Heterocyclic glp-1 agonists

Abstract

The present disclosure relates to GLP-1 agonists of Formula (I), including pharmaceutically acceptable salts and solvates thereof; and pharmaceutical compositions comprising the same.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of International Patent Application No. PCT / CN2020 / 0114319, filed on September 10, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] This document relates to GLP-1 agonists, pharmaceutical compositions and methods of use thereof. Background Technology

[0004] Incretin metabolism hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are important in the regulation of glucose homeostasis. Drugs targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0005] Diabetes mellitus refers to 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 more than 90% of diabetes cases. Typical onset occurs in obese or otherwise sedentary adults and involves the development of insulin resistance. While lifestyle modifications can effectively manage this disorder, patients with T2DM may require antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0006] In healthy individuals, the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose intake. Although this incretin effect is significantly diminished (if present) in cases of type 2 diabetes mellitus (T2DM), GLP-1 retains its insulinotropic properties, even when the endocrine pancreatic response to GIP is effectively terminated. Therefore, incretin mimics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Summary of the Invention

[0007] This application 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.

[0008] Therefore, this paper provides compounds of formula I:

[0009]

[0010] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0011] Ring A is C6-10 Aryl, C 5-10 Cycloalkyl, 5-10-membered heterocyclic, or 5-10-membered heteroaryl groups, each optionally substituted by 1-5 substituents independently selected from the following: halogenated, C... 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0012] R 1 R 2 and R 3 Each is independently selected from H and optionally by 1-6 groups, each independently selected from halogen groups, -OH and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0013] L 1 Selected from: -C(=O)-, -CH2-, -CH(C 1-6 Alkyl)- and -S(=O)2;

[0014] Ring B is selected from:

[0015]

[0016] Where bb represents L 1 Attachment point;

[0017] R 4 R 5 R 6 and R 7 Independently selected from: H, halogenated group and C 1-6 alkyl;

[0018] L 3 Is it a key or C? 1-3 Alkylene;

[0019] L 4 Is it a key or C? 1-5 Alkylene;

[0020] R 8a and R 8b Independently selected from: H and optionally by one or more halogenated groups and C 3-15 Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0021] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0022] R 9 Selected from: C(=O)OH, C(=O)(OC 1-6 Alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4):

[0023]

[0024] R 9a Is it H or C? 1-6 alkyl;

[0025] R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl groups), S(O) 0-2 (C 1-6 Alkyl or cyano groups;

[0026] R 9c R 9d R 9e R 9f and R 9g Each is independently selected from: H; optionally by 1-6 independently selected halogen groups and C. 1-6 alkoxy-substituted C 1-6 Alkyl groups; and C(=O)(C 1-6 alkyl);

[0027] Cycle C is selected from 3-12 membered heterocyclic groups; C 3-10 cycloalkyl; and 5-10 heteroaryl groups, each optionally surrounded by 1-3 R groups. Ca replace;

[0028] Each R Ca Independently selected from: halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ;

[0029] Or a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms attached to each ring, they form a carbon ring containing 3 to 8 ring atoms;

[0030] L 2 Selected from:

[0031]

[0032] Where aa represents the attachment point to Q;

[0033] n1 is an integer between 1 and 3;

[0034] L 2A Is it a key or C? 1-10 Alkylene;

[0035] R La Selected from H, C 1-6 Alkyl groups and C(=O)(C 1-6 alkyl);

[0036] R Lb and R Lc Each of them is independently selected from H and C. 1-6 alkyl;

[0037] Q is selected from: C 1-10 Alkyl; C 3-15 cycloalkyl; 3-12 membered heterocyclic; 5-10 membered heteroaryl; and C 6-10 Aryl groups, each of which is optionally selected by 1-6 independently chosen R groups. Q replace;

[0038] Each R Q Selected independently from:

[0039] (a) Halogenated group;

[0040] (b) Cyano group;

[0041] (c) OH or oxo group;

[0042] (d)-NR c R d ;

[0043] (e)-C(=O)NR c R d or -S(O)2NR c R d ;

[0044] (f)-S(=O) 0-2 R e ;

[0045] (g) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 alkyl;

[0046] (h) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 Alkoxy;

[0047] (i) R, which are arbitrarily selected from 1 to 6 independently selectedg Substituted 3-12 membered heterocyclic groups;

[0048] (j) R selected arbitrarily by 1-6 independently chosen g Replacement C 6-10 Aryl;

[0049] (k) R, which are arbitrarily selected from 1 to 6 independently selected g Substituted 5-10 heteroaryl groups;

[0050] (l) Optionally selected from 1 to 6 independently chosen R g Replacement C 3-8 cycloalkyl;

[0051] (m)P(=O)R a R b ;and

[0052] (n)-(CR h R h ) q1 -S(O)2-L e -R e , where q1 is 1, 2 or 3;

[0053] R a and R b Independently selected from, arbitrarily selected from, 1-6, each independently selected from C 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl group; optionally composed of 1-3 molecules, each independently selected from C10. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl; and optionally 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or

[0054] R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding those attached to R) a and R b (Apart from phosphorus) are heteroatoms independently selected from O, S, and N, wherein the ring is optionally surrounded by 1-3 independently selected C atoms. 1-6 Alkyl substitution;

[0055] Each R c and R d Selected independently from: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 Alkyl), C(=O)(C3-6 cycloalkyl), C(=O)O(C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Alkyl groups and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Alkyl groups and S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Substitution of alkoxy groups;

[0056] R e Is it H, or R? e Selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, each optionally substituted by 1-3 substituents independently selected from the following: halogroup, cyanogroup, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, NH2, NH(C) 1-3 Alkyl), N(C) 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0057] L e It is a key, NR c Or O;

[0058] Each R f Independently selected from halogenated groups, -OH, NR c R d C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally surrounded by 1-4 groups, each independently selected from -OH, C. 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups;

[0059] Each R g Selected independently from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, NR c R d cyano, halogenated, C 3-6 cycloalkyl groups and optionally one or more independently selected from C 1-6 Alkyl groups and C(=O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and

[0060] Each occurrence of R h Selected independently from: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halogenated groups; or

[0061] A pair of R atoms on the same or different carbon atoms h Together with the connection pair R h One or more carbon atoms form C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups, each optionally substituted by 1-3 substituents independently selected from the following: halogenated, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups.

[0062] This document also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

[0063] This article also provides a method for treating type 2 diabetes in patients in need, the method 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.

[0064] This article also provides a method for treating a patient with type 2 diabetes, the method comprising administering to a patient identified or diagnosed with 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.

[0065] This document also provides a method for treating diabetes in a patient, the method 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, the step of determining that the patient has type 2 diabetes includes performing a assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the HbA1c level is greater than or about 6.5%. In some embodiments, the fasting plasma glucose level is greater than or about 126 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 200 mg / dL.

[0066] In some embodiments, the method further includes obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is approximately 40 to approximately 70 years old and is overweight or obese. In some embodiments, the patient's body mass index (BMI) is greater than or approximately 22 kg / m². 2 In some implementation schemes, the patient's BMI is greater than or approximately 30 kg / m². 2 .

[0067] In some embodiments, the method for treating type 2 diabetes includes lowering fasting plasma glucose levels. In some embodiments, the fasting plasma glucose level is lowered to about or below 100 mg / dL.

[0068] In some implementations, treatment for type 2 diabetes includes lowering HbA1c levels. In some implementations, HbA1c levels are reduced to approximately or below 5.7%.

[0069] In some implementations, the method for treating type 2 diabetes includes lowering glucagon levels.

[0070] In some implementations, the method for treating type 2 diabetes includes lowering insulin levels.

[0071] In some embodiments, the method for treating type 2 diabetes includes reducing BMI. In some embodiments, BMI is reduced to about or below 25 kg / m². 2 .

[0072] In some embodiments, the compound of formula I orally is administered, orally, as a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0073] In some embodiments, treatment of type 2 diabetes further includes administering additional therapies or therapeutic agents to the patient. In some embodiments, the additional therapies or therapeutic agents are selected from antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, agents for treating non-alcoholic steatohepatitis (NASH), antiemetics, gastric electrical stimulation, dietary monitoring, physical activity, or any combination thereof. In some embodiments, the antidiabetic agent is selected from biguanide, sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, megglitinide, sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, GRP40 agonists, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose cotransporter 1 (SGLT1) inhibitors, or any combination thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human pro-insulin peptide (HIP), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, farnesol X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylamine phenylacetone, zonisamide, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, or any combination thereof. In some embodiments, the GLP-1 receptor agonist is selected from liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combination thereof. In some embodiments, the agent for treating NASH is selected from FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galactolectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinase (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, or any combination thereof.In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt or solvate, or its pharmaceutical composition, along with the additional therapeutic agent, are administered sequentially as individual doses in any order.

[0074] This document also provides a method for regulating insulin levels in patients who require such regulation, the method 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 regulation results in an increase in insulin levels.

[0075] This document also provides a method for regulating glucose levels in patients who require such regulation, the method 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 regulation results in a decrease in glucose levels.

[0076] This article also provides methods for treating GLP-1-related diseases, disorders, or conditions, the methods comprising administering to a patient in need an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some implementations, the disease, disorder, or condition is selected from type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), adult-onset diabetes in adolescents (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, 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 cell dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, and pulmonary hypertension. Restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic 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.In some implementations, the disease, disorder, or condition is selected from type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, 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, hyperglycemia, postprandial hyperlipidemia, metabolic acidosis, and ketosis. Hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof. In some implementations, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery 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 ulcers, or any combination thereof.

[0077] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is expressly and individually indicated to be incorporated by reference. Where a publication or patent or patent application incorporated by reference contradicts the disclosure included in this specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0078] Other features and advantages of the present invention will become apparent from the following embodiments and claims. Detailed Implementation

[0079] This article provides heterocyclic GLP-1 agonists for the management of type 2 diabetes mellitus (T2DM) and other conditions, in which activation of GLP-1 activity is useful.

[0080] definition

[0081] When a value is described as a range, it should be understood that such disclosure includes disclosure of all possible subranges within that range, as well as specific values ​​falling within that range, regardless of whether a specific value or a specific subrange is explicitly stated.

[0082] As used herein, the terms "halogen" or "halogen" refer to -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl (sometimes referred to herein as "chloro" or "chloros"), -Br (sometimes referred to herein as "bromo" or "bromos"), and -I (sometimes referred to herein as "iodo" or "iodos").

[0083] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing an indicated number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having one to six carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0084] As used herein, the term "alkylene" refers to a divalent alkyl group containing an indicated number of carbon atoms. For example, "C 1-3 "Alkylene" refers to a divalent alkyl group having three carbon atoms (e.g., -CH2-, -CH(CH3)-, -CH2CH2-, or -CH2CH2CH2-).

[0085] As used herein, the term "alkenyl" refers to a straight-chain or branched monounsaturated hydrocarbon chain containing an indicated number of carbon atoms. For example, "C 2-6 "Alkenyl" refers to a straight-chain or branched monounsaturated hydrocarbon chain having two to six carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propenyl, butenyl, or pentenyl.

[0086] As used herein, the term "alkynyl" refers to a straight-chain or branched diunsaturated hydrocarbon chain containing an indicated number of carbon atoms. For example, "C 2-6 "Alynyl" refers to a straight-chain or branched diunsaturated hydrocarbon chain having two to six carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, or pentylyl.

[0087] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cycloalkanes containing an indicated number of carbon atoms. For example, "C 3-6"Cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon having three to six ring carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl can include multiple fused rings and / or bridging rings. Non-limiting examples of fused / bridging cycloalkyl 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 (e.g., spirocyclic bicyclic, where the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl 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, etc.

[0088] As used herein, the term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring system (e.g., 3-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic system) containing an indicated number of ring atoms, wherein if monocyclic, it has 1-3 heteroatoms; if bicyclic, it has 1-6 heteroatoms; or if tricyclic or polycyclic, it has 1-9 heteroatoms selected from O, N, or S(O). 0-2 (For example, carbon atoms, and in the case of monocyclic, bicyclic, or tricyclic rings, having 1-3, 1-6, or 1-9 N, O, or S(O) atoms respectively.) 0-2Heterocyclic groups (heteroatoms) in which 0, 1, 2, or 3 atoms of each ring can be substituted by substituents. Examples of heterocyclic groups include piperazine, pyrrolyl, dioxane, morpholinyl, tetrahydrofuranyl, etc. Heterocyclic groups can include multiple fused rings and bridging rings. Non-limiting examples of fused / bridged heterocyclic groups 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, octahydrocyclopenten[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. Heterocyclic groups also include spirocyclic groups (e.g., spirobicyclo, where the two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclic groups 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[3.5]decane, and others. Spiro[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, etc.

[0089] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group containing an indicated number of carbon atoms, wherein at least one ring in the system is aromatic (e.g., C6 monocyclic, C6-cyclic, C6-cyclic). 10 Double ring or C 14(Tricyclic aromatic ring systems). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, etc.

[0090] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having an indicated number of ring atoms (e.g., 5-6 ring atoms; e.g., 5, 6, 9, 10, or 14 ring atoms); wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more elements independently selected from N, O, and S(O). 0-2 The heteroatom. The heteroaryl group can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroloyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl-benzothiophene, benzoxadiazolyl, benzofuranyl, benzoimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purine, thiophene-pyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3- [b]Pyridyl, Quinazolinyl, Quinolinyl, Thiopheno[2,3-c]pyridyl, Pyrazolo[3,4-b]pyridyl, Pyrazolo[3,4-c]pyridyl, Pyrazolo[4,3-c]pyridine, Pyrazolo[4,3-b]pyridyl, Tetrazolyl, Zorocan, 2,3-Dihydrobenzo[b][1,4]Dioxin, Benzo[d][1,3]m-Dioxacyclopentene, 2,3-Dihydrobenzofuran, Tetrahydroquinoline, 2,3-Dihydrobenzo[b][1,4]oxothionhexacyclohexadiene, Isoindoline, etc.

[0091] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms are replaced by 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.

[0092] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the group is on an oxygen atom. For example, "C 1-6 "Alkoxy" refers to -O-(C 1-6 An alkyl group, wherein the group is on an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Therefore, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein the group is on an oxygen atom.

[0093] As used in this article, Indicates either a single or double bond as allowed by the valence. As used herein, Indicates the attachment point to the parent molecule.

[0094] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. Unless otherwise stated, compounds identified herein by name or structure as a particular tautomer form are intended to include other tautomer forms.

[0095] As used herein, the term "tautomer" refers to a compound whose structure is significantly different in terms of atomic arrangement but exists in an easy and rapid equilibrium manner, and it should be understood that the compounds provided herein can be described as different tautomers, and when a compound has a tautomer form, all tautomer forms are intended to fall within the scope of the invention, and the naming of the compounds does not exclude any tautomer.

[0096] As used herein, the term “GLP-1R” or “GLP-1 receptor” is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologs, and / or orthologous GLP-1R molecules, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0097] As used herein, the term “GLP-1-related disease” is intended to include, but is not limited to, all such diseases, disorders or conditions in which glucagon-like peptide-1 (GLP-1) receptor signaling modulates the pathology and / or symptoms and / or progression of the disease, disorder or condition.

[0098] As used herein, the term “GLP-1 agonist” or “GLP-1RA” refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels in both fasting and postprandial states; and slow 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-April; 20(2):254-267. GLP-1RAs have been shown to be effective in treating type 2 diabetes. Examples of GLP-1RAs include, but are not limited to, abiglutide. Duraglutide (LY2189265, ), efpeglenatide, exenatide ( Venomous lizard exopeptide-4), liraglutide ( NN2211), Lixina peptide Semaglutide Tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. Also see, for example, other GLP-1 receptor agonists described in the following U.S. patent numbers: 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.

[0099] As used herein, the term "pharmaceutically acceptable" indicates that a compound or its salt or composition is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or with patients treated thereunder.

[0100] As used herein, the term "therapeutic compound" is intended to include, but is not limited to, all compounds of formula I or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA and IB or pharmaceutically acceptable salts or solvates thereof) and all compositions (e.g., pharmaceutical compositions) in which compounds of formula I or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA and IB or pharmaceutically acceptable salts or solvates thereof) are compositional components.

[0101] The term "administration" or "administering" refers to the method of administering a given dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). 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.

[0102] As used herein, the terms “effective amount” or “effective dose” or “pharmaceutically effective amount” or “therapeutic effective amount” refer to an amount of sufficient chemical entity (e.g., a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof)) applied that will alleviate one or more symptoms of the disease or condition being treated to a certain extent, and may include curing the disease. “Cure” means the elimination of symptoms of an active disease. Results include a reduction and / or mitigation of signs, symptoms, or causes of the disease or any other desired alteration of the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in symptoms of disease. The appropriate “effective” amount in any single case is determined using any suitable technique, such as dose escalation studies. In some embodiments, a “therapeutic effective amount” of a compound as provided herein refers to the amount of a compound that is effective as a monotherapy or combination therapy.

[0103] The term "excipient" or "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulation material. In some embodiments, a component is "pharmaceutically acceptable" in the sense that it is compatible with other components of the pharmaceutical formulation and suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th edition; edited by Rowe et al.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; edited by Gibson; CRC Press LLC: Boca Raton, FL, 2009.

[0104] The term "pharmaceutical composition" refers to a mixture of a compound of formula I as described herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof), with other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0105] In the context of treating a disease, disorder, or condition, the terms “treat,” “treating,” and “treatment” are intended to include relieving or eradicating a disorder, disease, or condition or one or more symptoms associated with said disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more symptoms thereof.

[0106] As used herein, the term “prevention” means the complete or partial prevention of the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0107] As used herein, the terms “subject,” “patient,” or “individual” are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject who desires or requires a diagnosis, prognosis, or therapy, particularly a mammalian subject. In some embodiments, a patient is a human being. In some embodiments, a subject has experienced and / or exhibits at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0108] The terms “treatment regimen” and “dosage regimen” are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the present invention.

[0109] As used herein, the term "drug combination" refers to a pharmaceutical treatment resulting from a mixture or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0110] As used herein, the term “combination therapy” refers to a dosing regimen of two different therapeutic agents (i.e., combined components or combination couples) wherein the therapeutic agents are administered together or separately in a manner prescribed by a healthcare professional or in accordance with a regulatory body as defined herein.

[0111] As used herein, the term “regulation” refers to control or adjustment (e.g., increase or decrease) and may include, for example, agonist, partial agonist or antagonist effects.

