Heterocyclic GLP-1 agonists

Abstract

The present document relates to GLP-1 agonists, pharmaceutical compositions, and methods of use thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of International Patent Application Nos. PCT / CN2022 / 079865, filed on March 9, 2022, and PCT / CN2022 / 141072, filed on December 22, 2022, each of which is incorporated herein by reference in its entirety. Technical Field

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

[0003] Incretin hormones including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (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.

[0004] Diabetes refers to a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, type 2 diabetes (T2DM), is an acquired condition that accounts for more than 90% of diabetes cases. The typical onset occurs in obese or otherwise sedentary adults and insulin resistance sets in. Although lifestyle changes can effectively manage this disorder, patients with T2DM may need to take antidiabetic medications, including drugs such as dipeptidyl peptidase 4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem regulation of the insulin secretory response to glucose ingestion. Although this incretin effect is significantly diminished (if present at all) in cases of T2DM, GLP-1 retains insulinotropic properties even though the endocrine pancreatic response to GIP is effectively terminated. Thus, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. Summary of the invention

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

[0007] Thus, provided herein are compounds of Formula I: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: X is C and Y is N, or Y is C and X is N, and the dashed line represents an optional bond, so that the moiety yes wherein bond y is attached to Y and bond x is attached to X; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; or the part-L 3 -C(R 8a R 8b )-L 4 -R 9 is C(=O)OH and optionally 1-4 independently selected from R f Phenyl substituted with another substituent; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H, optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl, and C(=O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups, C 3-15 Cycloalkyl and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca are independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; L 2 Selected from Where aa represents the point of attachment to Q; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Q is selected from C 1-10 Alkyl; C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, wherein Q is replaced by -P(=O)R a R b and optionally substituted by 1-6 independently selected from R Q Another substituent is substituted; Each R Q Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (i) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (j) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (k) optionally 1 to 6 independently selected R gsubstituted 5-10 membered heteroaryl; (l) optionally 1 to 6 independently selected R g Substituted 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; or Q is C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 each independently selected from R QA and R QB Substituents are substituted; Provided that either or both of (aa) or (bb) apply: (aa)Q is covered by at least one R QB replace; or (bb) Q is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Q contains an endocyclic S(O) 2 Group; each R QA Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (i) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (j) optionally 1 to 6 independently selected R gsubstituted 5-10 membered heteroaryl; and (k) optionally 1 to 6 independently selected R g Substituted C 3-8 Cycloalkyl; Each R QB Independently selected from: (a)-L a -S(O) 2 -L b -R e ;and (b) a 4-12 membered heterocyclic group or a 7-10 membered bicyclic heteroaryl group, each of which contains an endocyclic S(O) 2 A group wherein the heterocyclic group or heteroaryl group is optionally substituted by 1 to 6 independently selected R g replace; L a Selected from -N(H)-, -N(R c )- and -(CR h R h ) q1 -; L b Selected from -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 -; q1 and q2 are independently 0, 1, 2, 3 or 4; The condition is that when L a Yes-(CR h R h ) q1 - and q1 is 0, then -L b -R e Not unsubstituted C 1-3 alkyl; R a and R b Independently selected from optionally 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6 Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted C 3-6 Cycloalkyl; and optionally 1-3 independently selected C 1-3 Alkyl substituted C 6-10 aryl; or R a and R bTogether with the phosphorus atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R c and R d Independently selected 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), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; L e Yes key, NR c or O; Each R f are independently selected from halo, -OH, NRc R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms that connect them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0008] Also provided herein are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof and a pharmaceutically acceptable excipient.

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

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

[0011] Also provided herein is a method for treating diabetes in a patient, the method comprising determining that the patient suffers from type 2 diabetes; and administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the step of determining that the patient suffers from type 2 diabetes comprises performing an 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 level of HbA1c is greater than or about 6.5%. In some embodiments, the level of fasting plasma glucose is greater than or about 126 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 200 mg / dL.

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

[0013] In some embodiments, the method for treating type 2 diabetes comprises reducing fasting plasma glucose levels. In some embodiments, fasting plasma glucose levels are reduced to about or below 100 mg / dL.

[0014] In some embodiments, the method for treating type 2 diabetes comprises lowering HbA1c levels. In some embodiments, the HbA1c levels are lowered to about or below 5.7%.

[0015] In some embodiments, the method for treating type 2 diabetes comprises lowering glucagon levels.

[0016] In some embodiments, the method for treating type 2 diabetes comprises lowering insulin levels.

[0017] In some embodiments, the method for treating type 2 diabetes comprises reducing BMI. In some embodiments, the BMI is reduced to about or below 25 kg / m 2 .

[0018] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition thereof, is administered orally.

[0019] In some embodiments, the method of treating type 2 diabetes further includes applying another therapy or therapeutic agent to the patient. In some embodiments, the other therapy or therapeutic agent is selected from antidiabetic agents, anti-obesity agents, GLP-1 receptor agonists, agents for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity or any combination thereof. In some embodiments, the antidiabetic agent is selected from biguanide, sulfonylurea, glitazar, thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitor, meglitinide, sodium-glucose cotransporter 2 (SGLT2) inhibitor, glitazone, GRP40 agonist, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha glucosidase inhibitors, sodium-glucose cotransporter 1 (SGLT1) inhibitor or any combination thereof. In some embodiments, the biguanide is metformin. In some embodiments, the anti-obesity agent is selected from a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine / dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, or any combination thereof. In 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, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21) agonists, nicotinic acid analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinases (KHK) inhibitors, ileal bile acid transporter (IBAT) inhibitors, apoptosis signal-regulating kinase 1 (ASK1) inhibitors, or any combination thereof.In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered sequentially in any order as separate doses.

[0020] Also provided herein is a method for regulating the insulin level of a patient in need of such regulation, the method comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the regulation results in an increase in insulin levels.

[0021] Also provided herein are methods for regulating the glucose level of a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the regulation results in a decrease in glucose levels.

[0022] Also provided herein are methods for treating a GLP-1 related disease, disorder or condition comprising administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, 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), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain caused by the use of other agents, idiopathic intracranial hypertension, Wolfram's syndrome, gout, excessive sugar cravings, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, revascularization Stenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.In some embodiments, the disease, disorder or condition is selected from type 2 diabetes, early onset type 2 diabetes, obesity, weight gain caused by the use of other agents, gout, excessive sugar cravings, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial lipidosis, 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, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary 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 embodiments, the disease, disorder, or condition includes but is not limited to type 2 diabetes, early onset type 2 diabetes, obesity, weight gain due to use of other medications, gout, sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipidosis, 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 a combination thereof. DETAILED DESCRIPTION definition

[0023] The following description sets forth exemplary embodiments of the present technology. However, it should be appreciated that such description is not intended as a limitation on the scope of the present disclosure, but is intended to be provided as a description of exemplary embodiments.

[0024] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.

[0025] When values ​​are described as a range, it should be understood that such disclosure includes disclosure of all possible sub-ranges within such range, as well as specific values ​​falling within such range, regardless of whether a specific value or a specific sub-range is explicitly stated.

[0026] As used herein, the term "halo" or "halogen" refers 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").

[0027] As used herein, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical containing the indicated number of carbon atoms. For example, "C 1-6 "Alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical having one to six carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl and hexyl.

[0028] As used herein, the term "alkylene" refers to a divalent alkyl group containing the indicated number of carbon atoms. For example, "C 1-3 "Alkylene" refers to a divalent alkyl group having three carbon atoms (e.g., -CH 2 -、-CH(CH 3 )-、-CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -).

[0029] As used herein, the term "alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain containing the indicated number of carbon atoms. 2-6 "Alkenyl" refers to a straight or branched monounsaturated hydrocarbon chain having two to six carbon atoms. Non-limiting examples of alkenyl include ethenyl, propenyl, butenyl or pentenyl.

[0030] As used herein, the term "alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain containing the indicated number of carbon atoms. 2-6 "Alkynyl" refers to a straight or branched diunsaturated hydrocarbon chain having two to six carbon atoms. Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl or pentynyl.

[0031] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic hydrocarbon containing the 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 may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged 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, Cycloalkyl also includes spirocycle (for example, spirocycle bicyclic, wherein two rings are connected via only one atom). Non-limiting examples of spirocycle 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.

[0032] As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic non-aromatic ring system containing the indicated number of ring atoms (e.g., a 3-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), if monocyclic, it has 1-3 heteroatoms; if bicyclic, it has 1-6 heteroatoms, or if tricyclic or polycyclic, it has 1-9 heteroatoms, the heteroatoms selected from O, N or S (e.g., carbon atoms, and 1-3, 1-6 or 1-9 heteroatoms of N, O or S in the case of monocyclic, bicyclic or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclyls include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyls may include multiple fused rings and bridged 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, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3 1 .0]octane, 2-oxabicyclo[1 .1 .0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1 .1 .1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected via only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[4.5]decane, 2-oxaspiro[4.5]decane, 2-oxaspiro[3 ... 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-oxaspiro[5.5]undecane, and the like.

