Heterocyclic GLP-1 agonists

Abstract

The present invention relates generally to GLP-1 agonists and pharmaceutical compositions comprising same, as well as methods of treating GLP-1 associated diseases, disorders or conditions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of International Patent Application No. PCT / CN2022 / 082067, filed March 21, 2022, International Patent Application No. PCT / CN2022 / 085519, filed April 7, 2022, and International Patent Application No. PCT / CN2023 / 080471, filed March 9, 2023, each of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof. [Background technology]

[0003] background Incretin metabolic hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important in controlling glucose homeostasis. Medications that target this family of gut peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, decrease gastric motility, and increase satiety.

[0004] Diabetes mellitus is a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes mellitus (T2DM), is an acquired condition that accounts for over 90% of diabetes cases. Onset typically occurs in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle modifications can be useful in managing the disorder, patients with T2DM may require the use of antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose ingestion. Although this incretin action is significantly reduced (if at all) in cases of T2DM, GLP-1 retains its insulinotropic properties even when the endocrine pancreatic response to GIP is effectively shut down. Thus, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in T2DM patients. Summary of the Invention [Problem to be solved by the invention]

[0006] overview The present invention describes heterocyclic GLP-1 agonists and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating GLP-1-related diseases, disorders, and conditions are also provided.

[0007] In some embodiments, provided is a compound of formula I: [ka] [During the ceremony, Ring A is [ka] and; Ring B is C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X 1 , X 2 , X 3 and X 4 one of which is C covalently bonded to ring B via L; and X 1 , X 2 , X 3 and X 4 the remainder are each independently N or CR 4 where X 1 , X 2 , X 3 and X 4Not more than two of N; X 5 , X 6 and X 7 are each independently N or CR 5 and; X 8 and X 9 are each independently N or CR 6 and; X 10 is N or CR 6 and X 11 is S, O or NR 9 and; n is 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 1 -C(O)OR 9 , -C(O)N(R 9 )2, -C(O)N(R 9 )S(O)2R 9 , -NR 9 C(O)R 9 , 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl optionally has 1 to 4 R 11 is replaced by; R 2 is optionally -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-9 alkyl; where R 2 Each C 1-9 Alkyl, -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may optionally further comprise 1 to 5 Z 1 is replaced by; L is bond, C 1-9Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 Alkylene, 3- to 6-membered heterocyclylene, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 C(O)NR 10 -, -OC(O)NR 10 -or-NR 10 C(O)O-; where each C in L 1-9 Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 The alkylene or 3- to 6-membered heterocyclylene may independently optionally have 1 to 5 Z 1 is replaced by; Each R 3 are independently halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 4 are independently hydrogen, halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 5 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 5 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 6are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 6 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 9 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl; where R 9 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 R 11 is replaced by; Each R 10 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)R 20 , -S(O)2R 20 , -S(O)N(R 20 )2 or -S(O)2N(R20 )2; where R 10 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each R 11 are independently oxo, cyano, halo, hydroxy, C 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, C 3-9 Cycloalkyl, -C 1-9 Alkyl-C(O)OR 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -SR 12 or -S(O)2R 12 and; Each R 12 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 12 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-9 Alkyl, -L 1 -C 2-9 Alkenyl, -L 1-C 2-9 Alkynyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L 1 -heteroaryl; where Z 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L 1 are independently -O-, -S-, and -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 20 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 20 -or-NR 20 S(O)NR 20 - and; Each R 20 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano; However, ring A is [ka] If so, R 1 is other than -C(O)OH. or a pharmaceutically acceptable salt or solvate thereof.

[0008] Also provided herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0009] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0010] Also provided herein is a method of treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method for treating diabetes in a patient, comprising determining that the patient has type 2 diabetes and administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, determining that the patient has type 2 diabetes comprises performing an assay to determine the level of a test substance in a sample from the patient, wherein the test substance is selected from the group consisting of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof. In some embodiments, the HbA1c level is about 6.5% or higher. In some embodiments, the fasting blood glucose level is about 126 mg / dL or higher. In some embodiments, the non-fasting blood glucose level is about 200 mg / dL or higher.

[0012] In some embodiments, the method further comprises obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) of about 22 kg / m 2 In one embodiment, the patient's BMI is about 30 kg / m 2 That's all.

[0013] In certain embodiments, the method for treating type 2 diabetes comprises reducing fasting blood glucose levels, ie, reducing fasting blood glucose levels to about 100 mg / dL or less.

[0014] In certain embodiments, the method for treating type 2 diabetes comprises reducing HbA1c levels, hi certain embodiments, HbA1c levels are reduced to about 5.7% or less.

[0015] In certain embodiments, the method of treating type 2 diabetes comprises reducing glucagon levels.

[0016] In certain embodiments, the method of treating type 2 diabetes involves increasing insulin levels.

[0017] In certain embodiments, the method for treating type 2 diabetes includes reducing BMI. In certain embodiments, the BMI is about 25 kg / m 2 It decreases to the following:

[0018] In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof is administered orally.

[0019] In some embodiments, the method for treating type 2 diabetes further comprises administering an additional treatment or therapeutic agent to the patient.In some embodiments, the additional treatment or therapeutic agent is selected from the group consisting of antidiabetic agents, antiobesity agents, GLP-1 receptor agonists, non-alcoholic steatohepatitis (NASH) treatment agents, antiemetic agents, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof.In some embodiments, the antidiabetic agent is selected from the group consisting of biguanides, sulfonylureas, glitazars, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, meglitinides, sodium-glucose transporter 2 (SGLT2) inhibitors, glitazones, GRP40 agonists, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose transporter 1 (SGLT1) inhibitors, or any combination thereof.In some embodiments, the biguanide is metformin. In certain embodiments, the anti-obesity agent is selected from the group consisting of a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, human pleurodipeptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In certain embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof.In some embodiments, the NASH treatment agent is selected from the group consisting of FXR agonist, PF-05221304, synthetic fatty acid-bile conjugate, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibody, caspase inhibitor, MAPK5 inhibitor, galectin 3 inhibitor, fibroblast growth factor 21 (FGF21) agonist, niacin analog, leukotriene D4 (LTD4) receptor antagonist, acetyl-CoA carboxylase (ACC) inhibitor, ketohexokinase (KHK) inhibitor, bile acid transporter (IBAT) inhibitor, apoptosis signal-regulating kinase 1 (ASK1) inhibitor, or any combination thereof.In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate or its pharmaceutical composition and additional therapeutic agent are administered in separate preparations, in any order.

[0020] Also provided herein is a method for modulating insulin levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the modulation increases insulin levels.

[0021] Also provided herein is a method for modulating glucose levels in a patient in need of such modulation, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the modulation reduces glucose levels.

[0022] Also provided herein is a method of treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the disease, disorder, or condition is type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), slow-onset autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, or renal disease. , adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic The disease is selected from the group consisting of acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's, Alzheimer's disease, cognitive dysfunction, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, Selected from the group consisting of insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulceration, or any combination thereof.

[0023] All publications, patents, and patent applications mentioned herein are incorporated by reference to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated by reference herein. In the event that the publications and patents or patent applications incorporated by reference contradict the disclosure herein, the present specification supersedes and / or takes precedence over such conflicting material. [Means for solving the problem]

[0024] Detailed Description Before the present compounds and methods are described, it is to be understood that this disclosure is not limited to the described methodology, protocols, cell lines, assays, and reagents, as these may vary. It is also to be understood that the terminology used herein is intended to describe embodiments of the invention, but is not intended to limit the scope of the invention, which is defined by the appended claims.

[0025] definition It should be noted that as used in this specification and the appended claims, the singular forms "a," "the," and "the" include plural referents unless the context clearly dictates otherwise.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods, devices, and materials are described herein. All publications cited herein are incorporated by reference in their entirety for the purpose of describing and disclosing the methods, reagents, and tools described therein, which are used in connection with the present invention.

[0027] Provided herein are heterocyclic GLP-1 agonists for use in the management of T2DM and other conditions in which activation of GLP-1 activity is beneficial.

[0028] When values ​​are described in ranges, it is understood that such disclosure includes all possible subranges within such ranges as well as specific numerical values ​​falling within such ranges, whether or not a specific numerical value or specific subrange is explicitly stated.

[0029] The term "halo" or "halogen," as used herein, refers to -F (also referred to herein as "fluoro" or "fluorine"), -Cl (also referred to herein as "chloro" or "chlorine"), -Br (also referred to herein as "bromo" or "bromine"), and -I (also referred to herein as "iodo" or "iodine").

[0030] As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "(C 1-6 )Alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical of one to six carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0031] As used herein, the term "alkylene" refers to a divalent alkyl containing the indicated number of carbon atoms. For example, "(C 1-3 )Alkylene" refers to a divalent alkyl having 1 to 3 carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-). Similarly, the terms "cycloalkylene," "heterocyclylene," "arylene," and "heteroarylene" refer to divalent cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively.

[0032] As used herein, the term "alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "(C 2-6 ")Alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain of 2 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl, or pentenyl.

[0033] As used herein, the term "alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. For example, "(C 2-6")Alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain having 2 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, or pentynyl.

[0034] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing the indicated number of carbon atoms. For example, "(C 3-6 ") Cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon having 3 to 6 ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls can be partially unsaturated. Non-limiting examples of partially unsaturated cycloalkyls include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, and the like. Cycloalkyls can contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0035] As used herein, the term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system), having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, where the heteroatoms are O, N, S, or S(O). 1-2 (e.g., carbon atoms and N, O, S, or S(O) if monocyclic, bicyclic, or tricyclic, respectively) 1-2Heterocyclyl groups are selected from the group consisting of 1 to 3, 1 to 6, or 1 to 9 heteroatoms, where 0, 1, 2, or 3 atoms in each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl groups may be partially unsaturated. Non-limiting examples of partially unsaturated heterocyclyls include dihydropyrrolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrofuranyl, dihydropyranyl, and the like. Heterocyclyls may contain multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2. 2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0036] As used herein, the term "aryl" refers to a mono-, bi-, tri-, or polycyclic hydrocarbon group containing the indicated number of carbon atoms, in which at least one ring in the system is aromatic (e.g., C monocyclic, C 10 Bicyclic or C 14 Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0037] As used herein, the term "heteroaryl" refers to a mono-, bi-, tri-, or polycyclic group having the indicated number of ring atoms (e.g., 5 to 6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms), where at least one ring in the system is aromatic (but need not contain heteroatoms, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyri These include pyridinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others.

[0038] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with one or more halogen atoms. Non-limiting examples include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, dichloromethyl, chloroethyl, trichloroethyl, bromomethyl, and iodomethyl.

[0039] As used herein, the term "alkoxy" refers to an -O-alkyl group in which the radical is on the oxygen atom. For example, "C 1-6 "Alkoxy" means that the radical is on the oxygen atom -O-(C 1-6 "Alkoxy" refers to an -O-haloalkyl radical. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, the term "haloalkoxy," as used herein, refers to an -O-haloalkyl group in which the radical is on the oxygen atom.

[0040] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. A compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise indicated.

[0041] As used herein, when a ring is described as being "aromatic," it means that the ring has a contiguous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Examples of such rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like. When a ring system containing at least two rings is described as "aromatic," it means that the ring system contains one or more aromatic rings. Thus, when a ring system containing at least two rings is described as "non-aromatic," it means that none of the rings comprising the ring system are aromatic.

[0042] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation inherent in the ring itself; e.g., one or more double bonds between constituent ring atoms), unless the ring is aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. When a ring system containing at least two rings is described as "partially unsaturated," it means that the ring system contains one or more degrees of partial unsaturation, provided that none of the constituent rings of the ring system is aromatic.

[0043] As used herein, the term "tautomer" refers to a compound whose structure differs significantly in the arrangement of atoms, but which exists in ready and rapid equilibrium; the compounds provided herein may be described as various tautomers; it should be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the name of the compound does not exclude any tautomers.

[0044] As used herein, the term "GLP-1R" or "GLP-1 receptor" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, various species and active fragments thereof.

[0045] As used herein, the term "GLP-1 associated disease" is meant to include, but is not limited to, any disease, disorder, or condition in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0046] As used herein, the term "GLP-1 agonist" or "GLP-1 RA" refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 RAs enhance glucose-dependent insulin secretion; suppress inappropriate increases in glucagon levels in both fasting and postprandial states; and delay gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1 RAs have been shown to treat type 2 diabetes. Examples of GLP-1 RAs include, but are not limited to, albiglutide (TANZEUM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXUMIA®), semaglutide (OZEMPIC®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in U.S. Patents 10,370,426; 10,308,700; 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE45313.

[0047] As used herein, the term "pharmaceutically acceptable" refers to a compound or salt or composition thereof that is chemically and / or toxicologically compatible with other ingredients contained in the formulation and / or with the patient being treated therewith.

[0048] The terms "administration" or "administering" refer to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The method of administration can vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0049] As used herein, the term "effective amount" or "effective dosage" or "pharmaceutically effective amount" or "therapeutically effective amount" refers to a sufficient amount of a chemical entity (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof) to relieve to some extent one or more symptoms of the disease or condition being treated, and may include curing the disease. "Cure" means that the symptoms of active disease are eliminated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study. In certain embodiments, a "therapeutically effective amount" of a compound provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0050] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In certain embodiments, each component is "pharmaceutically acceptable" in that it is compatible with the other components of the pharmaceutical formulation, is suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21 sted.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC See Press LLC: Boca Raton, FL, 2009.

[0051] The term "pharmaceutical composition" refers to a mixture of a compound of Formula I, as described herein, or a pharmaceutically acceptable salt or solvate thereof, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques exist in the art for administering a compound, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0052] The terms "treatment" and "treating" in the context of treating a disease, disorder, or condition are intended to include alleviating or arresting the disorder, disease, or condition or one or more symptoms associated with the disorder, disease, or condition; or preventing the progression, spread, or worsening of the disease, disorder, or condition or one or more of its symptoms.

[0053] As used herein, the term "prevention" refers to the prevention of the onset, recurrence or spread of a disease or condition described herein or its symptoms, in whole or in part.

[0054] As used herein, the terms "subject," "patient," or "individual" are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or necessary. In some embodiments, the patient is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0055] The terms "treatment regimen" and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the present invention.

[0056] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (i.e., combination elements or combination partners), where the therapeutically active agents are administered together or separately as prescribed by a healthcare professional or in accordance with regulatory authorities as defined herein.

[0057] As used herein, the term "modulation" refers to regulation or adjustment (e.g., increase or decrease) and can include, for example, agonism, partial agonism, or antagonism.

[0058] It is to be understood that the substituents defined herein are not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluoro groups or a hydroxy group attached to an ethenyl group or an acetylene group), such impermissible substitution patterns being well known to those of skill in the art.

[0059] compound Formula I: [ka] [During the ceremony, Ring A is [ka] and; Ring B is C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X 1 , X 2 , X 3 and X 4 one of which is C covalently bonded to ring B via L; and X 1 , X 2 , X 3 and X 4 the remainder are each independently N or CR 4 where X 1 , X 2 , X 3 and X 4 Not more than two of N; X 5 , X 6 and X 7 are each independently N or CR 5 and; X 8 and X 9 are each independently N or CR 6 and; X 10 is N or CR 6 and X 11 is S, O or NR 9 and; n is 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 1 -C(O)OR 9 , -C(O)N(R 9 )2, -C(O)N(R 9 )S(O)2R 9 , -NR 9 C(O)R 9 , 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl optionally has 1 to 4 R 11 is replaced by; R 2 is optionally -O-(C 1-9 alkyl), -S-(C 1-9alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-9 alkyl; where R 2 Each C 1-9 Alkyl, -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may optionally further comprise 1 to 5 Z 1 is replaced by; L is bond, C 1-9 Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 Alkylene, 3- to 6-membered heterocyclylene, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 C(O)NR 10 -, -OC(O)NR 10 -or-NR 10 C(O)O-; where each C in L 1-9 Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 The alkylene or 3- to 6-membered heterocyclylene may independently optionally have 1 to 5 Z 1 is replaced by; Each R 3 are independently halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 4 are independently hydrogen, halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 5 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 5 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 6 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 6 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 8 are independently hydrogen or C 1-9 is alkyl; Each R 9 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl; where R 9 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 R 11 is replaced by; Each R 10 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)R 20 , -S(O)2R 20 , -S(O)N(R 20 )2 or -S(O)2N(R 20 )2; where R 10 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each R 11 are independently oxo, cyano, halo, hydroxy, C 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, C 3-9 Cycloalkyl, -C 1-9 Alkyl-C(O)OR 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -SR 12 or -S(O)2R 12 and; Each R 12 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 12 Each C1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-9 Alkyl, -L 1 -C 2-9 Alkenyl, -L 1 -C 2-9 Alkynyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L 1 -heteroaryl; where Z 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L 1 are independently -O-, -S-, and -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 20 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR20 S(O)NR 20 -or-NR 20 S(O)NR 20 - and; Each R 20 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and is substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt or solvate thereof.

[0060] In certain embodiments, ring A is [ka] If so, R 1 is other than -C(O)OH.

[0061] In certain embodiments, each R 8 are independently hydrogen. In some embodiments, one R 8 is methyl. In some embodiments, n is 1. In some embodiments, n is 1 and R 8 is hydrogen or methyl. In some embodiments, n is 1 and R 8 is hydrogen. In some embodiments, n is 1 and R 8 is methyl.

[0062] In some embodiments, provided is a compound of formula IA: [ka] [In the formula, each ring A, ring B, X 1 , X 2 , X 3 , X 4 , n, m, L and R 3 are independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0063] In some embodiments, provided is a compound of formula IA: [ka] [During the ceremony, Ring A is [ka] and; Ring B is C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X 1 , X 2 , X 3 and X 4 one of which is C covalently bonded to ring B via L; and X 1 , X 2, X 3 and X 4 the remainder are each independently N or CR 4 where X 1 , X 2 , X 3 and X 4 Not more than two of N; X 5 , X 6 and X 7 are each independently N or CR 5 and; X 8 and X 9 are each independently N or CR 6 and; X 10 is N or CR 6 and X 11 is S, O or NR 9 and; n is 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 1 -C(O)OR 9 , -C(O)N(R 9 )2, -C(O)N(R 9 )S(O)2R 9 , -NR 9 C(O)R 9 , 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl optionally has 1 to 4 R 11 is replaced by; R 2 is optionally -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-9 alkyl; where R 2 Each C 1-9 Alkyl, -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9alkyl), C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may optionally further comprise 1 to 5 Z 1 is replaced by; L is bond, C 1-9 Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 Alkylene, 3- to 6-membered heterocyclylene, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 C(O)NR 10 -, -OC(O)NR 10 -or-NR 10 C(O)O-; where each C in L 1-9 Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 The alkylene or 3- to 6-membered heterocyclylene may independently optionally have 1 to 5 Z 1 is replaced by; Each R 3 are independently halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 4 are independently hydrogen, halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 5 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 5 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 6 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 6 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 9 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl; where R 9 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 R 11 is replaced by; Each R 10 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20)2, -S(O)R 20 , -S(O)2R 20 , -S(O)N(R 20 )2 or -S(O)2N(R 20 )2; where R 10 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each R 11 are independently oxo, cyano, halo, hydroxy, C 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, C 3-9 Cycloalkyl, -C 1-9 Alkyl-C(O)OR 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -SR 12 or -S(O)2R 12 and; Each R 12 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 12 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L1 -C 1-9 Alkyl, -L 1 -C 2-9 Alkenyl, -L 1 -C 2-9 Alkynyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L 1 -heteroaryl; where Z 1 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L 1 are independently -O-, -S-, and -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 20 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 20 -or-NR 20 S(O)NR 20 - and; Each R 20 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and is substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt or solvate thereof.

[0064] Formula IA: [ka] [During the ceremony, Ring A is [ka] and; Ring B is C 3-10 is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X 1 , X 2 , X 3 and X 4 one of which is C covalently bonded to ring B via L; and X 1 , X 2 , X 3 and X4 the remainder are each independently N or CR 4 where X 1 , X 2 , X 3 and X 4 Not more than two of N; X 5 , X 6 and X 7 are each independently N or CR 5 and; X 8 and X 9 are each independently N or CR 6 and; n is 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 1 -C(O)OR 9 , -C(O)N(R 9 )2, -NR 9 C(O)R 9 , 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl optionally has 1 to 4 R 11 is replaced by; R 2 is optionally -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 C substituted with cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl 1-9 alkyl; where R 2 Each C 1-9 Alkyl, -O-(C 1-9 alkyl), -S-(C 1-9 alkyl), -S(O)2-(C 1-9 alkyl), C 3-6 Cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl may optionally further comprise 1 to 5 Z 1 is replaced by; L is bond, C 1-9 Alkylene, C 2-9 Alkenylene, C2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 Alkylene, 3- to 6-membered heterocyclylene, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 S(O)NR 10 -, -NR 10 C(O)NR 10 -, -OC(O)NR 10 -or-NR 10 C(O)O-; where each C in L 1-9 Alkylene, C 2-9 Alkenylene, C 2-9 Alkynylene, -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene, -NR 10 C(O)-C 1-9 The alkylene or 3- to 6-membered heterocyclylene may independently optionally have 1 to 5 Z 1 is replaced by; Each R 3 are independently halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10, -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10 , -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 4 are independently hydrogen, halo, cyano, nitro, oxo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OC(O)OR 10 , -C(O)N(R 10 )2, -NR 10 C(O)R 10 , -OC(O)N(R 10 )2, -NR 10 C(O)OR 10 , -NR 10 C(O)N(R 10 )2, -S(O)R 10 , -S(O)2R 10, -S(O)N(R 10 )2, -S(O)2N(R 10 )2, -NR 10 S(O)R 10 , -NR 10 S(O)2R 10 , -NR 10 S(O)N(R 10 )2, -NR 10 S(O)2N(R 10 )2, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1 is replaced by; Each R 5 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 5 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 6 are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl; where R 6 Each of -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 The alkynyl is independently optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, and cyano; Each R 9 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl; where R 9 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 R 11 is replaced by; Each R 10 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -S(O)R 20 , -S(O)2R 20 , -S(O)N(R 20 )2 or -S(O)2N(R 20 )2; where R 10 Each C 1-9 Alkyl, C 2-9Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each R 11 are independently oxo, cyano, halo, hydroxy, C 1-9 Alkyl, C 1-9 Alkoxy, C 1-9 Haloalkyl, C 1-9 Haloalkoxy, -C(O)OR 12 , -C(O)N(R 12 )2 or -S(O)2R 12 and; Each R 12 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 12 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1 are independently halo, cyano, nitro, oxo, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L 1 -C 1-9 Alkyl, -L 1 -C 2-9 Alkenyl, -L 1 -C 2-9 Alkynyl, -L 1 -C 3-10 Cycloalkyl, -L 1 -heterocyclyl, -L 1 -aryl or -L 1 -heteroaryl; where Z 1Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; Each L 1 are independently -O-, -S-, and -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 20 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 20 -or-NR 20 S(O)NR 20 - and; Each R 20 are independently hydrogen, C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 Each C 1-9 Alkyl, C 2-9 Alkenyl, C 2-9 Alkynyl, C 3-10 The cycloalkyl, heterocyclyl, aryl, or heteroaryl independently optionally has 1 to 5 Z 1a is replaced by; each Z 1a are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1a Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently optionally C 1-9 and is substituted with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano. or a pharmaceutically acceptable salt or solvate thereof.

[0065] In some embodiments, provided herein is a compound of formula II: [ka] [In the formula, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , ring B, m, and n are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0066] In some embodiments, X 6 is N.

[0067] In some embodiments, X 5 is N.