[0112] compound

[0113] On the one hand, this paper provides compounds of formula (I):

[0114]

[0115] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0116] Ring A is C 6-10 Aryl, C 5-10 Cycloalkyl, 5-10-membered heterocyclic, or 5-10-membered heteroaryl groups, each optionally substituted by 1-5 substituents independently selected from the following: halogenated, C... 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy;

[0117] R 1 R 2 and R 3 Each is independently selected from H and optionally by 1-6 groups, each independently selected from halogen groups, -OH and C. 1-6 alkoxy substituents of C 1-6 alkyl;

[0118] L 1 Selected from: -C(=O)-, -CH2-, -CH(C 1-6 Alkyl)- and -S(=O)2;

[0119] Ring B is selected from:

[0120]

[0121] Where bb represents L 1 Attachment point;

[0122] R 4 R 5 R 6 and R 7 Independently selected from: H, halogenated group and C 1-6 alkyl;

[0123] L 3 Is it a key or C? 1-3 Alkylene;

[0124] L 4 Is it a key or C? 1-5 Alkylene;

[0125] R 8a and R 8b Independently selected from: H and optionally by one or more halogenated groups and C 3-15Cycloalkyl substituents substituted C 1-6 Alkyl; or

[0126] R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace;

[0127] R 9 Selected from: C(=O)OH, C(=O)(OC 1-6 Alkyl), C(=O)NR 9a R 9b , (IX-1), (IX-2), (IX-3) and (IX-4):

[0128]

[0129] R 9a Is it H or C? 1-6 alkyl;

[0130] R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl groups), S(O) 0-2 (C 1-6 Alkyl or cyano groups;

[0131] R 9c R 9d R 9e R 9f and R 9g Each is independently selected from: H; optionally by 1-6 independently selected halogen groups and C. 1-6 alkoxy-substituted C 1-6 Alkyl groups; and C(=O)(C 1-6 alkyl);

[0132] Cycle C is selected from 3-12 membered heterocyclic groups; C 3-10 cycloalkyl; and 5-10 heteroaryl groups, each optionally surrounded by 1-3 R groups. Ca replace;

[0133] Each R Ca Independently selected from: halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ;

[0134] Or a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms attached to each ring, they form a carbon ring containing 3 to 8 ring atoms;

[0135] L 2 Selected from:

[0136]

[0137] Where aa represents the attachment point to Q;

[0138] n1 is an integer between 1 and 3;

[0139] L 2A Is it a key or C? 1-10 Alkylene;

[0140] R La Selected from H, C 1-6 Alkyl groups and C(=O)(C 1-6 alkyl);

[0141] R Lb and R Lc Each of them is independently selected from H and C. 1-6 alkyl;

[0142] Q is selected from: C 1-10 Alkyl; C 3-15 cycloalkyl; 3-12 membered heterocyclic; 5-10 membered heteroaryl; and C 6-10 Aryl groups, each of which is optionally selected by 1-6 independently chosen R groups. Q replace;

[0143] Each R Q Selected independently from:

[0144] (a) Halogenated group;

[0145] (b) Cyano group;

[0146] (c) OH or oxo group;

[0147] (d)-NR c R d ;

[0148] (e)-C(=O)NR c R d or -S(O)2NR c R d ;

[0149] (f)-S(=O) 0-2 R e ;

[0150] (g) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 alkyl;

[0151] (h) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 Alkoxy;

[0152] (i) R, which are arbitrarily selected from 1 to 6 independently selected g Substituted 3-12 membered heterocyclic groups;

[0153] (j) R selected arbitrarily by 1-6 independently chosen g Replacement C 6-10 Aryl;

[0154] (k) R, which are arbitrarily selected from 1 to 6 independently selected g Substituted 5-10 heteroaryl groups;

[0155] (l) Optionally selected from 1 to 6 independently chosen R g Replacement C 3-8 cycloalkyl;

[0156] (m)P(=O)R a R b ;and

[0157] (n)-(CR h R h ) q1 -S(O)2-L e -R e , where q1 is 1, 2 or 3;

[0158] R a and R b Independently selected from, arbitrarily selected from, 1-6, each independently selected from C 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl group; optionally composed of 1-3 molecules, each independently selected from C10. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl; and optionally 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or

[0159] R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding those attached to R) a and R b(Apart from phosphorus) are heteroatoms independently selected from O, S, and N, wherein the ring is optionally surrounded by 1-3 independently selected C atoms. 1-6 Alkyl substitution;

[0160] Each R c and R d Selected independently from: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 Alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Alkyl groups and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Alkyl groups and S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Substitution of alkoxy groups;

[0161] R e Is it H, or R? e Selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, each optionally substituted by 1-3 substituents independently selected from the following: halogroup, cyanogroup, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, NH2, NH(C) 1-3 Alkyl), N(C) 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0162] L e It is a key, NR c Or O;

[0163] Each R f Independently selected from halogenated groups, -OH, NR c R d C 1-6Alkoxy, C 1-6 The haloalkoxy group is optionally surrounded by 1-4 groups, each independently selected from -OH, C. 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups;

[0164] Each R g Selected independently from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR c R d cyano, halogenated, C 3-6 cycloalkyl groups and optionally one or more independently selected from C 1-6 Alkyl groups and C(=O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and

[0165] Each occurrence of R h Selected independently from: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halogenated groups; or

[0166] A pair of R atoms on the same or different carbon atoms h Together with the connection pair R h One or more carbon atoms form C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups, each optionally substituted by 1-3 substituents independently selected from the following: halogenated, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups.

[0167] The implementation may include any one or more of the features described below and / or in the claims.

[0168] In some implementations of formula (I), Q is selected from: C 3-15 cycloalkyl; 3-12 membered heterocyclic; 5-10 membered heteroaryl; and C 6-10 Aryl groups, each of which is optionally selected by 1-6 independently chosen R groups. Q Substitution. In some embodiments, Q is selected from: 5-10 membered heteroaryl and C. 6-10 Aryl groups, each of which is optionally selected by 1-6 independently chosen R groups. Q Replacement. In some implementations, Q is optionally replaced by 1-6 independently selected R. QThe 5-10 aryl group is replaced. In some embodiments, Q is optionally replaced by 1-6 independently selected R groups. Q The 9-10 aryl group is replaced. In some embodiments, Q is optionally replaced by 1-6 independently selected R groups. Q The 9-membered heteroaryl group is replaced. In some embodiments, Q is optionally replaced by 1-2 independently selected R groups. Q The substituted 9-membered heteroaryl group.

[0169] In some implementations of equation (I), Q is Among them: Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q Q 4 Q 5 Q 6 and Q 7 One of them is with L 2 Bonded carbon atoms; and Q 4 Q 5 Q 6 and Q 7 The other three are each independently N, CH, or CR. Q In some implementations, Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q Q 4 Q 5 Q 6 and Q 7 One of them is with L 2 Bonded carbon atoms; and Q 4 Q 5 Q 6 and Q 7 The other three are independently CH or CR. Q In some implementations, Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q Q 4 Q 5 Q 6 and Q 7 One of them is with L 2 Bonded carbon atoms; and Q 4 Q 5 Q 6 and Q7 The other three are independently CH or CR. Q .

[0170] In some implementation schemes, Q 1 It is NH. In some implementations, Q 1 It is NR Q .

[0171] In some implementation schemes, Q 2 It is N and Q 3 Is it N, CH or CR? Q .

[0172] In some implementation schemes, Q 4 Q 5 Q 6 and Q 7 One of them is with L 2 Bonded carbon atoms; Q 4 Q 5 Q 6 and Q 7 Both of them are CH; and Q 4 Q 5 Q 6 and Q 7 One of them is CH or CR Q (For example, CR) Q ).

[0173] In some implementations, there is an R Q In some implementations, there are two Rs. Q In some implementations, there are three Rs. Q In some implementations, at least one R Q Attached to a 6-membered ring. In some implementations, there are two R... Q And these two R Q At least one of them is attached to a 6-membered ring.

[0174] In some implementations of equation (I), Q is Among them: Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q And n1 is 0 or 1.

[0175] In some implementation schemes, Q 1 It is NH. In some implementations, Q 1 It is NR Q .

[0176] In some implementation schemes, Q 2 It is N and Q 3 Is it N, CH or CR? Q .

[0177] In some implementations, there is an R Q In some implementations, there are two Rs. Q In some implementations, there are three Rs. Q In some implementations, at least one R Q Attached to a 6-membered ring. In some implementations, there are two R... Q And these two R Q At least one of them is attached to a 6-membered ring.

[0178] In some implementations of equation (I), Q is Among them: Q 1 Is it NH or NR? Q And n1 is 0 or 1.

[0179] In some implementation schemes, Q 1 It is NH. In some implementations, Q 1 It is NR Q .

[0180] In some implementations, there is an R Q In some implementations, there are two Rs. Q In some implementations, there are two Rs. Q And these two R Q At least one of them is attached to a 6-membered ring.

[0181] In some implementations of equation (I), Q is Where n1 is 0 or 1.

[0182] In some implementations, Q is Where n1 is 0 or 1.

[0183] In some implementations, n1 is 0. In some implementations, n1 is 1.

[0184] In some implementations of equation (I), Q is

[0185] In some implementations of equation (I), Q is

[0186] In some embodiments of equation (I), when at least one R is present... Q (For example, R attached to ring N) Q When ), an R Q Selected from:

[0187] (a) Halogenated group;

[0188] (b) Cyano group;

[0189] (c)OH;

[0190] (d)-NR c R d ;

[0191] (e)-C(=O)NR c R d or -S(O)2NR c R d ;

[0192] (f)-S(=O) 0-2 R e ;

[0193] (g) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 alkyl;

[0194] (h) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 Alkoxy;

[0195] (i) R, which are arbitrarily selected from 1 to 6 independently selected g Substituted 3-12 membered heterocyclic groups;

[0196] (j) R selected arbitrarily by 1-6 independently chosen g Replacement C 6-10 Aryl;

[0197] (k) R, which are arbitrarily selected from 1 to 6 independently selected g Substituted 5-10 heteroaryl groups;

[0198] (l) Optionally selected from 1 to 6 independently chosen R g Replacement C 3-8 cycloalkyl;

[0199] (m)P(=O)R a R b ;and

[0200] (n)-(CR h R h ) q1 -S(O)2-L e -R e , where q1 is 1, 2 or 3;

[0201] And each remaining R QWhen present, it is independently selected from: halogenated, cyano, OH, C 1-6 Alkyl and C 1-6 Alkyl group. In some embodiments, when at least one R is present... Q At that time, an R Q (For example, R attached to ring N) Q (Selected from:)

[0202] (a) Halogenated group;

[0203] (b) Cyano group;

[0204] (c)OH;

[0205] (d)-NR c R d ;

[0206] (e)-C(=O)NR c R d or -S(O)2NR c R d ;

[0207] (f)-S(=O) 0-2 R e ;

[0208] (g) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 Alkyl; and

[0209] (h) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 Alkoxy;

[0210] And each remaining R Q The halogenated group is independently selected when it is present.

[0211] In some implementations, when at least one R Q At that time, an R Q (For example, R attached to ring N) Q ) is an independently chosen C 1-6 Alkyl groups, optionally composed of 1-6 independently selected R groups. f Replace; and each remaining R Q The halogenated group is independently selected when present. In some embodiments, when at least one R is present... Q At that time, an R Q (For example, R attached to ring N) Q ) is an independently chosen C 1-3 Alkyl groups, optionally composed of 1-6 independently selected R groups. f Replace; and each remaining RQ It is fluorine when present. In some embodiments, it is fluorine when at least one R is present. Q At that time, an R Q (For example, R attached to ring N) Q ) is an independently selected, unsubstituted C 1-3 Alkyl groups; and each remaining R Q It is fluorine when present. In some embodiments, it is fluorine when at least one R is present. Q At that time, an R Q (For example, R attached to ring N) Q ) is methyl; and each remaining R Q It is fluorine when it is present.

[0212] In some implementations, there are two Rs Q An R Q (For example, R attached to ring N) Q ) is an independently chosen C 1-6 Alkyl groups, optionally composed of 1-6 independently selected R groups. f Replace; and another R Q It is a halogenated group. In some implementations, there are two R groups. Q An R Q (For example, R attached to ring N) Q ) is an independently chosen C 1-3 Alkyl groups, optionally composed of 1-6 independently selected R groups. f Replace; and another R Q It is fluorine. In some implementations, there are two R... Q An R Q (For example, R attached to ring N) Q ) is an independently selected, unsubstituted C 1-3 Alkyl; and another R Q It is fluorine. In some implementations, there are two R... Q An R Q (For example, R attached to ring N) Q ) is methyl; and another R Q It's fluorine.

[0213] In some implementations, there is an R Q (For example, R attached to ring N) Q And it is an independently chosen C 1-6 Alkyl groups, optionally composed of 1-6 independently selected R groups. f Replacement. In some implementations, there exists an R. Q (For example, R attached to ring N) Q And it is an independently chosen C 1-3Alkyl groups, optionally composed of 1-6 independently selected R groups. f Replacement. In some implementations, there exists an R. Q (For example, R attached to ring N) Q And it is an independently chosen, unsubstituted C 1-3 Alkyl group. In some embodiments, an R is present. Q (For example, R attached to ring N) Q And it is methyl.

[0214] In some implementations, Q is

[0215] In some implementations of equation (I), Q is optionally selected from 1 to 6 independently chosen R. Q Replacement C 6-10 Aryl. In some embodiments, Q is optionally selected from 1 to 6 independently chosen R. Q Substituted phenyl groups. In some embodiments, Q is optionally replaced by one or two independently selected R groups. Q Substituted phenyl groups. In some embodiments, Q is optionally replaced by one or two independently selected R groups. Q Substituted phenyl groups.

[0216] In some implementations of equation (I), Q is: Where Y 1 Y 2 Y 4 and Y 5 Each is independently N, CH or CR Q In some implementation schemes, Y 1 Y 2 Y 4 and Y 5 Each is independently CH or CR Q In some implementation schemes, Y 1 Y 2 Y 4 and Y 5 One or both of them are CH or CR independently. Q ; and the remaining Y 1 Y 2 Y 4 and Y 5 It is CH.

[0217] In some implementations, Q is Where m1 is 0, 1 or 2.

[0218] In some implementations, in L 2 The opposite R Q Selected from:

[0219] (e)-C(=O)NR c R d or -S(O)2NR c R d ;

[0220] (f)-S(=O) 0-2 R e ;

[0221] (m)P(=O)R a R b ;and

[0222] (n)-(CR h R h ) q1 -S(O)2-L e -R e .

[0223] In some implementations, in L 2 The opposite R Q It is -P(=O)R a R b .

[0224] In some implementation schemes, R a and R b C is an independent choice. 1-6 Alkyl groups, optionally composed of 1 to 6 independently selected from C10. 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl and halogenated groups. In some embodiments, R a and R b C is an independent choice. 1-6 Alkyl groups, optionally composed of one or two independently selected C14 groups. 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl and halogenated groups. In some embodiments, R a and R b C is an independent choice. 1-3 The alkyl group is optionally substituted with one or two independently selected halogen groups. In some embodiments, R a and R b It is an independently selected, unsubstituted C 1-3 Alkyl group. In some embodiments, R a and R b Each is an ethyl group.

[0225] In some implementations, m1 is 0. In some implementations, m1 is 1. In some implementations, m1 is 2.

[0226] In some implementations, Q is In some implementations, in L 2 The interposition of R Q Yes -NR c R d In some implementations, each R c and R d Selected independently from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl groups and C(=O)(C 1-6 Alkyl groups are each optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Alkyl groups are substituted. In some embodiments, each R... c and R d Selected independently from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl groups and C(=O)(C 1-6 Alkyl groups are each optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Alkyl groups are substituted. In some embodiments, each R... c and R d Independently selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by 1 to 6 independently selected from -OH, halogroup, and C. 1-6 Alkyl groups are substituted. In some embodiments, each R... c and R d Independently selected from H and C 1-3 Alkyl group. In some embodiments, R c and R d One of them is H, and R c and R d The other one is C. 1-3 Alkyl group. In some embodiments, R c and R d One of them is H, and R c and R d The other one is methyl.

[0227] In some implementations, Q is

[0228] In some implementations of formula (I), R 1 It is H. In some implementations of formula (I), R 2 It is H. In some implementations of formula (I), R 3 It is C 1-6Alkyl group. For example, R 3 It can be C 1-3 Alkyl groups, such as methyl groups. In some embodiments, R 3 It is C 1-6 Alkyl, and R 3 The attached carbon atom has an (S)- configuration.

[0229] In some implementations of formula (I), R 1 R 2 and R 3 It's H.

[0230] In some implementations of formula (I), R 1 and R 2 It is H; and R 3 It is C 1-6 Alkyl group. In some embodiments, R 1 and R 2 It is H; and R 3 Methyl. In some embodiments, R 3 The attached carbon atom has an (S)- configuration.

[0231] In some implementations of formula (I), L 2 yes:

[0232] In some implementations of equation (I), ring A is C 6-10 aryl or 5-10 heteroaryl groups, each optionally substituted by 1-4 substituents independently selected from the following: halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl group.

[0233] In some embodiments of formula (I), ring A is phenyl or pyridyl, each optionally substituted by 2-4 substituents each independently selected from the following: halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl group.

[0234] In some embodiments of formula (I), ring A is a phenyl group, which is optionally surrounded by 2-4 groups, each independently selected from a halogenated group and a C-shaped group. 1-6 Alkyl substituents.

[0235] In some implementations of equation (I), ring A is: Where R AA R AB and R AC Independently, it is a halogenated group or C 1-6 Alkyl group. In some embodiments, RAA and R AC C is independent 1-6 Alkyl (e.g., C) 1-3 Alkyl groups, such as methyl groups. In some embodiments, R AB It is a halogenated group (e.g., -F).

[0236] In some embodiments of formula (I), ring A is a pyridinyl group, which is optionally surrounded by 2-4 groups, each independently selected from a halogenated group and a C-group. 1-6 Alkyl substituents.

[0237] In some implementations of formula (I), L 1 It is C (=O).

[0238] In some implementations of equation (I), ring B is:

[0239] In some implementations of formula (I), R 4 R 5 and R 6 Each is either an H group or a halogenated group. In some implementations, R... 4 R 5 and R 6 Each is either H or -F. For example, R 4 R 5 and R 6 Each can be H. As another non-restrictive example, R 4 and R 5 It can be H; and R 6 It can be -F.

[0240] In some implementations of formula (I), R 7 It is H. In some implementations of formula (I), R 7 Yes, it is -F.

[0241] In some implementations of equation (I), ring B is: In some implementation schemes, R 4 R 5 and R 6 Each is either an H group or a halogenated group. In some implementations, R... 4 R 5 and R 6 Each is either H or -F. For example, R 4 R 5 and R 6 Each can be H. As another non-restrictive example, R 4 and R 5 It can be H; and R 6 It can be -F. In some implementations, R7 It is H. In some implementations of formula (I), R 7 Yes, it is -F.

[0242] In some implementations of equation (I), ring B is: And R 4 R 5 R 6 and R 7 Each is H.

[0243] In some implementations of formula (I), L 3 and L 4 At least one of them is a key. In some implementations, L 3 and L 4 Both are keys. In some implementations, L 3 It is a key; and L 4 It is C 1-2 Alkylene. In some embodiments, L 4 It is a key; and L 3 It is C 1-2 Alkylene.

[0244] In some implementations of formula (I), L 3 and L 4 Each is C independently 1-2 Alkylene.

[0245] In some implementations of formula (I), R 8a and R 8b Together with their respective attached carbon atoms, they form optional 1-2 (e.g., 1) independently selected C atoms. 1-6 Alkyl-substituted C 3-8 cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally separated by 1-3 independently selected R groups. f Replacement. In some implementations, L 3 It is a key; and L 4 It is a key.

[0246] In some implementations of formula (I), R 8a and R 8b Together with their respective attached carbon atoms, they form optional 1-2 (e.g., 1) independently selected C atoms. 1-6 Alkyl-substituted C 3-5 (e.g., C3 or C4) cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally separated by 1-3 independently selected R groups. f Replacement. In some implementations, L 3 It is a key; and L 4 It is a key.

[0247] In some implementations of formula (I), R 8a and R 8b Together with their respective attached carbon atoms, they form optional 1-2 (e.g., 1) independently selected C atoms. 1-6 Alkyl-substituted C 3-4 Cycloalkyl rings.

[0248] In some implementations of formula (I), R 8a and R 8b Together with the carbon atoms attached to each one, they form:

[0249] In some implementations of formula (I), R 8a and R 8b Together with the carbon atoms attached to each one, they form:

[0250] In some implementations of formula (I), R 9 yes: In some implementation schemes, R 9d Is it H or C? 1-6 Alkyl group. For example, R 9d It can be H.