[0033] As used herein, the term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon radical containing the indicated number of carbon atoms, wherein at least one ring in the system is aromatic (e.g., C 6 Single ring, C 10 Bicyclic or C 14 A tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0034] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having the 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., tetrahydroisoquinolyl, e.g., tetrahydroquinolyl), and wherein at least one ring in the system contains one or more heteroatoms independently selected from N, O, and S. Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, b]pyridyl, quinazolinyl, quinolyl, thieno[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, chromane, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein in which 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.

[0036] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the group is on the oxygen atom. For example, "C 1-6 "Alkoxy" refers to -O-(C 1-6 The term "haloalkoxy" as used herein refers to an -O-haloalkyl group, wherein the group is on the oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Thus, as used herein, the term "haloalkoxy" refers to an -O-haloalkyl group, wherein the group is on the oxygen atom.

[0037] As used herein, indicates optional single or double bonds as allowed by the valence. As used herein, The point of attachment to the parent molecule is indicated.

[0038] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise stated, a compound identified herein as one particular tautomeric form by name or structure is intended to include the other tautomeric forms.

[0039] As used herein, the term "tautomer" refers to compounds whose structures differ significantly in the arrangement of atoms but exist in a readily and rapidly equilibrium manner, and it is understood that the compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to fall within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0040] 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, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0041] As used herein, the term "GLP-1 related disease" is intended to include, but is not limited to, all diseases, disorders or conditions in which modulation of glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder or condition.

[0042] 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-1RA enhances glucose-dependent insulin secretion; suppresses inappropriately elevated glucagon levels in both the fasting and postprandial states; and slows gastric emptying. Karla et al., Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267. GLP-1RA has been shown to treat type 2 diabetes. Examples of GLP-1RA include, but are not limited to, albiglutide Dulaglutide (LY2189265, ), efpeglenatide, exenatide Exendin-4), liraglutide ( NN2211), lixisenatide Semaglutide Tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401. See also, for example, additional GLP-1 receptor agonists described in the following U.S. Patent Nos.: 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.

[0043] As used herein, the term "pharmaceutically acceptable" indicates that the compound or salt thereof or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the patient to be treated therewith.

[0044] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, an addition salt (particularly a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, NH 3 or a salt of a primary, secondary or tertiary amine, such as a salt derived from a N-containing heterocyclic ring, a N-containing heteroaryl ring or a group of formula N(R N ) 3 Amine salts (e.g., HN + (R N ) 3 or (alkyl) N + (RN ) 3 ), where each R N is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each salt is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0045] 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., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), and all compositions (e.g., pharmaceutical compositions) in which a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is a component of the composition.

[0046] A "solvate" is formed by the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0047] The term "deuterated analogs" of compounds described herein, wherein one or more hydrogens (such as hydrogen on a carbon atom) are replaced by deuterium. The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom that is not specifically designated as a particular isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a position is explicitly designated as "H" or "hydrogen", the position is understood to be a hydrogen with its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom that is specifically designated as deuterium (D) is intended to represent deuterium.

[0048] The term "administration" or "administering" refers to a method of giving a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including a mammal, bird, fish or amphibian). The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

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

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

[0051] The term "pharmaceutical composition" refers to a mixture of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) and other chemical components (collectively referred to herein as "excipients") such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners. Pharmaceutical compositions facilitate administration of compounds to an organism. There are a variety of techniques for administering compounds in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

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

[0053] As used herein, the term "preventing" or "preventing" is the complete or partial prevention of the onset, recurrence, or spread of a disease or disorder as described herein, or symptoms thereof.

[0054] 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 terms refer to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired or required. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

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

[0056] As used herein, the term "pharmaceutical combination" refers to a medical therapy that results from the admixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0057] As used herein, the term "combination therapy" refers to a dosing regimen of two different therapeutically active agents (ie, components of the combination or combination partners) wherein the therapeutically active agents are administered together or separately in a manner prescribed by a healthcare practitioner or according to a regulatory regime as defined herein.

[0058] As used herein, the term "modulate" means to regulate or adjust (eg, increase or decrease), and may include, for example, agonism, partial agonism, or antagonism. Compound

[0059] Provided herein are heterocyclic GLP-1 agonists for use in the management of T2DM as well as other conditions where activation of GLP-1 activity is useful.

[0060] In some embodiments, compounds of Formula I are provided: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: X is C and Y is N, or Y is C and X is N, and the dashed line represents an optional bond, so that part yes wherein bond y is attached to Y and bond x is attached to X; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; or the part-L 3 -C(R 8a R 8b )-L 4 -R 9 is C(=O)OH and optionally 1-4 independently selected from R f Phenyl substituted with another substituent; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H, optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl, and C(=O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups, C 3-15 Cycloalkyl and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca are independently selected from halo, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; L 2 Selected from Where aa represents the point of attachment to Q; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Q is selected from C 1-10 Alkyl; C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, wherein Q is replaced by -P(=O)R a R b and optionally substituted by 1-6 independently selected from R Q Another substituent of ; Each R Q Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (h) optionally 1 to 6 independently selected Rf Substituted C 1-6 Alkoxy; (i) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (j) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (k) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; (l) optionally 1 to 6 independently selected R g Substituted 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; or Q is C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 each independently selected from R QA and R QB Substituents are substituted; Provided that either or both of (aa) or (bb) apply: (aa)Q is covered by at least one R QB replace; or (bb) Q is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Q contains an endocyclic S(O) 2 Group; each R QA Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (g) optionally 1 to 6 independently selected R fSubstituted C 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (i) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (j) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; and (k) optionally 1 to 6 independently selected R g Substituted C 3-8 Cycloalkyl; Each R QB Independently selected from: a)-L a -S(O) 2 -L b -R e ;and b) 4-12 membered heterocyclyl or 7-10 membered bicyclic heteroaryl, each of which contains an endocyclic S(O) 2 A group wherein the heterocyclic group or heteroaryl group is optionally substituted by 1 to 6 independently selected R g replace; L a Selected from -N(H)-, -N(R c )- and -(CR h R h ) q1 -; L b Selected from -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 -; q1 and q2 are independently 0, 1, 2, 3 or 4; The condition is that when L a Yes-(CR h R h ) q1 - and q1 is 0, then -L b -R e Not unsubstituted C 1-3 alkyl; R a and R b Independently selected from optionally 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted 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 atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R c and R d Independently selected 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), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; L e Yes key, NR c or O; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms that connect them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0061] In some embodiments, part yes wherein bond y is attached to Y, and bond x is attached to X;

[0062] In some embodiments, part yes Where bond y is attached to Y, and bond x is attached to X.

[0063] In some embodiments, a compound of Formula II is provided: or a pharmaceutically acceptable salt or solvate thereof, wherein: Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is defined as (AA) or (BB) below: (AA) Q 1 and Q 5 Independently selected from N, CH and CR QC ; Q 2 , Q 3 and Q 4 Independently selected from N, CH, CR QC and CR QD , provided that Q 2 , Q 3 and Q 4 At least one of them is CR QD ; Each is a single bond or a double bond, provided that it contains Q 1 -Q 5 The ring is aromatic; (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 Independently selected from O, S, N, NH, NR c , CH, CR QC and CR QD , provided that Q 2 , Q 3 , Q 4 and Q 5 At least one of them is CR QD ; Each is a single bond or a double bond, provided that it contains Q 1 -Q 5 The ring is aromatic; R QD is P(=O)R a R b , where R a and R b Independently selected from optionally 1-6 each independently selected from C 1-6Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6 Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted 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 atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R QC Independently selected from (a) halo; (b) cyano; (c) OH; (d) -NR c R d ; (e) C(=O)NR c R d ; (f) S(=O) 0-2 R e (g) optionally 1-6 independently selected R f Substituted C 1-6 (h) optionally substituted by 1-6 groups independently selected from hydroxy, halo and C 1-6 Alkoxy substituents substituted C 1-6 Alkoxy; (i) optionally substituted by one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituents; (j) optionally substituted by 1 to 3 independently selected C(═O)(C 1-6 Alkyl) substituted C 6-10 Aryl; and (k) optionally 1-6 independently selected R g substituted 5-10 membered heteroaryl; or a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form a ring containing 5-8 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from O, N and S, wherein the ring is optionally substituted with 1-2 independently selected R h Group substitution; L 2 Selected from Where aa represents the1 -Q 5 The attachment point of the ring; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5-7 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C3-15 Substituents of cycloalkyl substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H; optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(═O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups; 3-15 Cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca are independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; Each R c and Rd Independently selected from H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e It is H, C 1-6 Alkyl or C 1-6 Haloalkyl; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each R h independently selected from halo, cyano, C 1-6 Alkyl, C 1-6 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0064] In some embodiments, a compound of Formula III is provided: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: Ring D is selected from C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 each independently selected from R QA and R QB Substituents are substituted; Provided that either or both of (aa) or (bb) apply: (aa) Ring D is surrounded by at least one R QB replace; or (bb) Ring D is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Ring D contains an endocyclic S(O) 2 Group; Each R QA Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (i) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (j) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; and (k) optionally 1 to 6 independently selected R g Substituted C 3-8 Cycloalkyl; Each R QB Independently selected from a)-La -S(O) 2 -L b -R e ;and b) 4-12 membered heterocyclyl or 7-10 membered bicyclic heteroaryl, each of which contains an endocyclic S(O) 2 A group wherein the heterocyclic group or heteroaryl group is optionally substituted by 1 to 6 independently selected R g replace; L a Selected from -N(H)-, -N(R c )- and -(CR h R h ) q1 -; L b Selected from -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 -; q1 and q2 are independently 0, 1, 2, 3 or 4; The condition is that when L a Yes-(CR h R h ) q1 - and q1 is 0, then -L b -R e Not unsubstituted C 1-3 alkyl; L 2 Selected from where aa represents the point of attachment to ring D; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from: Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; 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): R 9a Is H or C1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H; optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(═O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups; 3-15 Cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca are independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; Each R a and R b Independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl) and C(=O)O(C 1-6 alkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl) and C(=O)O(C 1-6 alkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; Each R c and R d Independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1-6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c Rd , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms that connect them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0065] In some embodiments, a compound of Formula IV is provided: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from: Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H; optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(═O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups; 3-10Cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca are independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; L 2 Selected from Where aa represents the point of attachment to Q; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Q is selected from C 1-10 Alkyl; C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 independently selected R Q replace; Each R Q Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C1-6 alkyl; (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (i) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (j) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (k) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; (l) optionally 1 to 6 independently selected R g Substituted 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 optionally 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6 Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted 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 atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R c and R d Independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; L e Yes key, NR c or O; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Haloalkoxy, NR c R d , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms that connect them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0066] In some embodiments, Ring A is C 6-10 Aryl, which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl.