[0068] In some embodiments, X 5 is N or CR 5 and X 6 is N and X 7 is CR 5 is.

[0069] In some embodiments, provided herein is a compound of formula III: [ka] [In the formula, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 8 , X 9 , ring B, m, and n are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0070] In some embodiments, X 9 is CR 6 is.

[0071] In some embodiments, X 9 is N.

[0072] In some embodiments, X 8 is CR 6 and X 9 is N or CR 6 is.

[0073] In some embodiments, provided herein is a compound of formula IV: [ka] [In the formula, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 10 , X 11 , ring B, m, and n are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0074] In some embodiments, provided herein is a compound of formula V: [ka] [In the formula, R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , ring B, m, and n are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0075] In some embodiments, X 10 is CR 7 is.

[0076] In some embodiments, X 11 is S.

[0077] In some embodiments, n is 1.

[0078] In some embodiments, R 1 optionally, 1 to 5 R 11 is a 5-membered heteroaryl substituted with

[0079] In some embodiments, R 1 teeth [ka] is.

[0080] In some embodiments, R 1 teeth [ka] is.

[0081] In some embodiments, R 1optionally, 1 to 5 R 11 and 5-10 membered heterocyclyl substituted by [ka] Includes.

[0082] In some embodiments, R 1 teeth [ka] is.

[0083] In some embodiments, R 1 -C(O)OR 9 , -C(O)N(R 9 )2, -C(O)N(R 9 )S(O)2R 9 or -NR 9 C(O)R 9 is.

[0084] In some embodiments, R 1 -C(O)OR 9 , -C(O)NHR 9 , -C(O)NHS(O)R 9 or -NHC(O)R 9 is.

[0085] In some embodiments, R 1 is -C(O)OH.

[0086] In some embodiments, R 1 is -C(O)NH2.

[0087] In some embodiments, R 1 -C(O)NHR 9 or -NHC(O)R 9 and R は C 1-9 Alkyl, C 3-10 cycloalkyl or heteroaryl; 1-9 Alkyl, C 3-10The cycloalkyl or heteroaryl may independently optionally contain 1 to 5 R 11 is replaced by .

[0088] In some embodiments, R 1 -C(O)NHR 9 or -NHC(O)R 9 and R 9 is methyl, 2,2,2-trifluoroethyl, cyclopropyl substituted with cyano, or pyridyl. 1 -C(O)NHR 9 and R 9 is methyl, 2,2,2-trifluoroethyl, cyclopropyl substituted with cyano, or pyridyl. 1 Ha-NHC(O)R 9 and R 9 is methyl, 2,2,2-trifluoroethyl, cyano-substituted cyclopropyl, or pyridyl.

[0089] In some embodiments, R 1 -C(O)NHS(O)R 9 and R 9 is methyl.

[0090] In some embodiments, X 1 , X 2 and X 3 one of which is C covalently bonded to ring B via L; X 4 is N; and X 1 , X 2 and X 3 The rest are each independently CR 4 is.

[0091] In some embodiments, X 1 , X 2 , X 3 and X 4 one of which is C covalently bonded to ring B via L; and X 1 , X 2 , X 3 and X 4The rest are each independently CR 4 is.

[0092] In some embodiments, X 3 is C covalently bonded to ring B via L.

[0093] In certain embodiments, each R 4 are independently hydrogen, halo, or C 1-9 Haloalkyl or C 3-10 It is cycloalkyl.

[0094] In some embodiments, X 2 is CR 4 and R 4 is hydrogen, halo, C 1-9 Haloalkyl or C 3-10 It is cycloalkyl.

[0095] In certain embodiments, each R 4 are independently hydrogen, chloro, —CF 3 , or cyclopropyl.

[0096] In some embodiments, X 1 is CH.

[0097] In some embodiments, L is -OC 1-9 Alkylene, -NR 10 -C 1-9 Alkylene, -C(O)NR 10 -C 1-9 Alkylene or -NR 10 C(O)-C 1-9 It is alkylene.

[0098] In some embodiments, L is a bond, C 1-9 Alkylene, -OC 1-9 Alkylene, -NH-C 1-9 Alkylene, -C(O)NH-C 1-9 It is alkylene, 3- to 6-membered heterocyclylene, or -O-.

[0099] In certain embodiments, L is a bond, —CH 2 —, —O—CH 2 —, —OC(CH 3 )H—, —NH—CH 2 —, —C(O)NH—CH 2 —, or pyrrolidinyl.

[0100] In certain embodiments, L is —O—CH 2 —.

[0101] In some embodiments, ring B is C 3-6 In some embodiments, ring B is C 3-6 In some embodiments, Ring B is cycloalkyl. In some embodiments, Ring B is a 5- or 9-membered heterocyclyl. In some embodiments, Ring B is a 5- or 9-membered heteroaryl. In some embodiments, Ring B is phenyl.

[0102] In some embodiments, Ring B is phenyl, thiophenyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, cyclopropyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, or benzofuranyl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is thiophenyl. In some embodiments, Ring B is thiazolyl. In some embodiments, Ring B is pyridinyl. In some embodiments, Ring B is pyrazinyl. In some embodiments, Ring B is pyrimidinyl. In some embodiments, Ring B is cyclopropyl. In some embodiments, Ring B is 2,3-dihydrobenzofuranyl. In some embodiments, Ring B is benzo[d][1,3]dioxolyl. In some embodiments, Ring B is benzofuranyl.

[0103] In some embodiments, R 2 is C 1-9 C substituted with alkyl, 3-6 membered heterocyclyl 1-9 Alkyl or cyano substituted C 3-6 Cycloalkyl-substituted C 1-9 It is alkyl.

[0104] In some embodiments, R 2 is C 1-9 It is alkyl.

[0105] In some embodiments, R 2 is methyl.

[0106] In some embodiments, R 2 is a 3- to 6-membered heterocyclyl-substituted C 1-9 Alkyl or cyano substituted C 3-6 Cycloalkyl-substituted C 1-9 In some embodiments, R 2 is a 3- to 6-membered heterocyclyl-substituted C 1-9 In some embodiments, R 2 is a cyano-substituted C 3-6 Cycloalkyl-substituted C 1-9 It is alkyl.

[0107] In some embodiments, R 2 teeth [ka] is.

[0108] In some embodiments, R 2 teeth [ka] In some embodiments, R 2 teeth [ka] is.

[0109] In certain embodiments, m is 1, 2, or 3.

[0110] In certain embodiments, each R 3 are independently halo, cyano, -OR 10 , -C(O)N(R 10 )2, -S(O)2R 10, C 1-9 Alkyl, C 3-10 cycloalkyl or heteroaryl; where R 3 Each C 1-9 The alkyl is independently optionally substituted with 1 to 5 halo.

[0111] In certain embodiments, each R 3 are independently halos.

[0112] In some embodiments, ring B is phenyl, m is 2 or 3, and each R 3 are independently halos.

[0113] In one embodiment, the moiety [ka] teeth [ka] where the wavy lines indicate the points of attachment to L and each R 3 and are independently as defined herein. In certain embodiments, each R 3 are independently halos.

[0114] In some embodiments, provided herein is a compound of formula IIA: [ka] [In the formula, ring B, m, n, L, X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0115] In some embodiments, provided herein is a compound of formula IIB: [ka] [In the formula, ring B, m, n, L, X 1 , X 2 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0116] In some embodiments, provided herein is a compound of formula IIC: [ka] [In the formula, ring B, m, n, L, R 4 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0117] In some embodiments, provided herein is a compound of formula IID: [ka] [In the formula, ring B, m, n, L, R 4 , X 5 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0118] In some embodiments, provided herein is a compound of formula IIE: [ka] [In the formula, ring B, m, n, L, R 4 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0119] In some embodiments, provided herein is a compound of formula IIF: [ka] [In the formula, ring B, m, n, L, R 4 , X 5 , X 6 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0120] In some embodiments, provided herein is a compound of formula IIG: [ka] [In the formula, m, X 2 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0121] In some embodiments, provided herein is a compound of formula IIH: [ka] [In the formula, m, X 5 , X 6 , X 7 , R 1 , R 2 and R3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0122] In some embodiments, provided herein is a compound of formula IIJ: [ka] [In the formula, m, R 4 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0123] In some embodiments, provided herein is a compound of formula IIK: [ka] [In the formula, each m, R 4 , R 5 , R 1 , R 2 and R 3 are independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0124] In some embodiments, provided herein is a compound of formula IIL: [ka] [In the formula, m, R 4 , R 5 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0125] In some embodiments, provided herein is a compound of formula IIM: [ka] [In the formula, m, R 4 , R 5 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0126] In some embodiments, provided herein is a compound of formula IIN: [ka] [In the formula, m, R 4 , R 5 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments, provided herein is a compound of formula IIO: [ka] [In the formula, each m, R 4 , R 5 , R 1 , R 2 and R 3 are independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0128] In some embodiments, provided herein is a compound of formula IIP: [ka] [In the formula, each m, R 4 , R 5 , R 1 , R2 and R 3 are independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0129] In certain embodiments, each R 5 are independently hydrogen or halo.

[0130] In some embodiments, provided herein is a compound of formula IIIA: [ka] [In the formula, ring B, m, n, L, X 1 , X 2 , X 4 , X 8 , X 9 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0131] In some embodiments, provided herein is a compound of formula IIIB: [ka] [In the formula, each R 2 , R 3 , R 4 , Ring B, m, L, X 5 and X 6 are independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments, provided herein is a compound of formula IIIC: [ka] [In the formula, ring B, m, n, L, R 4 , X 8 , X 9 , R 1, R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0133] In some embodiments, provided herein is a compound of formula IIID: [ka] [In the formula, m, X 2 , X 8 , X 9 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0134] In some embodiments, provided herein is a compound of formula IIIE: [ka] [In the formula, m, X 8 , X 9 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0135] In some embodiments, provided herein is a compound of formula IIIF: [ka] [In the formula, m, R 4 , X 8 , X 9 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0136] In some embodiments, provided herein is a compound of formula IIIG: [ka] [In the formula, each m, R 4 , R 6 , X 8 , X 9 , R 1 , R 2 and R 3 are independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0137] In some embodiments, provided herein is a compound of formula IIIH: [ka] [In the formula, m, R 4 , R 6 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0138] In some embodiments, provided herein is a compound of formula IIIJ: [ka] [In the formula, m, R 4 , R 6 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0139] In some embodiments, provided herein is a compound of formula IVA: [ka] [In the formula, ring B, n, m, L, X1 , X 2 , X 4 , X 10 , X 11 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments, provided herein is a compound of formula IVB: [ka] [In the formula, ring B, n, m, L, X 1 , X 2 , X 10 , X 11 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0141] In some embodiments, provided herein is a compound of formula IVC: [ka] [In the formula, ring B, n, m, L, X 10 , X 11 , R 4 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0142] In some embodiments, provided herein is a compound of formula IVD: [ka] [In the formula, m, X 2 , X 10 , X 11 , R1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0143] In some embodiments, provided herein is a compound of formula IVE: [ka] [In the formula, m, X 10 , X 11 , R 4 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, provided herein is a compound of formula IVF: [ka] [In the formula, m, X 11 , R 4 , R 6 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0145] In some embodiments, provided herein is a compound of formula IVG: [ka] [In the formula, m, R 4 , R 6 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0146] In some embodiments, provided herein is a compound of formula VA: [ka] [In the formula, ring B, n, m, L, X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0147] In some embodiments, provided herein are compounds of formula VB: [ka] [In the formula, ring B, n, m, L, X 1 , X 2 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0148] In some embodiments, provided herein is a compound of formula VC: [ka] [In the formula, ring B, n, m, L, X 5 , X 6 , X 7 , R 4 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0149] In some embodiments, provided herein is a compound of formula VD: [ka] [In the formula, m, X 2 , X 5 , X 6 , X 7 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0150] In some embodiments, provided herein is a compound of formula VE: [ka] [In the formula, m, X 5 , X 6 , X 7 , R 4 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0151] In some embodiments, provided herein is a compound of formula VF: [ka] [In the formula, m, R 4 , R 5 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments, provided herein is a compound of formula VG: [ka] [In the formula, m, R 4 , R 1 , R 2 and R 3 are each independently as defined herein. or a pharmaceutically acceptable salt or solvate thereof.

[0153] In certain embodiments, each R 6 is independently hydrogen or halo. In certain embodiments, each R 6 is hydrogen.

[0154] In some embodiments, R 9 is other than hydrogen. In some embodiments, R 1 is other than -C(O)OH.

[0155] In certain embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0156] The compounds of Formula I include pharmaceutically acceptable salts thereof. Additionally, the compounds of Formula I include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, but which may be useful as intermediates in the preparation of compounds of Formula I and / or in the separation of enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0157] It is further recognized that the compounds of Formula I or their salts may be isolated in the form of solvates, and therefore, all such solvates are included within the scope of the present invention. For example, the compounds of Formula I and their salts can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0158] Pharmaceutical Compositions and Administration When used as pharmaceuticals, the compounds described herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof) can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes of administration, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (to mucous membranes, including transdermal, epithelial, ocular, and intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0159] Also provided herein are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient together with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed in a carrier, such as a capsule, sachet, paper, or other container form. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation, hi some embodiments, the composition is formulated as a tablet or capsule.

[0160] Also provided herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof as an active ingredient can be prepared by intimately mixing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0161] Suitable pharmaceutically acceptable carriers are well known in the art, and a description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0162] Methods for formulating pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0163] In some embodiments, compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical additives.Pharmaceutically acceptable additives include but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer or other similar polymeric delivery materials, serum proteins such as human serum albumin, buffer substances such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions can be prepared containing 0.005% to 100% of the chemicals described herein, with the remainder consisting of non-toxic additives. Contemplated compositions may contain 0.001% to 100%, in some embodiments 0.1 to 95%, in other embodiments 75 to 85%, and in further embodiments 20 to 80%, of the chemicals described herein. Actual methods for preparing such dosage forms are known or apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0164] In certain embodiments, the compounds and pharmaceutical compositions described herein or pharmaceutical compositions thereof can be administered to a patient in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intra-arterial, intrabronchial, intra-synovial, intracerebral, intracapsular, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intrathecal, intrasynovial, intratesticular, intrathecal, intraductal, intratumoral, intrauterine, intravascular, intravenous, intranasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal. In certain embodiments, the route of administration is parenteral (eg, intratumoral).

[0165] In some embodiments, the compound of Formula I described herein, or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, can be formulated for parenteral administration, for example, for injection via intraarterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal route.For example, such compositions can be prepared as injections in the form of liquid solutions or suspensions; solid forms suitable for preparing solutions or suspensions by adding liquid before injection can also be prepared; and formulations can also be emulsified.The preparation of such formulations is known to those skilled in the art in light of the present disclosure.In some embodiments, a device is used for parenteral administration.For example, such a device can include needle injectors, microneedle injectors, needleless injectors, and infusion techniques.

[0166] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions.In some embodiments, the form must be inorganic and fluid enough to be easily squirted.In some embodiments, the form must be stable under the conditions of manufacture and storage, and must be protected against the activity of microorganisms such as bacteria and fungi.

[0167] In some embodiments, the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In some embodiments, the prevention of microbial activity can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, for example, sugars or sodium chloride, are included. In some embodiments, prolonged absorption of injectable compositions can be brought about by the use of absorption delaying agents, for example, aluminum monostearate and gelatin in the composition.

[0168] In some embodiments, sterile injectable solution is prepared by incorporating the required amount of the compound of Formula I or its pharmaceutically acceptable salt or solvate into a solvent and optionally other ingredients as listed above, followed by filtration sterilization.In some embodiments, dispersion is prepared by incorporating various sterile active ingredients into a sterile medium that contains a basic dispersion medium and other necessary ingredients from those listed above.In some embodiments, sterile powder is used to prepare sterile injectable solution.In some embodiments, the preparation method is vacuum filtration and freeze-drying technology, which produces powder of active ingredient and other desired ingredients from the solution that has previously been sterilized by filtration.

[0169] In some embodiments, pharmaceutically acceptable additives that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide. The inactive ingredients may include, but are not limited to, one or more of SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, disodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0170] In some embodiments, suppositories can be prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or pharmaceutical composition described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0171] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof described herein, or a pharmaceutical composition thereof, is formulated for local delivery to the digestive or GI tract by oral administration (e.g., solid or liquid dosage form).

[0172] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids, and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, dosage forms may also comprise buffering agents. In some embodiments, solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0173] In some embodiments, the pharmaceutical composition is in the form of a unit dosage form such as a pill or tablet. Thus, the composition may contain a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc., together with the compound of Formula I provided herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, other solid dosage forms, such as powder, quince, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit dosage forms in which one or more compounds provided herein and pharmaceutical compositions or additional active agents are physically separated are also contemplated; for example, capsules (or tablets in capsules) of granules of each drug; bilayer tablets; two-compartment gel caps, etc. In some embodiments, enteric-coated or sustained-release oral dosage forms are also contemplated.

[0174] In certain embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful in preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0175] In some embodiments, the additives are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, sterility is not required for various oral dosage form additives, such as tablets and capsules. For example, the United States Pharmacopeia / National Formulary standard may be sufficient.

[0176] In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for ocular administration. In some embodiments, the ophthalmic composition may include any one or more of the following, but is not limited to: viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0177] In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, is formulated for topical administration to the skin or mucosa (e.g., dermal or transdermal). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are semi-solid formulations typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing a selected active agent are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the "internal" phase, generally consists of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, ointment bases, like other carriers or vehicles, should be inert, stable, non-irritating, and non-sensitizing.

[0178] In any of the above embodiments, the pharmaceutical compositions described herein can include one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0179] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In some embodiments, the compound is present at a level of about 1 to 80 wt%. Representative pharmaceutical formulations are described below.

[0180] Formulation Example 1 - Tablet Formulation The following ingredients are intimately mixed and compressed into scored tablets: [Table 23]

[0181] Formulation Example 2 - Capsule Formulation The following ingredients are intimately mixed and loaded into a hard shell gelatin capsule: [Table 24]

[0182] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration: [Table 25]

[0183] Formulation Example 4 - Injectable formulation The following ingredients are mixed to form an injectable formulation: [Table 26]

[0184] Formulation Example 5 - Suppository Formulation Suppositories weighing 2.5 g total are prepared by mixing a compound of the present disclosure with Witepsol® H-15 (saturated vegetable fatty acid triglyceride; Riches-Nelson, Inc., New York) and have the following composition: [Table 27]

[0185] In some embodiments, the dosage of the compound of Formula I or its pharmaceutically acceptable salt or solvate is determined based on multiple factors, including but not limited to the type of patient, age, weight, sex, medical condition, the severity of patient's medical condition, route of administration and the activity of the compound or its pharmaceutically acceptable salt or solvate.In some embodiments, the appropriate dosage in specific circumstances can be determined by those skilled in the medical field.In some embodiments, the total daily dosage can be divided and administered in portions throughout the day or by means of providing continuous delivery.

[0186] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of about 0.01 to about 1000 mg, for example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective amount.

[0187] In certain embodiments, a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a dose of from about 0.0002 mg / Kg body weight to about 100 mg / Kg body weight (e.g., from about 0.0002 mg / Kg to about 50 mg / Kg; from about 0.0002 mg / Kg to about 25 mg / Kg; from about 0.0002 mg / Kg to about 10 mg / Kg; from about 0.0002 mg / Kg to about 5 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 1 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 0.5 mg / Kg; approx. 0.0002 mg / Kg ~ approx. 0.1 mg / Kg; approx. 0.001 m g / Kg ~ approx. 50mg / Kg; approx. 0.001mg / Kg ~ approx. 25mg / Kg; approx. 0.001mg / Kg ~ approx. 10mg / Kg; approx. 0.001mg / Kg ~ approx. 5mg / Kg; approx. 0.00 1mg / Kg ~ approx. 1mg / Kg; approx. 0.001mg / Kg ~ approx. 0.5mg / Kg; approx. 0.001mg / Kg ~ approx. 0.1mg / Kg; approx. 0.01mg / Kg ~ approx. 50mg / Kg; approx. 0.01mg / Kg~about 25mg / Kg;about 0.01mg / Kg~about 10mg / Kg;about 0.01mg / Kg~about 5mg / Kg;about 0.01mg / Kg~about 1mg / Kg;about 0.0 In some embodiments, the compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dosage of about 100 mg / kg.

[0188] In certain embodiments, the dosage of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof may be administered daily (e.g., in a single dose or in two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, every two weeks, or once a month).

[0189] In certain embodiments, the administration period of a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period during which administration is stopped is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient for a period of time, followed by another period during which administration of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is stopped. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is administered for a first period of time, followed by a second period during which administration is stopped, followed by a third period during which administration of the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is initiated, and then a fourth period during which administration is stopped. For example, a period of administration of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, followed by a period during which administration is discontinued, is repeated for a determined or undetermined period. In some embodiments, the period of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more. In some embodiments, the period of time for which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more.

[0190] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof is orally administered to a patient one or more times daily (e.g., once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0191] In certain embodiments, the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, is parenterally administered to a patient one or more times daily (e.g., 1 to 4 times daily, once daily, twice daily, three times daily, four times daily, or in a single daily dose).

[0192] In certain embodiments, the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered parenterally to the patient weekly.

[0193] Treatment method In certain embodiments, the present invention relates to methods of treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., suppressed or impaired and / or elevated or unwanted GLP-1R) is beneficial to the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include, or further include, treatment of one or more concurrent or secondary conditions associated with any one or more of the conditions described herein.

[0194] Provided herein are methods for treating a GLP-1-associated disease, disorder, or condition, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as disclosed herein.

[0195] In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), slow-onset autoimmune diabetes in adults (LADA), obesity, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, Renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, hyperglycemia, postprandial lipemia These conditions include, but are not limited to, diabetes, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's, Alzheimer's disease, cognitive dysfunction, schizophrenia, and polycystic ovarian syndrome (PCOS).

[0196] In certain embodiments, the disease, disorder, or condition is selected from the group consisting of type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, insulin resistance, insulin-resistant steroid hormone (SSR), ... The present invention relates to a multi-catheter steroid hormone (SAH), a hormone-dependent metabolic syndrome (HDS), a metabolic syndrome (MSS), a metabolic syndrome (MSH), a metabolic syndrome (MSS ...

[0197] In certain embodiments, the disease, disorder, or condition includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulceration, or any combination thereof.

[0198] In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient described herein induce one or more of blood glucose reduction (e.g., lowering blood glucose levels), reducing blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing beta-cell mass, regulating gastric acid secretion, regulating gastric emptying, reducing body mass index (BMI), and / or reducing glucagon production (e.g., levels). In certain embodiments, the compounds, pharmaceutical compositions, and methods for treating a patient described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein is a method for regulating glucose or insulin levels in a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as disclosed herein.

[0199] In certain embodiments, provided herein is a method of reducing the risk of major adverse cardiovascular events (MACE) in a patient in need thereof (e.g., by approximately at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In some embodiments, the patient is an adult diagnosed with heart disease. In some embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In some embodiments, the patient is an adult with type 2 diabetes (T2D). In some embodiments, the patient is an adult with heart disease. In some embodiments, the patient has type 2 diabetes (T2D) and heart disease.

[0200] Indications obesity In some embodiments, the condition, disease, or disorder is obesity and conditions, diseases, or disorders associated with or related to obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal adiposity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, or beta-blocker-induced obesity).

[0201] In some embodiments, the condition, disease or disorder is associated with obesity. Examples of such condition, disease or disorder include, but are not limited to, impaired glucose tolerance, diabetes (e.g., type 2 diabetes, obese diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycle, menstrual flow and cycle abnormalities, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome and metabolic syndrome. In some embodiments, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients who show symptoms of both obesity and insulin deficiency.