[0251] In some implementations of formula (I), L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is:

[0252] In some implementations of formula (I), L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is:

[0253] In some implementations of formula (I), L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is: In some implementations of formula (I), L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is: Each of the three solid centers has an (S) configuration.

[0254] In some implementations of formula (I), R 9 It is (IX-2), where L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is: Where R 9d Is it H or C? 1-6 Alkyl group. For example, R 9d It can be H. In some implementations, Each solid center has an (S) configuration.

[0255] In some implementations of formula (I), R 9 It is C(=O)OH.

[0256] In some implementations of equation (I), ring C is optionally composed of 1-3 independently selected R... Ca The 3-12 membered heterocyclic group is replaced. In some embodiments, the ring C is optionally replaced by 1-3 independently selected R groups. Ca The 4-8 membered heterocyclic group is replaced. In some embodiments, the ring C is optionally replaced by 1-3 independently selected R groups. Ca Substituted 5-6 membered heterocyclic groups. For example, the ring C can optionally be replaced by 1-3 independent R groups. Ca Substituted tetrahydropyranyl group.

[0257] In some embodiments of equation (I), ring C is selected from... In some implementations, ring C is In some implementations, ring C is

[0258] In some implementations of formula (I), R Ca C is independent 1-6 alkyl.

[0259] In some embodiments of formula (I), a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms attached to each ring, they form a carbon ring containing 3 to 6 ring atoms.

[0260] In some embodiments of formula (I), a pair of R atoms on the same ring atom Ca Together with the ring atoms to which they are attached, they form a carbon ring containing 3-5 ring atoms.

[0261] In some embodiments, the compound of formula (I) is the same as the compound of formula (IA):

[0262]

[0263]

[0264] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0265] Q 1 Is it NH or NR? Q ;

[0266] Q 2 and Q 3 Each is independently N, CH or CR Q ;

[0267] n1 is 0 or 1;

[0268] Ring E is C 3-6 cycloalkyl; and

[0269] R 8c Selected from H and optionally 1-3 independently selected R f Replacement C 1-6 alkyl.

[0270] In some implementations of formula (IA), Q 1 It is NR Q .

[0271] In some implementations of formula (IA), R attached to N Q Selected from:

[0272] (a) Halogenated group;

[0273] (b) Cyano group;

[0274] (c)OH;

[0275] (d)-NR c R d ;

[0276] (e)-C(=O)NR c R d or -S(O)2NR c R d ;

[0277] (f)-S(=O) 0-2 R e ;

[0278] (g) R, which is arbitrarily selected from 1 to 6 independently selected f Replacement C 1-6 Alkyl; and

[0279] (h) R, which is arbitrarily selected from 1 to 6 independently selected fReplacement C 1-6 Alkyl group.

[0280] As a non-restrictive example, R attached to N Q It can be C without replacement. 1-3 alkyl.

[0281] In some implementations of formula (IA), Q 2 and Q 3 Each can be either N or CH independently. As a non-restrictive example, Q... 2 It is N and Q 3 It can be CH.

[0282] In some embodiments of equation (IA), n1 is 0. In some embodiments of equation (IA), n1 is 1.

[0283] In some implementations of formula (IA), R attached to the 6-membered ring Q Selected from halogenated groups, cyano groups, OH groups, and C groups. 1-6 Alkyl and C 1-6 Alkyl group. In some embodiments, the R group attached to the 6-membered ring... Q It is a halogenated group.

[0284] In some implementations of formula (IA), L 2 In Q 1 The corresponding attachment.

[0285] In some implementations of formula (IA), R attached to the 6-membered ring Q Attached to Q 3 The neighboring position.

[0286] In some embodiments, the compound of formula (I) is the compound of formula (IB):

[0287]

[0288] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0289] m1 is 0, 1, or 2;

[0290] In L 2 The opposite R Q It is -P(=O)R a R b ;

[0291] Ring E is C 3-6 cycloalkyl; and

[0292] R 8c Selected from H and optionally 1-3 independently selected R f Replacement C 1-6alkyl.

[0293] In some implementations of formula (IB), R a and R b C is an independent choice. 1-6 Alkyl groups, optionally composed of one or two independently selected C14 groups. 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl and halogenated groups. In some embodiments, R a and R b It is an independently selected, unsubstituted C 1-3 alkyl.

[0294] In some implementations of formula (IB), m1 is 1 and not in L. 2 The opposite R Q In L 2 The position of L. In some implementations, in L 2 The interposition of R Q Yes -NR c R d .

[0295] In some implementations of formula (IB), each R c and R d Selected independently from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl groups and C(=O)(C 1-6 Alkyl groups are each optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Alkyl group substitution. In some embodiments, R c and R d One of them is H, and R c and R d The other one is methyl.

[0296] In some embodiments of formula (IA) or (IB), ring E is cyclopropyl.

[0297] In some embodiments of formula (IA) or (IB), ring E is cyclobutyl.

[0298] In some implementations of formula (IA) or (IB), R 8c It's H.

[0299] In some implementations of formula (IA) or (IB), R 8c It is C 1-3 Alkyl group. For example, R 8c It can be methyl.

[0300] In some implementations of formula (IA) or (IB), R 9 yes: In some implementation schemes, R 9d It's H.

[0301] In some implementations of formula (IA) or (IB), Part of it is:

[0302] In some implementations of formula (IA) or (IB), Part of it is: Each of the three solid centers has an (S) configuration.

[0303] In some implementations of formula (IA) or (IB), Part of it is:

[0304] In some implementations of formula (IA) or (IB), Part of it is:

[0305] In some implementations of formula (IA) or (IB), R 9 It is C(=O)OH.

[0306] In some implementations of formula (IA) or (IB), ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted 3-12 membered heterocyclic groups.

[0307] In some implementations of formula (IA) or (IB), ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted 5-6 membered heterocyclic groups.

[0308] In some implementations of formula (IA) or (IB), ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted tetrahydropyranyl group.

[0309] In some embodiments of formula (IA) or (IB), ring C is selected from...

[0310] In some implementations of formula (IA) or (IB), each R Ca C is independent 1-6 alkyl.

[0311] In some embodiments of formula (IA) or (IB), a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms attached to each ring, they form a carbon ring containing 3 to 6 ring atoms.

[0312] In some implementations of formula (IA) or (IB), R 4 R 5 R 6 and R 7 Each is H.

[0313] In some implementations of formula (IA) or (IB), L 1 It is C (=O).

[0314] In some implementations of formula (IA) or (IB), R 1 and R 2 It's H.

[0315] In some implementations of formula (IA) or (IB), R 3 It is C 1-3 alkyl.

[0316] In some implementations of formula (IA) or (IB), R 3 It is a methyl group.

[0317] In some implementations of formula (IA) or (IB), R 1 and R 2 It is H; and R 3 It is C 1-3 Alkyl (e.g., methyl).

[0318] In some embodiments of formula (IA) or (IB), ring A is phenyl or pyridyl, each optionally substituted by 2-4 substituents each independently selected from the following: halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl group.

[0319] In some embodiments of formula (IA) or (IB), ring A is a phenyl group, which is optionally surrounded by 2-4 groups, each independently selected from a halogenated group and C. 1-6 Alkyl substituents.

[0320] In some implementations of formula (IA) or (IB), ring A is: Where R AA R AB and R AC Independently, it is a halogenated group or C 1-6 Alkyl group. In some embodiments, R AA and R AC C is independent 1-6 Alkyl group. For example, R AA and R AC C can be chosen independently. 1-3Alkyl groups, such as methyl groups. In some embodiments, R AB It is a halogenated group, such as -F.

[0321] In some implementations of formula (IA) or (IB), L 2 yes:

[0322] In some embodiments, the compounds of Formula I are selected from the compounds in Table C1 or their pharmaceutically acceptable salts or solvates.

[0323] Table C1

[0324]

[0325]

[0326]

[0327]

[0328] In some embodiments, the compound is selected from the compounds in Table C2 or their pharmaceutically acceptable salts or solvates.

[0329] Table C2

[0330]

[0331]

[0332]

[0333] Compounds of Formula I include their pharmaceutically acceptable salts. Furthermore, compounds of Formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for the preparation and / or purification of compounds of Formula I and / or the isolation of enantiomers of compounds of Formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetate salts.

[0334] It should be further understood that compounds of Formula I or their salts can be isolated in solvated form, and accordingly, any such solvates are included within the scope of this invention. For example, compounds of Formula I and their salts can exist in both non-solventized and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.).

[0335] Pharmaceutical composition and administration

[0336] When used as a medicine, compounds of Formula I (including their pharmaceutically acceptable salts or solvates) may be administered in the form of a pharmaceutical composition. These compositions may be prepared in ways well known in the pharmaceutical field and may be administered via a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration may be external (including transdermal, epidermal, ocular, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal), oral, or parenteral. Oral administration may include formulations for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, injection, or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or may be administered, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for external application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powder or oil-based matrices, thickeners, etc., may be necessary or desirable.

[0337] This document also provides pharmaceutical compositions comprising a compound of formula I as an active ingredient, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, pharmaceutical compositions prepared using a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compositions are suitable for external application. In manufacturing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in a carrier, such as a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that acts as a medium, carrier, or mediator of the active ingredient. Therefore, the compositions can be in the following forms: tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, 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. In some embodiments, the composition is formulated as tablets or capsules.

[0338] This document further provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvation thereof, and a pharmaceutically acceptable excipient. Pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvation thereof as an active ingredient can be prepared by uniformly mixing a compound of Formula I or a pharmaceutically acceptable salt or solvation thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take many forms, depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0339] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions 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.

[0340] Methods for preparing pharmaceutical compositions have been described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, 2nd 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. and published by Marcel Dekker, Inc.

[0341] In some embodiments, the compound or pharmaceutical composition may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer, or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing 0.005% to 100% of the chemical entities described herein, with the remainder supplemented by non-toxic excipients, can be prepared. The compositions covered may contain 0.001% to 100% of the chemical entities provided herein, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment. Practical methods for preparing such dosage forms are known to or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0342] In some embodiments, the compounds and pharmaceutical compositions described herein, or pharmaceutical compositions thereof, may be administered to patients in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intrasinus, trachea, intestine, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intracatheter, duodenal, intradural, intraepithelial, intraepithelial, esophageal, intragastric, intragingival, intraileum, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratestinal, intrasheath, intraduct, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, transdural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some implementations, the preferred route of administration is parenteral (e.g., intratumoral).

[0343] In some embodiments, compounds of formula I as described herein, or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA and IB, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions thereof, may be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions may be prepared as injectable preparations, as liquid solutions or suspensions; they may also be prepared in solid forms suitable for the preparation of solutions or suspensions after the addition of liquid prior to injection; and the formulations may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of this disclosure. In some embodiments, parenteral administration is performed using a device. For example, such devices may include needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[0344] In some embodiments, suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid in a manner that facilitates injection. In some embodiments, the form should be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi.

[0345] In some embodiments, the carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, suitable flowability can be maintained, for example, by using a coating (such as lecithin), in the case of a dispersion, by maintaining the desired particle size, and by using a surfactant. In some embodiments, the antimicrobial effect can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In some embodiments, isotonic agents, such as sugars or sodium chloride, are included. In some embodiments, the absorption of the injectable composition can be prolonged by using a delayed-absorption agent (e.g., aluminum monostearate and gelatin) in the composition.

[0346] In some embodiments, the sterile injectable solution is prepared by incorporating a desired amount of a compound of Formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of Formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof) into a suitable solvent having various other components listed above, followed by filtration sterilization. In some embodiments, the dispersion is prepared by incorporating various sterile active ingredients into a sterile medium containing a base dispersion medium and desired other components from those listed above. In some embodiments, sterile powder is used to prepare the sterile injectable solution. In some embodiments, the preparation method is a vacuum drying and freeze-drying technique, which produces a powder of the active ingredient plus any other desired components from its previously sterile filtered solution.

[0347] In some embodiments, pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: glyceryl cocoa butter, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin-treated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and polyethylene glycol fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, p-hydroxybenzoates in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol cetearyl ether, cocoyl caprylate (cocoyl ethyl ethyl decanoate). (caprylocaprate), isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium EDTA, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E) and potassium acetate.

[0348] In some embodiments, the suppository can be prepared by mixing a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof) or a pharmaceutical composition as described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, suppository wax, which is solid at ambient temperature but liquid at body temperature, and thus melts in the rectum and releases the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0349] In some embodiments, compounds of formula I as described herein, or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA and IB, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions thereof, may be formulated for local delivery to the digestive or gastrointestinal tract by means of oral administration (e.g., solid or liquid dosage forms).

[0350] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof) is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate and / or the following: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, and polyvinylpyrrolidone. The ingredients include: c) sucrose and gum arabic; d) humectants such as glycerin; e) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; f) solution blockers such as paraffin; g) absorption enhancers such as quaternary ammonium compounds; h) wetting agents such as cetyl alcohol and glyceryl monostearate; d) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the dosage form may also contain a buffer. In some embodiments, similar type of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0351] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as a pill or tablet, and therefore, the composition contains a diluent, such as lactose, sucrose, dicalcium phosphate, etc., together with a compound of formula I as provided herein or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA and IB or a pharmaceutically acceptable salt or solvate thereof); a lubricant, such as magnesium stearate; and a binder, such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) as another solid dosage form will be encapsulated in a capsule (gelatin or cellulose matrix capsule). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions or additional active agents as provided herein are physically separated are also contemplated; for example, capsules (or tablets in capsules) having particles of each drug; two-layer tablets; two-compartment gel caps, etc. Some implementations also cover enteric coatings or delayed-release oral dosage forms.

[0352] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives specifically designed to prevent microbial growth or activity. For example, various preservatives are well known and include, for instance, phenol and ascorbic acid.

[0353] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized using conventional, well-known sterilization techniques. In some embodiments, sterilization is not required for various oral dosage form excipients, such as tablets and capsules. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0354] In some embodiments, a compound of formula I as described herein, or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutical composition thereof, is formulated for ocular application. In some embodiments, the ocular composition may contain, but is not limited to, one or more of the following: viscogen (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0355] In some embodiments, compounds of formula I as described herein, or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA and IB, or pharmaceutically acceptable salts or solvates thereof), or pharmaceutical compositions thereof, may be formulated for topical application to the skin or mucous membranes (e.g., transdermal or percutaneous). In some embodiments, the topical composition may include ointments and creams. In some embodiments, ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, the cream base is typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes also referred to as the "internal" phase, generally includes paraffin esters and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not essential, the aqueous phase typically exceeds the volume of the oil phase and generally contains a humectant. In some embodiments, the emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some implementations, like other carriers or media, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

[0356] In any of the foregoing embodiments, the pharmaceutical composition described herein may comprise one or more of the following: lipids, interlayer cross-linked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA] or polyanhydride nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0357] In some embodiments, the dosage of a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof) is determined based on a variety of factors, including but not limited to patient type, age, weight, sex, medical condition; severity of the patient's medical condition; route of administration; and activity of the compound or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the appropriate dosage for a particular condition can be determined by a person skilled in the medical field. In some embodiments, the total daily dose can be divided into multiple doses and administered in multiple doses throughout the day or by means of a continuous delivery method.

[0358] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof) is administered in doses of about 0.01 mg to about 1000 mg. For example, about 0.1 mg to about 30 mg, about 10 mg to about 80 mg, about 0.5 mg to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 mg 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.

[0359] In some embodiments, compounds of formula I as described herein, or pharmaceutically acceptable salts or solvates thereof (e.g., compounds of any one of formulas IA and IB, or pharmaceutically acceptable salts or solvates thereof) are used at a concentration of about 0.0002 mg / kg to about 100 mg / kg (e.g., about 0.0002 mg / kg to about 50 mg / kg; about 0.0002 mg / kg to about 25 mg / kg; about 0.0002 mg / kg to about 10 mg / kg). About 0.0002 mg / kg to about 5 mg / kg; about 0.0002 mg / kg to about 1 mg / kg; about 0.0002 mg / kg to about 0.5 mg / kg; about 0.0002 mg / kg to about 0.1 mg / kg; about 0.001 mg / kg to about 50 mg / kg; about 0.001 mg / kg to about 25 mg / kg; about 0.001 mg / kg to about 10 mg / kg; about 0.001 mg / kg to about 5 mg / kg mg / Kg; about 0.001 mg / Kg to about 1 mg / Kg; about 0.001 mg / Kg to about 0.5 mg / Kg; about 0.001 mg / Kg to about 0.1 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 25 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 25 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg) are administered. In some embodiments, a compound of formula I as described herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof) is administered at a dose of about 100 mg / Kg.

[0360] In some embodiments, the aforementioned dose of a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof) may be administered daily (e.g., in a single dose or in two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0361] In some embodiments, the application period of the compound of formula I described herein or its pharmaceutically acceptable salt or solvation (e.g., the compound of any one of formulas IA and IB, or its pharmaceutically acceptable salt or solvation) 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 longer. In some implementations, the discontinuation period 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 longer. In some implementations, a compound of Formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of Formula IA or IB or a pharmaceutically acceptable salt or solvation thereof) is administered to the patient for a certain period of time, followed by separate periods of discontinuation of the compound of Formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of Formula IA or IB or a pharmaceutically acceptable salt or solvation thereof). In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of Formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof) is administered for a first time period followed by a second time period, during which administration is stopped, then a third time period in which administration of the compound of Formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of Formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof) is initiated, and then a fourth time period in which administration is stopped after the third time period. For example, after the time period of administration of the compound of Formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of Formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof), determined or undetermined time periods for stopping administration are subsequently repeated. In some implementation schemes, the application period 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, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.In some implementation plans, the period for ceasing application 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, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0362] In some implementations, a compound of formula I or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB or a pharmaceutically acceptable salt or solvation thereof) is administered orally to a patient once or more daily (e.g., once daily, twice daily, three times daily, four times daily, or a single daily dose).

[0363] In some implementations, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvate thereof) is administered to a patient via parenteral administration once or more daily (e.g., 1 to 4 times, once daily, twice daily, three times daily, four times daily, or a single daily dose).

[0364] In some implementations, a compound of formula I as described herein or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of either formula IA or IB, or a pharmaceutically acceptable salt or solvation thereof) is administered to a patient weekly via parenteral administration.

[0365] Treatment

[0366] In some embodiments, this disclosure is characterized by methods for treating patients (e.g., persons) suffering from diseases, disorders, or conditions, wherein modulating GLP-1R (e.g., inhibiting or weakening and / or increasing or detrimental GLP-1R) is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods described herein may include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions described herein.

[0367] This document provides methods for treating GLP-1-related diseases, disorders, or conditions, comprising administering to a patient in need an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof), or a pharmaceutical composition thereof.

[0368] In some implementations, the diseases, disorders, or conditions include, but are not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), adult-onset diabetes in adolescents (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, 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 cell dysfunction, impaired vascular compliance, restenosis, thrombosis, and hypertension. Pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic 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, and polycystic ovary syndrome (PCOS).

[0369] In some implementations, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, 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, hyperglycemia, postprandial hyperlipidemia, and metabolic acidosis. Ketoacidosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0370] In some implementations, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery 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 ulcers, or any combination thereof.

[0371] In some embodiments, the compounds and pharmaceutical compositions and methods used to treat the patients described herein induce one or more of the following: lowering blood glucose (e.g., lowering blood glucose levels), lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing β-cell mass, regulating gastric acid secretion, regulating gastric emptying, lowering body mass index (BMI), and / or lowering glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods used to treat the patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Methods for regulating glucose or insulin levels in patients requiring such regulation are also provided herein, the methods comprising administering to the patient an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof) or a pharmaceutical composition.