[0067] In some embodiments, Ring A is phenyl, which is optionally substituted with 1-3 substituents each independently selected from fluoro, methyl, and cyclopropyl.

[0068] In some embodiments, R 1 and R 2 It's H.

[0069] In some embodiments, R 3 It is C 1-6 alkyl.

[0070] In some embodiments, R 3 It's methyl.

[0071] In some embodiments, L 1 It is -C(=O)-.

[0072] In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

[0073] In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

[0074] In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

[0075] In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

[0076] In some embodiments, R 4 , R 5 , R 6 and R 7 It's H.

[0077] In some embodiments, L 3 is the key.

[0078] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-15 Cycloalkyl.

[0079] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached they form a cyclopropyl group.

[0080] In some embodiments, R9 yes

[0081] In some embodiments, R 9d It's H.

[0082] In some embodiments, the moiety -L 3 -C(R 8a R 8b )-L 4 -R 9 is C(=O)OH and optionally 1-4 independently selected from R f In some embodiments, the moiety -L 3 -C(R 8a R 8b )-L 4 -R 9 is phenyl substituted with C(=O)OH. In some embodiments, the moiety -L 3 -C(R 8a R 8b )-L 4 -R 9 yes

[0083] In some embodiments, Ring C is a 3-12 membered heterocyclyl.

[0084] In some embodiments, Ring C is tetrahydropyranyl.

[0085] In some embodiments, L 2 yes where aa represents the point of attachment to Q.

[0086] In some embodiments, L 2A is the key.

[0087] In some embodiments, a compound of Formula I or II, or a pharmaceutically acceptable salt or solvate thereof, is provided, comprising any one or more of the features detailed below.

[0088] In some embodiments, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 It is defined according to (AA).

[0089] In some embodiments, Q 3 Yes CR QD In some embodiments, Q 4 is N, CH or CR QC .

[0090] In some embodiments, Q 4 Yes CR QD In some embodiments, Q 3 is N, CH or CR QC .

[0091] In some embodiments, Q 1 Is CH or CR QC In some embodiments, Q 1 It is CH.

[0092] In some embodiments, Q 2 Is CH or CR QC In some embodiments, Q 2 It is CH.

[0093] In some embodiments, Q 5 Is CH or CR QC In some embodiments, Q 5 is CH. In some embodiments, Q 5 Yes CR QC .

[0094] In some embodiments, Q 3 Yes CR QD ; and Q 1 , Q 2 , Q 4 and Q 5 Each of is independently CH or CR QC In some embodiments, Q 1 , Q 2 , Q 4 and Q 5 Each of them is CH.

[0095] In some embodiments (when Q 3 Yes CR QD ; and Q 1 , Q 2 , Q 4 and Q 5 Each of is independently CH or CR QC ), Q 1 , Q 2 , Q 4 and Q 5 One of them is CR QC ; and Q 1 , Q 2 , Q 4 and Q 5 In some embodiments, each of the remaining CH is CH. 4 Yes CR QC ; and Q1 , Q 2 and Q 5 It is CH.

[0096] In some embodiments (when Q 3 Yes CR QD ; and Q 1 , Q 2 , Q 4 and Q 5 Each of is independently CH or CR QC ), Q 1 , Q 2 , Q 4 and Q 5 Two of them are independently selected CR QC ; and Q 1 , Q 2 , Q 4 and Q 5 Each of the remaining ones is CH.

[0097] In some embodiments, Q 3 Yes CR QD ;Q 1 , Q 2 , Q 4 and Q 5 One of them is N; and Q 1 , Q 2 , Q 4 and Q 5 Each of the remaining is independently CH or CR QC In some embodiments, Q 4 is N. In some embodiments, Q 1 , Q 2 and Q 5 It is CH.

[0098] In some embodiments, Q 3 Yes CR QD ;and Some selected from:

[0099] In some embodiments, Q 3 Yes CR QD ;and Some selected from:

[0100] In some embodiments, Part is

[0101] In some embodiments, Part is

[0102] In some embodiments, Q 3 Yes CR QD ;and Some selected from:

[0103] In some embodiments, Part is

[0104] In some embodiments, Part can be

[0105] In some embodiments, Q 4 Yes CR QD ; and Q 1 , Q 2 , Q 3 and Q 5 Each of is independently CH or CR QC In some embodiments, Q 1 , Q 2 , Q 3 and Q 5 Each of them is CH.

[0106] In some embodiments (when Q 4 Yes CR QD ; and Q 1 , Q 2 , Q 3 and Q 5 Each of is independently CH or CR QC ), Q 1 , Q 2 , Q 3 and Q 5 One of them is CR QC ; and Q 1 , Q 2 , Q 3 and Q 5 In some embodiments, each of the remaining CH is CH. 5 Yes CR QC ; and Q 1 , Q 2 and Q 3 It is CH.

[0107] In some embodiments (when Q 4 Yes CR QD ; and Q 1 , Q 2 , Q 3and Q 5 Each of is independently CH or CR QC ), Q 1 , Q 2 , Q 3 and Q 5 Two of them are independently selected CR QC ; and Q 1 , Q 2 , Q 3 and Q 5 In some embodiments, each of the remaining CH is CH. 2 and Q 3 is independently selected CR QC ; and Q 1 and Q 5 It is CH.

[0108] In some embodiments, Q 4 Yes CR QD ;Q 1 , Q 2 , Q 3 and Q 5 One of them is N; and Q 1 , Q 2 , Q 3 and Q 5 Each of the remaining is independently CH or CR QC .

[0109] In some embodiments, Q 4 Yes CR QD ;and Some selected from:

[0110] In some embodiments, Part is Where Q 4 and Q 5 Independently selected from N, CH and CR QC In some embodiments, Q 4 and Q 5 Each of is CH. In some embodiments, Q 4 Yes CR QC ; and Q 5 is CH. In some embodiments, Q 4 is N; and Q 5 Yes CR QC Or CH. In certain embodiments, Q 5 It is CH.

[0111] In some embodiments, Part is Where Q 2 , Q 3 and Q 5 Independently selected from N, CH and CR QC In some embodiments, Q 2 , Q 3 and Q 5 Each of is CH. In some embodiments, Q 5 Yes CR QC ; and Q 2 and Q 3 Each of is CH. In some embodiments, Q 5 is CH; and Q 2 and Q 3 is independently selected CR QC .

[0112] In some embodiments, R QD is P(=O)R a R b , where R a and R b Independently selected from C 1-6 Alkyl and C 3-6 In some embodiments, CR QD is P(=O)R a R b , where R a and R b Each independently is C 1-6 In some embodiments, CR QD is P(=O)R a R b , where R a and R b Each independently is C 1-3 alkyl.

[0113] In some embodiments, R a and R b are the same.

[0114] In some embodiments, R a and R b Each is a methyl group (ie, R QD is P(=O)Me 2 ).

[0115] In some embodiments, R a and R b Each is ethyl (ie, R QD is P(=O)Et 2 ).

[0116] In some embodiments, R a and R b Each is a propyl group, such as an isopropyl group. For example, R QD It can be P(=O)iPr 2 .