[0202] diabetes In some embodiments, the condition, disease or disorder is diabetes.Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity diabetes, autoimmune diabetes and borderline diabetes.In some embodiments, the condition, disease or disorder is type 2 diabetes (e.g., diet-treated type 2 diabetes, sulfonylurea-treated type 2 diabetes, extreme type 2 diabetes, long-term insulin-treated type 2 diabetes).

[0203] Provided herein are methods for treating diabetes in a patient, the method comprising: (a) determining that the patient has type 2 diabetes; and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as disclosed herein.

[0204] Provided herein is a method for treating type 2 diabetes in a patient, the method comprising administering to the patient identified or diagnosed as having type 2 diabetes a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein.

[0205] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, as disclosed herein.

[0206] In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce fasting blood glucose levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce non-fasting blood glucose levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce HbA1c levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce glucagon levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein increase insulin levels. In some embodiments, the compounds, pharmaceutical compositions, and methods for treating patients with conditions, diseases, or disorders (e.g., type 2 diabetes) described herein reduce BMI.

[0207] In certain embodiments, a reduction of about 5% to about 95% in fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction in fasting blood glucose levels to about 126 mg / dL or less, about 110 mg / dL or less, or about 90 mg / dL or less indicates treatment of type 2 diabetes.

[0208] In certain embodiments, a reduction of about 5% to about 95% in non-fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in non-fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in non-fasting blood glucose levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of non-fasting blood glucose levels to about 200 mg / L or less, about 150 mg / L or less, or about 130 mg / L or less indicates treatment of type 2 diabetes.

[0209] In certain embodiments, a reduction of about 5% to about 95% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 15% to about 80% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of about 25% to about 60% in HbA1c levels indicates treatment of type 2 diabetes. In certain embodiments, a reduction of HbA1c levels to about 6.5% or less, about 6.0% or less, or about 5.0% or less indicates treatment of type 2 diabetes.

[0210] In some embodiments, a decrease of about 5% to about 95% in glucagon levels indicates treatment of type 2 diabetes. In some embodiments, a decrease of about 15% to about 80% in glucagon levels indicates treatment of type 2 diabetes. In some embodiments, a decrease of about 25% to about 60% in glucagon levels indicates treatment of type 2 diabetes. In some embodiments, an increase of about 5% to about 95% in insulin levels indicates treatment of type 2 diabetes. In some embodiments, an increase of about 15% to about 80% in insulin levels indicates treatment of type 2 diabetes. In some embodiments, an increase of about 25% to about 60% in insulin levels indicates treatment of type 2 diabetes.

[0211] In certain embodiments, a reduction in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes. In certain embodiments, a reduction in BMI to 40 or less, 30 or less, or 20 or less indicates treatment of type 2 diabetes.

[0212] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., diabetic complications).Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmotic diabetic coma, infectious diseases (e.g., respiratory infection, urinary tract infection, digestive infection, skin and soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hyperacusis, cerebrovascular disease, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral blood circulation disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors associated with uncontrolled cholesterol and / or lipid levels and / or inflammation), NASH, fractures and cognitive impairment.

[0213] Non-limiting examples of other disorders associated with diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic syndrome X, a metabolic disorder in which activation of GLP-1R is beneficial), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0214] In some embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein are also useful for improving the effectiveness of metformin.

[0215] Disorders of metabolically important tissues In some embodiments, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of disorders of metabolically important tissue include the liver, adipose tissue, pancreas, kidney, and intestine.

[0216] In some embodiments, the condition, disease or disorder is fatty liver disease, including but not limited to non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy and lipodystrophy.

[0217] Nonalcoholic fatty liver disease (NAFLD) represents a group of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children, eventually leading to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, isolated, mainly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (birth to 1 month); infants (1 month to 2 years); children (2 to 12 years); and adolescents (12 to 21 years, up to but not including their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In certain embodiments, the pediatric patient is between birth and 28 days old, between 29 days old and under 2 years old, between 2 and under 12 years old, or between 12 and 21 years old, up to but not including their 22nd birthday.In certain embodiments, the pediatric patient is between birth and 28 days old, between 29 days old and under 1 year old, between 1 month old and under 4 months old, between 3 months old and under 7 months old, between 6 months old and under 1 year old, between 1 year old and under 2 years old, between 2 years old and under 3 years old, between 2 years old and under 7 years old, between 3 years old and under 5 years old, between 5 years old and under 10 years old, between 6 years old and under 13 years old, between 10 years old and under 15 years old, or between 15 years old and under 22 years old. In certain embodiments, the patient is an adult patient.

[0218] Non-limiting examples of other disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., hepatic); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by altered bone metabolism such as osteoporosis, including menopausal osteoporosis, decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and altered bone metabolism due to renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures and nutritional disorders, polycystic ovary syndrome; renal diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In certain embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving post-operative recovery and / or preventing the catabolic response caused by surgical trauma.

[0219] Cardiovascular and vascular diseases In some embodiments, the condition, disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular insufficiency, myocardial infarction, hypertension (e.g., 130 / 85 mmHg or higher), and prothrombotic conditions (exemplified by high fibrinogen or plasminogen activator inhibitor levels in the blood).

[0220] In some embodiments, the condition, disease, or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular insufficiency, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disease (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[0221] Neurological disorders In some embodiments, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity, mania, Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, intracerebral hemorrhage with amyloidosis I, brain inflammation, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, US2006 / 0275288A1.

[0222] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamines) and attention-deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein may be useful for improving behavioral responses to appropriate drugs, reducing drug dependence, preventing drug abuse relapse, and reducing anxiety caused by the absence of certain addictive substances. See, e.g., US 2012 / 0021979 A1.

[0223] In certain embodiments, the compounds and pharmaceutical compositions described herein are useful for learning and memory by promoting neuroplasticity and cell differentiation, and for preserving dopaminergic neuronal and motor function in Parkinson's disease.

[0224] Insulin-Related Conditions and Disorders In certain embodiments, the condition, disease or disorder is impaired fasting glucose (IFG), impaired fasting glucose (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, high blood levels of fatty acids or glycerol, hypoglycemic states, insulin resistance syndrome, paresthesia due to hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, elevated fasting glucose, dyslipidemia (e.g., atherogenic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and associated lethargic endpoints associated with insulin.

[0225] In certain embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, impaired fasting glucose, or impaired fasting glucose to diabetes.

[0226] autoimmune disorders In some embodiments, condition, disease or disorder is autoimmune disorder.Non-limiting examples of autoimmune disorder include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis and Graves' disease.See, for example, US20120148586A1.

[0227] Stomach and bowel related disorders In some embodiments, the condition, disease, or disorder is a stomach or intestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, and ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, blind-tube syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy- and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immune deficiency syndrome).

[0228] body weight In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need of treatment). In some embodiments, the weight gain in a patient can be due to excessive food intake or an unbalanced diet, or can be due to concomitant medication (e.g., an insulin sensitizer with PPARγ agonism, such as troglitazone, rosiglitazone, englitazone, ciglitazone, or pioglitazone). In some embodiments, the weight gain can be prior to reaching obesity or can be weight gain in an obese patient. In some embodiments, the weight gain can also be drug-induced weight gain or weight gain following smoking cessation.

[0229] In some embodiments, the condition, disease or disorder is an eating disorder such as binge eating, binge eating, overeating or compulsive eating.

[0230] inflammatory diseases In some embodiments, condition, disease or disorder is inflammatory disorder.Non-limiting examples of inflammatory disorder include rheumatoid arthritis, spondylitis deformans, osteoarthritis, lower back pain, gout, post-operative or post-traumatic inflammation, bloating, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), and the inflammation and pro-inflammatory state (for example, elevated blood levels of pro-inflammatory cytokines or inflammatory C-reactive protein markers) in the disorders of metabolically important tissues, including liver, fat, pancreas, kidney and intestine.

[0231] cancer In some embodiments, the condition, disease, or disorder is cancer. Examples of suitable cancers include breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung carcinoma, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). , colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small bowel cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, throat cancer. Head cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal gland astrocytoma, pilocytic astrocytoma, generalized astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g. For example, primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low malignant potential ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid carcinoma, These include esophageal adenocarcinoma, nasal cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumor, childhood solid tumors (e.g., Wilms' tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0232] Hypothalamic-pituitary disorders In some embodiments, the condition, disease, or disorder is associated with the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-ovarian axis. In other examples, the condition, disease, or disorder is associated with the hypothalamic-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis disorders include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0233] In certain embodiments, the condition, disease or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.

[0234] Pulmonary disease In some embodiments, the condition, disease, or disorder is associated with a pulmonary disease, including, but not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0235] In certain embodiments, the condition, disease or disorder associated with diabetes is a pulmonary disease.

[0236] Combination therapy In certain embodiments, the present invention contemplates both monotherapy and combination therapy regimens.

[0237] In certain embodiments, the methods described herein can further include the administration of one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of a compound described herein.

[0238] In some embodiments, the methods described herein include administration of a compound described herein in combination with dietary therapy (e.g., dietary monitoring, diabetic diet), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modifications.

[0239] In certain embodiments, the compounds of Formula I described herein, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with one or more additional therapeutic agents.

[0240] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, antidiabetic agents, antidiabetic complication agents, antihyperlipidemic agents, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutic agents, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis therapeutic agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, drugs for treating frequent urination or urinary incontinence, NAFLD therapeutic agents, NASH therapeutic agents, dysuria therapeutic agents, and antiemetic agents.

[0241] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists ( (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diabetics, Dysglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodasquemine), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821,compounds described in WO008 / 136428 and WO008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improving drugs, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obinineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 extracted from bovine or porcine pancreas), formulations; human FGF21 formulations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), human proizelet peptide (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0242] In certain embodiments, the one or more additional therapeutic agents include those useful as, for example, antidiabetic agents.Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs, and the like. glucagon (e.g., any of the glucagon analogues described in WO2010 / 011439), agents that antagonise the action of glucagon or reduce its secretion, sulfonylureas (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glycopyramide, glybuzole, glyburide), thiazolidinediones (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglita, insulin secretagogues, such as prandial glucose control agents (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, aviglutide, and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, alogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0243] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, bile acid transporters, and the like. Ingredients include: IBAT inhibitors, glycyrrhizin, Schisandra chinensis extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, antivirals and antioxidants.

[0244] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidodestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., propyl mesylate), voxistaurin), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), serotonin and noradrenaline reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulating kinase-1 (ASK-1) inhibitors.

[0245] In certain embodiments, the one or more additional therapeutic agents include, for example, those useful for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]azastatin, and the like). cetyl]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zetia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl esters 90).

[0246] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and β-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0247] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as diuretics.Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide).

[0248] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunopotentiating activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0249] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin drugs (e.g., argatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823, and WO2005 / 113504). Thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0250] In some embodiments, the one or more additional therapeutic agents include, for example, those useful for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitrol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium. Examples of suitable vitamins include vitamin B1 and vitamin B12. Examples of suitable erectile dysfunction medications include apomorphine and sildenafil citrate. Examples of suitable therapeutic agents for urinary frequency or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Examples of suitable therapeutic agents for dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs, such as aspirin, acetaminophen, and indomethacin.

[0251] Other examples of additional therapeutic agents include drugs that regulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), drugs indicated for treating complications of long-term hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), drugs used to treat complications associated with microangiopathy, anti-dyslipidemic agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), cholesterol-lowering agents, and the like. Antihypertensive agents, including sterol-lowering agents, bile acid sequestrants (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols, e.g., phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid-binding resins, nicotinic acid (niacin) and its analogs, antioxidants (e.g., probucol), omega-3 fatty acids, adrenergic receptor antagonists, e.g., beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta-blockers. -tablockers (e.g. labetalol), adrenergic receptor agonists including alpha-2 agonists (e.g. clonidine), angiotensin converting enzyme (ACE) inhibitors (e.g. lisinopril), calcium channel blockers such as dihydropyridines (e.g. nifedipine), phenylalkylamines (e.g. verapamil) and benzothiazepines (e.g. diltiazem), angiotensin II receptor antagonists (e.g. candesartan), aldosterone receptor antagonists (e.g. eplerenone), centrally acting adrenergic drugs, e.g. Hemostatic modulators, including, for example, central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, e.g., warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors, e.g., aspirin), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel),Phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission regulators, e.g., selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), noradrenaline reuptake inhibitors (NARIs), noradrenaline-serotonin reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., fasiglifam or its hydrate, WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-reducing agents, for example, cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetanus inhibitors, tetrahydrocannabinol agents, lipid metabolism improvers (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factors TNF-α, LIF, IL-6 and oncostatin M, metabolic modifying proteins or peptides, such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors, glycation inhibitors (e.g., ALT-711),Neuroregeneration promoting drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), arrhythmia drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT -627), anesthetic analgesics (e.g., morphine), alpha 2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anti-anxiety drugs (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T-cell receptor and IL-2 receptor specific antibodies), B cell depletion therapies (e.g., anti-CD20 antibodies (e.g., Rituxan), i-BLyS antibodies), drugs affecting T cell migration (e.g., anti-integrin alpha 4 / beta 1 antibodies (e.g., Tysabri), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating TNF receptors), immunosuppressants (e.g., mycophenolic acid), and These include metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide,

[0252] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antiemetic agents. As used herein, an "antiemetic" agent refers to any agent that counters (e.g., reduces or eliminates) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetic agents in combination with a compound of Formula I described herein may, for example, allow a patient to consume a normal diet, thereby allowing for the administration of a higher dose of the compound of Formula I, thereby resulting in a more rapid response to treatment.

[0253] Non-limiting examples of antiemetic agents include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopamines / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[0254] For example, the antiemetic agent may be selected from the group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopamines / dopamine receptor antagonists, benzodiazepines and non-psychoactive cannabinoids.

[0255] In certain embodiments, the antiemetic agent is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopiride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine. Non-limiting examples of other 5HT3 receptor antagonists (serotonin receptor antagonists) include cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (plus netupitant), quetiapine, camosetron, lamosterone, licasetron, risperidone, ziprasidone, and zatosetron.

[0256] In some embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopiride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine.

[0257] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[0258] In certain embodiments, the 5HT-3 receptor antagonists are granisetron, dolasetron and ondansetron.

[0259] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0260] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0261] In some embodiments, the antiemetic agent is an antihistamine. Non-limiting examples of antihistamines include piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0262] In some embodiments, the antiemetic agent is an anticholinergic (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include atropine, scopolamine, glycopyrone, hyoscine, Artane (trihexy-5-trihexyphenidyl hydrochloride), Cogentin (benztropine mesylate), Akineton (biperiden hydrochloride), Disipal (Norflex orphenadrine mesylate), diphenhydramine, hydroxyzine, hyoscyamine, and Kemadrin (procyclidine hydrochloride).

[0263] In some embodiments, the antiemetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[0264] In certain embodiments, the antiemetic agent is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[0265] Other non-limiting examples of NK1 receptor antagonists include MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY 303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974 j. Benserazide and carbidopa k. TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], PD 154075, ([(2-benzofuran)-CHOCO]-(R)-alpha-MeTrp-(S)-NHCH(CH)Ph), FK888, and (D-Pro, D-Trp, Phe)SP.

[0266] In some embodiments, the antiemetic agent is an antidopamine / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, e.g., a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0267] In some embodiments, the antiemetic agent is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetra-hydro-cannabinol (THC), a cannabinoid agonist such as WIN 55-212 (a CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0268] Other exemplary antiemetic agents include c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptic / antipsychotics (e.g., dixalazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0269] Still other exemplary antiemetic agents include those disclosed in US20120101089A1; US10,071,088B2; US6,673,792B1; US6,197,329B1; US10,828,297B2; US10,322,106B2; US10,525,033B2; WO2009080351A1; WO2019203753A2; WO2002020001A2; US8,119,697B2; US5,039,528; US20090305964A1; and WO2006 / 111169, each of which is incorporated by reference in its entirety.

[0270] In certain embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contacting or administering the compounds and pharmaceutical compositions (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0271] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or administration of the compound and pharmaceutical composition.For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are simultaneously provided to the patient in the same dosage form.In another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are simultaneously provided to the patient in separate dosage forms.

[0272] Patient Selection In certain embodiments, the methods described herein further include identifying a patient (e.g., a subject) in need of such treatment (e.g., by blood assay, body mass index, or other conventional methods known in the art).

[0273] In certain embodiments, the methods described herein further include identifying a patient (e.g., a subject) having a disease, disorder, or condition (e.g., a GLP-1-associated disease, disorder, or condition) provided herein.

[0274] In certain embodiments, the methods described herein further include identifying a patient (e.g., a patient) with type 2 diabetes. In certain embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine the level of hemoglobin A1c (HbA1c), fasting blood glucose, non-fasting blood glucose, or any combination thereof. In certain embodiments, the HbA1c level is between about 6.5% and about 24.0%. In certain embodiments, the HbA1c level is about 6.5% or greater. In certain embodiments, the HbA1c level is about 8.0% or greater. In certain embodiments, the HbA1c level is about 10.0% or greater. In certain embodiments, the HbA1c level is about 12.0% or greater. In certain embodiments, the HbA1c level is about 14.0% or greater. In certain embodiments, the HbA1c level is about 16.0% or greater. In certain embodiments, the HbA1c level is about 18.0% or greater. In certain embodiments, the HbA1c level is about 20.0% or greater. In some embodiments, the level of HbA1c is about 22.0% or greater, In some embodiments, the level of HbA1c is about 24.0% or greater.

[0275] In some embodiments, the fasting blood glucose level is about 120 mg / dL or more to about 750 mg / dL or more. In some embodiments, the fasting blood glucose level is about 200 mg / dL or more to about 500 mg / dL or more. In some embodiments, the fasting blood glucose level is about 300 mg / dL or more to about 700 mg / dL or more.

[0276] In some embodiments, the non-fasting blood glucose level is about 190 mg / dL or more to about 750 mg / dL or more. In some embodiments, the non-fasting blood glucose level is about 250 mg / dL or more to about 450 mg / dL or more. In some embodiments, the non-fasting blood glucose level is about 400 mg / dL or more to about 700 mg / dL or more.

[0277] In certain embodiments, determining whether a patient has type 2 diabetes further comprises determining the patient's BMI. In certain embodiments, the patient's BMI is about 22 kg / m2 More than ~ about 100kg / m 2 In one embodiment, the patient's BMI is about 30 kg / m 2 More than ~90kg / m 2 In one embodiment, the patient's BMI is about 40 kg / m 2 More than ~about 80kg / m 2 In one embodiment, the patient's BMI is about 50 kg / m 2 More than ~ about 70kg / m 2 That's all.

[0278] In some embodiments, additional factors (e.g., risk factors) used in determining whether a patient has type 2 diabetes further include the patient's age and ethnicity. In some embodiments, the patient is about 10 years or older. In some embodiments, the patient is about 15 years or older. In some embodiments, the patient is about 20 years or older. In some embodiments, the patient is about 25 years or older. In some embodiments, the patient is about 30 years or older. In some embodiments, the patient is about 35 years or older. In some embodiments, the patient is about 40 years or older. In some embodiments, the patient is about 42 years or older. In some embodiments, the patient is about 44 years or older. In some embodiments, the patient is about 46 years or older. In some embodiments, the patient is about 48 years or older. In some embodiments, the patient is about 50 years or older. In some embodiments, the patient is about 52 years or older. In some embodiments, the patient is about 54 years or older. In some embodiments, the patient is about 56 years or older. In some embodiments, the patient is about 58 years or older. In some embodiments, the patient is about 60 years or older. In some embodiments, the patient is about 62 years or older. In some embodiments, the patient is about 64 years or older. In some embodiments, the patient is about 66 years old or older. In some embodiments, the patient is about 68 years old or older. In some embodiments, the patient is about 70 years old or older. In some embodiments, the patient is about 72 years old or older. In some embodiments, the patient is about 74 years old or older. In some embodiments, the patient is about 76 years old or older. In some embodiments, the patient is about 78 years old or older. In some embodiments, the patient is about 80 years old or older. In some embodiments, the patient is about 85 years old or older. In some embodiments, the patient is about 90 years old or older. In some embodiments, the patient is about 95 years old or older. In some embodiments, the patient's ethnicity can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, Native Hawaiian, or Pacific Islander.

[0279] General synthesis method The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where certain process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressure, etc.) are given, it is recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0280] Furthermore, as will be recognized by those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references therein describe numerous protecting groups.

[0281] Furthermore, compounds of the present disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present invention, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0282] The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many of the starting materials are commercially available from sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, CA, USA), EMKA-Chemie GmbH & Co. KG (Eching, Germany), or Millipore Sigma (Burlington, MA, USA). Others are described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 5 th Organic synthesis compounds can be prepared by methods described in standard reference texts such as "The Organic Synthesis of Organic Compounds" (VCH Publishers Inc., 1989) and "The Organic Synthesis of Organic Compounds" (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0283] Scheme I shows the structure of each ring A, ring B, m, n, L, and R 3 , R 8 , X 1 , X 2 , X 3 and X 4

[0023] Described herein are general methods that can be used to synthesize compounds described herein, wherein LG is a leaving group such as halo (e.g., Cl, Br, or I) or an appropriate electrophilic moiety such as an aldehyde. Scheme I [ka]

[0284] A compound of Formula I can be provided by coupling Compound I-1 with Compound I-2 under suitable coupling reaction conditions, such as SN2 reaction conditions. Compound A of Formula I can be provided by coupling Compound I-1 with Compound IA-2 under suitable coupling reaction conditions, such as SN2 reaction conditions. Examples of suitable reaction conditions include, but are not limited to, polar aprotic solvents (e.g., acetonitrile), optionally in the presence of a base (e.g., potassium carbonate). Further derivatization of the resulting product via methods and chemical transformations known to those skilled in the art can be carried out to provide another compound of Formula I or IA. For example, when the leaving group is an electrophile, such as an aldehyde, the coupling reaction conditions can include reductive amination reaction conditions. Thus, a transformation can involve more than one reaction or set of reactants.

[0285] It should be understood that for any compound shown in Scheme I, various derivatives can be converted by functional group interconversion at any step. For example, R 3 With respect to R, various compounds of formula I or IA can be provided via transesterification or hydrolysis using methods known to those skilled in the art. Similarly, various compounds of formula I or IA can be provided via one or more R 4 is a leaving group (e.g., halo, e.g., Cl, Br, or I, or a pseudohalide such as a triflate, sulfonate, or phosphate) with a compound of formula (R 3 ) mThe compound of formula I can be provided by contact with a compound of formula -(Ring B)-M, where M is a suitable functional group such as, but not limited to, a boronic acid or derivative thereof, e.g., a boronic acid ester, a zinc or magnesium halide, an organotin compound, e.g., tributylstannane or trimethylstannane, a fluorosulfonyl ester, tin, sodium, hydrogen, etc. Such reactions are commonly used in aromatic functionalizations and are typically carried out in the presence of a suitable catalyst, such as a palladium catalyst including [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2, or tris(dibenzylideneacetone)dipalladium(0), or a copper catalyst, e.g., CuCl or CuI, and, if necessary, a suitable mediator, cocatalyst, and / or base known to those skilled in the art, using a suitable solvent / solvent mixture. After completion of the reaction, the compound of formula I can be recovered by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, etc. In certain embodiments, when control of stereochemistry is desired, appropriate control of reaction conditions and selection of substituents on reagents will direct or preserve, at least in part, the formation of various stereoisomers.