[0372] In some embodiments, this document provides a method for reducing the risk of major adverse cardiovascular events (MACE) in patients in need (e.g., a reduction of about 20%, 30%, 40%, 50%, 60%, 70%, or 80%), said method comprising administering to said patient an effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof) or a pharmaceutical composition. In some of these embodiments, said patient is an adult diagnosed with type 2 diabetes (T2D). In some embodiments, said patient is an adult diagnosed with heart disease. In some embodiments, said patient is an adult diagnosed with both type 2 diabetes (T2D) and heart disease. In some embodiments, said patient is an adult with type 2 diabetes (T2D). In some embodiments, said patient is an adult with heart disease. In some embodiments, said patient has both type 2 diabetes (T2D) and heart disease.

[0373] Indications

[0374] obesity

[0375] In some embodiments, the condition, disease, or disorder is obesity and conditions, diseases, or disorders related to or associated with 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 excessive abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, type II diabetes mellitus, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., obesity induced by steroids, phenobarbital, insulin, sulfonylureas, or beta-blockers).

[0376] In some embodiments, the condition, disease, or disorder is associated with obesity. Examples of such conditions, diseases, or disorders include, but are not limited to, glucose intolerance, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatosis (NASH)), coronary artery disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), skeletal or joint disorders (e.g., knee osteoarthritis, hip osteoarthritis, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity-related hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycles, abnormal menstrual flow and cycle, 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 exhibiting both obesity and insulin deficiency.

[0377] diabetes

[0378] In some embodiments, the condition, disease, or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline diabetes. In some embodiments, the condition, disease, or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy).

[0379] This article provides a method for treating a patient with diabetes, 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 disclosed herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutically acceptable salt or solvation thereof) or a pharmaceutical composition.

[0380] This article provides a method for treating a patient with type 2 diabetes, the method comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutically acceptable salt or solvation thereof) or a pharmaceutical composition.

[0381] This article also provides a method for treating type 2 diabetes in patients in need, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I disclosed herein, or a pharmaceutically acceptable salt or solvation thereof (e.g., a compound of any one of formulas IA and IB, or a pharmaceutically acceptable salt or solvation thereof, or a pharmaceutically acceptable salt or solvation thereof) or a pharmaceutical composition.

[0382] In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) increase insulin levels. In some embodiments, compounds and pharmaceutical compositions and methods for treating patients with the conditions, diseases, or disorders described herein (e.g., type 2 diabetes) reduce BMI.

[0383] In some embodiments, a reduction in fasting plasma glucose levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a reduction in fasting plasma glucose levels of about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment for type 2 diabetes.

[0384] In some embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment for type 2 diabetes.

[0385] In some embodiments, a reduction in HbA1c levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in HbA1c levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in HbA1c levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a reduction in HbA1c levels of about or less than 6.5%, about or less than 6.0%, or about or less than 5.0% indicates treatment for type 2 diabetes.

[0386] In some embodiments, a decrease in glucagon levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment for type 2 diabetes.

[0387] In some embodiments, a BMI reduction of about 5% to about 95% indicates treatment for type 2 diabetes. In some embodiments, a BMI reduction of about 15% to about 80% indicates treatment for type 2 diabetes. In some embodiments, a BMI reduction of about 25% to about 60% indicates treatment for type 2 diabetes. In some embodiments, a BMI reduction 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 for type 2 diabetes. In some embodiments, a BMI reduction of about or below 40, about or below 30, or about or below 20 indicates treatment for type 2 diabetes.

[0388] In some implementations, the condition, disease, or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of diabetes-related disorders include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular disease, osteoporosis, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors associated with unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0389] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic X syndrome, where activation of GLP-1R is a beneficial metabolic disorder), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0390] In some embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein can also be used to improve the therapeutic efficacy of metformin.

[0391] Metabolic barriers

[0392] In some embodiments, the condition, disease, or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0393] In some implementations, the condition, disease, or disorder is fatty liver disease. Fatty liver disease includes, but is 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, abeta-lipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman's disease, acute fatty liver of pregnancy, and lipid dystrophy.

[0394] Nonalcoholic fatty liver disease (NAFLD) refers to a range of diseases that occur in the absence of alcohol abuse and are typically characterized by the presence of steatosis (fat in the liver). NAFLD is believed to be associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and may eventually lead 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, predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17Suppl:S186-90). In some implementations, 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 subdivided into different subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 to 21 years (until, but not including, their twenty-second birthday)). (References: Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th edition Philadelphia: WBSaunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd edition Baltimore: Williams & Wilkins; 1994.) In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to under two years of age, two years old to under 12 years of age, or 12 years old to 21 years of age (up to but not including the twenty-second birthday). In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to under one year of age, one month old to under four months of age, three months old to under seven months of age, six months old to under one year of age, one year old to under two years of age, two years old to under three years of age, two years old to under seven years of age, three years old to under five years of age, five years old to under ten years of age, six years old to under 13 years of age, ten years old to under 15 years of age, or 15 years old to under 22 years of age. In some implementations, patients are adult patients.

[0395] Other non-limiting examples of disorders affecting metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), fatty degeneration (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; skeletal disorders characterized by changes in bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and malnutrition due to polycystic ovary syndrome; kidney 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 some embodiments, the compounds and pharmaceutical compositions described herein can be used to treat surgical trauma by improving postoperative recovery and / or by preventing catabolism caused by surgical trauma.

[0396] Cardiovascular and vascular diseases

[0397] In some implementations, the condition, disease, or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary artery disease, coronary artery disease, hypertension, heart failure, cerebrovascular disorders (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prethrombotic states (exemplified by high fibrinogen or plasminogen activator inhibitor levels in the blood).

[0398] In some implementations, the condition, disease, or disorder is related to vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, large vessel complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, nephropathy, and neuropathy.

[0399] Nervous system diseases

[0400] In some implementations, the condition, disease, or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a mental disorder. Non-limiting examples of neurological disorders include cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., Alzheimer's disease), traumatic brain injury, Huntington's chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurological trauma, brain trauma, angioamylindness, intracerebral hemorrhage with amyloidosis, encephalitis, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated central nervous system degenerative diseases (e.g., Creutzfeld-Jakob disease, bovine spongiform encephalopathy (BSE), and chronic wasting syndrome). See, for example, US20060275288 A1.

[0401] Non-limiting examples of mental illnesses include substance dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to improve behavioral responses to addictive substances, reduce substance dependence, prevent relapse into substance abuse, and alleviate anxiety caused by the lack of a given addictive substance. See, for example, US 20120021979 A1.

[0402] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and also to protect dopamine neurons and motor function in Parkinson's disease.

[0403] Insulin-related

[0404] In some implementations, the condition, disease, or disorder is impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemia, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related coma endpoints.

[0405] In some 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.

[0406] Autoimmune disorders

[0407] In some implementations, the condition, disease, or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders 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, US 20120148586 A1.

[0408] Gastrointestinal disorders

[0409] In some implementations, the condition, disease, or disorder is a gastrointestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption disorders, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), steatorrhea (Celiac sprue), hypogammaglobulinemic sprue, mucositis and diarrhea induced by chemotherapy and / or radiation therapy, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal damage (e.g., gastric mucosal damage caused by aspirin), small intestinal mucosal damage, 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 immunodeficiency syndrome).

[0410] weight

[0411] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce (e.g., excess weight) in a patient (e.g., a patient in need), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake. In some embodiments, a patient's weight gain may be attributed to excessive food intake or an unbalanced diet, or may be due to weight gain from accompanying medications (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, empaglitazone, cycloglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obesity weight gain or weight gain in an obese patient. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain following cessation of smoking.

[0412] In some implementations, the condition, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, or compulsive eating.

[0413] Inflammatory diseases

[0414] In some implementations, the condition, disease, or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colitis), inflammation in metabolically important tissues (including the liver, fat, pancreas, kidneys, and intestines), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers of inflammatory-like C-reactive protein in the blood).

[0415] cancer

[0416] In some implementations, the condition, disease, or obstacle is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), and colorectal cancer (e.g., gastrointestinal stromal tumor). Gastrointestinal stromal tumors (GISTs), colorectal cancers (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small bowel cancers (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannomas, liver cancers (e.g., primary liver cancer, ... Extrahepatic bile duct cancer, renal cell carcinoma (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 tumors, ovarian germ cell tumors, low-potency ovarian tumors), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid carcinoma, nasal cancer Cavity cancer, sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., Wilms' tumor, pediatric kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0417] Hypothalamic-pituitary disorders

[0418] In some implementations, the condition, disease, or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is related to the hypothalamic-pituitary-ovarian axis. In another example, the condition, disease, or disorder is related to 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.

[0419] In some implementations, conditions, diseases, or disorders associated with diabetes are linked to the hypothalamic-pituitary-gonadal axis.

[0420] pulmonary disease

[0421] In some implementations, the condition, disease, or disorder is related to lung disease. Lung diseases include, but are 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).

[0422] In some implementations, the condition, disease, or disorder associated with diabetes is lung disease.

[0423] Combination therapy

[0424] In some implementations, this disclosure considers both monotherapy regimens and combination therapy regimens.

[0425] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0426] In some embodiments, the methods described herein include administering the compounds described herein in combination with one or more of the following: diet therapy (e.g., diet monitoring, diet therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, and gastric electrical stimulation (e.g., And dietary changes.

[0427] In some implementations, a compound of X, as described herein, or a pharmaceutically acceptable salt or solvate thereof, may be administered in combination with one or more other therapeutic agents.

[0428] Other representative therapeutic agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, diabetes complication treatment agents, hyperlipidemia treatment agents, antihypertensive agents, diuretics, chemotherapy drugs, immunotherapy drugs, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis treatment agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, urinary frequency or incontinence treatment agents, NAFLD treatment agents, NASH treatment agents, dysuria treatment agents, and antiemetics.

[0429] In some embodiments, the one or more additional therapeutic agents include those suitable for use as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phenbutylide, 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)), and neuropeptide Y antagonists (e.g., virifibrate). Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), orexin antagonists, orexin receptor antagonists, orexin acylase 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), and pancreatic lipase inhibitors (e.g., orlistat). istat), cetilistat), β3 agonists (e.g., N-5984), diacylglycerol 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, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucoskinase activators (e.g.,Piraglitin, AZD-1656, AZD6370, TTP-355, compounds described in W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821, W0008 / 136428 and W0008 / 156757, leptin, leptin derivatives (e.g., metriptin), leptin resistance modifiers, CNTF (ciliary neurotrophic factor), BDNF ( Brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlinide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oximin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; using Escherichia coli). Human FGF21 preparations synthesized from genes of *C. coli* or yeast; fragments or derivatives of FGF21; appetite suppressants (e.g., P-57); human pro-insulin peptide (HIP); farnesoid X receptor (FXR) agonists; phenbutazone; zonisamide; norepinephrine / dopamine reuptake inhibitors; GDF-15 analogs; methionine aminopeptidase 2 (MetAP2) inhibitors; diethylamine acetone; benzotriazine; benzylphenamine; fibroblast growth factor receptor (FGFR) modulators; and AMP-activated protein kinase (AMPK) activators.

[0430] In some embodiments, the one or more additional therapeutic agents include those that can be used 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 synthesized using Escherichia coli or yeast genes; 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 its salts), biguanides (e.g., metformin, buformin or their salts (e.g., hydrochloride, fumarate, succinate)), and glucagon analogs (e.g., WO4). Any glucagon analogues described in 2010 / 011439, agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, acetohexamide, glipizide, glybuzole, glibenclamide), thiazolidinedione agents (e.g., roximately 2999), and agents that antagonize the action of glucagon or reduce glucagon secretion; sulfonylurea ... Glitter or pioglitazone), alpha-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as dietary glucose regulators (sometimes called "short-acting secretagogues"), such as megglitinide (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists GLP-1R agonists (e.g., LBT-2000, ZPD1-70), exenatide, liraglutide, abiglutide, duraglutide, abiglutide, tasglutide, lixinaglutide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin) Ptin), saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin.

[0431] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat 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, galactoglobulin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinase (KHK) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, glycyrrhizin, and schisandra extract. Extracts), ascorbic acid, glutathione, silymarin, lipoic acid and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteine, sulfonylureas, alpha-glucosidase inhibitors, megglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral agents and antioxidants.

[0432] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat complications of diabetes. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), and PKC inhibitors (e.g., rubosta mesylate). mesylate), AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., lipoic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulated kinase-1 (ASK-1) inhibitors.

[0433] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium, calcium salts)) and squalene synthase inhibitors (e.g., WO3). Compounds described in 97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazon-3-yl]acetyl]piperidin-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol). (oryzanol, γ-oryzanol), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and ω-3 fatty acid preparations (e.g., ω-3-fatty acid ethyl ester 90).

[0434] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, 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). medoxomil), calcium channel blockers (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0435] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazide preparations (e.g., ethiothiazide, cyclopenthiazine, trichlorothiazide, hydrochlorothiazide, hydrofluorothiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide)), anti-aldosterone preparations (e.g., spironolactone, triamterene)), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide)).

[0436] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunomodulatory activity (e.g., lentinan, sizofiran, krestin), cytokines obtained through genetic engineering (e.g., interferons, interleukins (ILs), such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0437] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antithrombin 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., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, described in WO 02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823 and WO Compounds listed in 2005 / 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 eicosapentaenoate, beraprost sodium, and sarpogrelate hydrochloride).

[0438] In some embodiments, the one or more additional therapeutic agents include those that can be used, for example, to treat osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronated sodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction medications include apomorphine and sildenafil citrate. Suitable examples of medications for treating urinary frequency or incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of medications for treating dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, acetaminophen, and indomethacin.

[0439] Other illustrative additional therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucosamine activators), agents designed to treat complications of long-term hyperglycemia such as aldose reductase inhibitors (e.g., epalrestat and ranisitar), agents for treating complications associated with microvascular complications, anti-dyslipidemia agents such as HMG-CoA reductase inhibitors (statins, such as rosuvastatin), cholesterol lowering agents, bile acid sequestrants (e.g., cholestyramine), and cholesterol absorption inhibitors (e.g., plant sterols). sterols, such as phytosterols, cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid conjugating resins, nicotinic acid (nicotinic acid) and its analogues, antioxidants (e.g., probucol), omega-3 fatty acids, antihypertensive agents (including adrenergic receptor antagonists such as beta-blockers (e.g., atenolol), alpha-blockers (e.g., doxazosin), and mixed alpha / beta receptor antagonists), are also mentioned. Intraocular blockers (e.g., labetalol), adrenergic receptor agonists (including α-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone), central nervous system effects Adrenergic drugs such as central alpha agonists (e.g., clonidine), diuretics (e.g., furosemide), hemostatic modifiers (including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists, such as 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)), and 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), norepinephrine agents (e.g., phentermine), serotonergic agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulators, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, and monoamine transfer modulators such as selective serotonin reuptake inhibitors (SSRIs) (e.g.,Fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., toloxatone and amiflamine), compounds described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639, and WO 2008 / 099794, GPR40 agonists (e.g., fasiglimum or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689, and WO Compounds listed in 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improvers (such as cyclooxygenase inhibitors (e.g., indomethacin)), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, agents for improving lipid metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6 and oncogene M, metabolically modified proteins or peptides such as glucoskinase (GK), glucoskinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDEs 5. Inhibitors, glycosylation inhibitors (e.g., ALT-711), neurotrophic drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), and antiepileptic drugs (e.g., lamotrigine, trileptal, levetiracetam, zonisamide). gran), pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., ... dopamine receptor agonists), and dopamine receptor agonists (e.g., dopamine receptor agonists).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 α4 / β1 antibodies (e.g., tysabri)), drugs acting on immunoaffinity (e.g., cyclosporine, tacrolimus, sirolimus, rapamicin)), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer)), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate mofetil). The following drugs are listed: olate, metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aglitazone, siglitazone, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl eicosapentaenoic acid, clonidine, azosemide, isosorbide, ethacrylic acid, piretanin, bumetanide, and etoposide.

[0440] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, antiemetics. As used herein, an "antiemetic" means any agent that resists (e.g., reduces or eliminates) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that administering one or more antiemetics in combination with a compound of formula (I) described herein may allow for the administration of higher doses of the compound of formula (I), for example, because the patient may be able to ingest food normally and therefore respond to treatment more quickly.

[0441] Non-limiting examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), nerve blockers / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (neurokine 1P substance receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0442] For example, the antiemetic may be selected from nerve blockers, antihistamines, anticholinergics, steroids, 5HT3 receptor antagonists, NK1 receptor antagonists, dopaminergic / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0443] In some embodiments, the antiemetic 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, bemistron, zatisetron, batanopirde, MDL-73147EF; metoclopramide, N-3389 (ne-3,9-dimethyl-3,9-diazabicyclo[3,3,1]one-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxaloline carboxylic acid, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: celanisetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+netostitan), quetiapine, qamosetron, ramosteron, licastron, risperidone, ziprasidone, and zatosetron.

[0444] In some implementations, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, zatisetron, batapirde, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropyl-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxaloline carboxylate maleic acid, zacopride hydrochloride, and mirtazapine.

[0445] In some embodiments, the 5HT3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, or zatisetron.

[0446] In some embodiments, the 5HT3 receptor antagonist is granisetron, dolasetron, or ondansetron.

[0447] In some embodiments, the 5HT3 receptor antagonist is granisetron.

[0448] In some embodiments, the 5HT3 receptor antagonist is ondansetron.

[0449] In some embodiments, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclazine, meclozine, and cinnarizine); promirtine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; bucrozine; and meclozine hydrochloride (chlorobenzamine (Bonine, Antivert)), doxylamine, and mirtazapine.

[0450] In some embodiments, the antiemetic is an anticholinergic agent (acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, Trihexy-5 (benhexol hydrochloride), benzalkonium chloride, bisperidone hydrochloride, disipal (olphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and carmatrazine (propiconazole hydrochloride).

[0451] In some embodiments, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, etc. And trimethoprim (Tigan).

[0452] In some embodiments, the antiemetic is an NK1 receptor antagonist (e.g., a substance neurokinin 1P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include aprepitant, cassopindant, elopitant, fosaprepitant, maropitant, netupitant, lorapitant, and vertepitant.

[0453] 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 (benzylsulfonamide / nomipitanamide chloride), LY 303870 (lanepitan), 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-11974j., Benserazide and Carbidopa, TAK-637[(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diaza-arantalopro[2,1-g][1,7]naphthyl-6,13-dione], PD 154075, ([(2-benzofuran)-CH2OCO]-(R)-α-MeTrp-(S)-NHCH(CH3)Ph), FK888, and (D-Pro4,D-Trp7,9,10,Phe11)SP4-11.

[0454] In some embodiments, the antiemetic is an antidopaminergic agent / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, such as a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., propranolol, chlorpromazine, prochlorazine, perphenazine, hydroxyzine, thiotetracycline, metoprolol); benzamides (e.g., metoclopramide, domperidone); butyrophenones (e.g., haloperidol, droperidol); aripiprazole, bromapride, clopride, domperidone, itopride, metoclopramide, trimebenzamide, and amisulpride.

[0455] In some embodiments, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabidiol (THC), cannabinoid agonists such as WIN 55-212 (CB1 and CB2 receptor agonists), dronabinol). And cemesamet).

[0456] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, cloxacillin); and nerve blockers / antipsychotics (e.g., diazepam, haloperidol, and prochloraz). ); 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.

[0457] Other exemplary antiemetics include those disclosed in US 20120101089A1; US ​​10,071,088B2; US 6,673,792B1; US ​​6,197,329B1; US ​​10,828,297B2; US 10,322,106B2; US 10,525,033B2; WO2009080351A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US 20090305964A1; and WO 2006 / 111169, each of which is incorporated herein by reference in its entirety.