[0117] In some embodiments, R QD is P(=O)R a R b ; R a and R b Each independently is C 1-6 alkyl; and R a and R b In some embodiments, R a It is C 1-3 alkyl (eg, methyl or ethyl); and R b It is C 4-6 Alkyl (e.g., butyl, such as tert-butyl). For example, R a may be methyl; and R b It may be tert-butyl (ie, R QD It may be P(=O)(Me)(tBu)). In some embodiments, R a and R b C is independently selected 1-3 Alkyl, provided that R a and R b are different.

[0118] In some embodiments, R QD is P(=O)R a R b , where R a and R b Each independently is C 3-6 In certain of these embodiments, R a and R b are the same. For example, R a and R b can be cyclopropyl (ie, R QD Can be ).

[0119] In some embodiments, R QD is P(=O)R a R b , where R a and R b Together with the phosphorus atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R bwherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution.

[0120] In some embodiments, R QD is P(=O)R a R b , where R a and R b Together with the phosphorus atom to which they are attached, they form a ring containing 5-6 ring atoms, of which 0-1 ring atoms (except the one attached to R a and R b ) is a heteroatom selected from: O, S and N, wherein the ring is optionally replaced by 1-2 independently selected C 1-6 Alkyl substitution.

[0121] In some embodiments, R QD Can be Where L Q is a key, CH 2 , O, S, NH or N(C 1-6 For example, R QD Can be

[0122] In some embodiments, each R QC Selected from: halo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, OH and NR c R d .

[0123] In some embodiments, each R QC Selected from: halo, cyano, OH and NR c R d .

[0124] In some embodiments, one occurrence of R QC In certain of these embodiments, one occurrence of R QC Yes -F.

[0125] In some embodiments, one occurrence of R QC It is -OH.

[0126] In some embodiments, one occurrence of R QC YesNR c R d .

[0127] In some embodiments, one occurrence of R QC is NH(C 1-3alkyl) (e.g., NHMe, NHEt or NHiPr).

[0128] In some embodiments, one occurrence of R QC Yes NH 2 .

[0129] In some embodiments, one occurrence of R QC is N(C 1-3 alkyl) 2 (For example, NMe 2 ).

[0130] In some embodiments, one occurrence of R QC Selected from NHC(=O)(C 1-6 alkyl), NHC(=O)(C 3-6 Cycloalkyl), NHC(=O)O(C 1-6 Alkyl), NHS(O) 1-2 (C 1-6 Alkyl) and NHS(O) 1-2 (C 3-6 cycloalkyl).

[0131] In some embodiments, one occurrence of R QC is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 Cycloalkyl) (e.g., NHC(═O)(cyclopropyl)) or NHS(O) 2 (C 1-3 Alkyl) (e.g., NHS(O) 2 Me).

[0132] In some embodiments, one occurrence of R QC is optionally one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 In some embodiments, one occurrence of R QC It is a morpholinyl group.

[0133] In some embodiments, one occurrence of R QC is C optionally substituted by 1 to 6 substituents each independently selected from the following 1-6 Alkoxy: hydroxy, halo and C 1-6 In some embodiments, one occurrence of R QC is C optionally substituted with 1-6 (e.g., 1-3) independently selected halo groups 1-6 In some embodiments, R QC Can be -OMe, -OCF3 or -OCHF 2 In some embodiments, R QC is -OMe. In some embodiments, R QC Yes - OCF 3 In some embodiments, R QC Yes - OCHF 2 .

[0134] In some embodiments, R QC is optionally 1-6 independently selected R f Substituted C 1-6 In some embodiments, R QC It is C 1-3 In some embodiments, R QC It's methyl.

[0135] In some embodiments, one occurrence of R QC is C substituted with 1 to 6 independently selected halo groups 1-3 In some embodiments, R QC It is CF 3 , CHF 2 or CH 2 F. In some embodiments, R QC It is CF 3 or CHF 2 .

[0136] In some embodiments, one occurrence of R QC It was NR c R d Substituted C 1-3 In some embodiments, R QC Yes CH 2 NHMe.

[0137] In some embodiments, each remaining R QC (when present) is an independently selected halo, such as -F.

[0138] In some embodiments, a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from O, N and S, wherein the ring is optionally substituted by 1-2 independently selected R h Group substitution.

[0139] In some embodiments, a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form:

[0140] In some embodiments, a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form:

[0141] In some embodiments, each remaining R QC (when present) is independently halo, cyano, or C 1-3 alkyl.

[0142] In some embodiments, L 2 yes In some embodiments, L 2A is a bond. In some embodiments, L 2A Yes CH 2 .

[0143] In some embodiments, L 2 yes

[0144] In some embodiments, L 2 yes In some embodiments, n1 is 1. In certain other embodiments, n1 is 2 or 3. In some embodiments, L 2A is a bond. In some embodiments, L 2A yes C 1-2 Alkylene.

[0145] In some embodiments, L 2 yes In some embodiments, L 2A is a bond. In some embodiments, L 2A It is C 1-2 Alkylene.

[0146] In some embodiments, L 2 yes

[0147] In some embodiments, Ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-4 substituents independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0148] In some embodiments, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2-4 substituents each independently selected from the group consisting of halo, C 1-6 Alkyl, C1-6 Haloalkyl and C 1-6 Alkoxy.

[0149] In some embodiments, Ring A is phenyl, which is optionally substituted by 2-4 groups, each independently selected from halo (eg, -F) and C 1-6 Alkyl (e.g., C 1-3 In some embodiments, ring A is Where R AA , R AB and R AC are independently halo or C 1-6 In some embodiments, R AA and R AC Independently selected from C 1-3 alkyl (eg, methyl); and / or R AB is a halo group (eg, -F).

[0150] In some embodiments, Ring A is pyridinyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 In some embodiments, ring A is 4-pyridyl, which is optionally substituted with 2-4 substituents each independently selected from halo and C 1-6 In some embodiments, ring A is 3-pyridyl, which is optionally substituted with 2-4 substituents each independently selected from halo and C 1-6 In some embodiments, ring A is 2-pyridyl, which is optionally substituted with 2-4 substituents each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0151] In some embodiments, R 1 is H. In some embodiments, R 1 It is C 1-6 alkyl.

[0152] In some embodiments, R 2 is H. In some embodiments, R 2 It is C 1-6 alkyl.

[0153] In some embodiments, R 3 is H. In some embodiments, R 3 It is C 1-6 Alkyl (e.g., C 1-3 alkyl group, such as methyl).

[0154] In some embodiments, R 1 , R 2 and R 3is H. In some embodiments, R 1 and R 2 is H; and R 3 It is C 1-6 In some embodiments, R 3 It's methyl.

[0155] In some embodiments, R 1 is H; and R 2 and R 3 C is independently selected 1-6 alkyl.

[0156] In some embodiments, L 1 It is C(=O).

[0157] In some embodiments, L 1 Yes-CH 2 - or -CH(C 1-6 alkyl)-.

[0158] In some embodiments, L 1 Yes-S(=O) 2 .

[0159] In some embodiments, R 4 , R 5 and R 6 Each is H or halo. In some embodiments, R 4 , R 5 and R 6 Each is H or -F. In some embodiments, R 4 , R 5 and R 6 Each is H. As another non-limiting example, R 4 and R 5 is H; and R 6 In some embodiments, R 7 is H. In some embodiments, R 7 Yes -F.

[0160] In some embodiments, R 4 , R 5 , R 6 and R 7 (when present) are each independently selected from -H and halo. In some embodiments, R 4 , R 5 , R 6 and R 7 Each of (when present) is independently selected from -H and -F.

[0161] In some embodiments, L3 and L 4 In some embodiments, at least one of L is a bond. 3 and L 4 Both are keys.

[0162] In some embodiments, L 3 is a key; and L 4 It is C 1-2 Alkylene.

[0163] In some embodiments, L 4 is a key; and L 3 It is C 1-2 Alkylene.

[0164] In some embodiments, L 3 and L 4 Each independently is C 1-2 Alkylene.

[0165] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 independently selected C 1-6 Alkyl substituted C 3-8 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f replace.

[0166] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 independently selected C 1-6 Alkyl substituted C 3-5 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f replace.

[0167] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 independently selected C 1-6 Alkyl substituted C 3-4 Cycloalkyl ring.

[0168] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form: (For example, )or In some embodiments, R 8a and R8b Together with the carbon atoms to which they are attached, they form:

[0169] In some embodiments, R 8a and R 8b Each independently selected from H and C 1-6 Alkyl. For example, R 8a and R 8b can all be H. In some embodiments, R 8a and R 8b Each independently is C 1-6 Alkyl (e.g., C 1-3 In some embodiments, R 8a is H; and R 8b It is C 1-6 Alkyl (e.g., C 1-3 alkyl).

[0170] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: In some embodiments, R 9d Is H or C 1-6 alkyl.

[0171] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: In certain of these embodiments, R 9d Is H or C 1-6 Alkyl. For example, R 9d It can be H.

[0172] In some embodiments, R 9 yes In some embodiments, R 9d Is H or C 1-6 In some embodiments, R 9d It's H.

[0173] In some embodiments, R 9 yes In some embodiments, R 9 yes In some embodiments, R 9 yes

[0174] In some embodiments, R 9 It is C(=O)OH.