[0286] In certain embodiments, the various substituents of Formula I-1, IA, or IA-2 are as defined herein. However, derivatization thereof prior to reaction at any step and / or optional further derivatization of the resulting reaction product provides various compounds of Formula I or IA. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After completion of each reaction, each intermediate or final compound can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modifications to arrive at compounds of the present disclosure are within the skill of those skilled in the art.

[0287] In certain embodiments, the compound of Formula I-2 or IA-2 used in Scheme I is represented by Formula II-1, III-1, IV-1, or V-1: [ka] [In the formula, n, R 1 , R 2 , R 8 , X 5 , X 6 and X 7 are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde.

[0288] In certain embodiments, the compound of formula I-2 or IA-2 used in Scheme I has formula IIA-1: [ka] [In the formula, n, R 1 , R 2 , X 5 , X 6 and X 7 are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde. It is expressed by:

[0289] In certain embodiments, the compound of formula I-2 has formula IIIA-1: [ka] [In the formula, n, R 1 , R 2 , X 8 and X 9 are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde. It is expressed by:

[0290] In certain embodiments, the compound of formula I-2 has formula IVA-1: [ka] [In the formula, n, R 1 , R 2 , X 10 and X 11are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde. It is expressed by:

[0291] In certain embodiments, the compound of formula I-2 has formula VA-1: [ka] [In the formula, n, R 1 , R 2 , X 5 , X 6 and X 7 are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde. It is expressed by:

[0292] In certain embodiments, provided are methods for preparing a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, comprising the step of: [ka] and a compound of formula I-1: [ka] The compound is divided into rings B, m, n, L, and R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 and X 11are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde, under conditions sufficient to provide a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the conditions are described in Scheme I or the procedures below.

[0293] In certain embodiments, provided are methods for preparing a compound of Formula I described herein, or a pharmaceutically acceptable salt or solvate thereof, comprising the step of: [ka] and a compound of formula I-1: [ka] The compound is divided into rings B, m, n, L, and R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are each independently as defined herein, and LG is a leaving group such as halo (e.g., Cl, Br, or I) or a suitable electrophilic moiety such as an aldehyde, under conditions sufficient to provide a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the conditions are described in Scheme I or the procedures below. [Example]

[0294] General information: All evaporations were performed under reduced pressure using a rotary evaporator. Analytical samples were dried under reduced pressure (1-5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized under UV light (214 and 254 nm). Purification by P column and flash chromatography was performed using silica gel (100-200 mesh). Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1H chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), and integration. LCMS spectra were obtained using electrospray ionization on a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series, 6110 or 6120 mass spectrometer unless otherwise indicated.

[0295] The present invention will be further understood with reference to the following procedures, which are intended to be purely exemplary of the invention. The present invention is not limited in scope by the exemplary embodiments, which are intended as illustrations of only one aspect of the invention. Any methods that are functionally equivalent are within the scope of the invention. Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing and accompanying drawings. Such modifications fall within the scope of the appended claims.

[0296] Step 1 (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 1) [ka] Step A: (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinonitrile [ka] A mixture of 6-chloro-5-nitronicotinonitrile (1.00 g, 5.45 mmol), (S)-oxetan-2-ylmethanamine 4-methylbenzenesulfonate (1.67 g, 6.54 mmol), and K2CO3 (3.20 g, 16.35 mmol) in THF (35 mL) was stirred at room temperature overnight. The mixture was filtered, washed with DCM (30 mL), and concentrated to give (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinonitrile (1.00 g, 79% yield). LC-MS: m / z 235.2 (M+H) + .

[0297] Step B: (S)-5-amino-6-((oxetan-2-ylmethyl)amino)nicotinonitrile [ka] To a mixture of (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)nicotinonitrile (1.00 g, 4.27 mmol) in MeOH (30 mL) was added Pd / C (10%) (200 mg) at room temperature. The mixture was stirred at room temperature under an H atmosphere overnight. The mixture was filtered, washed with MeOH (20 mL), and concentrated to give (S)-5-amino-6-((oxetan-2-ylmethyl)amino)nicotinonitrile (650 mg, 74% yield). LC-MS: m / z 205.1 (M+H) + .

[0298] Step C: (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)pyridin-3-yl)acetamide [ka] To a mixture of (S)-5-amino-6-((oxetan-2-ylmethyl)amino)nicotinonitrile (650 mg, 3.18 mmol) in THF (20 mL) was added 2-chloroacetic anhydride (673 mg, 3.97 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)pyridin-3-yl)acetamide (crude), which was used in the next step without further purification. LC-MS: m / z 281.1 (M+H) + .

[0299] Step D: (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile [ka] A mixture of (S)-2-chloro-N-(5-cyano-2-((oxetan-2-ylmethyl)amino)pyridin-3-yl)acetamide in THF / AcOH (10 mL / 0.5 mL) was stirred at 80° C. for 1 h under microwave irradiation. The mixture was concentrated, diluted with NaHCO (aq), extracted with EtOAc (20 mL), dried over NaSO, concentrated, and the residue was purified by preparative HPLC (0.1% formic acid in HO and MeOH) to give (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (85.0 mg, 10% yield). LC-MS: m / z 263.1 (M+H) + .

[0300] Step E: (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile [ka] To a mixture of (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (85.0 mg, 0.323 mmol) in ACN (3 mL) was added 2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridine (94.0 mg, 0.323 mmol) and TEA (162 mg, 1.61 mmol) at room temperature. The mixture was stirred at 80 °C for 1 hour under microwave irradiation. The mixture was concentrated and purified by pre-TLC (PE / EtOAc=1:1) to give (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (60.0 mg, 36% yield). LC-MS: m / z 519.0 (M+H) + .

[0301] Step F: (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide [ka] To a mixture of (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (60 mg, 0.115 mmol) in EtOH (10 mL) was added HCl NHOH (40.0 mg, 0.575 mmol) and TEA (58.0 mg, 0.575 mmol) at room temperature. The mixture was stirred at 85 °C for 2 h. The mixture was concentrated, and the residue was diluted with HO and extracted with DCM (8 mL × 3). The organic layer was dried over NaSO and concentrated to give (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide (63.4 mg) (crude, product and by-product with the same retention time). LC-MS: m / z 537.2, 552 (M+H). + .

[0302] Step G: (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one [ka] To a mixture of (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide (63.4 mg, 0.115 mmol) in DMSO (6 mL) was added CDI (37.2 mg, 0.230 mmol) and DBU (43.7 mg, 0.287 mmol) at room temperature. The mixture was stirred at 70 °C overnight. The mixture was adjusted to pH = 4 with dilute HCOOH, and then HO (6 mL) was added to the mixture. The mixture was filtered, and the filter residue was dissolved in DCM, dried over NaSO, and concentrated. The residue was purified by preparative HPLC (0.1% formic acid in HO and MeOH) to give (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (3.00 mg, 4% yield).

[0303] 1 H NMR (400MHz, CDCl3) δ 8.77 (s, 1H), 8.38 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.09 - 7.13 (m, 2H), 6.63 (d, J=8.4 Hz, 1H), 5.28 (s, 2H), 5.18 - 5.24 (m, 1H), 4.88 - 4.97 (m, 1H), 4.72 - 4.79 (m, 1H), 4.61 (dd, J=14.0, 7.6 Hz, 1H), 4.44 - 4.52 (m, 1H), 4.34 - 4.41 (m, 1H), 3.79 -4.00 (m, 2H), 3.00 - 3.27 (m, 1H), 2.85 - 2.97 (m, 2H), 2.67 - 2.81 (m, 2H), 2.39 - 2.49 (m, 2H). 19F NMR (376MHz, CDCl3) δ -115.57. LC-MS: m / z 578.0 (M+H) + .

[0304] Step 2 (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 2) [ka] Step A: (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile [ka] A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-ium chloride (50.0 mg, 0.152 mmol), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (39.8 mg, 0.152 mmol), and K2CO3 (62.9 mg, 0.456 mmol) in acetonitrile (4 mL) was stirred at 60 °C overnight. The mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated and purified by preparative TLC (PE / EtOAc=1 / 1) to give (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (72.0 mg, 91% yield). LC-MS: m / z 518.4 (M+H) + .

[0305] Step B: (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboximidamide [ka] A solution of (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (72.0 mg, 0.139 mmol), hydroxylamine hydrochloride (48.0 mg, 0.695 mmol), and triethylamine (78.0 mg, 0.765 mmol) in ethanol (5 mL) was stirred at 90 °C for 3 h. The mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was dried over NaSO and filtered. The filtrate was concentrated and purified by preparative TLC (DCM / MeOH=10 / 1) to give (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboximidamide (62.0 mg, 81% yield). LC-MS: m / z 551.4 (M+H) + .

[0306] Step C: (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-1,2,4-oxadiazol-5(4H)-one [ka] A mixture of (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboximidamide (72.0 mg, 0.139 mmol), 1,1'-carbonyldiimidazole (36.5 mg, 0.225 mmol), and DBU (42.9 mg, 0.283 mmol) in DMSO (3 mL) was stirred at 70 °C for 1 h. The mixture was diluted with HO (20 mL) and extracted with DCM (30 mL × 3). The combined organic phase was dried over NaSO and filtered. The filtrate was concentrated and purified by preparative HPLC (0.1% HCOOH in water / CHCN) to give (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-1,2,4-oxadiazol-5(4H)-one (30.0 mg, 38% yield).

[0307] 1H NMR (400MHz, DMSO-d6) δ 12.95 (br.s, 1H), 8.14 (d, J=1.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.44 (dd, J=10.0, 2.0 Hz, 1H), 7.28 (dd, J=8.4, 2.0 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 5.26 (s, 2H), 5.02 - 5.13 (m, 1H), 4.76 (dd, J=15.2, 7.2 Hz, 1H), 4.63 (dd, J=15.2, 3.2 Hz, 1H), 4.43 - 4.51 (m, 1H), 4.35 - 4.42 (m, 1H), 4.15 (d, J=13.6 Hz, 1H), 4.02 (d, J=13.6 Hz, 1H), 3.62 (q, J=16.0 Hz, 2H), 2.70 - 2.87 (m, 4H), 2.59 - 2.69 (m, 1H), 2.35 - 2.45 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -115.18. LC-MS: m / z 577.1 (M+H) + .

[0308] Step 3 2-[(4-chloro-2-fluorophenyl)methoxy]-3-cyclopropyl-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (compound 3) [ka] Step A: 2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt [ka] To a solution of tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (200 mg, 0.46 mmol) in DCM (5 mL) was added TFA (1 mL). The solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to give 2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (250 mg, crude). MS calculated: 332.1; MS found: 333.1 [M+H-TFA] + .

[0309] Step B: (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile [ka] A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,6,7,8-tetrahydro-1,7-naphthyridine TFA salt (250 mg, 0.75 mmol), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (100 mg, 0.38 mmol), and DIEA (492.37 mg, 3.82 mmol) in DMF (5.0 mL) was stirred at 70 °C for 1 h. The reaction mixture was diluted with HO (40 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH=100 / 1) to give (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (200 mg, yield: 94%). MS calculated: 558.19; MS found: 559.2 [M+H] + .

[0310] Step C: (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide [ka] A solution of (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile (200 mg, 0.36 mmol), HONH₂·HCl (149.46 mg, 2.15 mmol), and TEA (145.44 mg, 1.44 mmol) in EtOH (4 mL) was stirred at 70 °C for 1 h. The reaction mixture was filtered and dried to give (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide (130 mg, 61% yield). MS calculated: 591.22; MS found: 592.2 [M+H] + .

[0311] Step D: (S)-5-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3-(trifluoromethyl)-1,2,4-oxadiazole [ka] To a solution of (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide (130 mg, 0.22 mmol) in THF (2 mL) was added TFAA (92.23 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (5.0 mL) and extracted with EtOAc (15 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=30 / 1) to give (S)-5-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3-(trifluoromethyl)-1,2,4-oxadiazole (130 mg, yield: 89%). MS calculated: 669.19; MS found: 670.2 [M+H] + .

[0312] Step E: 2-[(4-chloro-2-fluorophenyl)methoxy]-3-cyclopropyl-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A mixture of (S)-5-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-cyclopropyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3-(trifluoromethyl)-1,2,4-oxadiazole (130 mg, 0.19 mmol) and N2H4·HO (19.43 mg, 0.39 mmol) in DMF (2 mL) was stirred at 70 °C for 1 h. The reaction mixture was directly purified by preparative HPLC (0.1% FA / HO / CHCN) to give 2-[(4-chloro-2-fluorophenyl)methoxy]-3-cyclopropyl-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (65.40 mg, yield: 51%).

[0313] 1 H NMR (400MHz, DMSO-d6) δ 9.00 (d, J=1.6 Hz, 1 H), 8.61 (d, J=1.6 Hz, 1 H), 7.56 (t, J=8.4 Hz, 1 H), 7.44 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.29 (dd, J=8.0 Hz, 1.6 Hz, 1 H), 7.06 (s, 1 H), 5.32 (s, 2 H), 5.09-5.20 (m, 1 H), 4.77-4.86 (m, 1 H), 4.65-4.74 (m, 1 H), 4.42-4.52 (m, 1 H), 4.30-4.39 (m, 1 H), 4.07-4.21 (m, 2 H), 3.61 (s, 2 H), 2.76-2.84 (m, 2 H), 2.60-2.74 (m, 3 H), 2.38-2.50 (m, 1 H), 1.91-2.00 (m, 1 H), 0.82-0.91 (m, 2 H), 0.60-0.68 (m, 2 H). 19F NMR (376MHz, DMSO-d6) δ -63.34, -115.25. LC-MS: m / z 669.0 (M+H) + .

[0314] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 4) [ka] Compound 4 was synthesized following a route similar to procedure 3, using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in step A and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in step B.

[0315] 1 H NMR (400MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.31 (s, 1 H), 7.93 (s, 1 H), 7.41-7.55 (m, 2 H), 7.31 (d, J=8.0 Hz, 1 H), 5.42 (s, 2 H), 5.05-5.16 (m, 1 H), 4.85-4.94 (m, 1 H), 4.70-4.79 (m, 1 H), 4.45-4.53 (m, 1 H), 4.34-4.42 (m, 1 H), 4.22, 4.11(ABq, J=14.0 Hz, 2 H), 3.66-3.80 (m, 2 H), 2.78-2.90 (m, 4 H), 2.61-2.72 (m, 1 H), 2.33-2.44 (m, 1 H). 19F NMR (376MHz, DMSO-d6) δ -61.69, -63.42, -115.00. LC-MS: m / z 697.0 (M+H) + .

[0316] 3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 5) [ka] Compound 5 was synthesized following a route similar to Procedure 3, using tert-butyl 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B.

[0317] 1 H NMR (400MHz, DMSO-d6) δ 9.17 (d, J=0.8 Hz, 1 H), 8.32 (d, J=0.4 Hz, 1 H), 7.73 (s. 1 H), 7.55 (t, J=8.0 Hz, 1 H), 7.45 (dd, J=10.0 Hz, J=2.0 Hz, 1 H), 7.31 (dd, J=8.0 Hz, J=1.6 Hz, 1 H), 5.35 (s, 2 H), 5.06-5.14 (m. 1 H), 4.86-4.95 (m, 1 H), 4.70-4.79 (m, 1 H), 4.45-4.52 (m, 1 H), 4.36-4.41 (m, 1 H), 4.20, 4.09(ABq, J=13.6 Hz, 2 H), 3.58-3.73 (m, 2 H), 2.72-2.88 (m, 4 H), 2.62-2.70 (m, 1 H), 2.34-2.44 (m, 1 H).19 F NMR (376MHz, DMSO-d6) δ -63.73, -114.99. LC-MS: m / z 663.2 (M+H) + .

[0318] Step 4 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 6) [ka] [ka] Step A: 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt [ka] To a solution of tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (400 mg, 0.87 mmol) in DCM (6 mL) was added TFA (2 mL). The solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to give 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (980 mg, crude). MS calculated: 360.07; MS found: 361.0 [M+H-TFA] + .

[0319] Step B: (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((3-chloro-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (480 mg, 1.33 mmol), (S)-3-chloro-6-(chloromethyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine (254 mg, 0.93 mmol), and DIEA (1.70 g, 13.30 mmol) in DMF (5.0 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with HO (60 mL) and extracted with EtOAc (40 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH=60 / 1) to give (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((3-chloro-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (430 mg, yield: 78%). MS calculated: 596.11; MS found: 597.2 [M+H] + .

[0320] Step C: Ethyl (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylate [ka] To a mixture of (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((3-chloro-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-6-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (390 mg, 0.65 mmol) in EtOH (10.0 mL) was added PdCl(dppf) (48.00 mg, 0.065 mmol) and KOAc (127.00 mg, 1.30 mmol). The mixture was stirred at 75 °C for 4 hours under CO. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=60 / 1) to give ethyl (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylate (450 mg, yield: 98.5%). MS calculated: 634.17; MS found: 635.4 [M+H] + .

[0321] Step D: (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid [ka] To a mixture of ethyl (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylate (420 mg, 0.66 mmol) in MeOH (10.0 mL) was added NaOH (2 M, 0.66 mL, aq.). The mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH = 7 with 1 N HCl (aq) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid (410 mg, crude). MS calculated: 606.14; MS found: 607.0 [M+H] + .

[0322] Step E: (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide [ka] A mixture of (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxylic acid (380 mg, 0.63 mmol), NH4Cl (49.85 mg, 0.94 mmol), HATU (357.20 mg, 0.94 mmol), DIEA (162.54 mg, 1.26 mmol) in DMF (4.0 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=80 / 1) to give (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide (530 mg, impure). MS calculated: 605.16; MS found: 606.0 [M+H] + .

[0323] Step F: (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile [ka] A mixture of (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboxamide (530 mg, 0.88 mmol), Burgess reagent (833.98 mg, 3.50 mmol) in DCM (4.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH=80 / 1) to give (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile (380 mg, yield: 74%) (2 steps). MS calculated: 587.15; MS found: 588.2 [M+H] + .

[0324] Step G: (S,Z)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboximidamide [ka] A solution of (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile (350 mg, 0.60 mmol), HONH₂·HCl (248.64 mg, 3.60 mmol), and TEA (242.40 mg, 2.40 mmol) in EtOH (4.0 mL) was stirred at 90 °C for 1 h. The reaction mixture was filtered and dried to give (S,Z)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboximidamide (360 mg, 98% yield). MS calculated: 620.17; MS found: 620.9 [M+H] + .

[0325] Step H: (S)-3-(6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole [ka] To a solution of (S,Z)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carboximidamide (200 mg, 0.32 mmol) in THF (4.0 mL) was added DIEA (206.40 mg, 1.60 mmol) and TFAA (135.48 mg, 0.65 mmol), and the mixture was stirred at 40 °C for 2 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10.0 mL) and extracted with EtOAc (15 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=40 / 1) to give (S)-3-(6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, yield: 36%). MS calculated: 698.14; MS found: 699.1 [M+H] + .

[0326] Step I: 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A mixture of (S)-3-(6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (80 mg, 0.11 mmol) and N2H4·HO (11.46 mg, 0.23 mmol) in DMF (1.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative HPLC (0.1% FA / HO / CHCN) to give 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (37.18 mg, yield: 46%).

[0327] 1 H NMR (400MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.94 (s, 1 H), 7.43-7.57 (m, 2 H), 7.32 (d, J=8.4 Hz, 1 H), 5.43 (s, 2 H), 5.18-5.29 (m, 1 H), 4.94-5.04 (m, 1 H), 4.81-4.91 (m, 1 H), 4.45-4.54 (m, 1 H), 4.33-4.42 (m, 1 H), 4.22-4.32 (m, 2 H), 3.80 (s, 2 H), 2.81-2.98 (m, 4 H), 2.65-2.77 (m, 2 H). 19 F NMR (376MHz, DMSO-d6) δ -61.67, -63.08, -115.03. LC-MS: m / z 698.0 (M+H) + .

[0328] 3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 7) [ka] Compound 7 was synthesized following a route similar to Procedure 4, using tert-butyl 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0329] 1 H NMR (400MHz, DMSO-d6) δ 8.50 (s, 1 H), 8.23 ​​(s, 1 H), 7.74 (s, 1 H), 7.56 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0 Hz, J=1.6 Hz, 1 H), 7.32 (dd, J=8.0 Hz, J=1.6 Hz, 1 H), 5.37 (s, 2 H), 5.30-5.34 (m, 1 H), 5.19-5.27 (m, 1 H), 4.93-5.01 (m, 1 H), 4.81-4.89 (m, 1 H), 4.45-4.52 (m, 1 H), 4.33-4.40 (m, 1 H), 4.23-4.27 (m, 2 H), 3.72 (s, 2 H), 2.84-2.90 (m, 2 H), 2.77-2.82 (m, 2 H), 2.69-2.76 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -62.81, -115.00. LC-MS: m / z 664.0 (M+H) + .

[0330] Step 5 (S)-3-(2-((2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-1,2,4-oxadiazol-5(4H)-one (Compound 8) [ka] Step A: 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt [ka] To a solution of tert-butyl 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (200 mg, 0.47 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (206 mg, crude). MS calculated: 326.04; MS found: 327.2 [M+H-TFA] + .

[0331] Step B: (S)-2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile [ka] A mixture of 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (206 mg, 0.47 mmol), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (123 mg, 0.47 mmol), and TEA (142 mg, 1.41 mmol) in DMF (4 mL) was stirred at 50° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=95:5) to give (S)-2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (250 mg, 97% yield). MS calculated: 552.12; MS found: 553.4 [M+H] + .

[0332] Step C: Methyl (S)-2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate [ka] To a solution of (S)-2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (250 mg, 0.45 mmol) in DCM (2 mL) / MeOH (2 mL) was added MeONa (254 mg, 4.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with HO (20 mL) and extracted with DCM (20 mL × 3). The organic layers were combined, washed with brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM:MeOH=95:5) to give methyl (S)-2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboimidate (270 mg, crude). MS calculated: 584.15; MS found: 585.4 [M+H] + .

[0333] Step D: (S)-5-(2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide [ka] Step E: 5-[2-({3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile [ka] To a solution of (S)-5-(2-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (150 mg, 0.24 mmol) in THF (2 mL) was added Burgess reagent (112 mg, 0.48 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to give 5-[2-({3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (2.45 mg, 2% yield).

[0334] 1 H NMR (400MHz, CD3OD) δ 9.03 (s, 1 H), 8.34 (s, 1 H), 7.47-7.54 (m, 2 H), 7.13-7.21 (m, 2 H), 5.37 (s, 2 H), 5.15-5.25 (m, 1 H), 4.69-4.81 (m, 2 H), 4.55-4.63 (m, 1 H), 4.39-4.46 (m, 1 H), 4.21, 4.12(ABq, J=13.6 Hz, 2 H), 3.58-3.71 (m, 2 H), 2.77-2.89 (m, 4 H), 2.66-2.77 (m, 1 H), 2.40-2.52 (m, 1 H). 19 F NMR (376MHz, CD3OD) δ -117.40. LC-MS: m / z 620.1 (M+H) + .

[0335] 5-[2-({3-chloro-2-[(4-chloro-2,6-difluorophenyl)methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 9) [ka] Compound 9 was synthesized following a route similar to Procedure 5, using tert-butyl 3-chloro-2-((4-chloro-2,6-difluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0336] 1 H NMR (400MHz, DMSO-d6) δ 9.22 (s, 1 H), 8.37 (s, 1 H), 7.78 (s, 1 H), 7.40 (d, J=7.6 Hz, 2 H), 5.34 (s, 2 H), 5.06-5.17 (m, 1 H), 4.87-4.96 (m, 1 H), 4.72-4.80 (m, 1 H), 4.30-4.54 (m, 4 H), 3.87-3.96 (m, 2 H), 3.03-3.14 (m, 2 H), 2.80-2.89 (m, 2 H), 2.63-2.75 (m, 1 H), 2.32-2.43 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -62.81, -112.02. LC-MS: m / z 638.3 (M+H) + .