[0458] In some embodiments, an additional therapeutic agent or regimen is administered to the patient before contact with or application of the compound and pharmaceutical composition (e.g., about one hour, about six hours, about 12 hours, about 24 hours, about 48 hours, about one week, or about one month prior to contact with or application of the compound and pharmaceutical composition).

[0459] In some embodiments, an additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact with or application of the compound and pharmaceutical composition. For example, the additional therapeutic agent or regimen, along with the compound and pharmaceutical composition, is provided to the patient simultaneously in the same dosage form. Another example is that the additional therapeutic agent or regimen, along with the compound and pharmaceutical composition, is provided to the patient in parallel in separate dosage forms.

[0460] Patient selection

[0461] In some implementations, the method described herein further includes the step of identifying a patient (e.g., a subject) who requires such treatment (e.g., by blood tests, body mass index, or other conventional methods known in the art).

[0462] In some implementations, the methods described herein further include the step of identifying a patient (e.g., a patient) suffering from a disease, disorder, or condition as described herein (e.g., a GLP-1 related disease, disorder, or condition).

[0463] In some embodiments, the method described herein further includes the step of identifying a patient with type 2 diabetes (e.g., a patient). In some embodiments, determining whether a patient has type 2 diabetes includes performing measurements to determine the levels of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the HbA1c level is from about 6.5% to about 24.0%. In some embodiments, the HbA1c level is greater than or about 6.5%. In some embodiments, the HbA1c level is greater than or about 8.0%. In some embodiments, the HbA1c level is greater than or about 10.0%. In some embodiments, the HbA1c level is greater than or about 12.0%. In some embodiments, the HbA1c level is greater than or about 14.0%. In some embodiments, the HbA1c level is greater than or about 16.0%. In some embodiments, the HbA1c level is greater than or about 18.0%. In some embodiments, the HbA1c level is greater than or about 20.0%. In some embodiments, the HbA1c level is greater than or about 22.0%. In some implementations, the HbA1c level is greater than or approximately 24.0%.

[0464] In some embodiments, the fasting plasma glucose level is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0465] In some embodiments, the non-fasting plasma glucose level is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[0466] In some implementations, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some implementations, the patient's BMI is greater than or about 22 kg / m². 2 Up to or greater than 100 kg / m 2In some implementation schemes, the patient's BMI is greater than or approximately 30 kg / m². 2 Up to or approximately 90 kg / m 2 In some implementation schemes, the patient's BMI is greater than or approximately 40 kg / m². 2 Up to or approximately 80 kg / m 2 In some implementation schemes, the patient's BMI is greater than or approximately 50 kg / m². 2 Up to or approximately 70 kg / m 2 .

[0467] In some embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or approximately 10 years. In some embodiments, the patient's age is greater than or approximately 15 years. In some embodiments, the patient's age is greater than or approximately 20 years. In some embodiments, the patient's age is greater than or approximately 25 years. In some embodiments, the patient's age is greater than or approximately 30 years. In some embodiments, the patient's age is greater than or approximately 35 years. In some embodiments, the patient's age is greater than or approximately 40 years. In some embodiments, the patient's age is greater than or approximately 42 years. In some embodiments, the patient's age is greater than or approximately 44 years. In some embodiments, the patient's age is greater than or approximately 46 years. In some embodiments, the patient's age is greater than or approximately 48 years. In some embodiments, the patient's age is greater than or approximately 50 years. In some embodiments, the patient's age is greater than or approximately 52 years. In some embodiments, the patient's age is greater than or approximately 54 years. In some embodiments, the patient's age is greater than or approximately 56 years. In some embodiments, the patient's age is greater than or approximately 58 years. In some embodiments, the patient's age is greater than or approximately 60 years. In some embodiments, the patient's age is greater than or approximately 62 years. In some embodiments, the patient's age is greater than or approximately 64 years. In some embodiments, the patient's age is greater than or approximately 66 years. In some embodiments, the patient's age is greater than or approximately 68 years. In some embodiments, the patient's age is greater than or approximately 70 years. In some embodiments, the patient's age is greater than or approximately 72 years. In some embodiments, the patient's age is greater than or approximately 74 years. In some embodiments, the patient's age is greater than or approximately 76 years. In some embodiments, the patient's age is greater than or approximately 78 years. In some embodiments, the patient's age is greater than or approximately 80 years. In some embodiments, the patient's age is greater than or approximately 85 years. In some embodiments, the patient's age is greater than or approximately 90 years. In some embodiments, the patient's age is greater than or approximately 95 years. In some implementation schemes, the patient's race can be African American, American Indian or Alaskan Native, Asian American, Hispanic or Latino or Native Hawaiian or Pacific Islander.

[0468] Example

[0469] The present invention is further described in the following embodiments, which do not limit the scope of the invention as described in the claims.

[0470] Example 1

[0471] 3-((1S,2S)-1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 105a)

[0472]

[0473] Step A: N-(2-hydroxyethyl)carbamate tert-butyl ester

[0474]

[0475] NaOH (327.4 mg) and (Boc)₂O (19.65 g, 20.69 mL) in THF (30 mL) were added dropwise to a solution of 2-aminoethanol (5.00 g, 4.95 mL) in H₂O (30 mL). The yellow mixture was stirred at 25 °C for 17 h. The yellow mixture was extracted three times with ethyl acetate (30 mL). The organic layer was washed with brine (60 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated to give a crude product (18.60 g) as a yellow oil. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, between 20% and 80%) to give a colorless oil of N-(2-hydroxyethyl)carbamate tert-butyl ester (12.10 g, 91.7% yield).

[0476] 1 H NMR(400MHz, CDCl3)δppm 4.96(br s,1H)3.67-3.75(m,2H)3.27-3.32(m,2H)2.43(br s,1H)1.45(s,9H)

[0477] Step B: Ethyl 5-bromo-2-[2-(tert-butoxycarbonylamino)ethyl]pyrazole-3-carboxylate

[0478]

[0479] DEAD (4.77 g, 27.39 mmol) was added dropwise to a solution of ethyl 3-bromo-1H-pyrazole-5-carboxylate (4.00 g, 18.26 mmol), N-(2-hydroxyethyl)carbamate tert-butyl ester (2.94 g, 18.26 mmol), and PPh3 (9.58 g, 36.52 mmol) in THF (50 mL) at 0 °C–10 °C. The yellow solution was stirred at 20 °C for 16 h. The yellow solution was diluted with water (80 mL) and extracted twice with ethyl acetate (50 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product (22.60 g) as a yellow gel. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, from 10% to 25%) to give ethyl 5-bromo-2-[2-(tert-butoxycarbonylamino)ethyl]pyrazole-3-carboxylate as a white solid (5.42 g, 81.9% yield).

[0480] 1 H NMR (400MHz, CDCl3) δppm 6.84 (s, 1H) 4.84 (br s,1H)4.61-4.68(t,J=5.60Hz,2H)4.35(q,J=7.20Hz,2H)3.56-3.61(m,2H)1.41(s,9H)1.38(t,J=7.15Hz,3H)

[0481] Step C: Ethyl 2-(2-aminoethyl)-5-bromopyrazole-3-carboxylate

[0482]

[0483] HCl / dioxane (4M, 56.11 mL) was added to a solution of ethyl 5-bromo-2-[2-(tert-butoxycarbonylamino)ethyl]pyrazole-3-carboxylate (5.42 g, 14.96 mmol) in dioxane (40 mL). The solution was stirred at 20 °C for 7 h. The white suspension was concentrated to give ethyl 2-(2-aminoethyl)-5-bromo-pyrazole-3-carboxylate (4.10 g, crude product, HCl salt) as a white solid.

[0484] ¹H NMR (400MHz, methanol-d⁴) δppm 6.96 (s, ¹H) 4.79–4.86 (m, 2H) 4.38 (q, J = 7.15Hz, 2H) 3.46 (m, 2H) 1.38 (t, J = 7.15Hz, 3H)

[0485] Step D: 2-Bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

[0486]

[0487] TEA (6.95 g, 68.66 mmol, 9.56 mL) was added to a suspension of ethyl 2-(2-aminoethyl)-5-bromo-pyrazole-3-carboxylate (4.10 g, HCl salt) in EtOH (50 mL). The solution was stirred at 80 °C for 1 h. The solution was concentrated to remove the solvent and then suspended in 25 mL of MeOH. The suspension was stirred at 20 °C for 0.5 h. The mixture was filtered. The filter cake was dried under vacuum to give 2-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (2.51 g, crude product) as a white solid.

[0488] 1 H NMR (400MHz, DMSO-d6) δppm 8.34 (br s, 1H) 6.84 (s, 1H) 4.28 (t, J = 6.17Hz, 2H) 3.54 -3.65 (m, 2H)

[0489] Step E: 2-(4-fluoro-3,5-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[0490]

[0491] To a solution of 5-bromo-2-fluoro-1,3-dimethylbenzene (253.0 mg, 1.25 mmol) in dioxane (3 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (348.0 mg, 1.37 mmol), KOAc (366.8 mg, 3.74 mmol), and Pd(dppf)Cl2 (91.1 mg, 124.50 μmol) were added. The yellow suspension was stirred at 80 °C for 2 h under N2. The black suspension was diluted with water (5 mL) and extracted twice with ethyl acetate (5 mL). The organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated to give a crude product (418.6 mg) as a yellow gel. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 0-10%) to give 2-(4-fluoro-3,5-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (258.3 mg, 82.9% yield) as a colorless oil.

[0492] 1H NMR(400MHz, CDCl3)δppm 7.45-7.52(m,2H)2.23-2.28(m,6H)1.35(s,12H)

[0493] Step F: 2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

[0494] Pd(dppf)Cl2 (850.1 mg, 1.16 mmol), K2CO3 (4.82 g, 34.86 mmol), and H2O (10 mL) were added to a solution of 2-bromo-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (2.51 g) and 2-(4-fluoro-3,5-dimethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (2.91 g, 11.62 mmol) in dioxane (30 mL). The suspension was stirred at 80 °C for 3 h under N2. The yellow mixture was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product (4.10 g) as a yellow solid. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 70%–100%) to give 2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (2.54 g, 84.3% yield) as a yellow solid.

[0495] 1 ¹H NMR (400MHz, methanol-d⁴) δppm 7.46-7.53 (m, 2H) 7.08 (s, 1H) 4.35-4.43 (m, 2H) 3.73-3.79 (m, 2H) 2.24-2.31 (m, 6H)

[0496] Step G: 2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0497]

[0498] LAH (370.4 mg, 9.76 mmol) was added in portions to a solution of 2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (2.53 g, 9.76 mmol) in THF (35 mL) under N2. The yellow solution was stirred at 65 °C for 16 h. Water (40 mL) was added dropwise to the deep yellow solution at 0 °C to quench the reaction. The mixture was diluted with ethyl acetate (30 mL). The mixture was filtered through diatomaceous earth. The filtrate was separated. The organic layer was washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give 2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (2.00 g, crude) as a yellow solid.

[0499] 1 H NMR (400MHz, CDCl3) δppm 7.39-7.43 (m, 2H) 6.22 (s, 1H) 4.12 -4.20 (m, 2H) 4.09 (br s, 2H) 3.34 (br t, J = 5.38Hz, 2H) 2.26-2.35 (m, 6H)

[0500] Step H: 2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0501]

[0502] TEA (2.48 g, 24.46 mmol) and (Boc)₂O (1.96 g, 8.97 mmol, 2.06 mL) were added to a solution of 2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (2.00 g) in DCM (30 mL) at 0 °C. The deep yellow solution was stirred at 20 °C for 1.5 h. The yellow solution was concentrated to give a crude product (4.32 g) as a deep yellow gel. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 15%–35%) to give a yellow solid of tert-butyl 2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (1.56 g, 55.4% yield).

[0503] 1H NMR (400MHz, CDCl3) δppm 7.35-7.45(m,2H)6.29(s,1H)4.68(s,2H)4.22(t,J=5.27Hz,2H)3.92(t,J=5.27Hz,2H)2.26-2.33(m,6H)1.43-1.60(m,9H)

[0504] Step I: 3-Bromo-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0505]

[0506] NBS (803.8 mg, 4.52 mmol) was added to a yellow solution of 2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid tert-butyl ester (1.56 g, 4.52 mmol) in MeCN (20 mL). The solution was stirred at 20 °C for 2 h under N2. The yellow solution was concentrated to give a crude product (2.72 g) as a yellow solid. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, 15%–35%) to give 3-bromo-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid tert-butyl ester (1.63 g, 85.1% yield) as a white solid.

[0507] 1 H NMR (400MHz, CDCl3) δppm 7.47-7.54 (m, 2H) 4.59 (br s, 2H) 4.19 (t, J = 5.25Hz, 2H) 3.93 (br t, J = 5.13Hz, 2H) 2.27-2.35 (m, 6H) 1.53 (s, 9H)

[0508] Step J: 3-(diphenylmethyleneamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0509]

[0510] To a solution of tert-BuONa (1.48 g, 15.37 mmol), Pd2(dba)3 (351.8 mg, 384.18 μmol), and Xantphos (355.6 mg, 614.57 μmol) in dioxane (25 mL), t-BuONa (1.48 g, 15.37 mmol), Pd2(dba)3 (351.8 mg, 384.18 μmol), and Xantphos (355.6 mg, 614.57 μmol) were added. The suspension was stirred at 90 °C for 16 h under N2. The dark suspension was diluted with water (50 mL) and extracted twice with ethyl acetate (40 mL). The organic layer was washed with brine (60 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product (4.10 g) as a yellow gel. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, from 15% to 35%) to give tert-butyl 3-(diphenylmethyleneamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5a]pyrazine-5-carboxylate (2.02 g, 100.00% yield) as a yellow gel.

[0511] 1 H NMR(400MHz, CDCl3)δppm 7.74-7.80(m,2H)7.38-7.62(m,8H)7.06(m,2H)4.04-4.11(m,2H)3.82(br s,2H)3.61-3.72(m,2H)2.17-2.24(m,6H)1.46(s,9H)

[0512] Step K: 3-amino-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0513]

[0514] Under N2, tert-butyl 3-(diphenylmethyleneamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylate (2.02 g, 3.85 mmol) in a yellow solution of 3-(diphenylmethyleneamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylate (35 mL) was added to NaOAc (947.6 mg, 11.55 mmol) and NH2OH·HCl (535.2 mg, 7.70 mmol). The yellow turbid solution was stirred at 20 °C for 17 h. The yellow solution was concentrated to remove most of the MeOH and then diluted with water (30 mL). The mixture was extracted twice with ethyl acetate (25 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product (2.01 g) as a yellow gel. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, from 20% to 70%) to give a yellow gel-like tert-butyl 3-amino-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (960.5 mg, 69.2% yield).

[0515] 1 H NMR(400MHz, CDCl3)δppm 7.32-7.38(m,2H)4.57(s,2H)4.08-4.20(m,2H)3.90(br d,J=5.00Hz,2H)2.99(br s,2H)2.26-2.34(m,6H)1.52(s,9H)

[0516] Step L: 2-Isocyano-1,1-dimethoxy-ethane

[0517]

[0518] Under N2 and at 0°C, a solution of 2,2-dimethoxyethylamine (4.12 g, 39.19 mmol, 4.27 mL) and TEA (7.93 g, 78.37 mmol, 10.91 mL, 2 equivalents) in DCM (100 mL) were added dropwise over 0.2 h. The white suspension was stirred at 20°C for 0.3 h. Then the suspension was stirred at 45°C for 0.3 h, and then at 20°C for 3.5 h. The turbid solution was washed with water (150 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product (4.12 g). The crude product was suspended in 20 mL of petroleum ether and then filtered. The filtrate was concentrated to obtain 2-isocyano-1,1-dimethoxy-ethane (3.85 g, crude product), which was a colorless oil.

[0519] 1 H NMR (400MHz, CDCl3) δppm 4.48 (t, J = 5.32Hz, 1H) 3.42 (s, 6H) 3.32 (d, J = 5.38Hz, 2H)

[0520] Step M: 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0521]

[0522] To a solution of 3-amino-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid tert-butyl ester (910.5 mg, 2.53 mmol) in pyridine (12 mL), 2-isocyano-1,1-dimethoxy-ethane (397.5 mg) was added. The yellow solution was stirred at 20 °C for 2 h under N2. MeOH (5 mL) was added to the solution to quench the reaction. The solution was concentrated to give a crude product (1.26 g) as a yellow solid. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, from 50% to 100%) to give tert-butyl 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (961.2 mg, 77.4% yield) as a yellow solid.

[0523] 1 H NMR (400MHz, CDCl3) δppm 7.38-7.43 (m, 2H) 5.61 (br s, 1H) 4.81 (t, J = 6.02Hz, 1H) 4.59 (s, 2H) 4.24 (t, J = 5.27Hz, 1H) 4.20 (br t, J = 5.14Hz, 2H) 3.93 (br t,J=5.27Hz,2H)3.26-3.34(m,8H)2.25-2.31(d,J=2.01Hz,6H)1.51(s,9H)

[0524] Step N: 2-(4-fluoro-3,5-dimethyl-phenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0525]

[0526] Methanesulfonic acid (185.7 mg, 1.93 mmol, 137.56 μL) was added to a yellow suspension of 3-(2,2-dimethoxyethylcarbamoylamino)-2-(4-fluoro-3,5-dimethyl-phenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester (950.0 mg, 1.93 mmol) in THF (14 mL) at 60 °C under N2. The yellow solution was stirred at 60 °C for 1.5 h. The yellow suspension was diluted with 1N NaHCO3 (15 mL) and then extracted twice with ethyl acetate (12 mL). The organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated to give tert-butyl 2-(4-fluoro-3,5-dimethyl-phenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (851.2 mg, crude product), which was a yellow solid.

[0527] 1 H NMR (400MHz, CDCl3) δppm 10.39 (br s,1H)7.14-7.20(m,2H)6.33-6.40(m,1H)6.11(t,J=4.00Hz,1H)4.68(s,2H) 4.10-4.27(m,2H)3.97(t,J=4.89Hz,2H)2.20-2.27(m,6H)1.44-1.52(m,9H)

[0528] Step O: 2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazol-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester

[0529]

[0530] Under N2, K2CO3 (116.4 mg, 842.22 μmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (17.6 mg, 123.73 μmol), and CuI (10.7 mg, 56.18 μmol) were added to a solution of 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-1H-imidazol-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid tert-butyl ester (120.0 mg) and 5-bromo-1-methyl-indazole (118.5 mg, 561.46 μmol) in NMP (5 mL). The suspension was stirred at 130 °C for 3 h under N2. The brown suspension was diluted with water (3 mL) and then extracted three times with ethyl acetate (2 mL). The organic layer was dried over Na₂SO₄ and then filtered. The filtrate was concentrated to give a crude product (226.5 mg) as a yellow gel. The crude product was purified by Combi-flash (silica gel, 0% to 15% MeOH in DCM) to give a yellow solid of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylate (132.6 mg, 84.7% yield). (ESI)m / z(M+H) + =558.1

[0531] Step P: 1-[2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one

[0532]

[0533] To a solution of 2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid tert-butyl ester (132.6 mg, 237.80 μmol) in EtOAc (2.00 mL), HCl / dioxane (4 M, 5.30 mL, 89.22 equivalents) was added. The solution was stirred at 15 °C for 2 h. The yellow suspension was filtered. The filter cake was dried under vacuum to give 1-[2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one (122.4 mg, crude, HCl salt) as a yellow solid. (ESI)m / z(M+H) + =458.1

[0534] Step Q: 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0535]

[0536] T3P (145.60 mg, 228.80 μmol, 50% purity) and TEA (71.26 mg, 704.23 μmol) were added to a suspension of 1-[(1S,2S)-2-methyl-1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid (67.5 mg, 176.06 μmol; which can be prepared in a similar manner to compound 28 in Example 3) and 1-[2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one (86.9 mg HCl salt) in THF (1.5 mL). The suspension was stirred at 25°C for 1 h under N2. The yellow solution was diluted with water (2 mL) and then extracted three times with ethyl acetate (2 mL). The organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated to give a crude product (155.2 mg) as a yellow solid. The crude product was purified by preparative HPLC. Column: Phenomenex Gemini C18 250*50mm*10um; mobile phase [water (0.225% FA)-ACN]; B%: 50%-70%, 10 min. The fraction was lyophilized to give 3-[(1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carbonyl]-5-tetrahydropyran-4-yl-indol-1-yl]-2-methyl-cyclopropyl]-4H-1,2,4-oxadiazol-5-one (40.18 mg, 27.2% yield) as a white solid.