[0175] In some embodiments, R 9 is C(=O)(OC 1-6 alkyl).

[0176] In some embodiments, R 9 is C(=O)NR 9a R 9b In some embodiments, R 9a is H. In some embodiments, R 9b is H. In some embodiments, R 9b It is C 1-6 In some embodiments, R 9b Selected from: C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) and cyano.

[0177] In some embodiments, Part is Where ring D is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 Alkyl. Non-limiting examples include: (For example, )or

[0178] In some embodiments (when Part is ), R 9 yes (IX-2). In some embodiments, R 9d Is H or C 1-6 In some embodiments, R 9d It's H.

[0179] In some embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 3- to 12-membered heterocyclic group.

[0180] In some embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 4- to 8-membered heterocyclic group.

[0181] In some embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 5-6 membered heterocyclic group.

[0182] In some embodiments, Ring C is optionally substituted with 1-3 independent R Ca In some embodiments, ring C is selected from: (For example, In some embodiments, Ring C is (For example, ).

[0183] In certain embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca For example, ring C can be (For example, ).

[0184] In some embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 5-6 membered heteroaryl.

[0185] In some embodiments, Ring C is optionally substituted with 1-3 R Ca Substituted C 3-10 In some embodiments, Ring C is optionally substituted by 1-3 independently selected R Ca Substituted C 3-8 In some embodiments, ring C is (For example, ).

[0186] In some embodiments, each R Ca are independently selected from halo, C 1-6 Alkyl, C 1-6 Alkoxy and NR c R d .

[0187] In some embodiments, each R Ca Independently selected from: halo and C 1-6 alkyl.

[0188] In some embodiments, each R Ca Independently C 1-6 For example, each R Ca It may be methyl.

[0189] In some embodiments, each R Ca is an independently selected halo group. For example, each R Ca Can be -F.

[0190] In some embodiments, a pair of R on the same or different ring atoms CaTogether with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3-6 ring atoms. Ca Together with the respective ring atoms to which they are attached they form a carbocyclic ring containing 3-5 ring atoms.

[0191] In some embodiments, the compound of Formula I is a compound of Formula IIA: Where Q 4 and Q 5 Independently selected from: N, CH and CR QC ; or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0192] In some embodiments of Formula IIA, Q 4 and Q 5 Each of them is CH.

[0193] In some embodiments of Formula IIA, Q 4 Yes CR QC ; and Q 5 It is CH.

[0194] In some embodiments of Formula IIA, Q 4 Yes CR QC ; and Q 5 Yes CR QC In certain of these embodiments, Q 4 Yes CR QC ; and Q 5 is a C-halo group, such as CF.

[0195] In some embodiments of Formula IIA, Q 4 is N; and Q 5 Yes CR QC or CH. In certain of these embodiments, Q 5 It is CH.

[0196] In some embodiments, the compound of Formula I is a compound of Formula IIB: Where Q 2 , Q 3 and Q 5 Independently selected from: N, CH and CR QC ; or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

[0197] In some embodiments of Formula IIB, Q 2, Q 3 and Q 5 Each of them is CH.

[0198] In some embodiments of Formula IIB, Q 5 Yes CR QC ; and Q 2 and Q 3 Each of them is CH.

[0199] In some embodiments of Formula IIB, Q 5 is CH; and Q 2 and Q 3 is independently selected CR QC .

[0200] In some embodiments, L 3 and L 4 In some embodiments, at least one of L is a bond. 3 and L 4 Both are keys.

[0201] In some embodiments of Formula IIA or IIB, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 independently selected C 1-6 Alkyl substituted C 3-5 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f replace.

[0202] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 independently selected C 1-6 Alkyl substituted C 3-4 Cycloalkyl ring.

[0203] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form:

[0204] In some embodiments of Formula IIA or IIB, Ring C is optionally substituted with 1-3 independently selected R Ca In some embodiments, ring C is optionally substituted by 1-3 independently selected R Ca In some embodiments, ring C is optionally substituted by 1-3 independent R CaIn some embodiments, ring C can be selected from: In certain embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca For example, ring C can be

[0205] In some embodiments of Formula (IA) or (IB), Ring C is optionally substituted with 1-3 R Ca Substituted C 3-8 Cycloalkyl. For example, ring C can be

[0206] In some embodiments of Formula IIA or IIB, each R Ca Independently C 1-6 In some embodiments, each R Ca is H. In some embodiments, each R Ca It is C 1-3 In some embodiments of Formula IIA or IIB, each R Ca is an independently selected halo (eg, -F).

[0207] In some embodiments of Formula IIA or IIB, a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 6 ring atoms.

[0208] In some embodiments of Formula IIA or IIB, a pair of R on the same ring atom Ca Together with the respective ring atoms to which they are attached they form a carbocyclic ring containing 3-5 ring atoms.

[0209] In some embodiments, the compound of Formula I is a compound of Formula IIC: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: Ring D is C 3-6 Cycloalkyl; R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 Alkyl; and Each R Cb Independently selected from H and R Ca .

[0210] In some embodiments of Formula IIC, Ring D is cyclopropyl.

[0211] In some embodiments of Formula IIC, Ring D is cyclobutyl.

[0212] In some embodiments of Formula IIC, R 8c It's H.

[0213] In some embodiments of Formula IIC, R 8c It is C 1-3 Alkyl. For example, R 8c It may be methyl.

[0214] In some embodiments of Formula IIC, each R Cb It's H.

[0215] In some embodiments of Formula IIC, each R Cb Independently C 1-6 Alkyl (e.g., C 1-3 alkyl (eg, methyl)).

[0216] In some embodiments of Formula IIC, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is as defined according to (AA).

[0217] In some embodiments of Formula IIC, Part is Where Q 4 and Q 5 Independently selected from N, CH and CR QC .

[0218] In some embodiments, Q 4 and Q 5 Each of them is CH.

[0219] In some embodiments, Q 4 Yes CR QC ; and Q 5 It is CH.

[0220] In some embodiments, Q 4 Yes CR QC ; and Q 5 Yes CR QC In some embodiments, Q 4 Yes CR QC ; and Q 5 is a C-halo group, such as CF.

[0221] In some embodiments, Q 4 is N; and Q 5 Yes CR QCOr CH. In some embodiments, Q 5 It is CH.

[0222] In some embodiments of Formula IIC, Part is Where Q 2 , Q 3 and Q 5 Independently selected from N, CH and CR QC .

[0223] In some embodiments, Q 2 , Q 3 and Q 5 Each of them is CH.

[0224] In some embodiments, Q 5 Yes CR QC ; and Q 2 and Q 3 Each of them is CH.

[0225] In some embodiments, Q 5 is CH; and Q 2 and Q 3 is independently selected CR QC .

[0226] In some embodiments of Formula IIC, L 1 It is C(=O).

[0227] In some embodiments of Formula IIA, IIB or IIC, R a and R b Each independently selected from C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0228] In some embodiments of Formula IIA, IIB or IIC, R a and R b Each independently is C 1-3 In some embodiments, R a and R b In some embodiments, R a and R b In some embodiments, R a and R b Each is isopropyl.

[0229] In some embodiments of Formula IIA, IIB or IIC, R a is methyl; and R b It is tert-butyl.

[0230] In some embodiments of Formula IIA, IIB or IIC, R a and R b C is independently selected 3-6 Cycloalkyl. For example, R a and R b They may all be cyclopropyl.

[0231] In some embodiments of Formula IIA, IIB or IIC, each R QC Selected from: halo; cyano; OH; NR c R d ; optionally 1-6 independently selected R f Substituted C 1-6 Alkyl; C optionally substituted by 1-6 substituents each independently selected from the following 1-6 Alkoxy: hydroxy, halo and C 1-6 Alkoxy; and optionally one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituted 3- to 12-membered heterocyclic group.

[0232] In some embodiments, each R QC Selected from: -F, OH, NH 2 NHMe, NHEt, NHiPr, N(Me) 2 、NHC(=O)(cyclopropyl), NHS(O) 2 Me, methyl, CF 3 , CHF 2 、OMe、OCF 3 , OCHF 2 and morpholinyl.

[0233] In some embodiments, R QC Selected from: -F, OH, NH 2 NHMe, NHEt, NHC(=O)(cyclopropyl), NHS(O) 2 Me, methyl, OMe, OCF 3 and morpholinyl.

[0234] In some embodiments of Formula IIA, IIB or IIC, each R QC Selected from: halo, cyano, OH and NR c R d .

[0235] In some embodiments, each R QC Selected from: -F, OH and NHMe.

[0236] In some embodiments of Formula IIA, IIB or IIC, a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form a ring containing 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms each independently selected from O, N and S, wherein the ring is optionally substituted by 1-2 independently selected R h In some embodiments, a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form: In some embodiments, a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form: (For example, R h is methyl).