[0337] Step 6 1-{[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (10) [ka] Step A: 1-((2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile [ka] A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (34 mg, 0.09 mmol) and TEA (48 mg, 0.48 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. 1-((2-formyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (30 mg, 0.09 mmol) was added, and the mixture was stirred for 2 h. NaBH(OAC) (80 mg, 0.38 mmol) was then added, and the resulting mixture was stirred at room temperature for an additional 16 h. The mixture was poured into water (50 mL) and extracted with DCM (2×50 mL), the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the residue was concentrated to give 1-((2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (70 mg, yield: >99.9%). MS calculated: 666.1; MS found: 667.2 [M+H] + .

[0338] Step B: 1-{[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile [ka] 1-((2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)methyl)cyclopropane-1-carbonitrile (70 mg, 0.11 mmol) and NH . A mixture of HO (0.15 mL) in EtOH (2 mL) was stirred for 1 h at 70° C. The reaction mixture was purified by preparative HPLC to give 1-{[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (10.32 mg, yield: 14.7%).

[0339] 1 H NMR (400MHz, CD3OD) δ 9.11 (d, J=2.4 Hz, 1 H), 8.54 (d, J=2.0 Hz, 1 H), 7.75 (s, 1 H), 7.47 (t, J=8.4 Hz, 1 H), 7.22 - 7.16 (m, 2 H), 5.44 (s, 2 H), 4.05 (s, 2 H), 3.70 (s, 2 H), 3.23 (s, 2 H), 2.83 - 2.90 (m, 4 H), 1.37 - 1.42 (m, 2 H), 1.18 - 1.23 (m, 2 H). 19F NMR (376MHz, CD3OD) δ -64.52, -66.01, -117.38. LC-MS: m / z 666.2 (M+H) + .

[0340] 1-{[2-({3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-3-yl]methyl}cyclopropane-1-carbonitrile (Compound 11) [ka] Compound 11 was synthesized following a route similar to Procedure 6, using 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt in Step A.

[0341] 1 H NMR (400MHz, CD3OD) δ 9.11 (s, 1 H), 8.54 (s, 1 H), 7.54 - 7.48 (m, 2 H), 7.20 - 7.16 (m, 2 H), 5.38 (s, 2 H), 4.10 (s, 2 H), 3.70 (s, 2 H), 3.22(s, 2 H), 2.92-2.83 (m, 4 H), 1.41-1.38 (m, 2 H), 1.23-1.19 (m, 2 H). 19 F NMR (376MHz, CD3OD) δ -66.36, -117.42. LC-MS: m / z 632.2 (M+H) + .

[0342] Step 7 3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-7-({3-methyl-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 12) [ka] Step A: 6-Formyl-5-methylnicotinonitrile [ka] A mixture of 5,6-dimethylnicotinonitrile (400 mg, 3.03 mmol) and SeO (3.36 g, 30.30 mmol) in dioxane (15 mL) was stirred at 80° C. for 16 hours. The reaction mixture was filtered to give 6-formyl-5-methylnicotinonitrile (320 mg, yield: 72.40%). 1 H NMR (400MHz, CDCl3) δ 10.21 (s, 1 H), 8.90 (s, 1 H), 7.93 (s, 1 H), 2.72 (s, 3 H).

[0343] Step B: 6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-methylnicotinonitrile [ka] A mixture of 3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (46 mg, 0.141 mmol) and TEA (71 mg, 0.703 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. To the mixture was added 6-formyl-5-methylnicotinonitrile (21 mg, 0.141 mmol), and the mixture was stirred for 2 h. Then, NaBH(OAC) (119 mg, 0.563 mmol) was added, and the resulting mixture was stirred at room temperature for another 16 h. The mixture was poured into water (50 mL) and extracted with DCM (2 x 50 mL), the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the residue was concentrated and purified by TLC to give 6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-methylnicotinonitrile (20 mg, yield: 31.25%). MS calculated: 456.1; MS found: 457.3 [M+H] + .

[0344] Step C: (Z)-6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-5-methylnicotinimidamide [ka] A mixture of 6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-methylnicotinonitrile (20 mg, 0.044 mmol) and aqueous NHOH (50% aqueous solution, 3.47 mg, 0.053 mmol) in EtOH (2 mL) was stirred at 90° C. for 0.5 h. The mixture was concentrated to give (Z)-6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N′-hydroxy-5-methylnicotinimidamide (22 mg, crude). MS calculated: 489.1; MS found: 490.2 [M+H] + .

[0345] Step D: 3-(6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole [ka] To a solution of (Z)-6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-5-methylnicotinimidamide (22 mg, 0.045 mmol) in THF (3 ml) was added TFAA (47 mg, 0.225 mmol) at 0°C, and then the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into aqueous NaHCO (20 mL) and extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-(6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (43 mg, crude). MS calculated: 567.1; MS found: 568.4 [M+H] + .

[0346] Step E: 3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-7-({3-methyl-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A mixture of 3-(6-((3-chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-5-methylpyridin-3-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (43 mg, 0.076 mmol) and NHNH.HO (0.47 ml) in EtOH (2 ml) was stirred at 70 °C for 1 h under N. The reaction mixture was purified by preparative HPLC to give 3-chloro-2-[(4-chloro-2-fluorophenyl)methoxy]-7-({3-methyl-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (19.01 mg, yield: 44.19%).

[0347] 1 H NMR (400MHz, CD3OD) δ 9.00 (s, 1 H), 8.23 ​​(s, 1 H), 7.56 (s, 1 H), 7.49 (t, J=8.0 Hz, 1 H), 7.23 - 7.15 (m, 2 H), 5.39 (s, 2 H), 4.06 (s, 2 H), 3.75 (s, 2 H), 2.97 - 2.95 (m, 2 H), 2.86 - 2.83 (m, 2 H), 2.54 (s, 3 H). 19 F NMR (376MHz, CD3OD) δ -66.47, -117.43. LC-MS: m / z 567.2 (M+H) + .

[0348] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-({4-methyl-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]pyridazin-3-yl}methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 13) [ka] Compound 13 was synthesized following a route similar to Procedure 7, using 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt and 6-formyl-5-methylpyridazine-3-carbonitrile in Step B.

[0349] 1 H NMR (400MHz, CD3OD) δ 8.24 (s, 1 H), 7.78 (s, 1 H), 7.49 (t, J=8.0 Hz, 1 H), 7.24 - 7.18 (m, 2 H), 5.47 (s, 2 H), 4.18 (s, 2 H), 3.75 (s, 2 H), 2.97 - 2.90 (m, 2 H), 2.89 - 2.84 (m, 2 H), 2.64 (s, 3 H). 19 F NMR (376MHz, CD3OD) δ -64.53, -66.46, -117.43. LC-MS: m / z 602.3 (M+H) + .

[0350] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 16) [ka] Compound 16 was synthesized following a route similar to Procedure 3, using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0351] 1 H NMR (400MHz, DMSO-d6) δ 9.00 (d, J=1.6 Hz, 1 H), 8.62 (d, J=1.6 Hz, 1 H), 7.93 (s, 1 H), 7.52 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0, 2.0 Hz, 1 H), 7.31 (dd, J=8.0, 2.0 Hz, 1 H), 5.43 (s, 2 H), 5.11-5.19 (m, 1 H), 4.77-4.86 (m, 1 H), 4.64-4.72 (m, 1 H), 4.43-4.51 (m, 1 H), 4.30-4.38 (m, 1H), 4.13-4.24 (m, 2 H), 3.74 (s, 2 H), 2.80-2.91 (m, 4 H), 2.61-2.70 (m, 1 H), 2.36-2.46 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.67, -63.33, -115.00. LC-MS: m / z 697.5 (M+H) + .

[0352] 5-[2-({2-[(4-chlorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 19) [ka] Compound 19 was synthesized following a route similar to Example 5, using tert-butyl 2-((4-chlorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0353] 1 H NMR (400MHz, DMSO-d6) δ 15.75 (br s, 1 H), 9.18 (s, 1 H), 8.34 (s, 1 H), 7.93 (s, 1 H), 7.35-7.50 (m, 4 H), 5.39 (s, 2 H), 5.05-5.15 (m, 1 H), 4.85-4.96 (m, 1 H), 4.70-4.80 (m, 1 H), 4.43-4.52 (m, 1 H), 4.33-4.42 (m, 1 H), 4.08-4.28 (m, 2 H), 3.66-3.80 (m, 2 H), 2.78-2.95 (m, 4H), 2.61-2.72 (m, 1 H), 2.31-2.36 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.65. LC-MS: m / z 636.6 (M+H) + .

[0354] 5-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 20) [ka] Compound 20 was synthesized following a route similar to Procedure 5, using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0355] 1 H NMR (400MHz, DMSO-d6) δ 9.20 (s, 1 H), 8.36 (s, 1 H), 7.97 (s, 1 H), 7.52 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0, 2.0 Hz, 1 H), 7.31 (dd, J=8.0, 1.2 Hz, 1 H), 5.43 (s, 2 H), 5.06-5.15 (m, 1 H), 4.87-4.96 (m, 1 H), 4.71-4.79 (m, 1 H), 4.43-4.52 (m, 1 H), 4.31-4.42 (m, 1 H), 3.80-3.95 (m, 2 H), 2.95-3.08 (m, 2 H), 2.81-2.92 (m, 2 H), 2.62-2.74 (m, 2 H), 2.29-2.42 (m, 2 H). 19 F NMR (376MHz, DMSO-d6) δ -61.73, -114.99. LC-MS: m / z 654.2 (M+H) + .

[0356] Step 8 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 18) [ka] Step A: (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide [ka] A solution of (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (80 mg, 0.14 mmol), HONH₂·HCl (37.95 mg, 0.55 mmol), and TEA (84.99 mg, 0.84 mmol) in EtOH (4.0 mL) was stirred at 40 °C for 2 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered and evaporated to give (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (65 mg, yield: 76.9%). LC-MS: m / z 620.3 (M+H) + .

[0357] Step B: 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one [ka] A mixture of (S,Z)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-N'-hydroxy-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (45 mg, 0.073 mmol), TEA (22.12 mg, 0.22 mmol), and CDI (17.67 mg, 0.11 mmol) in DMF (2.0 mL) was stirred at 50°C for 16 hours. The reaction mixture was directly purified by preparative HPLC (0.1% NH3HO / HO / CH3CN) to give 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (5.46 mg, yield: 11.6%).

[0358] 1 H NMR (400MHz, DMSO-d6) δ 9.13 (s, 1 H), 8.18 (s, 1 H), 7.93 (s, 1 H), 7.52 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0, 2.0 Hz, 1 H), 7.32 (dd, J=8.4, 2.0 Hz, 1 H), 5.43 (s, 2 H), 5.05-5.14 (m, 1 H), 4.84-4.93 (m, 1 H), 4.70-4.77 (m, 1 H), 4.43-4.51 (m, 1 H), 4.33-4.41 (m, 1 H), 4.21 (d, J=13.6 Hz, 1 H), 4.11 (d, J=13.6 Hz, 1 H), 3.67-3.80 (m, 2 H), 2.77-2.93 (m, 4 H), 2.61-2.71 (m, 1 H), 2.31-2.43 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -1.68, -114.99. LC-MS: m / z 646.1 (M+H)+ .

[0359] Step 9 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-(1H-1,2,3,4-tetrazol-5-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 14) [ka] Step A: 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-(1H-1,2,3,4-tetrazol-5-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A mixture of (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (50 mg, 0.085 mmol), TMSN3 (49.06 mg, 0.43 mmol), and DBTO (42.31 mg, 0.17 mmol) in dioxane (2.0 mL) was stirred at 100° C. for 16 hours. The mixture was cooled to room temperature and then directly purified by preparative HPLC (0.1% FA / HO / CHCN) to give 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-(1H-1,2,3,4-tetrazol-5-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (4.41 mg, yield: 7.6%).

[0360] 1 H NMR (400MHz, DMSO-d6) δ 9.20 (s, 1 H), 8.42 (s, 1 H), 7.93 (s, 1 H), 7.51 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0, 2.0 Hz, 1 H), 7.31 (dd, J=8.4, 1.6 Hz, 1 H), 5.42 (s, 2 H), 5.06-5.16 (m, 1 H), 4.86-4.96 (m, 1 H), 4.71-4.79 (m, 1 H), 4.34-4.52 (m, 2 H), 4.22 (d, J=14.0 Hz, 1 H), 4.12 (d, J=14.0 Hz, 1 H), 3.67-3.81 (m, 2 H), 2.77-2.93 (m, 4 H), 2.61-2.73 (m, 1 H), 2.30-2.45 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.68, -114.99. LC-MS: m / z 630.2 (M+H) + .

[0361] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-(1H-1,2,3,4-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 15) [ka] Compound 15 was synthesized following a route similar to Procedure 9, using (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile in Step A.

[0362] 1H NMR (400MHz, DMSO-d6) δ 9.02 (s, 1 H), 8.59 (s, 1 H), 7.93 (s, 1 H), 7.52 (t, J=8.4 Hz, 1 H), 7.45 (d, J=9.6 Hz, 1 H), 7.31 (d, J=7.6 Hz, 1 H), 5.43 (s, 2 H), 5.12-5.20 (m, 1 H), 4.76-4.86 (m, 1 H), 4.63-4.73 (m, 1 H), 4.42-4.52 (m, 1 H), 4.30-4.38 (m, 1 H), 4.13-4.24 (m, 2 H), 3.75 (s, 2 H), 2.79-2.94 (m, 4 H), 2.60-2.71 (m, 1 H), 2.36-2.49 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.67, -114.99. LC-MS: m / z 630.2 (M+H) + .

[0363] 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 29) [ka] Compound 29 was synthesized following a route similar to procedure 1 using 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt.

[0364] 1H NMR (400MHz, DMSO-d6) δ 13.09 (s, 1 H), 8.79 (d, J=2.0 Hz, 1 H), 8.44 (s, 1 H), 7.92 (s, 1 H), 7.53-7.44 (m, 2 H), 7.32-7.30 (m, 1 H), 5.42 (s, 2 H), 5.15-5.12 (m, 1 H), 4.83-4.77 (m, 1 H), 4.70-4.65 (m, 1 H), 4.48-4.43 (m, 1 H), 4.35-4.29 (m, 1 H), 4.19-4.18 (m, 2 H), 3.71-3.76 (m, 2 H), 2.86-2.83 (m, 4 H), 2.67-2.62 (m, 1 H), 2.39-2.31 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.84, -115.01. LC-MS: m / z 646.1 (M+H) + .

[0365] 3-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 30) [ka] Compound 30 was synthesized following a route similar to Procedure 1, using 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt in Step E.

[0366] 1H NMR (400MHz, DMSO-d6) δ 13.11 (s, 1 H), 8.80 (s, 1 H), 8.46 (s, 1 H), 7.92-7.88 (m, 1 H), 7.38-7.31 (m, 2 H), 5.39 (s, 2 H), 5.12-5.15 (m, 1 H), 4.69-4.79 (m, 2 H), 4.28-4.46 (m, 4 H), 3.82-3.89 (m, 2 H), 2.85-2.95 (m, 4 H), 2.61-2.70 (m, 1 H), 2.39-2.43 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.82, -112.04. LC-MS: m / z 666.2 (M+H) + .

[0367] 3-[2-({2-[(4-chlorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 31) [ka] Compound 31 was synthesized following a route similar to Procedure 1, using 2-((4-chlorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt, and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step E.

[0368] 1H NMR (400MHz, DMSO-d6) δ 9.25 (s, 1 H), 8.27 (s, 1 H), 8.05 (s, 1 H), 7.44-7.48 (m, 4 H), 5.42 (s, 2 H), 5.05-5.13 (m, 1 H), 4.88-4.94 (m, 1 H), 4.58-4.76 (m, 4 H), 4.45-4.50 (m, 1 H), 4.34-4.39 (m, 1 H), 4.17-4.24 (m, 2 H), 3.31-3.39 (m, 2 H), 2.94-3.03 (m, 1 H), 2.67-2.75 (m, 1H), 2.32-2.41 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.84, -74.36. LC-MS: m / z 628.1 (M+H) + .

[0369] 3-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 32) [ka] Compound 32 was synthesized following a route similar to Procedure 1, using 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, HCl salt and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step E.

[0370] 1H NMR (400MHz, DMSO-d6) δ 13.02 (br s, 1 H), 9.24 (s, 1 H), 8.24 (s, 1 H), 7.99 (s, 1 H), 7.31-7.40 (m, 2 H), 5.42 (s, 2 H), 5.04-5.14 (m, 1 H), 4.84-4.97 (m, 1 H), 4.71-4.79 (m, 1 H), 4.45-4.53 (m, 3 H), 4.32-4.42 (m, 1 H), 3.96-4.03 (m, 2 H), 3.11-3.16 (m, 2 H), 2.88-2.96 (m, 2H), 2.65-2.72 (m, 1 H), 2.32-2.43 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.86, -112.07. LC-MS: m / z 664.4 (M+H) + .

[0371] 3-[2-({2-[(2-chloro-4-methylphenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 33) [ka] Compound 33 was synthesized following a route similar to Procedure 1, using 2-((2-chloro-4-methylbenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step E.

[0372] 1H NMR (400MHz, DMSO-d6) δ 13.00 (s, 1H), 9.17 (s, 1H), 8.21 (s, 1H), 7.93 (s 1H), 7.41 (d, J=7.6 Hz, 1H), 7.32 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 5.06-5.11 (m, 1H), 4.87-4.93 (m, 1H), 4.72-4.77 (m, 1H), 4.44-4.49 (m, 1H), 4.34-4.39 (m, 1H), 4.20-4.23 (m, 1H), 4.09-4.13 (m, 1H), 3.67-3.79 (m, 2H), 2.82-2.86 (m, 4H), 2.62-2.68 (m, 1H), 2.33-2.42 (m, 1H), 2.29 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ -61.62. LC-MS: m / z 642.2 (M+H) + .

[0373] 3-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 34) [ka] Compound 34 was synthesized following a route similar to Procedure 1, using 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step E.

[0374] 1H NMR (400MHz, DMSO-d6) δ 13.06 (s, 1H), 9.25 (s, 1H), 8.28 (s, 1H), 7.38-7.43 (m, 3H), 5.29 (s, 2H), 5.08-5.12 (m, 1H), 4.90-4.94 (m, 1H), 4.73-4.78 (m, 1H), 4.50 (dd, J=12.4 Hz, 6.4 Hz, 1H), 4.33-4.39 (m, 1H), 4.10-4.30 (m, 2H), 3.60-3.85 (m, 2H), 2.87-2.96 (m, 2H), 2.67-2.73 (m, 2H), 2.57-2.66 (m, 1H), 2.32-2.40 (m, 1H), 2.06 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ -112.28. LC-MS: m / z 610.3 (M+H) + .

[0375] 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 36) [ka] Compound 36 was synthesized following a route similar to procedure 1 using 4-fluoro-3-nitrobenzonitrile in step A and 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in step E.

[0376] 1H NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.46 (dd, J=10.0 Hz, 1.2 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 5.42 (s, 2H), 5.03-5.09 (m, 1H), 4.73-4.79 (m, 1H), 4.62 (dd, J=15.2 Hz, 2.4Hz, 1H), 4.42-4.48 (m, 1H), 4.32-4.37 (m, 1H), 4.15 (d, J=13.6 Hz, 1H), 4.04 (d, J=13.6 Hz, 1H), 3.64-3.74 (m, 2H), 2.82-2.83 (m, 4H), 2.59-2.67 (m, 1H), 2.32-2.40 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -61.68, -114.99. LC-MS: m / z 645.2 (M+H) + .

[0377] 3-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 37) [ka] Compound 37 was synthesized following a route similar to Procedure 1 using 4-fluoro-3-nitrobenzonitrile in Step A and 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine in Step E.

[0378] 1H NMR (400MHz, DMSO-d6) δ 12.84 (s, 1H), 8.07 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 7.35-7.39 (m, 2H), 7.31 (s, 1H), 5.26-5.29 (m, 2H), 5.03-5.09 (m, 1H), 4.72-4.78 (m, 1H), 4.62 (dd, J=14.8 Hz, J=2.8 Hz, 1H), 4.42-4.48 (m, 1H), 4.32-4.37 (m, 1H), 4.11 (d, J=13.6 Hz, 1H), 4.00 (d, J=13.6 Hz, 1H), 3.51-3.60 (m, 2H), 2.73-2.80 (m, 2H), 2.69-2.70 (m, 2H), 2.57-2.66 (m, 1H), 2.32-2.40 (m, 1H), 2.02 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ -112.29. LC-MS: m / z 609.3 (M+H) + .

[0379] 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-6-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 38) [ka] Compound 38 was synthesized following a route similar to Procedure 1 using 2,4-difluoro-5-nitrobenzonitrile in Step A and 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step E.

[0380] 1H NMR (400MHz, DMSO-d6) δ 12.85 (br s, 1 H), 8.08 (d, J=6.0 Hz, 1 H), 8.03 (s, 1 H), 7.90 (d, J=10.8 Hz, 1 H), 7.52 (t, J=8.0 Hz, 1 H), 7.47 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.32 (dd, J=8.0 Hz, 1.6 Hz, 1 H), 5.45 (s, 2 H), 5.00-5.08 (m, 1 H), 4.71-4.80 (m, 1 H), 4.58-4.64 (m, 1 H), 4.38-4.55 (m, 3 H), 4.32-4.37 (m, 1 H), 4.06-4.20 (m, 2 H), 3.21-3.35 (m, 2 H), 2.93-3.02 (m, 2 H), 2.62-2.71 (m, 1 H), 2.28-2.40 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.83, -114.97, -116.74. LC-MS: m / z 663.1 (M+H) + .

[0381] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-[(7-{[(2S)-oxetan-2-yl]methyl}-3-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-7H-imidazo[4,5-c]pyridazin-6-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 39) [ka] Compound 39 was synthesized following a route similar to Procedure 4, using 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step B.

[0382] 1H NMR (400MHz, DMSO-d6) δ 15.98 (s, 1 H), 8.55 (s, 1 H), 7.92 (s, 1 H), 7.41-7.38 (m, 2 H), 5.39 (s, 2 H), 5.23-5.22 (m, 1 H), 4.98-4.96 (m, 1 H), 4.88-4.84 (m, 1 H), 4.49-4.48 (m, 1 H), 4.38-4.36 (m, 1 H), 4.29 (s, 2 H), 3.79 (s, 2 H), 2.91-2.88 (m, 2 H), 2.84-2.82 (m, 2 H), 2.71-2.66 (m, 1 H), 2.32 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.77, -63.57, -112.10. LC-MS: m / z 716.2 (M+H) + .

[0383] 5-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 40) [ka] Compound 40 was synthesized following a route similar to Procedure 5, using tert-butyl 2-((4-chloro-2,6-di-fluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0384] 1H NMR (400MHz, DMSO-d6) δ 15.80 (s, 1 H), 9.25 (s, 1 H), 8.39 (s, 1 H), 7.41-7.37 (m, 3 H), 5.28 (s, 2 H), 5.15-5.07 (m, 1 H), 4.94-4.88 (m, 1 H), 4.78 (m, 1 H), 4.52-4.47 (m, 1 H), 4.38-4.34 (m, 1 H), 4.15-3.99 (m, 2 H), 2.90-2.84 (m, 2 H), 2.71-2.63 (m, 2 H), 2.41-2.32 (m, 4 H), 2.11 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -112.27. LC-MS: m / z 618.4 (M+H) + .