[0537] 1H NMR(400MHz,DMSO-d6)δppm 11.57(br s,1H)8.02-8.09(m,1H)7.98(s,1H)7.66(s,2H)7.50(s,1H)7.42(d,J=8.56Hz,1 H)7.21-7.32(m,3H)7.15(d,J=3.18Hz,1H)6.93(s,1H)6.67(d,J=3.18Hz,1H)4. 88-5.06(m,2H)4.22-4.38(m,4H)4.08(s,3H)3.88-4.01(m,2H)3.38-3.55(m,2H )2.85(m,1H)2.22(m,6H)1.86-1.97(m,1H)1.58-1.78(m,6H)1.18-1.32(m,3H). 19 F NMR (377MHz, DMSO-d6) δppm-122.19. (ESI)m / z(M+H) + =823.1

[0538] Example 2

[0539] 3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 101)

[0540]

[0541] Step A: 3-[1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazol-5-yl)-2-oxo] [1,5-a]pyrazine-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1- [cyclopropyl]-4H-1,2,4-oxadiazol-5-one

[0542]

[0543] TEA (90.4 mg, 0.893 mmol) and T3P (148 mg, 0.232 mmol, 50% in ethyl acetate) were added to a suspension of 1-[1-(5-oxo-2H-1,2,4-oxadiazol-3-yl)cyclopropyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid (66.0 mg, 0.179 mmol) and 1-[2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one (81.8 mg, 0.179 mmol) in THF (1.5 mL). The yellow suspension was stirred at 15 °C for 16 h under N2. The suspension was diluted with water (3 mL) and extracted twice with ethyl acetate (3 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to obtain a crude product (111 mg) as a yellow gel. The crude product was purified by preparative HPLC. Column: Phenomenex Gemini C18 250*50mm*10um; Mobile phase: [water (0.225% FA)-ACN]; B%: 50%-70%, 10 min. The fraction was lyophilized to give 3-[1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carbonyl]-5-tetrahydropyran-4-yl-indol-1-yl]cyclopropyl]-4H-1,2,4-oxadiazol-5-one as a white solid (20.64 mg, 14.0% yield).

[0544] 1 H NMR(400MHz,DMSO-d6)δppm 12.12(brs,1H),8.06(s,1H),8.00(br.s,1H),7.71(brs,2H),7.58-7.39(m,2H),7.35-7.10(m,4H),6.87(s,1H),6.67(brs,1H),5.12-4.68(m ,2H),4.41-4.28(m,2H),4.26-4.02(m,4H),4.00-3.85(m,2H),3.52-3 .30(m,3H,overlap with H2O),2.89-2.77(m,1H),2.21(s,6H),1.81-1.54(m,8H).

[0545] Example 3

[0546] 3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)cyclobutyl)-1,2,4-oxadiazol-5(4H)-one (Compound 102)

[0547]

[0548] Step A: Ethyl 1-(1-cyanocyclobutyl)-5-tetrahydropyran-4-yl-indole-2-carboxylate

[0549]

[0550] Ethyl 1-(cyanomethyl)-5-tetrahydropyran-4-yl-indole-2-carboxylate (365 mg, 1.17 mmol) was added to a suspension of NaH (117 mg, 2.92 mmol, 60% purity in mineral oil) in DMF (4.5 mL) at 0 °C. The suspension was stirred at 0 °C for 0.5 h. 1,3-Diiodopropane (484 mg, 1.64 mmol) was added to the suspension. The suspension was stirred at 50 °C for 18 h under N2. Water (12 mL) was added to the yellow solution to quench the reaction. The mixture was extracted twice with ethyl acetate (10 mL). The organic layer was washed with water (15 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a crude product (328 mg) as a yellow gel. The crude product was purified by Combi-flash (silica gel, ethyl acetate in petroleum ether, from 7% to 35%) to give ethyl 1-(1-cyanocyclobutyl)-5-tetrahydropyran-4-yl-indole-2-carboxylate (51.2 mg, 12.4% yield) as a yellow gel.

[0551] 1 H NMR (400MHz, CDCl3) δppm 7.52(s,1H),7.36-7.30(m,1H),7.30-7.24(m,2H),4.40(q,J=6.8Hz,2H),4.17-4.08(m,2H),3.62-3.51( m,2H),3.33-3.25(m,1H),2.96-2.77(m,3H),2.46-2.33(m,1H),2.05-1.79(m,6H),1.44(t,J=6.8Hz,3H).

[0552] Step B: ethyl 1-[1-(N-hydroxymethylamidinyl)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylate

[0553]

[0554] Hydroxylamine (111 mg, 1.67 mmol, 50% purity) was added to a solution of ethyl 1-(1-cyanocyclobutyl)-5-tetrahydropyran-4-yl-indole-2-carboxylate (59 mg, 0.167 mmol) in DMSO (0.7 mL). The solution was stirred at 20 °C for 16 h under N2. The white suspension was diluted with water (2 mL) and extracted three times with ethyl acetate (2 mL). The organic layer was washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give ethyl 1-[1-(N-hydroxymethylamidine)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylate (59 mg, crude) as a white solid.

[0555] Step C: 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole- ethyl 2-formate

[0556]

[0557] CDI (49.6 mg, 0.306 mmol) and DBU (58 mg, 0.383 mmol) were added to a solution of ethyl 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylate (59 mg, crude) in DMSO (0.7 mL). The solution was stirred at 25 °C for 0.5 h under N2. 0.06 mL of FA was added to the yellow solution to quench the reaction. The mixture was diluted with water (2 mL) and extracted twice with ethyl acetate (2 mL). The organic layer was washed with water (3 mL) and concentrated to give ethyl 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylate (50 mg, crude) as a pale yellow solid.

[0558] Step D: 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole- 2-Formic acid

[0559]

[0560] Add NaOH (29 mg, 0.73 mmol) and H₂O (0.3 mL) to a suspension of 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid ethyl (50 mg, crude) in MeOH (0.9 mL). Stir the solution at 15 °C for 18 h. Dilute the solution with water (2 mL) and extract with DCM / MeOH (1.5 mL, 10:1). Treat the aqueous layer with 1 N HCl to adjust the pH to 5–6. Extract the mixture twice with DCM / MeOH (2 mL, 10:1). Dry the organic layer with Na₂SO₄ and filter. The filtrate was concentrated to obtain 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid (41 mg, crude product), which was a yellow gel.

[0561] Step E: 3-[1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazol-5-yl)-2-oxo] [1,5-a]pyrazine-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1- [cyclobutyl]-4H-1,2,4-oxadiazol-5-one

[0562]

[0563] TEA (41 mg, 0.405 mmol) and T3P (67 mg, 0.105 mmol, 50% purity) were added to a solution of 1-[2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one (40 mg, crude) and 1-[1-(5-oxo-4H-1,2,4-oxadiazol-3-yl)cyclobutyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid (0.108 mmol) in THF (0.6 mL). The solution was stirred at 15 °C for 16 h under N2. The yellow suspension was diluted with water (2 mL) and extracted three times with ethyl acetate (2 mL). The organic layer was concentrated to give a crude product (68.0 mg) as a yellow solid. The crude product was purified by preparative HPLC. Column: Phenomenex Gemini C18250*50mm*10um; Mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 55%-75%, 10 min. The fraction was lyophilized to give 3-[1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1-yl]cyclobutyl]-4H-1,2,4-oxadiazol-5-one (4.96 mg, 3.5% yield for 4 steps).

[0564] 1 H NMR(400MHz,DMSO-d6)δppm 8.11(s,1H),8.05(d,J=1.2Hz,1H),7.97(d,J=8.8Hz,1H),7.78-7.70(m,2H),7.64(s,1H),7.38(dd,J =8.8,1.6Hz,1H),7.32(s,1H),7.28(d,J=3.2Hz,1H),7.22(d,J=6.8Hz,2H),6.78(d,J=2.8Hz,1H),4.9 9-4.58(m,2H),4.37-4.14(m,2H),4.07(s,3H),4.00-3.93(m,2H),3.51-3.42(m,2H),3.32-3.30(m,2 H),3.29-3.19(m,2H),2.95-2.83(m,3H),2.35-2.22(m,2H),2.19(d,J=1.2Hz,6H),1.81-1.67(m,4H).

[0565] Example 4

[0566] (1S,2S)-1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropanecarboxylic acid (compound 106a)

[0567]

[0568] Step A: 1-[(2S)-1-cyano-2-methyl-cyclopropyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid

[0569]

[0570] Add 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (223 mg, 1.60 mmol) to a suspension of 1-[(2S)-1-cyano-2-methyl-cyclopropyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid ethyl ester (188 mg, 0.533 mmol) in MeCN (2.0 mL) and H₂O (0.4 mL). Stir the solution at 25 °C for 4 h. Concentrate the solution to obtain a residue. Treat the residue with 1 N HCl to adjust the pH to 5. Extract the mixture four times with ethyl acetate (1.5 mL). Wash the organic layer with water (4 mL), dry to Na₂SO₄, and filter. The filtrate was concentrated to obtain 1-[(2S)-1-cyano-2-methyl-cyclopropyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid (196 mg, crude product), which is a yellow solid.

[0571] Step B: (2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazol-5-yl)-2-oxo] [1,5-a]pyrazine-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1- 1,2-methyl-cyclopropanecarboxynitrile

[0572]

[0573] TEA (78 mg, 0.771 mmol) and T3P (128 mg, 0.200 mmol, 50 % purity) were added to a suspension of 1-[(2S)-1-cyano-2-methyl-cyclopropyl]-5-tetrahydropyran-4-yl-indole-2-carboxylic acid (50 mg) and 1-[2-(4-fluoro-3,5-dimethyl-phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]-3-(1-methylindazole-5-yl)imidazol-2-one (71 mg, HCl salt) in THF (0.7 mL). The turbid solution was stirred at 15 °C for 18 h under N2. The turbid yellow solution was diluted with water (2 mL) and extracted twice with ethyl acetate (1.5 mL). The organic layer was concentrated to give a crude product (111 mg) as a yellow gel. The crude product was purified by Combi-flash (silica gel, methanol in methyl acetate, from 0 to 12%) to give (2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1-yl]-2-methyl-cyclopropanecarboxylate (45.0 mg, 43.2% yield for 2 steps).

[0574] MS(ESI) m / z 764.1(M+H) +

[0575] Step C: (1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)- [2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carbonyl]-5-tetrahydropyran-4-yl-indole- 1-yl]-2-methyl-cyclopropanecarboxylic acid

[0576]

[0577] A solution of (2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1-yl]-2-methyl-cyclopropanecarboxynitrile (36 mg, 0.047 mmol) in concentrated HCl (0.4 mL) and AcOH (0.2 mL). The solution was stirred at 65 °C for 18 h. The solution was concentrated to give a crude product (82 mg) as a red gel. The crude product was purified by preparative HPLC. Column: Phenomenex Gemini C18 250*50 mm*10 μm; Mobile phase: [water (0.225% FA)-ACN]; B%: 45%-65%, 10 min. The fraction was lyophilized to give (1S,2S)-1-[2-[2-(4-fluoro-3,5-dimethyl-phenyl)-3-[3-(1-methylindazole-5-yl)-2-oxo-imidazol-1-yl]-6,7-dihydro-4Hpyrazolo[1,5-a]pyrazin-5-carbonyl]-5-tetrahydropyran-4-yl-indole-1-yl]-2-methyl-cyclopropanecarboxylic acid (8.95 mg, 24.4% yield) as a white solid.

[0578] 1 H NMR(400MHz,DMSO-d6,80℃)δppm 8.09-8.03(m,1H),8.02-7.92(m,1H),7.72-7.62(m,2H),7.52-7.41(m,1H),7.37(d,J=8. 6Hz,1H),7.30-7.21(m,3H),7.14(d,J=3.2Hz,1H),6.95-6.76(m,1H),6.70-6.62(m,1H), 5.05-4.80(m,2H),4.49-4.14(m,4H),4.03(s,3H),4.01-3.93(m,2H),3.55-3.41(m,2H), 2.90-2.77(m,1H),2.22(s,6H),2.18-1.56(m,7H),1.19-1.04(m,2H),0.92-0.81(m,1H).

[0579] Synthesis of key intermediate: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

[0580] Chiral separation: Enantiomers 1 and 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl formate.

[0581]

[0582] Step A: (2-Hydroxyethyl)carbamate tert-butyl ester

[0583] A solution of NaOH (327 mg, 8.19 mmol) and (Boc)₂O (19.6 g, 90.0 mmol) in THF (30 mL) was added dropwise to a solution of 2-aminoethanol (5.00 g, 81.8 mmol) in H₂O (30 mL). The yellow mixture was stirred at room temperature for 17 h. The mixture was extracted three times with ethyl acetate (30 mL). The organic layer was washed with brine (60 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EtOAc = 10:1) to give N-(2-hydroxyethyl)carbamate tert-butyl ester (12.0 g, 91% yield) as a colorless oil.

[0584] 1 H NMR (400MHz, CDCl3) δppm 4.96 (br s, 1H) 3.67-3.75 (m, 2H) 3.27-3.32 (m, 2H) 2.43 (br s, 1H), 1.45 (s, 9H).

[0585] Step B: Ethyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate

[0586] DEAD (2.38 g, 13.7 mmol) was added dropwise to a solution of ethyl 3-bromo-1H-pyrazole-5-carboxylate (2.00 g, 9.13 mmol), N-(2-hydroxyethyl)carbamate tert-butyl ester (1.47 g, 9.13 mmol), and PPh3 (4.78 g, 18.3 mmol) in THF (35 mL) at 0–10 °C. The yellow solution was stirred overnight at room temperature. The mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EtOAc = 10:1) to give ethyl 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylate (2.60 g, 78% yield) as a white solid. LC-MS: m / z 306.1, 308.1 (M-56+H) + .

[0587] Step C: 3-Bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid

[0588] LiOH (344 mg, 14.4 mmol) was slowly added to a mixture of 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid (2.60 g, 7.18 mmol) in THF / H₂O (40 mL / 10 mL) at 0 °C. The mixture was stirred overnight at room temperature. The mixture was concentrated to remove THF. The pH of the mixture was then adjusted to 4 with 1 M aqueous HCl. The mixture was filtered and the filter cake was dried to give 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-5-carboxylic acid (2.35 g, 98% yield) as a white solid. LC-MS: m / z 278.1, 280.1 (M-56+H) + .

[0589] Step D: (2-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazol-1-yl)ethyl)carbamic acid tert-butyl ester

[0590] DIPEA (3.90 g, 30.5 mmol) was added dropwise to a solution of 3-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazol-5-carboxylic acid (3.40 g, 10.2 mmol), N,O-dimethylhydroxylamine hydrochloride (1.48 g, 15.3 mmol), and HATU (5.80 g, 15.3 mmol) in DMF (35 mL) at 0 °C. The solution was stirred overnight at room temperature. The mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL). The organic layer was washed with brine (80 mL x 6), dried over Na2SO4, and filtered. The filtrate was concentrated to give tert-butyl (2-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazol-1-yl)ethyl)carbamate (3.00 g, 78% yield, crude) as a yellow solid. LC-MS:m / z 276.8,278.8(M-100+H) + .

[0591] Step E: (2-(5-acetyl-3-bromo-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate

[0592] MeMgBr (3M, 10.6 mL, 31.8 mmol in THF) was slowly added to a mixture of (2-(3-bromo-5-(methoxy(methyl)carbamoyl)-1H-pyrazol-1-yl)ethyl)carbamate (3.00 g, 7.95 mmol) in THF (30 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. The mixture was quenched with NH4Cl (80 mL) and extracted twice with ethyl acetate (80 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE / EtOAc = 7:1) to give (2-(5-acetyl-3-bromo-1H-pyrazol-1-yl)ethyl)carbamate (2.12 g, 80% yield, crude) as a white solid. LC-MS: m / z 276.1, 278.1 (M-56+H) + .

[0593] Step F: 2-Bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine

[0594] To a mixture of (2-(5-acetyl-3-bromo-1H-pyrazol-1-yl)ethyl)carbamate tert-butyl ester (2.80 g, 8.43 mmol) in dioxane (30 mL), HCl-dioxane (4 M, 18 mL) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, diluted with NaHCO3 (aqueous solution) (30 mL), and extracted twice with ethyl acetate (50 mL). The organic layer was washed with brine (80 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated to give 2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine (1.90 g, 80% yield, crude) as a yellow solid. LC-MS: m / z 214.0, 216.0 (M+H) + .

[0595] Step G: 2-Bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0596] NaBH4 (636 mg, 16.8 mmol) was slowly added to a mixture of 2-bromo-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine (900 mg, 4.20 mmol) in MeOH (8 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (15 mL) and extracted twice with DCM (20 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EtOAc = 40:1) to give 2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (782 mg, 86% yield) as a yellow solid.

[0597] 1 H NMR (400MHz, CDCl3) δppm 6.02 (s, 1H), 3.94-4.18 (m, 3H), 3.34-3.45 (m, 1H), 3.18-3.25 (m, 1H), 1.42 (d, J = 6.4Hz, 3H).

[0598] Step H: 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

[0599] At room temperature, 2-bromo-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (760 mg, 3.52 mmol), K2CO3 (1.30 g, 9.59 mmol), and Pd(dppf)Cl2 were added to a mixture of 2-(4-fluoro-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (800 mg, 3.19 mmol) in dioxane / H2O (10 mL / 2 mL). .DCM (160 mg, 0.196 mmol). The mixture was stirred at 90 °C for 2 h under microwave irradiation with N2. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 40:1 to 20:1) to give 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (700 mg, 84% yield) as a black oil. LC-MS: m / z 260.2 (M+H) + .

[0600] Step I: 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)- tert-butyl formate

[0601] TEA (822 mg, 8.10 mmol) and (Boc)₂O (1.17 g, 5.40 mmol) were added to a solution of 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (700 mg, 2.70 mmol) in DCM (7 mL) at 0 °C. The mixture was stirred overnight at room temperature. The mixture was concentrated to give a crude product as a deep yellow gel. The crude product was purified by silica gel column chromatography (PE / EtOAc = 40:1) to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (940 mg, 97% yield) as a colorless oil. LC-MS: m / z 360.4 (M+H) + .

[0602] Step J: 3-Bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5 (4H)-tert-butyl formate

[0603] NBS (465 mg, 2.61 mmol) in 5 mL of MeCN was added to a solution of 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (940 mg, 2.61 mmol) in 20 mL of MeCN under N2 at 0 °C. The solution was stirred at 0 °C for 1 h under N2. The mixture was concentrated and purified by silica gel column chromatography (PE / EtOAc = 10:1) to give tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (470 mg, 42% yield) as a white solid. LC-MS: m / z 438.3, 440.3 (M+H) + .