[0237] In some embodiments of Formula IIA, IIB or IIC, L 2 yes

[0238] In some embodiments of Formula IIA, IIB or IIC, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2-4 substituents each independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0239] In some embodiments of Formula IIA, IIB or IIC, Ring A is phenyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0240] In some embodiments, Ring A is Where R AA , R AB and R AC are independently halo or C 1-6 Alkyl. For example, R AA and R AC Each of these can be independently C 1-6 Alkyl groups, such as C 1-3 alkyl (eg, methyl); and / or R AB It may be a halo group (eg, -F).

[0241] In some embodiments of Formula IIA, IIB or IIC, R 1 and R 2 It's H.

[0242] In some embodiments of Formula IIA, IIB or IIC, R 3 It's H.

[0243] In some embodiments of Formula IIA, IIB or IIC, R 3 It is C 1-6 alkyl.

[0244] In some embodiments of Formula IIA, IIB or IIC, R 1 and R 2 is H; and R 3 It is C 1-6 Alkyl. For example, R 3 It may be methyl.

[0245] In some embodiments of Formula IIA, IIB or IIC, R 4 , R 5 and R 6 Each is H or halo.

[0246] In some embodiments of Formula IIA, IIB or IIC, R 4 , R 5 and R 6 Each is H or -F. In certain embodiments of Formula IIA, IIB or IIC, R 4 , R 5 and R 6 Each is H. In some embodiments of Formula IIA, IIB or IIC, R 4 and R 5 is H; and R 6 Yes -F.

[0247] In some embodiments of Formula IIA, IIB or IIC, R 7 It's H.

[0248] In some embodiments of Formula IIA, IIB or IIC, R 7 Yes -F.

[0249] In some embodiments of Formula IIA, IIB or IIC, R 9 yes In some embodiments, R 9d It's H.

[0250] In some embodiments, the compound of Formula I is a compound of Formula IID: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: R AA , R AB and R AC are independently halo or C 1-6 alkyl; RQC is H or halo; and Each R Cb Independently selected from H and R Ca .

[0251] In some embodiments of Formula IID, R 1 and R 2 It's H.

[0252] In some embodiments of Formula IID, R 3 It is C 1-3 In some embodiments, R 3 It's methyl.

[0253] In some embodiments of Formula IID, R 4 , R 5 , R 6 and R 7 It's H.

[0254] In some embodiments of Formula IID, R 9d It's H.

[0255] In some embodiments of Formula IID, R AA and R AC Independently C 1-6 In certain of these embodiments, R AA and R AC It's methyl.

[0256] In some embodiments of Formula IID, R AB In some embodiments, R AB Yes -F.

[0257] In some embodiments of Formula IID, each R Cb is H. In some embodiments of Formula IID, each R Cb It is C 1-3 In some embodiments, each R Cb It's methyl.

[0258] In some embodiments of Formula IID, R a and R b Independently C 1-3 In certain of these embodiments, R a and R b In some embodiments, R a and R b In some embodiments, R a and R b It is isopropyl.

[0259] In some embodiments of Formula IID, R a is methyl; and R b It is tert-butyl.

[0260] In some embodiments of Formula IID, R a and R b Independently C 3-6 Cycloalkyl. For example, R a and R b They may all be cyclopropyl.

[0261] In some embodiments of Formula IID, P(=O)R a R b yes Where L Q is a key, CH 2 , O, S, NH or N(C 1-6 In some embodiments, P(=O)R a R b yes

[0262] In some embodiments of Formula IID, R QC Yes -F.

[0263] In some embodiments of Formula IID, R QC It is -OH.

[0264] In some embodiments of Formula IID, R QC YesNR c R d In some embodiments, R QC is NH(C 1-3 In some embodiments, R QC Yes NH 2 In some embodiments, R QC is N(C 1-3 alkyl) 2 (For example, NMe 2 ). In some embodiments, R QC is NHC(=O)(C 1-3 alkyl), NHC(=O)(C 3-6 Cycloalkyl) or NHS(O) 2 (C 1-3 alkyl).

[0265] In some embodiments of Formula IID, R QC is optionally one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6alkyl) substituted 5-6 membered heterocyclic group.

[0266] In some embodiments of Formula IID, R QC is C optionally substituted by 1-6 independently selected halo 1-6 In some embodiments, R QC Yes -OMe, -OCF 3 or -OCHF 2 .

[0267] In some embodiments of Formula IID, R QC It is C 1-3 In some embodiments, R QC In some embodiments of Formula IID, R QC is C substituted with 1 to 3 independently selected halo groups 1-3 In some embodiments, R QC Yes - CF 3 or -CHF 2 .

[0268] In some embodiments of Formula IID, R QC It's H.

[0269] In some embodiments of Formula IID, R QC In some embodiments, R QC In some embodiments, R QC In P(=O)R a R b In some embodiments, R QC In P(=O)R a R b The meta position and in R QC In some embodiments, R QC is in R QC In some embodiments, R QC is -F, which is in P(=O)R a R b The meta position and in R QC The adjacent position.

[0270] In some embodiments of Formula IID, the compound is a compound of Formula (S,S,S)-IID: or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 1-3 alkyl.

[0271] In some embodiments, the compound of Formula I is a compound of Formula IIE: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: R AA , R AB and R AC are each independently halo or C 1-3 alkyl; R 3 Is H or C 1-3 alkyl; R QC is H or a halide; R QD Selected from: (a) H; (b) -NH 2 ; (c)-NH(C 1-3 (d) halo; (e) C optionally substituted by 1-3 independently selected halo 1-3 and (f) C optionally substituted by 1-3 independently selected halo groups 1-3 alkyl; R a and R b Each independently selected from: C 1-4 Alkyl and C 3-6 Cycloalkyl; or R a and R b Together with the phosphorus atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-1 ring atoms (except the one attached to R a and R b ) are heteroatoms independently selected from the group consisting of O, S and N; R 8c Is H or C 1-3 alkyl; X B is CH or N; and Each R Cb Independently selected from H and C 1-3 alkyl.

[0272] In some embodiments, R QD Selected from: (a) H; (b) -NH 2 ; (c)-NH(CD 3 ); (d) halo; (e) C optionally substituted by 1-3 independently selected halo 1-3 and (f) C optionally substituted by 1-3 independently selected halo groups 1-3 alkyl.

[0273] In some embodiments, Ring B of the compound of Formula IIC, IID, (S,S,S)-IID, IIE, or (S,S,S)-IIE is selected from: wherein R4, R5, R6 and R7 are each independently as defined herein; bb represents the point of attachment to -C(O)-; and xx represents the point of attachment to the Ring C moiety as described in Formula I.

[0274] In some embodiments, the compound of Formula I is a compound of Formula IIE: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: Ring B is selected from: Where bb represents the point of attachment to -C(O)- and xx represents the point of attachment to X b Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; R AA , R AB and R AC are independently hydrogen, halo, C 1-3 Alkyl or C 3-6 Cycloalkyl; R 3 Is H or C 1-3 alkyl; R QC is H or a halide; R QD Selected from: (a) H; (b) -NH 2 ; (c)-NH(C 1-3 (d) halo; (e) C optionally substituted by 1-3 independently selected halo 1-3 and (f) C optionally substituted by 1-3 independently selected halo groups 1-3 alkyl; R a and R b Each independently selected from: C 1-4 Alkyl and C 3-6 Cycloalkyl; or R a and R b Together with the phosphorus atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-1 ring atoms (except the one attached to Ra and R b ) are heteroatoms independently selected from the group consisting of O, S and N; R 8c Is H or C 1-3 alkyl; X B is CH or N; and Each R Cb Independently selected from H and C 1-3 alkyl.

[0275] In some embodiments of Formula IIE, R AA and R AC Each independently is C 1-3 Alkyl. For example, R AA and R AC Each may be a methyl group.

[0276] In some embodiments of Formula IIE, R AB is a halo group. For example, R AB It can be F.

[0277] In some embodiments of Formula IIE, R AA and R AC Each independently is C 1-3 alkyl; and R AB is a halo group. For example, R AA and R AC may each be methyl; and R AB It can be F.

[0278] In some embodiments of Formula IIE, R 3 It is C 1-3 Alkyl. For example, R 3 It may be methyl.

[0279] In some embodiments of Formula IIE, R QD It's H.

[0280] In some embodiments of Formula IIE, R QD Selected from -NH 2 and -NH(C 1-3 For example, R QD It can be -NH 2 As another non-limiting example, R QD Can be -NHMe. As another non-limiting example, R QD It can be -NHEt.

[0281] In some embodiments of Formula IIE, R QD is a halo group. For example, R QDCan be -F or -Cl.

[0282] In some embodiments of Formula IIE, R QD is C optionally substituted by 1-3 independently selected halo 1-3 Alkoxy. For example, R QD As another non-limiting example, R QD Can be OCF 3 As another non-limiting example, R QD Can be OCHF 2 .

[0283] In some embodiments of Formula IIE, R QD is C optionally substituted by 1-3 independently selected halo 1-3 Alkyl. For example, R QD As another non-limiting example, R QD Can be CF 3 As another non-limiting example, R 3 Can be -CHF 2 .