[0385] 5-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 41) [ka] Compound 41 was synthesized following a route similar to Procedure 5 using tert-butyl 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile in Step B.

[0386] 1H NMR (400MHz, DMSO-d6) δ 8.98-9.06 (m, 1 H), 8.64 (s, 1 H), 7.37 (d, J=7.2 Hz, 2 H), 7.32 (s, 1 H), 5.26 (s, 2 H), 5.09-5.20 (m, 1 H), 4.77-4.86 (m, 1 H), 4.65-4.74 (m, 1 H), 4.42-4.51 (m, 1 H), 4.33-4.38 (m, 1 H), 4.11-4.29 (m, 2 H), 3.58-3.71 (m, 1 H), 3.47 (s, 2 H), 2.79-2.91 (m, 1 H), 2.60-2.78 (m, 3 H), 2.36-2.47 (m, 1 H), 2.03 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -112.29. LC-MS: m / z 618.3 (M+H) + .

[0387] 5-[6-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-7-{[(2S)-oxetan-2-yl]methyl}-7H-imidazo[4,5-c]pyridazin-3-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 42) [ka] Compound 42 was synthesized following a route similar to Procedure 5, using (S)-6-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-(oxetan-2-ylmethyl)-7H-imidazo[4,5-c]pyridazine-3-carbonitrile in Step C.

[0388] 1H NMR (400MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.95 (s, 1 H), 7.52 (t, J=8.0 Hz, 1 H), 7.47 (d, J=10.0 Hz, 1 H), 7.32 (d, J=8.0 Hz, 1 H), 5.43 (s, 2 H), 5.18-5.28 (m, 1 H), 4.94-5.04 (m, 1 H), 4.81-4.91 (m, 1 H), 4.45-4.53 (m, 1 H), 4.33-4.41 (m, 1 H), 4.24-4.32 (m, 2 H), 3.81 (s, 2 H), 2.89-2.97 (m, 2 H), 2.80-2.88 (m, 2 H), 2.65-2.77 (m, 2 H). 19 F NMR (376MHz, DMSO-d6) δ -61.67, -115.04. LC-MS: m / z 655.4 (M+H) + .

[0389] 5-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carboxamide (Compound 43) [ka] Compound 43 was synthesized following a route similar to Procedure 5, using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0390] 1H NMR (400MHz, DMSO-d6) δ 9.12 (s, 1 H), 8.31 (s, 1 H), 7.92 (s, 1 H), 7.83 (s, 1 H), 7.58 (s, 1 H), 7.51 (t, J=10.8 Hz, 1 H), 7.44 (d, J=9.6 Hz, 1 H), 7.30 (d, J=8.0 Hz, 1 H), 5.42 (s, 2 H), 5.05-5.17 (m, 1 H), 4.82-4.93 (m, 1 H), 4.69-4.78 (m, 1 H), 4.43-4.53 (m, 1 H), 4.33-4.42 (m, 1 H), 4.20 (d, J=13.6 Hz, 1 H), 4.10 (d, J=13.6 Hz, 1 H), 3.64-3.82 (m, 2 H), 2.78-2.93 (m, 4 H), 2.67-2.71 (m, 1 H), 2.35-2.44 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.66, -115.00. LC-MS: m / z 672.3 (M+H) + .

[0391] 5-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-6-yl]-4H-1,2,4-triazole-3-carboxamide (Compound 44) [ka] Compound 44 was synthesized following a route similar to Procedure 5, using tert-butyl 2-((4-chloro-2,6-di-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0392] 1H NMR (400MHz, DMSO-d6) δ 9.18 (s, 1 H), 8.35 (s, 1 H), 7.97-7.89 (m, 2 H), 7.64 (s, 1 H), 7.39 (d, J=7.2 Hz, 2 H), 5.41 (s, 2 H), 5.11-5.09 (m, 1 H), 4.92-4.87 (m, 1 H), 4.76-4.72 (m, 1 H), 4.48-4.45 (m, 1 H), 4.40-4.36 (m, 1 H), 3.91-4.03 (m, 2 H), 3.00-3.11 (m, 2 H), 2.89-2.87 (m, 2 H), 2.67-2.66 (m, 2 H), 2.40-2.36 (m, 1 H), 2.33-2.32 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.85, -112.07. LC-MS: m / z 691.0 (M+H) + .

[0393] Step 10 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-imidazo[4,5-b]pyridin-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 45) [ka] Step A: (S)-3-Fluoro-2-nitro-N-(oxetan-2-ylmethyl)aniline [ka] A mixture of (S)-oxetan-2-ylmethanamine, TsOH salt (4.7 g, 54.0 mmol), 1,3-difluoro-2-nitrobenzene (12.6 g, 79.2 mmol), and DIEA (34.4 g, 267.0 mmol) in CHCN (120 mL) was stirred at 50 °C for 5 h. The resulting mixture was concentrated and then purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to give (S)-3-fluoro-2-nitro-N-(oxetan-2-ylmethyl)aniline (4.1 g, yield: 36.3%). MS calculated: 226.08; MS found: 227.3 [M+H] + .

[0394] Step B: (S)-4-Bromo-3-fluoro-2-nitro-N-(oxetan-2-ylmethyl)aniline [ka] A solution of (S)-3-fluoro-2-nitro-N-(oxetan-2-ylmethyl)aniline (4.1 g, 18.1 mmol) and NBS (3.8 g, 21.3 mmol) in DMF (80 mL) was stirred at room temperature for 2 hours. The mixture was poured into saturated NaSO, extracted with EtOAc (100 mL), and washed with brine (100 mL × 3). The organic layer was separated, dried over NaSO, filtered, and purified by reverse-phase column (PE / EtOAc = 1 / 1) to give (S)-4-bromo-3-fluoro-2-nitro-N-(oxetan-2-ylmethyl)aniline (6.5 g, yield: 97.0%). MS calculated: 303.99; MS found: 348.3 [M+H+41]. + .

[0395] Step C: (S)-4-Bromo-3-fluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine [ka] A solution of (S)-4-bromo-3-fluoro-2-nitro-N-(oxetan-2-ylmethyl)aniline (6.5 g, 21.4 mmol), Fe (6.0 g, 107.1 mmol), and NHCl (5.72 g, 106.0 mmol) in EtOH / HO (50 mL / 10 mL) was stirred at 80 °C for 2 h. The mixture was diluted with DCM (50 mL) and washed with brine (50 mL × 3). The organic layer was separated, dried over NaSO, filtered, and purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to give (S)-4-bromo-3-fluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (5.3 g, 90.4% yield). MS calculated: 274.01; MS found: 274.9 [M+H] + .

[0396] Step D: (S)-3-Amino-2-fluoro-4-((oxetan-2-ylmethyl)amino)benzonitrile [ka] A mixture of (S)-4-bromo-3-fluoro-N1-(oxetan-2-ylmethyl)benzene-1,2-diamine (2.2 g, 8.03 mmol), Zn(CN)2 (1.41 g, 12.05 mmol), RuPhos Pd G3 (0.67 g, 0.80 mmol), and XPhos (383 mg, 0.80 mmol) in NMP (10 mL) was stirred at 120 °C for 1.5 h under Ar. The mixture was diluted with EtOAc (100 mL), washed with saturated NaCl (100 mL × 3), dried over Na2SO4, filtered, concentrated, and then purified by column silica gel chromatography (PE / EtOAc = 1 / 1) to give (S)-3-amino-2-fluoro-4-((oxetan-2-ylmethyl)amino)benzonitrile (1.13 g, yield: 63.8%). MS calculated: 221.10; MS found: 222.4 [M+H] + .

[0397] Step E: (S)-2-chloro-N-(3-cyano-2-fluoro-6-((oxetan-2-ylmethyl)amino)phenyl)acetamide [ka] A mixture of (S)-3-amino-2-fluoro-4-((oxetan-2-ylmethyl)amino)benzonitrile (1.13 g, 5.11 mmol) and 2-chloroacetic anhydride (875 mg, 5.12 mmol) in THF (15 mL) was stirred at room temperature for 1 hour. The mixture was poured into saturated Na2CO3, extracted with EtOAc (100 mL), and washed with brine (100 mL × 3). The organic layer was separated, dried over Na2SO4, filtered, and purified by column silica gel chromatography (PE / EtOAc = 1 / 1) to give (S)-2-chloro-N-(3-cyano-2-fluoro-6-((oxetan-2-ylmethyl)amino)phenyl)acetamide (1.2 g, yield: 79.0%). MS calculated: 297.07; MS found: 298.1 [M+H] + .

[0398] Step F: (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile [ka] A mixture of (S)-2-chloro-N-(3-cyano-2-fluoro-6-((oxetan-2-ylmethyl)amino)phenyl)-acetamide (1.2 g, 4.04 mmol) in AcOH / dioxane (2 mL / 20 mL) was stirred at 110 °C for 16 h. The mixture was poured into saturated Na2CO3, extracted with EtOAc (100 mL), and washed with brine (100 mL × 3). The organic layer was filtered and purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to give (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile (354 mg, yield: 31%). MS calculated: 279.06; MS found: 280.1 [M+H] + .

[0399] 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-imidazo[4,5-b]pyridin-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 45) [ka] Compound 45 was then synthesized following a route similar to Procedure 1, using ((S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile and (2-((2-chloro-4-methylbenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step E.

[0400] 1 H NMR (400MHz, DMSO-d6) δ 12.82 (s, 1H), 7.92 (s, 1H), 7.57-7.66 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 5.41 (s, 2H), 5.05-5.08 (m, 1H), 4.76 (dd, J=15.2 Hz, 6.8 Hz, 1H), 4.73 (dd, J=15.2 Hz, 2.8 Hz, 1H), 4.42-4.48 (m, 1H), 4.32-4.38 (m, 1H), 4.16 (d, J=13.6 Hz, 1H), 4.06 (d, J=13.6 Hz, 1H), 3.67-3.77 (m, 2H), 2.82-2.84 (m, 4H), 2.57-2.67 (m, 1H), 2.33-2.45 (m, 1H), 2.23 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ -61.60, -126.09. LC-MS: m / z 659.3 (M+H) + .

[0401] 3-[2-({2-[(4-chlorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 46) [ka] Compound 46 was synthesized following a route similar to Procedure 1, using ((S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((4-chlorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step E.

[0402] 1 H NMR (400MHz, DMSO-d6) δ 12.86 (br s,1 H), 8.03 (s, 1 H), 7.76 (d, J=8.4 Hz, 1 H), 7.59-7.66 (m, 1 H), 7.40-7.47 (m, 4 H), 5.42 (s, 2 H), 5.01-5.10 (m, 1 H), 4.74-4.84 (m, 1 H), 4.61-4.69 (m, 1 H), 4.41-4.50 (m, 2 H), 4.29-4.38 (m, 2 H), 4.02-4.17 (m, 2 H), 3.12-3.35 (m, 2 H), 2.91-3.01 (m, 2 H), 2.62-2.73 (m, 1 H), 2.28-2.39 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.79, -125.63. LC-MS: m / z 663.0 (M+H) + .

[0403] 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 47) [ka] Compound 47 was synthesized following a route similar to Procedure 1, using ((S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step E.

[0404] 1 H NMR (400MHz, DMSO-d6) δ 12.85 (br s, 1 H), 8.03 (s, 1 H), 7.77 (d, J=8.8 Hz, 1 H), 7.59-7.66 (m, 1 H), 7.53 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.32 (dd, J=8.4 Hz, 1.6 Hz, 1 H), 5.45 (s, 2 H), 5.01-5.10 (m, 1 H), 4.74-4.84 (m, 1 H), 4.61-4.70 (m, 1 H), 4.38-4.59 (m, 3H), 4.29-4.38 (m, 1 H), 4.06-4.26 (m, 2 H), 3.19-3.45 (m, 2 H), 2.92-3.06 (m, 2 H), 2.61-2.73 (m, 1 H), 2.27-2.40 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.84, -114.96, -125.47. LC-MS: m / z 663.0 (M+H) + .

[0405] 3-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-4-fluoro-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 48) [ka] Compound 48 was synthesized following a route similar to Procedure 1, using ((S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step E.

[0406] 1 H NMR (400MHz, CD3OD) δ 7.78 (s, 1 H), 7.72-7.68 (m, 1 H), 7.64-7.54 (m, 1 H), 7.20-7.16 (m, 2 H), 5.74-5.64 (m, 2 H), 5.50 (m, 1 H), 4.91 (m, 4 H), 4.48-4.40 (m, 2 H), 4.07-4.02 (m, 2 H), 3.46-3.33 (m, 2 H), 3.22-3.11 (m, 2 H), 2.98-2.82 (m, 2 H). 19 F NMR (376MHz, CD3OD) δ -64.64, -114.33, -129.63. LC-MS: m / z 681.3 (M+H) + .

[0407] Step 11 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-imidazo[4,5-b]pyridin-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 49) [ka] Step A: (S)-7-((5-bromo-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A mixture of 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (114 mg, 0.317 mmol), (S)-5-bromo-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine (110 mg, 0.439 mmol), and TEA (96 mg, 0.951 mmol) in MeCN (3.0 mL) was stirred at 60° C. for 2 hours. The mixture was diluted with DCM (50 mL) and washed with brine (50 mL × 3). The organic phase was dried over NaSO and concentrated to give (S)-7-((5-bromo-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (208 mg, 102% yield). MS calculated: 639.1; MS found: 640.1 [M+H] + .

[0408] Step B: S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-5-carbonitrile [ka] A solution of (S)-7-((5-bromo-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (208 mg, 0.326 mmol), Zn(CN) (114 mg, 0.977 mmol), dppf (9 mg, 0.016 mmol), and Pd(dba) (30 mg, 0.026 mmol) in DMF (3 mL) was stirred at 125 °C for 3 h under Ar. The mixture was diluted with DCM (50 mL) and washed with brine (50 mL × 3). The organic phase was dried over NaSO, filtered, and concentrated. The mixture was purified by reverse phase column chromatography to give (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-5-carbonitrile (160 mg, yield: 84%). MS calculated: 586.2; MS found: 587.3 [M+H] + .

[0409] tert-Butyl 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-imidazo[4,5-b]pyridin-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one [ka] Compound 49 was then synthesized following a route similar to Procedure 8, using ((S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-5-carbonitrile in Step A.

[0410] 1 H NMR (400MHz, DMSO-d6) δ 13.17 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.87-7.92 (m, 2H), 7.49-7.54 (m, 1H), 7.46 (dd, J=10.0 Hz, 2Hz, 1H), 7.30-7.33 (m, 1H), 5.43 (s, 2H), 5.04-5.10 (m, 1H), 4.77-4.82 (m, 1H), 4.64-4.68 (m, 1H), 4.43-4.48 (m, 1H), 4.34-4.38 (m, 1 H), 4.21 (d, J=14.0 Hz, 1H), 4.12 (d, J=14.0 Hz, 1H), 3.70-3.80 (m, 2H), 2.81-2.88 (m, 4H), 2.56-2.69 (m, 1H),2.36-2.40 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -61.67, -115.00. LC-MS: m / z 646.5 (M+H) + .

[0411] 3-[2-({2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-imidazo[4,5-b]pyridin-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 50) [ka] Compound 50 was synthesized following a route similar to Procedure 11, using 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine in Step A.

[0412] 1 H NMR (400MHz, DMSO-d6) δ 13.12 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.38 (d, J=7.2 Hz, 2H), 7.31 (s, 1H), 5.26 (s, 2H), 5.06-5.07 (m, 1H), 4.77-4.79 (m, 1H), 4.65-4.69 (m, 1H), 4.45-4.46 (m, 1H), 4.34-4.36 (m, 1H), 4.17 (d, J=13.6 Hz, 1H), 4.07 (d, J=13.6 Hz, 1H), 3.58-3.62 (m, 2H), 2.79-2.82 (m, 2H), 2.67-2.73 (m, 2H), 2.58-2.65 (m, 1H), 2.32-2.43 (m, 1H), 1.99-2.03 (m, 3H). 19 F NMR (376MHz, DMSO-d6) δ -112.29. LC-MS: m / z 610.3 (M+H) + .

[0413] 5-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]-4H-1,2,4-triazole-3-carbonitrile (Compound 17) [ka] Compound 17 was synthesized following a route similar to procedure 5 using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in step A and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile in step B.

[0414] 1 H NMR (400MHz, DMSO-d6) δ 9.01 (d, J=1.6 Hz, 1 H), 8.65 (d, J=1.6 Hz, 1 H), 7.95 (s, 1 H), 7.52 (t, J=8.4 Hz, 1 H), 7.46 (dd, J=1.6 Hz, J=8.8 Hz, 1 H), 7.31 (dd, J=2.0 Hz, J=8.4 Hz, 1 H), 5.43 (s, 2 H), 5.11-5.17 (m, 1 H), 4.79-4.84 (m, 1 H), 4.66-4.71 (m, 1 H), 4.44-4.49 (m, 1 H), 4.30-4.36 (m, 2 H), 4.21-4.28 (m, 1 H), 3.75-3.88 (m, 1 H), 3.45-3.48 (m, 1 H), 2.91-3.01 (m, 1 H), 2.84-2.90 (m, 2 H), 2.63-2.71 (m, 1 H), 2.38-2.45 (m, 2 H). 19 F NMR (376MHz, DMSO-d6) δ -61.71, -115.00. LC-MS: m / z 654.2 (M+H) + .

[0415] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-b]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 51) [ka] Compound 51 was synthesized following a route similar to Procedure 3, using tert-butyl 2-((4-chloro-2,6-di-fluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A.

[0416] 1 H NMR (400MHz, DMSO-d6) δ 15.42 (s, 1 H), 9.00 (d, J=1.6 Hz, 1 H), 8.62 (s, 1 H), 7.37 (d, J=7.2 Hz, 2 H), 7.31 (s, 1 H), 5.26 (s, 2 H), 5.16-5.13 (m, 1 H), 4.84-4.79 (dd, J1=6.0 Hz, J2=6.4 Hz, 1 H), 4.71-4.67 (dd, J1=4.0 Hz, J2=3.6 Hz, 1 H), 4.48-4.44 (m, 1 H), 4.37-4.31 (m, 1 H), 4.19-4.10 (m, 2 H), 3.61 (s, 2 H), 2.81-2.80 (m, 2 H), 2.72-2.71 (m, 2 H), 2.63-2.54 (m, 1 H), 2.44-2.32 (m, 1 H), 2.02 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -63.51, -112.29. LC-MS: m / z 661.3 (M+H) + .

[0417] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-({6-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-2-yl}methyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 52) [ka] Compound 52 was synthesized following a route similar to Procedure 3 using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A and 2,2-difluoroacetic anhydride in Step D.

[0418] 1 H NMR (400MHz, DMSO-d6) δ 15.04 (s, 0.8 H), 9.00 (d, J=2 Hz, 1 H), 8.60 (d, J=2 Hz, 1 H), 7.54 (t, J=16.4 Hz, 1 H), 7.43 (dd, J1 =2 Hz, J2 =2 Hz, 1 H), 7.33 (s, 1 H), 7.29-7.04 (m, 2 H), 5.29 (s, 2 H), 5.16-5.13 (m, 1 H), 4.86-4.78 (m, 1 H), 4.71-4.66 (m, 1 H), 4.49-4.44 (m, 1 H), 4.36-4.31 (m, 1 H), 4.18-4.09 (m, 2 H), 3.60 (s, 2 H), 2.80-2.79 (m, 2 H), 2.73-2.70 (m, 2 H), 2.67-2.66 (m, 1 H), 2.33-2.28 (m, 1 H), 2.10 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -115.33, -115.84. LC-MS: m / z 625.4 (M+H) + .

[0419] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-({6-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-2-yl}methyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 53) [ka] Compound 53 was synthesized following a route similar to Procedure 3, using tert-butyl 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A and 2,2-difluoroacetic anhydride in Step D.

[0420] 1 H NMR (400MHz, CD3OD) δ 9.06 (d, J=2 Hz, 1 H), 8.65 (d, J=2 Hz, 1 H), 7.23 (s, 1 H), 7.08 (d, J=7.2 Hz, 2 H), 6.91 (t, J=107.2 Hz, 1 H), 5.30-5.27 (m, 3 H), 4.98-4.92 (m, 2 H), 4.62-4.60 (m, 1 H), 4.43-4.40 (m, 1 H), 4.27-4.18 (m, 2 H), 3.65 (s, 2 H), 2.89-2.86 (m, 2 H), 2.81-2.78 (m, 2 H), 2.71-2.77 (m, 1 H), 2.54-2.51 (m, 1 H), 2.06 (s, 3 H). 19 F NMR (376MHz, CD3OD) δ -114.24, -117.86. LC-MS: m / z 643.4 (M+H) + .

[0421] 2-[(4-chlorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 54) [ka] Compound 54 was synthesized following a route similar to Procedure 3, using 2-((4-chlorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt, and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B.

[0422] 1 H NMR (400MHz, DMSO-d6) δ 15.42 (br s, 1 H), 9.17 (s, 1 H), 8.33 (s,1 H), 7.93 (s,1 H), 7.40-7.46 (m, 4 H), 5.39 (s, 2 H), 5.05-5.16 (m, 1 H), 4.85-4.97 (m, 1 H), 4.69-4.80 (m, 1 H), 4.42-4.52 (m, 1 H), 4.33-4.42 (m, 1 H), 4.18-4.26 (m, 1 H), 4.06-4.15 (m, 1 H), 3.64-3.80 (m, 2H), 2.78-2.90 (m, 2 H), 2.61-2.72 (m, 2 H), 2.31-2.43 (m, 2 H). 19 F NMR (376MHz, DMSO-d6) δ -61.63, -63.74. LC-MS: m / z 679.4 (M+H) + .

[0423] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-3-methyl-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 55) [ka] Compound 55 was synthesized following a route similar to Procedure 3 using tert-butyl 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B.

[0424] 1 H NMR (400MHz, DMSO-d6) δ 15.43 (s, 1 H), 9.18 (s, 1 H), 8.33 (s, 1 H), 7.38-7.35 (m, 2 H), 7.32 (s, 1 H), 5.25 (s, 2 H), 5.13-5.07 (m, 1 H), 4.94-4.88 (m, 1 H), 4.78-4.73 (m, 1 H), 4.52-4.45 (m, 1 H), 4.40-4.35 (m, 1 H), 4.24-4.04 (m, 2 H), 3.64-3.54 (m, 2 H), 2.91-2.79 (m, 2H), 2.72-2.64 (m, 3 H), 2.43-2.37 (m, 1 H), 2.03 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -61.73, -112.29. LC-MS: m / z 661.3 (M+H) + .

[0425] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-({6-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl}methyl)-3-methyl-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 56) [ka] Compound 56 was synthesized following a route similar to Procedure 3 using tert-butyl 2-((4-chloro-2,6-difluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A, (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B, and 2,2-difluoroacetic anhydride in Step D.

[0426] 1 H NMR (400MHz, DMSO-d6) δ 9.25 (s, 1 H), 8.41 (s, 1 H), 7.45 (s, 1 H), 7.35 (d, J=7.6 Hz, 2 H), 7.01-7.27 (m, 1 H), 5.30 (s, 2 H), 5.06-5.15 (m, 1 H), 4.86-4.95 (m, 1 H), 4.69-4.79 (m, 1 H), 4.45-4.54 (m, 1 H), 4.33-4.42 (m, 1 H), 4.19-4.32 (m, 2 H), 3.39-3.53 (m, 2 H), 2.91-3.02 (m, 2 H), 2.66-2.81 (m, 1 H), 2.52-2.55 (m, 2 H), 2.31-2.44 (m, 1 H), 2.08 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -112.13, -115.79. LC-MS: m / z 643.1 (M+H) + .

