1R agonist for use according to any one of claims 1 to 3, wherein the GLP1R agonist can be administered one or more times daily and the subject is a human.

5. A GLP1R agonist for use as described in claim 4, wherein the administration comprises a single administration with food.

6. A GLP1R agonist for use as described in claim 4, wherein the administration comprises one or more doses per day, two of which are administered with food.

7. The GLP1R agonist for use according to any one of claims 1 to 6, wherein the GLP1R agonist can be administered for a period of 1 week or more, or 2 weeks or more, or 3 weeks or more, or 6 weeks or more, or 9 weeks or more, or 12 weeks or more.

8. A GLP1R agonist for use according to any one of claims 1 to 7, wherein the GLP1R agonist can be co-administered to the subject with metformin.

9. The GLP1R agonist for use according to claim 8, wherein the GLP1R agonist is 1 to 30 mg / kg metformin per day and can be co-administered orally with metformin at least once per day.

10. A GLP1R agonist for use according to any one of claims 1 to 9, wherein the GLP1R agonist is capable of being administered to a human subject in need thereof at 150 mg once daily.

11. A GLP1R agonist for use according to any one of claims 1 to 9, wherein the GLP1R agonist is capable of being administered to a human subject in need thereof at 150 mg twice daily.

12. The GLP1R agonist for use according to any one of claims 8 to 11, wherein the GLP1R agonist can be co-administered with metformin to a subject in need thereof at 1 to 25 mg / kg / day, or 1 to 20 mg / kg / day, or 1 to 18 mg / kg / day, or 1 to 16 mg / kg / day, or 3 to 25 mg / kg / day, or 3 to 20 mg / kg / day, or 3 to 18 mg / kg / day, or 3 to 16 mg / kg / day, or 5 to 25 mg / kg / day, or 5 to 20 mg / kg / day, or 5 to 18 mg / kg / day, or 5 to 16 mg / kg / day of metformin.

13. The GLP1R agonist for use according to any one of claims 8 to 12, wherein the GLP1R agonist can be co-administered with metformin to a subject in need thereof at 100-1500 mg / day, or 100-1400 mg / day, or 100-1300 mg / day, or 100-1200 mg / day, or 200-1500 mg / day, or 200-1400 mg / day, or 200-1300 mg / day, or 200-1200 mg / day, or 300-1500 mg / day, or 300-1400 mg / day, or 300-1300 mg / day, or 300-1200 mg / day of metformin.

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