[0604] Step K: 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyridine Azo[1,5-a]pyrazine-5(4H)-tert-butyl formate

[0605] To a solution of tert-butyl 3-bromo-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (280 mg, 0.638 mmol) and benzophenone imine (173 mg, 0.958 mmol) in dioxane (25 mL), t-BuONa (245 mg, 2.55 mmol), Pd2(dba)3 (59.0 mg, 0.0640 mmol), and Xantphos (60.0 mg, 0.102 mmol) were added. The suspension was stirred at 90 °C for 16 h under N2. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The organic layer was concentrated and purified by silica gel column chromatography (PE / EtOAc = 20:1) to give tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (212 mg, 61% yield) as a yellow solid. LC-MS: m / z 539.4 (M+H) + .

[0606] Step L: 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyridine tert-butyl 5-(4H)-formate

[0607] To a solution of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (380 mg, 0.706 mmol) in MeOH (7 mL), NaOAc (174 mg, 2.12 mmol) was added. The mixture was stirred at room temperature for 10 min, and then NH₂OH·HCl (98.0 mg, 1.41 mmol) was added under N₂. The resulting yellow turbid solution was stirred at room temperature for 48 h. The mixture was concentrated to remove MeOH and then diluted with water (10 mL). The mixture was extracted twice with ethyl acetate (15 mL). The organic layer was washed with brine (15 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EtOAc = 20:1) to give tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (210 mg, 79% yield) as a yellow solid. LC-MS: m / z 375.3 (M+H).

[0608] Step M: 3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6, 7-Dihydropyrazolo[1,5-a]pyrazine-5(4H)-tert-butyl formate

[0609] A solution of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (140 mg, 0.374 mmol) and N-(2,2-dimethoxyethyl)-1H-imidazolium-1-carboxamide (149 mg, 0.748 mmol) in THF (2 mL) was stirred at 100 °C for 2 h under microwave irradiation. The solution was concentrated and purified by preparative TLC (PE:EtOAc = 1:1) to give tert-butyl 3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (170 mg, 90% yield) as a yellow solid. LC-MS: m / z 506.4 (M+H) + .

[0610] Step N: 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1- 6,7-dihydropyrazole [1,5-a]pyrazine-5(4H)-tert-butyl formate

[0611] Methanesulfonic acid (32.0 mg, 0.336 mmol) was added to a solution of tert-butyl 3-(3-(2,2-dimethoxyethyl)ureo)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (170 mg, 0.336 mmol) in THF (5 mL) at room temperature. The solution was stirred at 60 °C for 1.5 h. The mixture was diluted with 1 N NaHCO3 aqueous solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to give tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (130 mg, 88% yield) as a yellow solid. LC-MS: m / z 442.3 (M+H) + .

[0612] Step O: 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1- Chiral separation of butyl 5(4H)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-formate

[0613] Chiral separation of 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (110 mg) was performed using an SFC (column: AD-H, elution: CO2:EtOH(0.1% DEA) = 80:20; flow rate: 2.5 mL / min; temperature: 25 °C) to obtain two enantiomers.

[0614] Enantiomer 1: 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (40 mg, 36% yield), retention time: 2.77 min. LC-MS: m / z 442.3 (M+H) + .

[0615] Enantiomer 2: 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (35 mg, 32% yield), retention time: 3.84 min. LC-MS: m / z 442.3 (M+H) + .

[0616] Example 5: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 108a)

[0617]

[0618] Step A: 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazolium) (-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester

[0619] 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (50.0 mg, 0.110 mmol), (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (36.0 mg, 0.120 mmol), (1S,2S)-N 1 N 2 A mixture of dimethylcyclohexane-1,2-diamine (25.0 mg, 0.170 mmol), CuI (32.0 mg, 0.170 mmol), and K₂CO₃ (31.0 mg, 0.220 mmol) in NMP (3 mL) was stirred at 130 °C for 3 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine (10 mL), dried, and concentrated. The residue was purified by column chromatography to give tert-butyl 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (53.0 mg, 72% yield). LC-MS: m / z 651.2 (M+H) + .

[0620] Step B: 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylbenzene) 3-yl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-imidazol-2(3H)-one

[0621] The mixture of 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (57.0 mg, 0.0880 mmol) in 4 mol / L hydrochloride-1,4-dioxane solution (2 mL) was stirred overnight at room temperature. LCMS showed that the reaction was complete. The mixture was quenched with Na2CO3 (aqueous solution) (10 mL) and extracted with DCM (10 mL * 3). The organic layer was washed with brine (10 mL), dried, and concentrated to give 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-imidazol-2(3H)-one (39.0 mg, crude) as a grayish-white solid, which was used in the next step without purification. LC-MS: m / z 551.2 (M+H) + .

[0622] Step C: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo (-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazol) [1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4- Oxadiazole-5(4H)-one

[0623] A mixture of 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-imidazol-2(3H)-one (39 mg, crude), 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (30.0 mg, 0.0800 mmol), HATU (81.0 mg, 0.210 mmol), and DIPEA (55 mg, 0.42 mmol) in DMF (4 mL) was stirred overnight at room temperature. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine (10 mL), dried, and concentrated. The residue was purified by preparative HPLC (0.1% HCl in water and acetonitrile) to give 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (18.0 mg, 28% yield) as a white solid. 1HNMR(400MHz,DMSO-d6,80℃)δppm 11.73(br.s,1H),7.49(d,J=7.6Hz,1H),7.40(d,J=8.0Hz,1H),7.10-7.30(m,5H),6.90-7.02(m,2H),6.86 (s,1H),6.72(s,1H),5.70(br.s,1H),4.52-4.75(m,1H),4.20-4.45(m,2H),3.97(d,J=10.8Hz,2H),3.80-3 .97(m,1H),3.43-3.53(m,2H),2.81-2.97(m,2H),2.72(s,3H),2.18(s,6H),1.85-1.97(m,4H),1.67-1.80 (m,5H),1.55-1.66(m,1H),1.40-1.53(m,3H),1.20-1.35(m,3H),1.10-1.22(br.s,1H),0.97-1.09(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 53.08. 19 F NMR (377MHz, DMSO-d6) δppm-122.01,-122.08. LC-MS:m / z 458.8(M / 2+H) + .

[0624] Example 6: 3-((1S,2S)-1-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 109a)

[0625]

[0626] According to the approach of Example 5, compound 109a was synthesized using 5-bromo-4-fluoro-1-methyl-1H-indazole in step A.

[0627] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.52-11.90(m,1H),8.20(s,1H),7.49-7.55(m,2H),7.38-7.48(m,2H),7.23-7.30(m, 3H),6.86-6.96(m,2H),6.69(t,J=2.4Hz,1H),5.72(br.s,1H),4.57-4.65(m,1H),4.30 -4.40(m,2H),4.09(s,3H),3.82-4.00(m,3H),3.42-3.60(m,2H),2.80-2.93(m,1H),2. 23(s,6H),1.92-2.04(m,1H),1.60-1.85(m,5H),1.44-1.58(m,3H),1.05-1.32(m,4H). 19 F NMR (377MHz, DMSO-d6) δppm-122.10,-126.78. LC-MS:m / z 855.7(M+H) + .

[0628] Example 7: 3-(1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 104)

[0629]

[0630] According to the approach of Example 5, compound 104 was synthesized using 1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid in step C.

[0631] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.80(br.s,1H),7.45-7.51(m,2H),7.15-7.26(m,5H),6.89-6.98(m,2H),6.86( s,1H),6.72(d,J=2.8Hz,1H),5.70(s,1H),4.60(d,J=14.4Hz,1H),4.24-4.35(m, 2H),3.97(d,J=10.8Hz,2H),3.78-3.90(m,1H),3.43-3.52(m,2H),2.80-2.91(m, 1H),2.72(s,3H),2.18(s,6H),1.85-1.97(m,4H),1.62-1.82(m,8H),1.47-1.60(m 1H), 1.43 (d, J = 6.4Hz, 3H), 0.95-1.07 (m, 6H). 31 P NMR (162MHz, DMSO-d6) δppm 52.96. 19 F NMR (377MHz, DMSO-d6) δppm-122.09. LC-MS:m / z 902.4(M+H) + .

[0632] Example 8: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 1, compound 108a)

[0633]

[0634] According to the route of Example 5, compound 108a was synthesized using the enantiomer 1 of 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester from step A.

[0635] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.76(s,1H),7.48(s,1H),7.40(d,J=8.4Hz,1H),7.14-7.29(m,5H),6.89-6.99(m,2H),6.86(s,1H),6.72( d,J=2.8Hz,1H),5.71(br.s,1H),4.50–4.70(m,1H),4.25-4.40(m,2H),3.97(d,J=10.8Hz,2H),3.80-3.92(m ,1H),3.42-3.53(m,2H),2.79-2.97(m,2H),2.72(s,3H),2.18(d,J=1.2Hz,6H),1.85-2.04(m,5H),1.69-1.7 9(m,4H),1.59-1.69(m,1H),1.49-1.59(m,1H),1.45(d,J=6.8Hz,3H),1.20–1.35(m,3H),0.96-1.09(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 52.93. 19 FNMR (377MHz, DMSO-d6) δppm-122.08. LC-MS:m / z 916.4(M+H) + .

[0636] Example 9: 3-((1S,2S)-1-(2-((S)-3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(4,4-difluorocyclohexyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 116a)

[0637]

[0638] Step A: 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazolium) (-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (enantiomer 2-A)The enantiomers of 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester were 2 (100 mg, 0.230 mmol), (4-bromo-2-(methylamino)phenyl)diethylphosphine oxide (73.0 mg, 0.253 mmol), and (1S,2S)-N 1 N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (51.0 mg, 0.345 mmol), CuI (66.0 mg, 0.345 mmol), and K₂CO₃ (22.0 mg, 0.460 mmol) in NMP (3 mL) was stirred at 130 °C for 3 h. Water was added to the mixture and it was extracted with ethyl acetate. The organic layer was washed with brine, dried, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give tert-butyl 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (enantiomer 2-A) as a yellow solid (100 mg, 68% yield). LC-MS: m / z 651.4 (M+H) + .

[0639] Step B: 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylbenzene) )-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-imidazol-2(3H)-one (enantiomer 2- B)

[0640] A mixture of 3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (enantiomer 2-A) (100 mg, 0.150 mmol) in 4 mol / L hydrogen chloride / 1,4-dioxane solution was stirred at room temperature for 4 h. LC-MS showed the reaction was complete. The mixture was quenched with Na₂CO₃ (2 M aqueous solution) and extracted with DCM. The organic layer was washed with brine, dried, and concentrated to give a yellow oily substance, 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-imidazol-2(3H)-one (enantiomer 2-B), which was used in the next step without purification (80.0 mg crude). LC-MS: m / z 551.3 (M+H)+ .

[0641] Step C: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo (-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazol) [1,5-a]pyrazine-5-carbonyl)-5-(4,4-difluorocyclohexyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadi Azazole-5(4H)-one (compound 116a, Single diastereomer 2)

[0642] A mixture of 1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-1H-imidazol-2(3H)-one (enantiomer 2-B) (80.0 mg, crude), 5-(4,4-difluorocyclohexyl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (69.0 mg, 0.165 mmol), HATU (171 mg, 0.450 mmol), and DIPEA (116 mg, 0.900 mmol) in DMF (5 mL) was stirred overnight at room temperature. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, and concentrated. The residue was purified by preparative HPLC to give 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-5-carbonyl)-5-(4,4-difluorocyclohexyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (compound 116a, single diastereomer 2) (63.0 mg, 46% yield) as a white solid.

[0643] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.46(br.s,1H),7.51(s,1H),7.40(d,J=8.8Hz,1H),7.13-7.30(m,5H),6.92-7.00(m,3H),6 .72(d,J=2.4Hz,1H),5.70(br.s,1H),4.61(d,J=14.0Hz,1H),4.28-4.50(m,2H),3.85-3.96(m ,1H),2.80(t,J=11.6Hz,1H),2.71(s,3H),2.18(d,J=1.6Hz,6H),2.06-2.16(m,2H),1.85-2. 06(m,9H),1.66-1.85(m,4H),1.56-1.65(m,1H),1.48(s,3H),1.17(s,3H),0.95-1.08(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 52.92. 19 F NMR (377MHz, DMSO-d6) δppm-88.94,-88.97,-89.57,-89.59,-99.73,-100.35,-122.04. LC-MS:m / z 476.0(M / 2+H) + .

[0644] Example 10: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 113a)

[0645]

[0646] According to the route of Example 9, compound 113a was synthesized using 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid from step C.

[0647] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.51(br.s,1H),7.50(s,1H),7.40(d,J=8.4Hz,1H),7.13-7.28(m,5H),6.90-7.00(m,3H), 6.72(d,J=2.4Hz,1H),5.70(br.s,1H),4.56-4.65(m,1H),4.27-4.46(m,2H),3.82-3.97(m,1 H),3.72(d,J=7.6Hz,2H),2.97-3.08(m,2H),2.72(s,3H),2.19(s,6H),1.85-1.97(m,4H),1 .75-1.88(m,1H),1.66-1.75(m,3H),1.42-1.68(m,6H),1.28(s,3H),1.10-1.23(m,6H),0.97 -1.09(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 52.93. 19 F NMR (377MHz, DMSO-d6) δppm-122.03. LC-MS:m / z 472.7(M / 2+H) + .

[0648] Example 11: 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 117a)

[0649]

[0650] According to the route of Example 9, compound 117a was synthesized using 5-bromo-4-fluoro-1-methyl-1H-indazole in step A and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid in step C.

[0651] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.50(br.s,1H),8.20(s,1H),7.48-7.57(m,2H),7.36-7.49(m,2H),7.25-7.27(m,3H), 6.93(s,2H),6.69(d,J=2.8Hz,1H),5.72(br.s,1H),4.61(d,J=12.8Hz,1H),4.27-4.54( m,2H),4.09(s,3H),3.85-3.98(m,1H),3.71-3.76(m,2H),2.96-3.10(m,1H),2.23(s,6H ),1.82(br.s,1H),1.66-1.75(m,3H),1.42-1.66(m,6H),1.28(s,3H),1.14-1.23(m,6H). 19 F NMR (377MHz, DMSO-d6) δppm-122.08,-126.79.

[0652] Example 12: 3-((1S,2S)-1-(2-(3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 110a)

[0653]

[0654] According to the route of Example 9, compound 110a was synthesized using 5-bromo-4-fluoro-1-methyl-1H-indazole in step A and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid in step C.

[0655] 1H NMR(400MHz,DMSO-d6,80℃)δppm 8.22(s,1H),7.50-7.61(m,2H),7.40-7.50(m,2H),7.25-7.32(m,3H),6.94(s,2H) ,6.72(d,J=2.4Hz,1H),5.75(br.s,1H),4.63(d,J=12.8Hz,1H),4.27-4.50(m,2H) ,4.11(s,3H),3.85-4.03(m,3H),3.45-3.55(m,2H),2.82-2.96(m,1H),2.25(s,6H ),1.80-1.93(m,1H),1.70-1.80(m,5H),1.60-1.70(m,1H),1.50-1.60(m,3H),1.15 -1.30(m,3H). 19 F NMR (377MHz, DMSO-d6) δppm-122.09,-126.79. LC-MS:m / z 855.4(M+H) + .

[0656] Example 13: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 111a)

[0657]

[0658] According to the route of Example 9, compound 111a was synthesized using 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid from step C.

[0659] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.48(br.s,1H),7.50(s,1H),7.40(d,J=8.8Hz,1H),7.15-7.29(m,5H),6.80-7.10(m,3H),6 .74(d,J=2.4Hz,1H),5.60-5.80(m,1H),4.62(d,J=15.2Hz,1H),4.28–4.50(m,2H),3.85-4.05 (m,3H),3.45-3.55(m,2H),2.80-2.95(m,1H),2.72(s,3H),2.18(s,6H),1.89-2.00(m,5H),1 .66-1.80(m,6H),1.58-1.68(m,1H),1.41-1.55(m,3H),1.10-1.30(m,3H),0.96-1.10(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 52.92. 19 F NMR (377MHz, DMSO-d6) δppm-122.02. LC-MS:m / z 458.8(M / 2+H) + .

[0660] Example 14: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-morpholino-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 114a)

[0661]

[0662] According to the route of Example 9, compound 114a was synthesized using 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-morpholino-1H-indole-2-carboxylic acid from step C.

[0663] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.49(br.s,1H),7.39-7.52(m,2H),7.20-7.39(m,5H),6.80-7.10(m,3H),6.74(s,1H ),5.71(br.s,1H),4.55-4.75(m,1H),4.37-4.51(m,2H),3.80–4.05(m,5H),3.15–3.55 (m,5H),2.70-2.85(m,3H),2.20(s,6H),1.89-2.03(m,4H),1.75-1.90(m,1H),1.70-1. 75(m,1H),1.60-1.70(m,1H),1.48-1.59(m,3H),1.15-1.28(m,3H),0.95-1.13(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 53.11. 19 FNMR (377MHz, DMSO-d6) δppm-122.00. LC-MS:m / z 917.3(M+H) + .

[0664] Example 15: 3-((1S,2S)-1-(2-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(2,2-dimethylmorpholino)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 115a)

[0665]

[0666] According to the route of Example 9, compound 115a was synthesized using 5-(2,2-dimethylmorpholino)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid from step C.

[0667] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.50(br.s,1H),7.35(d,J=9.6Hz,1H),7.20-7.25(m,4H),7.05-7.15(m,2H),6.94(s,2H),6.85(s,1H),6.72( d,J=3.2Hz,1H),5.68(br.s,1H),4.60(d,J=14.8Hz,1H),4.28-4.42(m,3H),3.85-4.00(m,1H),3.75-3.82(m,2H ),2.98-3.05(m,2H),2.87(s,2H),2.68-2.76(m,3H),2.18(s,6H),1.85-1.98(m,4H),1.75–1.85(m,1H),1.69( t,J=6.4Hz,1H),1.55-1.65(m,1H),1.42-1.52(m,3H),1.25-1.30(m,6H),1.10-1.20(m,3H),0.96-1.08(m,6H). 31 P NMR (162MHz, DMSO-d6) δppm 52.92. 19 FNMR (377MHz, DMSO-d6) δppm-122.03. LC-MS:m / z 473.2(M / 2+H) + .

[0668] Example 16: 3-((1S,2S)-1-(2-(3-(3-(4-(dimethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (single diastereomer 2, compound 118a)

[0669]

[0670] According to the route of Example 9, compound 118a was synthesized using (4-bromo-2-(methylamino)phenyl)dimethylphosphine oxide from step A and 1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid from step C.

[0671] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.52(br.s,1H),7.50(s,1H),7.40(d,J=8.4Hz,1H),7.19-7.31(m,5H),6.85- 7.00(m,3H),6.70-6.75(m,1H),5.70(br.s,1H),4.62(d,J=15.6Hz,1H),4.30- 4.40(m,2H),3.80-4.00(m,3H),3.40-3.52(m,2H),2.80-2.92(m,1H),2.74(br .s,3H),2.18(s,6H),1.56-1.78(m,14H),1.43-1.55(m,3H),1.05-1.25(m,3H). 31 P NMR (162MHz, DMSO-d6) δppm 42.49. 19 F NMR (377MHz, DMSO-d6) δppm-122.04. LC-MS:m / z 444.8(M / 2+H) + .

[0672] Example 17: 3-(1-(2-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carbonyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 103)

[0673]

[0674] According to the route of Example 2, compound 103 was synthesized using tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate in step A.