[0427] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-({6-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl}methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 57) [ka] Compound 57 was synthesized following a route similar to Procedure 3 using tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate in Step A, (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B, and 2,2-difluoroacetic anhydride in Step D.

[0428] 1 H NMR (400MHz, DMSO-d6) δ 15.02 (s, 1 H), 9.15 (s, 1 H), 8.31 (s, 1 H), 7.92 (s, 1 H), 7.49-7.53 (m, 1 H), 7.45 (d, J=10.4 Hz, 1 H), 7.30 (d, J=8.0 Hz, 1 H), 7.13 (t, J=52.0 Hz, 1 H), 5.42 (s, 2 H), 5.05-5.16 (m, 1 H), 4.84-4.95 (m, 1 H), 4.67-4.80 (m, 1 H), 4.43-4.52 (m, 1 H), 4.33-4.41 (m, 1 H), 4.21 (d, J=13.6 Hz, 1 H), 4.11 (d, J=13.6 Hz, 1 H), 3.66-3.82 (m, 2 H), 2.77-2.93 (m, 4 H), 2.62-2.70 (m, 1 H), 2.35-2.44 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.67, -115.00, -115.76. LC-MS: m / z 679.2 (M+H) + .

[0429] Step 12 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-thieno[2,3-d]imidazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 58) [ka] Step A: Methyl 4-bromo-5-nitrothiophene-2-carboxylate [ka] To a solution of methyl 4-bromothiophene-2-carboxylate (10.0 g, 45.25 mmol, 1.0 equiv.) in concentrated HSO (33 mL) was added a solution of fuming HNO (6.67 mL, 3.5 equiv.) in concentrated HSO (20 mL) at -5 to 10 °C. The reaction mixture was stirred at -10 °C for 1 h under N. After completion of the reaction, the mixture was added to ice (500 g) and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent PE / EA = 10 / 1) to give methyl 4-bromo-5-nitrothiophene-2-carboxylate (9.625 g, 80.27% yield). MS calculated: 264.9; MS found: 235.9 [M+H-30]. + .

[0430] Step B: Methyl (S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate [ka] To a solution of methyl 4-bromo-5-nitrothiophene-2-carboxylate (6 g, 22.64 mmol) in MeCN (200 mL), (S)-oxetan-2-ylmethanamine p-toluenesulfonate (11.7 g, 45.3 mmol) and DIEA (8.76 g, 67.9 mmol) were added, and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: DCM / MeOH = 50 / 1) to give methyl (S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (5.15 g, 83.63% yield). MS calculated: 272.05; MS found: 273.1 [M+H]. + .

[0431] Step C: Methyl (S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate [ka] To a solution of methyl (S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (500 mg, 1.84 mmol) in MeOH (40 mL) and THF (40 mL) was added Raney-Ni (200 mg), and the reaction mixture was stirred at 60 °C for 4 h under a H balloon. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give crude methyl (S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (445 mg, crude), which was used in the next step without further purification. MS calculated: 242.07; MS found: 243.1 [M+H] + .

[0432] Step D: Methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate [ka] To a solution of crude methyl (S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (445 mg, 1.84 mmol) in MeCN (50 mL) was added 1,1,1-trimethoxy-2-chloroethane (426 mg, 2.76 mmol), followed by TsOH.HO (70 mg, 0.368 mmol), and the reaction mixture was stirred at 25 °C for 6 h under N. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent PE / EA = 1 / 1) to give methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (170 mg, 25.7% yield). MS calculated: 300.03; MS found: 301.0 [M+H]. + .

[0433] 1 H NMR (400MHz, DMSO-d6) δ 7.96 (s, 1 H), 5.08-5.02 (m, 3 H), 4.67-4.63 (m, 1 H), 4.62-4.46 (m, 2 H), 4.37-4.31 (m, 1 H), 3.84 (s, 3 H), 2.71-2.66 (m, 1 H), 2.38-2.32 (m, 1 H).

[0434] Step E: Methyl (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate [ka] To a solution of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (170 mg, 0.567 mmol) in DMF (5 mL) was added 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (295 mg, 0.623 mmol) and DIEA (366 mg, 2.835 mmol), and the reaction mixture was stirred at 60° C. for 3 h under N. The reaction mixture was added to water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent PE / EA=2 / 1) to give methyl (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (160 mg, 45.2% yield). MS calculated: 624.12; MS found: 625.2 [M+H] + .

[0435] 3-[2-({2-[(4-chloro-2-fluorophenyl)methoxy]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl}methyl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-thieno[2,3-d]imidazol-5-yl]-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 58) [ka] Compound 58 was then synthesized following a route similar to Procedure 4 using methyl (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate in Step D and H in Step CDI.

[0436] 1 H NMR (400MHz, DMSO-d6) δ 13.18 (s, 1 H), 8.02 (s, 1 H), 7.82 (s, 1 H), 7.54-7.50 (t, J=16.4 Hz, 1 H), 7.49-7.46 (dd, J1=2 Hz, J2=2 Hz, 1 H), 7.33-7.31 (dd, J1=2 Hz, J2=1.6 Hz, 1 H), 5.46 (s, 2 H), 5.05-5.02 (m, 1 H), 4.68-4.62 (m, 1 H), 4.58-4.57 (m, 1 H), 4.54-4.48 (m, 2 H), 4.46-4.43 (m, 2 H), 4.34-4.31 (m, 1 H), 4.05-4.13 (m, 2 H), 3.21-3.34 (m, 2 H), 2.91-3.01 (m, 2 H), 2.70-2.65 (m, 1 H), 2.36-2.32 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.84, -114.95. LC-MS: m / z 651.1 (M+H) + .

[0437] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-[(1-{[(2S)-oxetan-2-yl]methyl}-5-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-1H-thieno[2,3-d]imidazol-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 59) [ka] Compound 59 was synthesized following a route similar to Procedure 3, using (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carbonitrile in Step C.

[0438] 1 H NMR (400MHz, DMSO-d6) δ 15.31 (s, 1 H), 7.90 (d, J=8.8 Hz, 2 H), 7.53-7.45 (m, 2 H), 7.31 (dd, J1=2 Hz, J2=1.6 Hz, 1 H), 5.43 (s, 2 H), 5.07-5.04 (m, 1 H), 4.66-4.60 (m, 1 H), 4.55-4.45 (m, 2 H), 4.34-4.31 (m, 1 H), 4.03-3.93 (m, 2 H), 3.67 (s, 2 H), 2.80-2.73 (m, 4 H), 2.62-2.60 (m, 1 H), 2.37-2.32 (m, 1 H).. 19 F NMR (376MHz, DMSO-d6) δ -61.68, -63.82, -114.98. LC-MS: m / z 702.2 (M+H) + .

[0439] Step 13 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-thieno[2,3-d]imidazol-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 60) [ka] Step A: Methyl (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboimidate [ka] A mixture of (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carbonitrile (250 mg, 0.42 mmol) and MeONa (228.43 mg, 4.23 mmol) in MeOH / DCM (2.0 mL / 2.0 mL) was stirred at 30° C. for 5 hours. The reaction mixture was concentrated and purified by column chromatography (DCM / MeOH=100 / 1) to give methyl (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboimidate (198 mg, yield: 75.1%). MS calculated: 623.14; MS found: 624.1 [M+H] + .

[0440] Step B: 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-thieno[2,3-d]imidazol-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 60) [ka] A mixture of methyl (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboimidate (188 mg, 0.30 mmol), acetohydrazide (4.69 mg, 0.60 mmol), and DIEA (116.10 mg, 0.90 mmol) in n-BuOH (4.0 mL) was stirred at 120 °C for 16 h. The reaction mixture was diluted with HO (20 mL) and extracted with DCM / MeOH (15 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The mixture was directly purified by preparative HPLC (0.1% FA / HO / CHCN) to give 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-thieno[2,3-d]imidazol-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (95.24 mg, yield: 48.8%).

[0441] 1 H NMR (400MHz, DMSO-d6) δ 13.67 (br s, 1 H), 7.91 (s, 1 H), 7.61 (s, 1 H), 7.52 (t, J=8.0 Hz, 1 H), 7.46 (dd, J=10.0 Hz, 1.6 Hz, 1 H), 7.32 (dd. J=13.6 Hz, 1 H), 3.91 (d, J=13.6 Hz, 1 H), 3.60-3.72 (m, 2 H), 2.76-2.83 (m, 4 H), 2.56-2.69 (m, 1 H), 2.29-2.41 (m, 4 H). 19F NMR (376MHz, DMSO-d6) δ -61.67, -114.96. LC-MS: m / z 648.3 (M+H) + .

[0442] 2-[(4-chlorophenyl)methoxy]-7-{[6-(5-methyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 61) [ka] Compound 61 was synthesized following a route similar to Procedure 13, using (S)-2-((2-((4-chlorophenyl)methoxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step A.

[0443] 1 H NMR (400MHz, DMSO-d6) δ 9.26 (s, 1 H), 8.41 (s, 1 H), 8.02 (s, 1 H), 7.42-7.46 (m, 4 H), 5.42 (s, 2 H), 5.05-5.15 (m, 1 H), 4.90-4.99 (m, 1 H), 4.74-4.83 (m, 1 H), 4.57-4.65 (m, 1 H), 4.45-4.55 (m, 2 H), 4.35-4.43 (m, 1 H), 4.06-4.15 (m, 2 H), 3.21-3.30 (m, 2 H), 2.92-3.01 (m, 2H), 2.65-2.75 (m, 1 H), 2.46 (s, 3 H), 2.33-2.43 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.79. LC-MS: m / z 625.2 (M+H) + .

[0444] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[6-(5-methyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 62) [ka] Compound 62 was synthesized following a route similar to Procedure 13, using (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step A.

[0445] 1 H NMR (400MHz, DMSO-d6) δ 9.08 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.46 (dd, J=10.0 Hz, 2.0 Hz, 1H), 7.31 (dd, J=8.0 Hz, 1.6 Hz, 1H), 5.42 (s, 2H), 5.07-5.12 (m, 1H), 4.84-4.89 (m, 1H), 4.69-4.73 (m, 1H), 4.44-4.50 (m, 1H), 4.35-4.40 (m, 1H), 4.19 (d, J=13.6 Hz, 1H), 4.09 (d, J=13.6 Hz, 1H), 3.68-3.77 (m, 2H), 2.82-2.88 (m, 4H), 2.64-2.68 (m, 1H), 2.33-2.41 (m, 4H). 19 F NMR (376MHz, DMSO-d6) δ -61.68, -114.99. LC-MS: m / z 643.2 (M+H) + .

[0446] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-{[6-(5-methyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 63) [ka] Compound 63 was synthesized following a route similar to Procedure 13, using (S)-2-((2-((4-chloro-2,6-difluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step A.

[0447] 1 H NMR (400MHz, DMSO-d6) δ 14.10 (s, 1 H), 9.09 (s, 1 H), 8.21 (s, 1 H), 7.90 (s, 1 H), 7.38 (d, J=7.6 Hz, 2 H), 5.39 (s, 2 H), 5.10-5.09 (m, 1 H), 4.90-4.84 (m, 1 H), 4.73-4.69 (m, 1 H), 4.50-4.44 (m, 1 H), 4.40-4.34 (m, 1 H), 4.21-4.17 (m, 1 H), 4.10-4.07 (m, 1 H), 3.76-3.66 (m, 2H), 2.85-2.82 (m, 4 H), 2.68-2.63 (m, 1 H), 2.43-2.38 (m, 1 H), 2.32 (s, 3 H). 19 F NMR (376MHz, DMSO-d6) δ -61.77, -112.08. LC-MS: m / z 661.4 (M+H) + .

[0448] 2-[(4-chlorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-(4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 64) [ka] Compound 64 was synthesized following a route similar to Procedure 13 using (S)-2-((2-((4-chlorophenyl)methoxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step A and formohydrazide in Step B.

[0449] 1 H NMR (400MHz, DMSO-d6) δ 9.26 (s, 1 H), 8.42 (s, 1 H), 8.37 (s, 1 H), 8.05 (s, 1 H), 7.41-7.48 (m, 4 H), 5.43 (s, 2 H), 5.07-5.15 (m, 1 H), 4.88-4.98 (m, 1 H), 4.74-4.82 (m, 1 H), 4.53-4.72 (m, 2 H), 4.43-4.50 (m, 1 H), 4.34-4.40 (m, 1 H), 4.16-4.26 (m, 2 H), 3.31-3.42 (m, 2 H), 2.95-3.06 (m, 2 H), 2.66-2.77 (m, 1 H), 2.33-2.44 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.83. LC-MS: m / z 611.1 (M+H) + .

[0450] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[6-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 65) [ka] Compound 65 was synthesized following a route similar to Procedure 13 using (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step A and cyclopropanecarbohydrazide in Step B.

[0451] 1 H NMR (400MHz, CD3OD) δ 9.06 (s, 1 H), 8.49 (s, 0.7 H), 8.35 (s, 1 H), 7.77 (s, 1 H), 7.464 (t, J=16 Hz, 1 H), 7.18-7.12 (m, 2 H), 5.43 (s, 2 H), 5.22-5.20 (m, 1 H), 4.93-4.91 (m, 1 H), 4.76-4.73 (m, 1 H), 4.61-4.58 (m, 1 H), 4.44-4.41 (m, 1 H), 4.26-4.22 (d, J=13.2 Hz, 1 H), 4.15-4.12 (d, J=13.2 Hz, 1 H), 3.73-3.71 (m, 2 H), 2.89-2.87 (m, 4 H), 2.72 (m, 1 H), 2.48-2.46 (m, 1 H), 2.11 (m, 1 H), 1.08-1.02 (m, 4 H). 19 F NMR (376MHz, CD3OD) δ -64.55, -117.35. LC-MS: m / z 669.2 (M+H) + .

[0452] 2-[(4-chloro-2-fluorophenyl)methoxy]-7-({6-[5-(1,1-difluoroethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl}methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 66) [ka] Compound 66 was synthesized following a route similar to Procedure 13 using (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step A and 2,2-difluoropropanehydrazide in Step B.

[0453] 1 H NMR (400MHz, DMSO-d6) δ 14.93 (br s, 1 H), 9.15 (s, 1 H), 8.30 (s, 1 H), 7.93 (s, 1 H), 7.51 (t, J=8.0 Hz, 1 H), 7.45 (dd, J=10.0 Hz, 2.0 Hz, 1 H), 7.31 (dd, J=8.4 Hz, 2.0 Hz, 1 H), 5.42 (s, 2 H), 5.06-5.16 (m, 1 H), 4.86-4.94 (m, 1 H), 4.70-4.79 (m, 1 H), 4.44-4.51 (m, 1 H), 4.35-4.42 (m, 1 H), 4.21 (d, J=14.0 Hz, 1 H), 4.10 (d, J=14.0 Hz, 1 H), 3.67-3.80 (m, 2 H), 2.78-2.91 (m, 4 H), 2.61-2.72 (m, 1 H), 2.34-2.45 (m, 1 H), 2.09 (t, J=18.8 Hz, 3 H). 19F NMR (376MHz, DMSO-d6) δ -61.68, -86.46, -115.00. LC-MS: m / z 693.3 (M+H) + .

[0454] Step 14 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[6-(5-methyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 67) [ka] Step A: (S)-7-((6-bromo-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] A solution of (S)-6-bromo-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine (500 mg, 1.587 mmol), 2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (628 mg, 1.746 mmol), and DIEA (1.023 g, 7.935 mmol) in DMF (10 mL) was stirred at 60 °C for 4 h under N. After completion of the reaction, the mixture was added to water (50 mL), and the mixture was extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent PE / EA=1 / 1) to give (S)-7-((6-bromo-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (800 mg, 78.89% yield). MS calculated: 639.07; MS found: 640.1 [M+H] + .

[0455] Step B: (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((6-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine [ka] To a solution of (S)-7-((6-bromo-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-2-((4-chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (200 mg, 0.313 mmol) in toluene (10 mL), 3-methyl-4-((2-(trifluoromethyl)benzyl)oxy)- Methylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (200 mg, 0.939 mmol), pivalic acid (2 mg, 0.019 mmol), PCyHBF (23 mg, 0.0626 mmol), Pd(II) acetate (7 mg, 0.03 mmol) and KCO (259 mg, 1.878 mmol) were added and the reaction mixture was stirred at 120 °C for 18 h under N. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluent: DCM / MeOH=25 / 1) to give (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((6-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (43 mg, 17.8% yield). MS calculated: 772.27; MS found: 773.4 [M+H] + .

[0456] Step C: 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[6-(5-methyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 67) [ka] To a solution of (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((6-(5-methyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (43 mg, 0.056 mmol) in THF (10 mL) was added TBAF 1 M in THF, 0.17 mL), and the reaction mixture was stirred at 50° C. for 4 hours under N. After completion of the reaction, the mixture was added to EtOAc (50 mL), washed with aqueous NHCl (20 mL×5), dried over NaSO, filtered, and concentrated under reduced pressure. The filtrate was purified by preparative HPLC (elution with aqueous MeCN, 0.1% TFA) to give 2-[(4-chloro-2-fluorophenyl)methoxy]-7-{[6-(5-methyl-4H-1,2,4-triazol-3-yl)-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-b]pyridin-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (1.1 mg, 2.6% yield).

[0457] 1 H NMR (400MHz, CD3OD) δ 9.05 (s, 1 H), 8.62 (s,1 H), 7.77 (s, 1 H), 7.47 (t, J=16 Hz, 1 H), 7.18-7.16 (m, 2 H), 5.44 (s, 2 H), 4.57 (m, 2 H), 4.21-4.29 (m, 2 H), 3.74 (s, 2 H), 3.55-3.53 (m, 1 H), 3.48-3.47 (m, 2 H), 3.13-3.12 (m, 2 H), 2.91-2.90 (m, 4 H), 2.53 (s, 3 H). 19 F NMR (376MHz, CD3OD) δ -64.54, -117.64. LC-MS: m / z 643.2 (M+H) + .

[0458] 2-[(4-chlorophenyl)methoxy]-7-{[4-fluoro-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-{[(2S)-oxetan-2-yl]methyl}-1H-1,3-benzodiazol-2-yl]methyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 68) [ka] Compound 68 was synthesized following a route similar to Procedure 14, using (S)-5-bromo-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole in Step A.

[0459] 1 H NMR (400MHz, DMSO-d6) δ 8.06 (s, 1 H), 7.87 (dd, J=8.4 Hz, J=6.8 Hz, 1 H), 7.63 (d, J=8.8 Hz 1 H), 7.41-7.46 (m, 4 H), 5.43 (s, 2 H), 5.01-5.09 (m, 1 H), 4.72-4.79 (m, 1 H), 4.59-4.66 (m, 2 H), 4.42-4.49 (m, 1 H), 4.29-4.36 (m, 1 H), 4.13-4.25 (m, 3 H), 3.32-3.43 (m, 2 H), 2.97-3.05 (m, 2 H), 2.62-2.72 (m, 1 H), 2.41 (s, 3 H), 2.29-2.38 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -61.83, -128.26. LC-MS: m / z 642.2 (M+H) + .

[0460] Step 15 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-({6-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl}methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 69) [ka] (S)-2-((4-chloro-2,6-difluorobenzyl)oxy)-7-((6-(5-difluoromethyl)-4H-1,2,4-dihydro-2-methylbenzyl)oxy)-3-iodo-5,6,7,8-tetrahydro-1,7-naphthyridine and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B and 2,2-difluoroacetic anhydride in Step D. To a mixture of (3-(oxetan-2-ylmethyl-3H-triazol-3-yl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)-3-iodo-5,6,7,8-tetrahydro-1,7-naphthyridine (140 mg, 0.185 mmol) in DMF (6 mL), Zn(CN) (43.55 mg, 0.371 mmol), Pd(dba) (16.98 mg, 0.019 mmol), and dppf (10.47 mg, 0.019 mmol) were added under N, and the reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction, the reaction mixture was quenched with HO (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and purified by column chromatography on silica gel (DCM / MeOH / NH3.HO=8 / 1 / 0.1) to give 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-({6-[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]-3-{[(2S)-oxetan-2-yl]methyl}-3H-imidazo[4,5-c]pyridin-2-yl}methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (18.46 mg, 15.22% yield).

[0461] 1H NMR (400MHz, DMSO-d6) δ 15.02 (s, 1H), 9.15 (s, 1H), 8.31 (s, 1H), 8.09 (s 1H), 7.43 (d, J=7.2 Hz, 2H), 7.14 (t, J=53.6, 1H), 5.41-5.43 (m, 2H), 5.09-5.11 (m, 1H), 4.86-4.92 (m, 1H), 4.72-4.76 (m, 1H), 4.45-4.50 (m, 1H), 4.35-4.40 (m, 1H), 4.21 (d, J=13.6 Hz, 1 H), 4.11 (d, J=13.6 Hz, 1H), 3.69-3.79 (m, 2H), 2.81-2.90 (m, 2H), 2.77-2.79 (m, 2H), 2.64-2.69 (m, 1H), 2.38-2.42 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -111.93, -115-75. LC-MS: m / z 654.6 (M+H) + .

[0462] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-[(1-{[(2S)-oxetan-2-yl]methyl}-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-1,3-benzodiazol-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 70) [ka] Compound 70 was synthesized following a route similar to Procedure 15, using (S)-2-((4-chloro-2,6-difluorobenzyl)oxy)-7-((6-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)-3-iodo-5,6,7,8-tetrahydro-1,7-naphthyridine in Step A.

[0463] 1H NMR (400MHz, DMSO-d6) δ 12.91 (s, 1H), 8.08-8.09 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.4Hz, 1.6 Hz, 1H), 7.40-7.44 (m, 2H), 5.40-5.43 (m, 2H), 5.04-5.07 (m, 1H), 4.72-4.78 (m, 1H), 4.63 (dd, J=14.8 Hz, 2.4 Hz, 1H), 4.42-4.48 (m, 1H), 4.31-4.36 (m, 1H), 4.15 (d, J=13.6 Hz, 1H), 4.04 (d, J=13.6 Hz, 1H), 3.71 (dd, J=24.4 Hz, 17.2 Hz, 1H), 2.76-2.85 (m, 4H), 2.60-2.68 (m, 1H), 2.33-2.40 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -111.93. LC-MS: m / z 620.5 (M+H) + .

[0464] 2-[(4-chloro-2,6-difluorophenyl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitrile (Compound 71) [ka] Compound 71 was synthesized following a route similar to Procedure 15, using (S)-2-((4-chloro-2,6-difluorobenzyl)oxy)-3-iodo-7-((3-(oxetan-2-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)methyl)-5,6,7,8-tetrahydro-1,7-naphthyridine in Step A.

[0465] 1 H NMR (400MHz, DMSO-d6) δ 9.15 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.43 (dd, J=10.8Hz, 3.2 Hz, 2H), 5.41-5.43 (m, 2H), 5.09-5.11 (m, 1H), 4.86-4.92 (m, 1 H), 4.71-4.76 (m, 1 H), 4.45-4.50 (m, 1H), 4.36-4.38 (m, 1 H), 4.23 (d, J=14 Hz, 1H), 4.12 (d, J=14 Hz, 1H), 3.69-3.81 (m, 2H), 2.85-2.89 (m, 2H), 2.77-2.79 (m, 2H), 2.64-2.69 (m, 1H), 2.38-2.41 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -63.38, -111.93. LC-MS: m / z 672.6 (M+H) + .