[0284] In some embodiments of Formula IIE, R a and R b Each is independently selected C 1-4 Alkyl. For example, R a and R b As another non-limiting example, R a and R b As another non-limiting example, R a and R b As another non-limiting example, R a may be methyl; and R b It may be tert-butyl.

[0285] In some embodiments of Formula IIE, R a and R b Each is independently selected C 3-6 Cycloalkyl. For example, R a and R b They may each be cyclopropyl.

[0286] In some embodiments of Formula IIE, R a and R b Together with the phosphorus atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-1 ring atoms (except the one attached to R a and R b) are independently selected from the group consisting of O, S and N. For example, R a and R b Together with the phosphorus atoms to which they are attached, they can form

[0287] In some embodiments of Formula IIE, R QC It's H.

[0288] In some embodiments of Formula IIE, R QC is a halo group. For example, R QC Can be -F. In some embodiments, R QC In R QD In some embodiments, R QC In R QD In some embodiments, R QC In R QD The interposition.

[0289] In some embodiments of Formula IIE, R 8c is H. In some embodiments of Formula IIE, R 8c It is C 1-3 Alkyl. For example, R 8c It may be methyl.

[0290] In some embodiments of Formula IIE, X B is CH. In some embodiments of Formula IIE, X B It is N.

[0291] In some embodiments of Formula IIE, each R Cb is H. In some embodiments of Formula IE, each R Cb C is independently selected 1-3 For example, each R Cb It may be methyl.

[0292] In some embodiments of Formula IIE, X B is CH; and each R Cb is H. In some embodiments of Formula IIE, X B is CH; and each R Cb C is independently selected 1-3 In some embodiments of Formula IIE, X B is N; and each R Cb is H. In some embodiments of Formula IIE, X B is N; and each R Cb C is independently selected 1-3 Alkyl (eg, methyl).

[0293] In some embodiments of Formula IIE, the compound is a compound of formula (S,S,S)-IIE: or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 1-3 alkyl.

[0294] In some embodiments of Formula IIE: R AA and R AC It is methyl; R AB Yes - F; R 3 It is methyl; R QC is H or -F; R QD Selected from: H, -NHMe, -NHEt, -NH 2 , -OMe, -OCF 3 、-OCHF 2 、-Me、-CF 3 and -CHF 2 ; R a and R b independently selected from: methyl, ethyl, isopropyl, tert-butyl and cyclopropyl; R 8c is H or methyl; X B is CH; and Each R Cb is independently H or methyl.

[0295] In certain of these embodiments, the compound is of formula (S,S,S)-IIE.

[0296] In some embodiments, a compound of Formula III or a pharmaceutically acceptable salt or solvate thereof is provided, comprising any one or more of the features detailed below.

[0297] In some embodiments of Formula I or III, (aa) is applicable.

[0298] In some embodiments, Ring D is selected from: C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is represented by an R QB and further optionally substituted by 1-5 independently selected R QA replace.

[0299] In some embodiments, ring D is selected from: 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is represented by an R QB and further optionally substituted by 1-5 independently selected R QA In some embodiments, ring D is a 5-6 membered heteroaryl or phenyl group, each of which is replaced by one R QB and further optionally substituted by 1-5 independently selected R QA replace.

[0300] In some embodiments, Ring D is: Where Q 1 , Q 2 , Q 4 and Q 5 are independently N, CH or CR QA In some embodiments, Q 1 , Q 2 , Q 4 and Q 5 independently CH or CR QA In some embodiments, Q 1 , Q 2 , Q 4 and Q 5 Each of is CH. In some embodiments, Q 1 , Q 2 , Q 4 and Q 5 1-2 (e.g., 1) of them can be CR QA ; and Q 1 , Q 2 , Q 4 and Q 5 In some embodiments, each of the remaining CH is CH. 1 , Q 2 , Q 4 and Q 5 One of them is N; and Q 1 , Q 2 , Q 4 and Q 5 Each of the remaining is independently CH or CR QA In some embodiments, Q 1 , Q 2 , Q 4 and Q 5 Each of the remaining ones is CH.

[0301] In some embodiments, Ring D is: wherein m1 is 0, 1 or 2. For example, m1 can be 0. In some embodiments, m1 can be 1; and optionally R QA In R QB The interposition.

[0302] In some embodiments, Ring D is: Where Q 1 , Q 2 , Q 3 and Q 5 are independently N, CH or CR QA In some embodiments, Q 1 , Q 2 , Q 3 and Q 5 independently CH or CR QA In some embodiments, Q 1 , Q 2 , Q 3 and Q 5 Each of is CH. In some embodiments, Q 1 , Q 2 , Q 3 and Q 5 1-2 (e.g., 1) of them are CR QA ; and Q 1 , Q 2 , Q 3 and Q 5 Each of the remaining ones is CH.

[0303] In some embodiments, Ring D is: wherein m1 is 0, 1 or 2. In some embodiments, m1 is 0. In some embodiments, m1 is 1.

[0304] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e In some embodiments, L a Yes-(CR h R h ) q1 -; and q1 is 1, 2, 3, or 4. For example, q1 can be 1. As another non-limiting example, q1 can be 2. In some embodiments, each occurrence of R h is H. In some embodiments, one occurrence of R h It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or halo; and each remaining Rh is H. In some embodiments, one occurrence of R h It is C 1-3 alkyl (eg, methyl); and each remaining R h is H. In some embodiments, L b Yes-(CR h R h ) q2 -. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0305] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e ; L a Yes-(CR h R h ) q1 -; q1 is 1, 2, 3, or 4; and each occurrence of R his H. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, L b Yes-(CR h R h ) q2 -. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0306] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e ; L a Yes-(CR h R h ) q1 -; q1 is 1, 2, 3 or 4; one occurrence of R h It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or halo; and each remaining R his H. In some embodiments, one occurrence of R h It is C 1-3 alkyl (eg, methyl); and each remaining R h is H. In some embodiments, q1 is 1. For example, R QB Can be In some embodiments, q1 is 2. In some embodiments, L b Yes-(CR h R h ) q2 -. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0307] In some embodiments, R QB Yes-(CR h R h ) q1 -S(O) 2 -(CR h R h ) q2 -R e ; q1 is 1 or 2; and Re It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, q2 is 0. In some embodiments, q1 is 1. In some embodiments, q1 is 2. In some embodiments, each occurrence of R h Is H or C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 For example, R e Can be C 1-6 Alkyl groups, such as C 1-3 Alkyl (eg, methyl or ethyl).

[0308] In some embodiments, R QB Yes-CH 2 -S(O) 2 (C 1-6 For example, R QB Can be -CH 2 -S(O) 2 Me or -CH 2 -S(O) 2 Et.

[0309] In some embodiments, R QB It is -CH(C 1-6 Alkyl)-S(O) 2 (C 1-6 For example, R QB It can be -CH(Me)S(O) 2 (C1-3 alkyl), such as -CH(Me)S(O) 2 Me.

[0310] In some embodiments, R QB Yes-CH 2 CH 2 -S(O) 2 (C 1-6 For example, R QB Can be -CH 2 CH 2 S(O) 2 Me.

[0311] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where L a Yes-(CR h R h ) q1 -; and q1 is 0. In some embodiments, L b is -NH- or -N(R c )-. In some embodiments, L b is -NH- or -N(C 1-3 For example, L b Can be -NH-. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 In some embodiments, R e It is C 3-6 Cycloalkyl. For example, R e It may be cyclopropyl.

[0312] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where L a Yes-(CR h R h ) q1 -; q1 is 0; and L b Yes-(CR h R h ) q2 -. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy, provided that R e Not unsubstituted C 1-3 In some embodiments, R e It is C 3-6 Cycloalkyl. For example, R e It may be cyclopropyl.

[0313] In some embodiments, wherein R QB Yes-S(O) 2 NH-R e ; and R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R eIt may be methyl or ethyl, such as methyl.

[0314] In some embodiments, wherein R QB Yes-S(O) 2 -R e ; and R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy, provided that R e Not unsubstituted C 1-3 In some embodiments, R e It is C 3-6 Cycloalkyl. For example, R e It may be cyclopropyl.

[0315] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where L a is -NH- or -N(R c )-. In some embodiments, L a is -NH- or -N(C 1-3 For example, L a is -NH-. In some embodiments, L b Yes-(CR h R h ) q2 -. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 For example, R e Can be C 1-6 Alkyl groups, such as C 1-3 Alkyl (eg, methyl or ethyl).

[0316] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where L a is -NH- or -N(R c )-; and L b Yes-(CR h R h ) q2 -. In some embodiments, L a is -NH- or -N(C 1-3 In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 For example, R e Can be C 1-6 Alkyl groups, such as C 1-3 Alkyl (eg, methyl or ethyl).

[0317] In some embodiments, R QB Yes - NHS(O) 2 -(CR h R h ) q2 -R e ; and R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0318] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where L b is -NH- or -N(R c )-. For example, L b It can be -NH- or -N(C 1-3 For example, L b It can be -NH-. In some embodiments, L a Yes-(CR h R h ) q1In some of these embodiments, q1 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 In some embodiments, R e It is C 3-6 Cycloalkyl. For example, R e It may be cyclopropyl.