[0675] 1H NMR(400MHz,DMSO-d6,80℃)δppm 11.81(br.s,1H),8.04(s,1H),7.96(s,1H),7.58-7.70(m,2H),7.48-7.50(m,2H),7.20-7.26(m, 3H),7.15(d,J=3.2Hz,1H),6.87(s,1H),6.69(d,J=2.8Hz,1H),5.73(br.s,1H),4.62(d,J=12.8H z,1H),4.26-4.40(m,2H),4.05(s,3H),3.96(d,J=11.2Hz,2H),3.80-3.92(m,1H),3.42-3.50(m, 2H), 2.83-2.90 (m, 1H), 2.19 (s, 6H), 1.64-1.82 (m, 7H), 1.50-2.01 (m, 1H), 1.45 (d, J = 6.8Hz, 3H). 19 F NMR (377MHz, DMSO-d6) δppm-122.14. LC-MS:m / z 823.5(M+H) + .

[0676] Example A: cAMP assay

[0677] It is known that activation of the GLP-1 receptor can stimulate the production of cyclic AMP (cAMP) in cells, which suggests that GLP-1 receptors are associated with the G protein heterotrimeric complex. αs The main coupling of the subunit. Evidence suggests this is through G. αs Induced cAMP-stimulated signaling triggers the desired pharmacological response regarding the release of insulin from pancreatic β cells.

[0678] To optimize for G αs The conjugated functional activity was determined using the HEK293 / CRE-Luc cell line generated from HDB cells stably expressing the GLP-1 receptor. A 200× concentration working solution of the compound was prepared in 384-well Echo LDV plates (Labcyte, catalog LP-0200) with 1 / 2 log serial dilutions (Agilent Technologies Bravo). 50 nL / well of the 200× concentration working solution was transferred to 384-well white low-volume plates (Greiner, catalog 784075) using a Labcyte ECHO550. 1×10⁻¹⁰ assay buffer was prepared using DPBS containing 0.5 mM IBMX (Sigma, catalog 15879) and 0.1% BSA (GENVIEW, catalog FA016-100g). 510 μL of HEK293 / GLP1R / CRE-LUC (HD Biosciences) cell suspension was added to each well of a previously prepared assay plate (1000 cells / well) using a ThermoFisher Multidrop Combi. The assay plate already contained 50 nL of a 200× compound. The plate was sealed and incubated at 37 °C and 5% CO2 for 30 min.

[0679] After incubation, cAMP assay signals were generated using a cAMP dynamic 2 kit (Cisbio). Using a ThermoFisher Multidrop Combi, 5 μL of cAMP-d2 working solution was added to each well, followed by 5 μL of anti-cAMP antibody-camber compound working solution. Incubation was performed at room temperature in the dark for 1 hour. Fluorescence at 665 and 615 nm was read using a ReaderPerkinElmer EnVision.

[0680] Activity % = 100% x (mean RLU of test sample - mean RLU of medium control) / (mean RLU of maximum control - mean RLU of medium control)

[0681] Table 1 shows the bioactivity of the compounds in the GLP-1R agonist cAMP stimulation assay (ECG). 50 [nM]

[0682]

[0683]

[0684] Other implementation plans

[0685] It should be understood that although the invention has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate rather than limit the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. A compound of formula (I): Formula (I) Or its pharmaceutically acceptable salt, wherein: Ring A is , where R AA R AB and R AC Independently, it is a halogenated group or C 1-6 alkyl; R 1 R 2 and R 3 Each is independently selected from H and optionally by 1-6 groups, each independently selected from halogen groups, -OH and C. 1-6 alkoxy substituents of C 1-6 alkyl; L 1 It is -C(=O)-; Ring B is: in bb Indicates with L 1 Attachment point; R 4 R 5 R 6 and R 7 Independently selected from: H, halogenated group and C 1-6 alkyl; L 3 It is a key; L 4 It is a key; R 8a and R 8b Together with their respective attached carbon atoms, they form 1-3 independently selected carbon atoms. 1-6 Alkyl-substituted C 3-15 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-6 independently selected R groups. f replace; R 9 Selected from: C(=O)OH and (IX-2): (IX-2); R 9d Selected from: H; optionally by 1-6 independently selected halogenated groups and C 1-6 alkoxy-substituted C 1-6 Alkyl groups; and C(=O)(C 1-6 alkyl); The ring C is selected from 3-12 membered heterocyclic groups and C 3-10 Cycloalkyl groups, each optionally marked with 1-3 R groups. Ca replace; Each R Ca Independently selected from: halogenated group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; L 2 yes: ， in aa Indicates the attachment point to Q; L 2A It is a key; Q is selected from: 5-10 aryl groups and C 6-10 Aryl groups, each of which is optionally selected by 1-6 independently chosen R groups. Q replace; Each R Q Selected independently from: (a) Halogenated group; (b) Cyano group; (c) OH or oxo group; (d) -NR c R d ; (e) -C(=O)NR c R d or -S(O)2NR c R d ; (f) -S(=O) 0-2 R e ; (g) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 alkyl; (h) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkoxy; (i) Optionally selected from 1 to 6 independently chosen R g Substituted 3-12 membered heterocyclic groups; (j) Optionally selected by 1-6 independently chosen R g Replacement C 6-10 Aryl; (k) Optionally selected from 1 to 6 independently chosen R g Substituted 5-10 heteroaryl groups; (l) Optionally selected from 1 to 6 independently chosen R g Replacement C 3-8 cycloalkyl; (m) -P(=O)R a R b ;and (n) -(CR h R h ) q1 -S(O)2-L e -R e , where q1 is 1, 2 or 3; R a and R b Independently selected from, arbitrarily chosen from, 1-6, each independently selected from C 1-6 Alkoxy, C 3-6 C-substitution of cycloalkyl and halogenated groups 1-6 Alkyl group; optionally composed of 1-3 molecules, each independently selected from C10. 1-3 Substituents of alkyl and halogen groups at C 3-6 cycloalkyl; and optionally 1-3 independently selected C 1-3 Alkyl-substituted C 6-10 Aryl; or R a and R b Together with the phosphorus atoms to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding those attached to R) a and R b (Apart from phosphorus) are heteroatoms independently selected from O, S, and N, wherein the ring is optionally separated by 1-3 independently selected C atoms. 1-6 Alkyl substitution; Each R c and R d Selected independently from: H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 Alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Alkyl groups and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), C(=O)(C 3-6 cycloalkyl), C(=O)O(C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Alkyl groups and S(O) 1-2 (C 3-6 Each of the cycloalkyl groups is optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Substitution of alkoxy groups; R e Is it H, or R? e Selected from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, each optionally substituted by 1-3 substituents independently selected from the following: halogenated, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, NH2, NH(C) 1-3 alkyl), N(C) 1-3 Alkyl)2, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; L e It is a key, NR c Or O; Each R f Independently selected from halogenated groups, -OH, NR c R d C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally surrounded by 1-4 groups, each independently selected from -OH, C. 1-6 3-12-membered heterocyclic groups substituted with alkyl groups and 3-12-membered heterocyclic groups; Each R g Selected independently from: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR c R d , cyano, halogenated, C 3-6 cycloalkyl groups and optionally one or more independently selected from C 1-6 Alkyl groups and C(=O)C 1-6 Alkyl substituents of 3 to 12-membered heterocyclic groups; and Each occurrence of R h Selected independently from: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halogenated groups; or A pair of R atoms on the same or different carbon atoms h Together with the connection pair R h One or more carbon atoms form C 3-6 Cycloalkyl or 4-8 membered heterocyclic groups, each optionally substituted by 1-3 substituents independently selected from the following: halogenated, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; The condition is that the compound is not selected from the following compounds: and .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally one to six independently selected Rs. Q Substituted 5-10 heteroaryl groups.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally composed of 1-6 independently selected Rs. Q Substituted 9-10 heteroaryl groups.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally one to six independently selected Rs. Q The substituted 9-membered heteroaryl group.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally one or two independently selected Rs. Q The substituted 9-membered heteroaryl group.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is... ,in: Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q Q 4 Q 5 Q 6 and Q 7 One of them is with L 2 Bonded carbon atoms; and Q 4 Q 5 Q 6 and Q 7 The other three are each independently N, CH, or CR. Q .

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is... ,in: Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q Q 4 Q 5 Q 6 and Q 7 One of them is with L 2 Bonded carbon atoms; and Q 4 Q 5 Q 6 and Q 7 The other three are independently CH or CR. Q .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is... ,in: Q 1 Is it NH or NR? Q Q 2 and Q 3 Each is independently N, CH or CR Q And n1 is 0 or 1.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is... ,in: Q 1 Is it NH or NR? Q ; And n1 is 0 or 1.

10. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein Q 1 It is NH.

11. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein Q 1 It is NR Q .

12. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein two Rs are present. Q And these two R Q At least one of them is attached to a 6-membered ring.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is... , where n1 is 0 or 1.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is , where n1 is 0 or 1.

15. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

16. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein n1 is 1.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is .

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is .

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R is present. Q At that time, an R Q Selected from: (a) Halogenated group; (b) Cyano group; (c) OH; (d) -NR c R d ; (e) -C(=O)NR c R d or -S(O)2NR c R d ; (f) -S(=O) 0-2 R e ; (g) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 alkyl; (h) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkoxy; (i) Optionally selected from 1 to 6 independently chosen R g Substituted 3-12 membered heterocyclic groups; (j) Optionally selected by 1-6 independently chosen R g Replacement C 6-10 Aryl; (k) Optionally selected from 1 to 6 independently chosen R g Substituted 5-10 heteroaryl groups; (l) Optionally selected from 1 to 6 independently chosen R g Replacement C 3-8 cycloalkyl; (m) P(=O)R a R b ;and (n) -(CR h R h ) q1 -S(O)2-L e -R e , where q1 is 1, 2 or 3; And each remaining R Q When present, it is independently selected from: halogenated, cyano, OH, C 1-6 Alkyl and C 1-6 Alkyl group.

20. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R is present. Q At that time, an R Q Selected from: (a) Halogenated group; (b) Cyano group; (c) OH; (d) -NR c R d ; (e) -C(=O)NR c R d or -S(O)2NR c R d ; (f) -S(=O) 0-2 R e ; (g) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl; and (h) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkoxy; And each remaining R Q The halogenated group is independently selected when it is present.

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R is present. Q At that time, an R Q R is arbitrarily selected from 1 to 6 independently. f Replacement C 1-6 Alkyl groups; and each remaining R Q The halogenated group is independently selected when it is present.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R is present. Q At that time, an R Q R is arbitrarily selected from 1 to 6 independently. f Replacement C 1-3 Alkyl groups; and each remaining R Q It is fluorine when it is present.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R is present. Q At that time, an R Q It is unreplaced C 1-3 Alkyl groups; and each remaining R Q It is fluorine when it is present.

24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one R is present. Q At that time, an R Q It is methyl; and each remaining R Q It is fluorine when it is present.

25. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein the first defined R Q Attached to cyclic nitrogen.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally composed of 1-6 independently selected Rs. Q Replacement C 6-10 Aryl.

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally one to six independently selected Rs. Q Substituted phenyl groups.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally one or two independently selected Rs. Q Substituted phenyl groups.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is optionally one or two independently selected Rs. Q Substituted phenyl groups.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is: , where Y 1 Y 2 Y 4 and Y 5 Each is independently N, CH or CR Q .

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Y 4 and Y 5 Each is independently CH or CR Q .

32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is... , where m1 is 0, 1 or 2.

33. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein in L 2 The opposite R Q Selected from: (e) -C(=O)NR c R d or -S(O)2NR c R d ; (f) -S(=O) 0-2 R e ; (m) P(=O)R a R b ;and (n) -(CR h R h ) q1 -S(O)2-L e -R e 。 34. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein in L 2 The opposite R Q It is -P(=O)R a R b .

35. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R a and R b C is an independent choice. 1-6 Alkyl groups, optionally composed of 1 to 6 independently selected from C10. 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogenated groups.

36. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R a and R b C is an independent choice. 1-6 Alkyl groups, optionally composed of one or two independently selected C14 groups. 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogenated groups.

37. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R a and R b C is an independent choice. 1-3 Alkyl groups, which are optionally substituted with one or two independently selected halogroups.

38. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R a and R b It is an independently selected, unsubstituted C 1-3 alkyl.

39. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R a and R b Each is an ethyl group.

40. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein m1 is 1.

41. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein Q is .

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein in L 2 The interposition of R Q Yes -NR c R d .

43. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein each R c and R d Selected independently from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl groups and C(=O)(C 1-6 Alkyl groups are each optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Substitution of alkoxy groups.

44. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein each R c and R d Selected independently from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl groups and C(=O)(C 1-6 Alkyl groups are each optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Substitution of alkoxy groups.

45. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein each R c and R d Independently selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by 1 to 6 independently selected from -OH, halogroup, and C. 1-6 Substitution of alkoxy groups.

46. ​​The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein each R c and R d Independently selected from H and C 1-3 alkyl.

47. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R c and R d One of them is H, and R c and R d The other one is C. 1-3 alkyl.

48. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R c and R d One of them is H, and R c and R d The other one is methyl.

49. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 and R 3 It's H.

50. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 It is H; and R 3 It is C 1-6 alkyl.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a methyl group.

52. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 and R 6 Each is either an H group or a halogenated group.

53. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 and R 6 Each is either H or -F.

54. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 and R 6 Each is H.

55. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 It is H; and R 6 Yes -F.

56. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 It's H.

57. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 Yes -F.

58. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b Together with their respective attached carbon atoms, they form optional 1-2 independently selected C atoms. 1-6 Alkyl-substituted C 3-8 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-3 independently selected R groups. f replace.

59. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b Together with their respective attached carbon atoms, they form optional 1-2 independently selected C atoms. 1-6 Alkyl-substituted C 3-5 cycloalkyl ring, wherein the C 1-6 Alkyl groups are optionally separated by 1-3 independently selected R groups. f replace.

60. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b Together with their respective attached carbon atoms, they form optional 1-2 independently selected C atoms. 1-6 Alkyl-substituted C 3-4 Cycloalkyl rings.

61. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b Together with the carbon atoms attached to each one, they form: , or .

62. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b Together with the carbon atoms attached to each one, they form: .

63. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 yes (IX-2).

64. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is: .

65. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is: .

66. The compound of claim 65 or a pharmaceutically acceptable salt thereof, wherein... Each solid center in the matrix has ( S )-configuration.

67. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 -C(R 8a R 8b )-L 4 -R 9 Part of it is: .

68. The compound of claim 63 or a pharmaceutically acceptable salt thereof, wherein R 9d Is it H or C? 1-6 alkyl.

69. The compound of claim 63 or a pharmaceutically acceptable salt thereof, wherein R 9d It's H.

70. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 It is C(=O)OH.

71. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted 3-12 membered heterocyclic groups.

72. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally composed of 1-3 independently selected R groups. Ca Substituted 4-8 membered heterocyclic groups.

73. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted 5-6 membered heterocyclic groups.

74. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally bounded by 1-3 independent R... Ca Substituted tetrahydropyranyl group.

75. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring C is selected from: and .

76. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R Ca C is independent 1-6 alkyl.

77. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein a pair of R atoms on the same or different ring atoms Ca Together with one or more ring atoms attached to each ring, they form a carbon ring containing 3 to 6 ring atoms.

78. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein a pair of R atoms on the same ring atom Ca Together with the ring atoms to which they are attached, they form a carbon ring containing 3-5 ring atoms.

79. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IA): Formula (IA) in: Q 1 Is it NH or NR? Q ; Q 2 and Q 3 Each is independently N, CH or CR Q ; n1 is 0 or 1; Ring E is C 3-6 cycloalkyl; and R 8c Selected from H and optionally 1-3 independently selected R f Replacement C 1-6 alkyl.

80. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein Q 1 It is NR Q .

81. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein the R attached to N Q Selected from: (a) Halogenated group; (b) Cyano group; (c) OH; (d) -NR c R d ; (e) -C(=O)NR c R d or -S(O)2NR c R d ; (f) -S(=O) 0-2 R e ; (g) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl; and (h) Optionally selected from 1 to 6 independently chosen R f Replacement C 1-6 Alkyl group.

82. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein the R attached to N Q It is unreplaced C 1-3 alkyl.

83. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein Q 2 and Q 3 Each can be either N or CH independently.

84. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein Q 2 It is N; and Q 3 It is CH.

85. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

86. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein n1 is 1.

87. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R attached to the 6-membered ring Q Selected from halogenated groups, cyano groups, OH groups, and C groups. 1-6 Alkyl and C 1-6 Alkyl group.

88. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R attached to the 6-membered ring Q It is a halogenated group.

89. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein L 2 Attached to Q 1 The alignment.

90. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R attached to the 6-membered ring Q Attached to Q 3 The neighboring position.

91. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IB): Formula (IB) in: m1 is 0, 1, or 2; In L 2 The opposite R Q It is -P(=O)R a R b ; Ring E is C 3-6 cycloalkyl; and R 8c Selected from H and optionally 1-3 independently selected R f Replacement C 1-6 alkyl.

92. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R a and R b C is an independent choice. 1-6 Alkyl groups, optionally composed of one or two independently selected C14 groups. 1-6 Alkoxy, C 3-6 Substitution of cycloalkyl and halogenated groups.

93. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein R a and R b It is an independently selected, unsubstituted C 1-3 alkyl.

94. The compound of claim 91 or a pharmaceutically acceptable salt thereof, wherein m1 is 1; and not in L 2 The opposite R Q In L 2 The interval.

95. The compound of claim 94 or a pharmaceutically acceptable salt thereof, wherein in L 2 The interposition of R Q Yes -NR c R d .

96. The compound of claim 95 or a pharmaceutically acceptable salt thereof, wherein each R c and R d Selected independently from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl groups and C(=O)(C 1-6 Alkyl groups are each optionally surrounded by 1-6 independently selected from -OH, halogroups, and C. 1-6 Substitution of alkoxy groups.

97. The compound of claim 95 or a pharmaceutically acceptable salt thereof, wherein R c and R d One of them is H, and R c and R d The other one is methyl.

98. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein ring E is cyclopropyl.

99. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein ring E is cyclobutyl.

100. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 8c It's H.

101. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 8c It is C 1-3 alkyl.

102. The compound of claim 101 or a pharmaceutically acceptable salt thereof, wherein R 8c It is a methyl group.

103. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 9 yes (IX-2).

104. The compound of claim 103 or a pharmaceutically acceptable salt thereof, wherein R 9d It's H.

105. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein... Part of it is .

106. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein... Each solid center in the matrix has ( S )-configuration.

107. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein... Part of it is .

108. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein... Part of it is .

109. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 9 It is C(=O)OH.

110. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted 3-12 membered heterocyclic groups.

111. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally composed of 1-3 independently selected Rs. Ca Substituted 5-6 membered heterocyclic groups.

112. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally bounded by 1-3 independent R... Ca Substituted tetrahydropyranyl group.

113. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein ring C is selected from: and .

114. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein each R Ca C is independent 1-6 alkyl.

115. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each is H.

116. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 It's H.

117. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 1-3 alkyl.

118. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a methyl group.

119. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R AA and R AC C is independent 1-6 alkyl.

120. The compound of claim 119 or a pharmaceutically acceptable salt thereof, wherein R AA and R AC C is independent 1-3 alkyl.

121. The compound of claim 79 or a pharmaceutically acceptable salt thereof, wherein R AB It is a halogenated group.

122. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the compounds in Table C1. Table C1 。 123. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from the compounds in Table C2. Table C2 。 124. A pharmaceutical composition comprising a compound according to any one of claims 1-123 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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