[0466] Step 16 2-[(4-chloro-2-fluorophenyl)methoxy]-3-(difluoromethyl)-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 72) [ka] Step A: tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-formyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate [ka] To a mixture of tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (300 mg, 0.580 mmol) in THF (5 mL) was added 10 mL of tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (300 mg, 0.580 mmol) at 0 °C under N i PrMgCl LiCl (1.3 M in THF, 0.6 mL) was added slowly. After 10 min, DMF (84 mg, 1.16 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with HO (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 5), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 10:1) to give tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-formyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (200 mg, 82.3% yield).

[0467] 1 H NMR (400MHz, DMSO-d6) δ 10.21 (s, 1 H), 7.95 (s, 1 H), 7.68 (t, J=8.4 Hz, 1 H), 7.50 (dd, J=1.6 Hz, 10.0 Hz, 1 H), 7.33 (dd, J=2.0 Hz, 8.4 Hz, 1 H), 5.76 (s, 2 H), 4.51 (s, 2 H), 3.59 (t, J=5.6 Hz, 2 H), 2.78 (t, J=5.6 Hz, 2 H), 1.44 (s, 9 H). 19 F NMR (376MHz, DMSO-d6) δ -115.03. LC-MS: m / z 295.2 (M+H) + .

[0468] Step B: tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(difluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate [ka] To a solution of tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-formyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (200 mg, 0.476 mmol) in DCM (5 mL) was added DAST (153 mg, 0.952 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EtOAc = 10: 1) to give tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(difluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (150 mg, 71.4% yield). LC-MS: m / z 443.2 (M+H) + .

[0469] Step C: 2-((4-chloro-2-fluorobenzyl)oxy)-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, HCl salt [ka] To a solution of tert-butyl 2-((4-chloro-2-fluorobenzyl)oxy)-3-(difluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (150 mg, 0.339 mmol) in dioxane (2 mL), HCl / dioxane (2 mL, 4 M) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 2-((4-chloro-2-fluorobenzyl)oxy)-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, HCl salt (200 mg, crude). LC-MS: m / z 343.5 (M+H-HCl). + .

[0470] 2-[(4-chloro-2-fluorophenyl)methoxy]-3-(difluoromethyl)-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 72) [ka] Compound 72 was then synthesized following a route similar to Procedure 3, using 2-((4-chloro-2-fluorobenzyl)oxy)-3-(difluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, HCl salt and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B.

[0471] 1 H NMR (400MHz, DMSO-d6) δ 15.48 (br s, 1 H), 9.26 (s, 1 H), 8.38 (s, 1 H), 7.87 (s, 1 H), 7.57 (t, J=8.0 Hz, 1 H), 7.46 (d, J=9.6 Hz, 1 H), 7.31 (d, J=8.0 Hz, 1 H), 7.08 (t, J=55.2 Hz, 1 H), 5.41 (s, 2 H), 5.05-5.17 (m, 1 H), 4.86-4.98 (m, 1 H), 4.64-4.80 (m, 3 H), 4.43-4.57 (m, 1 H), 4.34-4.42 (m, 1 H), 4.11-4.31 (m, 2 H), 3.26-3.48 (m, 2 H), 2.91-3.05 (m, 2 H), 2.67-2.77 (m, 1 H), 2.35-2.43 (m, 1 H). 19 F NMR (376MHz, DMSO-d6) δ -63.74, 74.29, -115.06. LC-MS: m / z 654.2 (M+H) + .

[0472] Step 17 2-{[4-(Difluoromethyl)phenyl]methoxy}-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 73) [ka] Step A: tert-Butyl 2-((4-formylbenzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate [ka] To a mixture of tert-butyl 2-hydroxy-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (1.0 g, 2.66 mmol) and 4-(bromomethyl)benzaldehyde (688 mg, 3.46 mmol) in toluene (30 mL), AgCO (1.47 g, 5.32 mmol) was added, and the mixture was stirred at room temperature at 90 °C for 4 h. The reaction mixture was quenched with HO (80 mL) and extracted with ethyl acetate (60 mL × 3). The organic layers were combined, washed with brine (60 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (EA:PE = 0-15%) to give tert-butyl 2-((4-formylbenzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (880 mg, yield: 66.9%). MS calculated: 494.07; MS found: 495.4 [M+H] + .

[0473] Step B: tert-Butyl 2-((4-(difluoromethyl)benzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate [ka] A mixture of tert-butyl 2-((4-formylbenzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (770 mg, 1.56 mmol) and DAST (1.25 g, 7.78 mmol) in DCM (30 mL) was stirred at 45 °C for 4 h. After completion of the reaction, the mixture was added to HO (20 mL) at 0 °C and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (EA: PE = 0-17%) to give tert-butyl 2-((4-(difluoromethyl)benzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (520 mg, yield: 64.6%). MS calculated: 516.07; MS found: 517.4 [M+H] + .

[0474] Step C: tert-butyl 2-((4-(difluoromethyl)benzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate [ka] A solution of tert-butyl 2-((4-(difluoromethyl)benzyl)oxy)-3-iodo-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (290 mg, 0.56 mmol), FSOCFCOOCH (324 mg, 1.68 mmol), and CuI (11 mg, 0.06 mmol) in DMF (3.0 mL) was stirred at 80 °C for 24 h under N. After completion of the reaction, the mixture was filtered and evaporated to remove DMF. The residue was purified by reverse-phase column chromatography (ACN: 0.1% FA / HO = 0-68.2%) to give tert-butyl 2-((4-(difluoromethyl)benzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (120 mg, yield: 46.7%). MS calculated: 458.16; MS found: 403.4 [M+H - 56]. + .

[0475] Step D: 2-((4-(difluoromethyl)benzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt [ka] A solution of tert-butyl 2-((4-(difluoromethyl)benzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (100 mg, 0.26 mmol) in DCM / TFA (5:1, 3 mL) was stirred at 25° C. for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure to give 2-((4-(difluoromethyl)benzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt (200 mg, crude) as a yellow solid. MS calculated: 358.11; MS found: 400.4 [M+H+41-TFA] + .

[0476] 2-{[4-(Difluoromethyl)phenyl]methoxy}-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 73) [ka] Compound 73 was then synthesized following a route similar to Procedure 3, using 2-((4-(difluoromethyl)benzyl)oxy)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine, TFA salt and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile in Step B.

[0477] 1 H NMR (400MHz, DMSO-d6) δ 15.44 (s, 1H), 9.17 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H), 7.52-7.58 (m, 4H), 7.01 (t, J=56.0 Hz, 1H), 5.46 (s, 2H), 5.09-5.11 (m, 1H), 4.88-4.94 (m, 1H), 4.77 (d, J=12.8 Hz, 1H), 4.50 (dd, J=12.8 Hz, 7.6 Hz, 1H), 4.40 (dd, J=11.6 Hz, 5.6 Hz, 1H), 4.24 (d, J=13.6 Hz, 1H), 4.13 (d, J=14.0 Hz, 1H), 3.67-3.77 (m, 2H), 2.83-2.87 (m, 4H), 2.65-2.69 (m, 1H), 2.37-2.46 (m, 1H). 19 F NMR (376MHz, DMSO-d6) δ -61.64, -63.73, -109.41. LC-MS: m / z 695.5 (M+H) + .

[0478] Step 18 2-[(5-chloropyridin-2-yl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 74) [ka] Step A: (5-chloropyridin-2-yl)methanol [ka] A mixture of methyl 5-chloropicolinate (500 mg, 2.92 mmol) and NaBH4 (333 mg, 8.76 mmol) in MeOH (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated and then purified by column chromatography on silica gel (PE / EtOAc = 1 / 1) to give (5-chloropyridin-2-yl)methanol (343 mg, yield: 82%). MS calculated: 143.01; MS found: 144.1 [M+H] + .

[0479] Step B: tert-butyl 2-((5-chloropyridin-2-yl)methoxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate [ka] To a solution of (5-chloropyridin-2-yl)methanol (107 mg, 0.75 mmol), tert-butyl 2-hydroxy-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (250 mg, 0.79 mmol), and PPh (235 mg, 0.90 mmol) in THF (6 mL) was added DIAD (181 mg, 0.90 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h under N. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL × 3). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give tert-butyl 2-((5-chloropyridin-2-yl)methoxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate (157 mg, 47% yield). MS calculated: 443.12; MS found: 444.1 [M+H] + .

[0480] 2-[(5-chloropyridin-2-yl)methoxy]-7-[(3-{[(2S)-oxetan-2-yl]methyl}-6-[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]-3H-imidazo[4,5-c]pyridin-2-yl)methyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (Compound 74) [ka] Compound 74 was then synthesized following a route similar to Procedure 3 using tert-butyl 2-((5-chloropyridin-2-yl)methoxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naph...

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, Ring A is 【Chemistry 2】 And; Ring B is C ３－１０ They are cycloalkyl, heterocyclyl, aryl, or heteroaryl; X １ 、 X ２ 、 X ３ and X ４ of which one is C that is covalently bonded to ring B via L; and X １ 、 X ２ 、 X ３ and X ４ the remainder are each independently N or CR ４ ; provided that no more than two of X １ 、 X ２ 、 X ３ and X ４ are N; X ５ , X ６ and X ７ Each is independently N or CR ５ And; X ８ and X ９ Each is independently N or CR ６ And; X １０ is N or CR ６ X １１ is S, O or NR ９ And; n is 1, 2, or 3; m is 0, 1, 2, 3, 4, or 5; R １ ha-C(O)OR ９ , -C(O)N(R ９ ) ２ , -C(O)N(R ９ )S(O) ２ R ９ , -NR ９ C(O)R ９ , a 5-10 membered heterocyclyl or a 5-10 membered heteroaryl, where the 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally has 1-4 R １１ It has been replaced with; R ２ (C) is available upon request. １－９ Alkyl), -S-(C １－９ Alkyl), -S(O) ２ -(C) １－９ Alkyl), C ３－６ C is substituted with cycloalkyl, 3-6 member heterocyclyl, phenyl, or 5-6 member heteroaryl. １－９ It is alkyl; here, R ２ Each C １－９ Alkyl, -O-(C １－９ Alkyl), -S-(C １－９ Alkyl), -S(O) ２ -(C) １－９ Alkyl), C ３－６ Cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl may optionally have an additional 1-5 Z １ It has been replaced with; L is bond, C １－９ Alkylene, C ２－９ Alkenylene, C ２－９ Alkynylene, -O-C １－９ Alkylene, -NR １０ -C １－９ Alkylene, -C(O)NR １０ -C １－９ Alkylene, -NR １０ C(O)-C １－９ Alkylene, 3-6 member heterocyclylene, -O-, -S-, -S(O)-, -S(O) ２ -, -NR １０ -, -C(O)NR １０ -, -NR １０ C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR １０ S(O)-, -S(O)NR １０ -, -NR １０ S(O)NR １０ -, -NR １０ S(O) ２ NR １０ -, -NR １０ C(O)NR １０ -, -OC(O)NR １０ - or - NR １０ C(O)O-; where each C in L １－９ Alkylene, C ２－９ Alkenylene, C ２－９ Alkynylene, -O-C １－９ Alkylene, -NR １０ -C １－９ Alkylene, -C(O)NR １０ -C １－９ Alkylene, -NR １０ C(O)-C １－９ Alkylenes or 3-6 membered heterocyclylenes can be independently and optionally have 1-5 Z groups. １ It has been replaced with; Each R ３ is independently halo, cyano, nitro, oxo, -OR １０ , -SR １０ , -N(R １０ ), ２ , -C(O)R １０ , -C(O)OR １０ , -OC(O)R １０ , -OC(O)OR １０ , -C(O)N(R １０ ), ２ , -NR １０ C(O)R １０ , -OC(O)N(R １０ ), ２ , -NR １０ C(O)OR １０ , -NR １０ C(O)N(R １０ ), ２ , -S(O)R １０ , -S(O) ２ R １０ , -S(O)N(R １０ ), ２ , -S(O) ２ N(R １０ ), ２ , -NR １０ S(O)R １０ , -NR １０ ]S(O) ２ R １０ , -NR １０ S(O)N(R １０ ), ２ , -NR １０ S(O) ２ N(R １０ ), ２ , C １－９ alkyl, C ２－９ alkenyl, C ２－９ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl or heteroaryl; where each C ３ of R １－９ alkyl, C ２－９ alkenyl, C ２－９ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with 1 to 5 Z １ ; Each R ４ These are independently hydrogen, halo, cyano, nitro, oxo, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)OR １０ , -OC(O)R １０ , -OC(O)OR １０ , -C(O)N(R １０ ) ２ , -NR １０ C(O)R １０ , -OC(O)N(R １０ ) ２ , -NR １０ C(O)OR １０ , -NR １０ C(O)N(R) １０ ) ２ , -S(O)R １０ , -S(O) ２ R １０ , -S(O)N(R １０ ) ２ , -S(O) ２ N(R) １０ ) ２ , -NR １０ S(O)R １０ , -NR １０ S(O) ２ R １０ , -NR １０ S(O)N(R) １０ ) ２ , -NR １０ S(O) ２ N(R) １０ ) ２ , C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ４ Each C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may independently contain 1 to 5 Z groups as desired. １ It has been replaced with; Each R ５ These are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, and -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenyl or C ２－６ It is alkinyl; here, R ５ Each -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenyl or C ２－６ The alkynyl is independently substituted with 1 to 5 substituents, optionally selected independently from halo, hydroxy, and cyano; Each R ６ These are independently hydrogen, halo, cyano, nitro, oxo, -OH, -SH, and -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenyl or C ２－６ It is alkinyl; here, R ６ Each -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenyl or C ２－６ The alkynyl is independently substituted with 1 to 5 substituents, optionally selected independently from halo, hydroxy, and cyano; Each R ８ These are independently hydrogen or C １－９ It is alkyl; Each R ９ Hydrogen and C are independent of each other. １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ These are cycloalkyl, heterocyclyl, aryl, and heteroaryl; where R ９ Each C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently have 1 to 5 R groups as desired. １１ It has been replaced with; Each R １０ Hydrogen and C are independent of each other. １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ２０ , -C(O)OR ２０ , -C(O)N(R ２０ ) ２ , -S(O)R ２０ , -S(O) ２ R ２０ , -S(O)N(R ２０ ) ２ or -S(O) ２ N(R) ２０ ) ２ And here, R １０ Each C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may independently contain 1 to 5 Z groups as desired. １ａ It has been replaced with; Each R １１ These are independently oxo, cyano, halo, hydroxy, and C. １－９ Alkyl, C １－９ Alkoxy, C １－９ Haloalkyl, C １－９ Haloalkoxy, C ３－９ Cycloalkyl, -C １－９ Alkyl-C(O)OR １２ , -C(O)OR １２ , -C(O)N(R １２ ) ２ , -SR １２ or -S(O) ２ R １２ And; Each R １２ Hydrogen and C are independent of each other. １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R １２ Each C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may independently contain 1 to 5 Z groups as desired. １ａ It has been replaced with; Each Z １ These are independently halo, cyano, nitro, oxo, and C. １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L １ -C １－９ Alkyl, -L １ -C ２－９ Alkenyl, -L １ -C ２－９ Alkinyl, -L １ -C ３－１０ Cycloalkyl, -L １ -heterocyclyl, -L １ -aryl or -L １ - is a heteroaryl; here, Z １ Each C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may independently contain 1 to 5 Z groups as desired. １ａ It has been replaced with; Each L １ These are independently -O-, -S-, and -NR ２０ -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR ２０ -, -NR ２０ C(O)-, -OC(O)NR ２０ -, -NR ２０ C(O)O-, -NR ２０ C(O)NR ２０ -, -S(O)-, -S(O) ２ -, -S(O)NR ２０ -, -S(O) ２ NR ２０ -, -NR ２０ S(O)-, -NR ２０ S(O) ２ -, -NR ２０ S(O)NR ２０ - or - NR ２０ S(O) ２ NR ２０ - and; Each R ２０ Hydrogen and C are independent of each other. １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ２０ Each C １－９ Alkyl, C ２－９ Alkenil, C ２－９ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may independently contain 1 to 5 Z groups as desired. １ａ It has been replaced with; Each Z １ａ These are independently halo, hydroxy, cyano, nitro, oxo, -SH, and -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Z is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z １ａ Each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are independently C as desired. １－９ Substituting with 1 to 5 substituents selected from alkyl, oxo, halo, hydroxy, and cyano; However, ring A 【Transformation 3】 If so, R １ It is anything other than -C(O)OH. Compounds thereof or their pharmaceutically acceptable salts or solvates.

2. Formula II: 【Chemistry 4】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

3. X ６ The compound according to claim 1, wherein is N.

4. X ５ The compound according to claim 1, wherein is N.

5. X ５ is N or CR ５ X ６ N is X ７ CR ５ The compound according to claim 1.

6. Formula III: 【Transformation 5】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

7. X ９ CR ６ The compound according to claim 1.

8. X ９ The compound according to claim 1, wherein is N.

9. X ８ CR ６ X ９ is N or CR ６ The compound according to claim 1.

10. Formula IV: 【Transformation 6】 The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, as shown by [formula].

11. X １０ CR ７ The compound according to claim 1.

12. X １１ The compound according to claim 1, wherein is S.

13. Formula V: 【Transformation 7】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

14. X ５ , X ６ and X ７ CR ７ The compound according to claim 1.

15. The compound according to claim 1, wherein n is 1.

16. R １ 1 to 5 R as desired １１ The compound according to claim 1, wherein it is a five-membered heteroaryl substituted with [a specific compound].

17. R １ but 【Transformation 8】 The compound according to claim 1.

18. R １ 1 to 5 R as desired １１ It is a 5-10 membered heterocyclyl that is substituted, and here the heterocyclyl is intraring 【Chemistry 9】 The compound according to claim 1, comprising:

19. R １ but 【Chemistry 10】 The compound according to claim 18.

20. R １ ga-C(O)OR ９ , -C(O)N(R ９ ) ２ , -C(O)N(R ９ )S(O) ２ R ９ or -NR ９ C(O)R ９ The compound according to claim 1.

21. R １ The compound according to claim 1, wherein is -C(O)OH.

22. R １ ga-C(O)NH ２ The compound according to claim 1.

23. R １ ga-C(O)NHR ９ or -NHC(O)R ９ And R ９ C １－９ Alkyl, C ３－１０ It is a cycloalkyl or heteroaryl; where C １－９ Alkyl, C ３－１０ Cycloalkyl or heteroaryl groups, optionally with 1 to 5 R groups. １１ The compound according to claim 1, which is substituted with

24. R １ ga-C(O)NHR ９ or -NHC(O)R ９ And R ９ The compound according to claim 1, wherein is a cyclopropyl or pyridyl substituted with methyl, 2,2,2-trifluoroethyl, or cyano.

25. R １ ga-C(O)NHS(O) ２ R ９ And R ９ The compound according to claim 1, wherein is methyl.

26. X １ , X ２ and X ３ One of them is C covalently bonded to ring B via L; X ４ N is N; and X １ , X ２ and X ３ The remaining ones each independently become CR ４ The compound according to claim 1.

27. X １ , X ２ , X ３ and X ４ One of them is C which is covalently bonded to ring B via L; and X １ , X ２ , X ３ and X ４ The remaining ones each independently become CR ４ The compound according to claim 1.

28. X ３ The compound according to claim 1, wherein C is covalently bonded to ring B via L.

29. Each R ４ These independently produce hydrogen, halo, and C. １－９ Haloalkyl or C ３－１０ The compound according to claim 1, wherein it is a cycloalkyl compound.

30. X ２ CR ４ And R ４ Hydrogen, halo, C １－９ Haloalkyl or C ３－１０ The compound according to claim 1, wherein it is a cycloalkyl compound.

31. Each R ４ These independently produce hydrogen, chlorophyll, and -CF ３ The compound according to claim 1, or cyclopropyl.

32. X １ The compound according to claim 1, wherein is CH.

33. Each R ５ The compound according to claim 1, wherein is independently hydrogen or a halo.

34. Each R ６ The compound according to claim 1, wherein is independently hydrogen or a halo.

35. L is -O-C １－９ Alkylene, -NR １０ -C １－９ Alkylene, -C(O)NR １０ -C １－９ Alkylene or -NR １０ C(O)-C １－９ The compound according to claim 1, wherein it is an alkylene.

36. L is -O-CH ２ - The compound according to claim 1.

37. Ring B is C ３－６ The compound according to claim 1, wherein it is a cycloalkyl, phenyl, a 5-membered or 9-membered heterocyclyl, or a 5-membered or 9-membered heteroaryl.

38. The compound according to claim 1, wherein ring B is phenyl.

39. Formula IIG: 【Chemistry 11】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

40. Formula IIID: 【Chemistry 12】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

41. Formula IVD: 【Chemistry 13】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

42. Formula VD: 【Chemistry 14】 The compound according to claim 1, as shown by [formula], or a pharmaceutically acceptable salt or solvate thereof.

43. R ２ C １－９ C substituted with alkyl or 3-6 member heterocyclyl groups １－９ C substituted with alkyl or cyano ３－６ Cycloalkyl-substituted C １－９ The compound according to claim 1, wherein it is alkyl.

44. R ２ C １－９ The compound according to claim 1, wherein it is alkyl.

45. R ２ The compound according to claim 1, wherein is methyl.

46. R ２ C is substituted with a 3-6 member heterocyclyl group. １－９ C substituted with alkyl or cyano ３－６ Cycloalkyl-substituted C １－９ The compound according to claim 1, wherein it is alkyl.

47. R ２ but 【Chemistry 15】 The compound according to claim 1.

48. The compound according to claim 1, wherein m is 1, 2, or 3.

49. Each R ３ These are independently Halo, Cyano, -OR １０ , -C(O)N(R １０ ) ２ , -S(O) ２ R １０ , C １－９ Alkyl, C ３－１０ It is a cycloalkyl or heteroaryl; where R ３ Each C １－９ The compound according to claim 1, wherein the alkyl group is optionally substituted with 1 to 5 halos.

50. Each R ３ The compound according to claim 1, wherein is independently a halo.

51. The compound according to claim 1, which is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof, stereoisomer, stereoisomer mixture, or prodrug.

52. A pharmaceutical composition comprising an effective amount of the compound described in claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

53. An agent for treating a GLP-1 related disease, disorder, or condition in a patient requiring treatment, the agent comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 52.

54. Diseases, disorders, or conditions including type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), slowly-onset adult-onset autoimmune diabetes (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, renal disease, adipocyte dysfunction, sleep Sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial steatosis, metabolic acidosis, ketosis The agent according to claim 53, selected from the group consisting of, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulceration, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

55. An agent for treating type 2 diabetes in patients requiring treatment, the agent comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 52.

56. An agent for making such adjustments in patients requiring adjustment of insulin levels, the agent comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 52.

57. An agent for making such adjustment in patients requiring adjustment of glucose levels, the agent comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 52.

58. The pharmaceutical composition according to claim 52, further comprising a further treatment or therapeutic agent.

59. An agent comprising the pharmaceutical composition according to claim 58 for treating GLP-1 related diseases, disorders or conditions, for treating type 2 diabetes, for regulating insulin levels or for regulating glucose levels.

60. The pharmaceutical composition according to claim 58, or the agent according to claim 59, wherein the further treatment or therapeutic agent is selected from the group consisting of antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, antiemetic agents, non-alcoholic steatohepatitis (NASH) treatment agents, gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

61. A method for producing a compound of formula I according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, comprising formula II-1, III-1, IV-1 or V-1: 【Chemistry 16】 Compound and formula I-1: 【Chemistry 17】 A method comprising contacting a compound of formula I under conditions sufficient to provide a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.

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