[0319] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where L b Yes-(CR h R h ) q2 -. In some embodiments, q2 is 0. In some embodiments, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 In some embodiments, R e It is C 3-6 In some embodiments, L a is -NH- or N(C1-3 In some embodiments, L a Yes-(CR h R h ) q1 -. In some embodiments, q1 is 1 or 2. In some embodiments, q1 is 0.

[0320] In some embodiments, R QB Yes-L a -S(O) 2 -L b -R e , where R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl or C 1-6 haloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0321] In some embodiments, R QB is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, each of which contains an endocyclic S(O) 2 A group wherein the heterocyclic group or heteroaryl group is optionally substituted by 1 to 6 independently selected R g replace.

[0322] In some embodiments, RQB Contains the inner ring A 4-10 membered heterocyclic group, wherein ** represents the point of attachment to ring D, and the heterocyclic group is optionally substituted by 1-6 independently selected R g replace.

[0323] In some embodiments, R QB yes: Among them, ring Q 2 Contains 0-2 additional ring heteroatoms (except NS(O) 2 The heterocyclic group is a 4-8 membered group, wherein the heteroatoms are independently selected from the group consisting of N, O and S(O). 0-2 , where ring Q 2 Optionally 1-4 independently selected R g In some embodiments, R QB yes: m2 is 0, 1, 2 or 3; and R QB Optionally 1-4 independently selected R g For example, R QB It can be: As another non-limiting example, R QB Can be selected from:

[0324] In some embodiments, one occurrence of R QA is -halo. For example, one occurrence of R QA Can be -F.

[0325] In some embodiments of Formula I or III, (bb) is applicable.

[0326] In some embodiments, ring D is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein ring D contains an endocyclic S(O) 2 wherein ring D is optionally substituted by 1-4 R QA replace.

[0327] In some embodiments, ring D is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein ring D comprises an endocyclic -N(H)S(O) 2 -group or -N(C 1-3 Alkyl)S(O) 2 - group; wherein ring D is further optionally 1-3 R QA replace.

[0328] In some embodiments, Ring D is a 7-10 membered bicyclic heteroaryl, wherein Ring D comprises an endocyclic -N(H)S(O) 2 -group or -N(C1-3 Alkyl)S(O) 2 - group; and ring D is further optionally substituted with 1-3 R QA For example, ring D can be: Where R N1 Is H or C 1-3 alkyl.

[0329] In some embodiments, R 1 is H. In some embodiments, R 2 is H. In some embodiments, R 3 It is C 1-6 Alkyl. For example, R 3 It is C 1-3 In some embodiments, R 3 It is C 1-6 Alkyl, and R 3 The attached carbon atom has the (S)-configuration.

[0330] In some embodiments, R 1 , R 2 and R 3 It's H.

[0331] In some embodiments, R 1 and R 2 is H; and R 3 It is C 1-6 In some embodiments, R 1 and R 2 is H; and R 3 In some embodiments, R 3 The attached carbon atom has the (S)-configuration.

[0332] In some embodiments, L 2 yes:

[0333] In some embodiments, Ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-4 substituents independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0334] In some embodiments, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2-4 substituents each independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0335] In some embodiments, Ring A is phenyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0336] In some embodiments, Ring A is: Where R AA , R AB and R AC are independently halo or C 1-6 In some embodiments, R AA and R AC Independently C 1-6 Alkyl (e.g., C 1-3 In some embodiments, R AB is a halo group (eg, -F).

[0337] In some embodiments, Ring A is pyridinyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0338] In some embodiments, L 1 It is C(=O).

[0339] In some embodiments, R 4 , R 5 and R 6 Each is H or halo. In some embodiments, R 4 , R 5 and R 6 Each is H or -F. For example, R 4 , R 5 and R 6 can each be H. As another non-limiting example, R 4 and R 5 can be H; and R 6 Can be -F.

[0340] In some embodiments, R 7 is H. In some embodiments, R 7 Yes -F.

[0341] In some embodiments, L 3 and L 4 In some embodiments, at least one of L is a bond. 3 and L 4 Both are bonds. In some embodiments, L 3 is a key; and L 4 It is C 1-2 In some embodiments, L4 is a key; and L 3 It is C 1-2 Alkylene.

[0342] In some embodiments, L 3 and L 4 Each independently is C 1-2 Alkylene.

[0343] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 (e.g., 1) independently selected C 1-6 Alkyl substituted C 3-8 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f In some embodiments, L 3 is a key; and L 4 is the key.

[0344] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 (e.g., 1) independently selected C 1-6 Alkyl substituted C 3-5 (For example, C 3 or C 4 ) cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f In some embodiments, L 3 is a key; and L 4 is the key.

[0345] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 (e.g., 1) independently selected C 1-6 Alkyl substituted C 3-4 Cycloalkyl ring.

[0346] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form:

[0347] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form:

[0348] In some embodiments, R 9 yes: In some embodiments, R 9d Is H or C 1-6 Alkyl. For example, R 9d It can be H.

[0349] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are:

[0350] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: Each stereogenic center has the (S)-configuration.

[0351] In some embodiments, R 9 is (IX-2), where L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: Where R 9d Is H or C 1-6 Alkyl. For example, R 9d is H. In some embodiments, Each stereogenic center of has the (S)-configuration.

[0352] In some embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca In some embodiments, ring C is optionally substituted by 1-3 independently selected R Ca In some embodiments, Ring C is optionally substituted by 1-3 independently selected R Ca For example, ring C may be optionally substituted with 1 to 3 independent R Ca Substituted tetrahydropyranyl.

[0353] In some embodiments, Ring C is selected from: In some embodiments, Ring C is In some embodiments, Ring C is

[0354] In some embodiments, R CaIndependently C 1-6 alkyl.

[0355] In some embodiments, a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 6 ring atoms.

[0356] In some embodiments, a pair of R on the same ring atom Ca Together with the respective ring atoms to which they are attached they form a carbocyclic ring containing 3-5 ring atoms.

[0357] In some embodiments, the compound of Formula I is a compound of Formula IIIA: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: m1 is 0, 1, or 2; R QB Yes-(CR h R h ) q1 -S(O) 2 -(CR h R h ) q2 -R e , where R QB In relation to L 2 meta or para position; q1 is 1 or 2; Ring E is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 alkyl.

[0358] In some embodiments of Formula IIIA, q2 is 0.

[0359] In some embodiments of Formula IIIA, q1 is 1.

[0360] In some embodiments of Formula IIIA, q1 is 2.

[0361] In some embodiments of Formula IIIA, each occurrence of R h Is H or C 1-3 For example, each R h It can be H. As another non-limiting example, one occurrence of R h Can be C 1-3 alkyl (eg, methyl); and each remaining R h It can be H.

[0362] In some embodiments of Formula IIIA, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 In some embodiments, R e It is C 1-6 Alkyl. For example, R e Can be C 1-3 Alkyl groups such as methyl or ethyl.

[0363] In some embodiments of Formula IIIA, R QB Yes-CH 2 -S(O) 2 (C 1-6 For example, R QB Can be -CH 2 -S(O) 2 (C 1-3 alkyl), such as -CH 2 -S(O) 2 Me or -CH 2 -S(O) 2 Et.

[0364] In some embodiments of Formula IIIA, R QB It is -CH(C 1-6 Alkyl)-S(O) 2 (C 1-6 For example, R QB It can be -CH(C 1-3 Alkyl)S(O) 2 (C 1-3 alkyl), such as -CH(Me)S(O) 2 Me.

[0365] In some embodiments of Formula IIIA, R QB Yes-CH 2 CH 2 -S(O) 2 (C 1-6 For example, R QB Can be -CH2 CH 2 -S(O) 2 (C 1-3 alkyl), such as -CH 2 CH 2 -S(O) 2 Me.

[0366] In some embodiments, the compound of Formula I is a compound of Formula IIIB: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: m1 is 0, 1, or 2; R QB Yes-S(O) 2 N(R N2 )-R e , where R QB In relation to L 2 meta or para position; R N2 Is H or C 1-3 alkyl; Ring E is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 alkyl.

[0367] In some embodiments of Formula IIIB, R QB Yes-S(O) 2 N(H)-R e .

[0368] In some embodiments of Formula IIIB, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0369] In some embodiments of Formula IIIB, R e It is C 1-6Alkyl. For example, R e Can be C 1-3 An alkyl group, such as a methyl group.

[0370] In some embodiments, the compound of Formula I is a compound of Formula IIIC: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: m1 is 0, 1, or 2; R QB Yes-N(R N2 )S(O) 2 -(CR h R h ) q2 -R e , where R QB In relation to L 2 meta or para position; R N2 Is H or C 1-3 alkyl; Ring E is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 alkyl.

[0371] In some embodiments of Formula IIIC, R N2 It's H.

[0372] In some embodiments of Formula IIIC, q2 is 0.

[0373] In some embodiments of Formula IIIC, R e It is C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

[0374] In some embodiments of Formula IIIC, R e It is C 1-6 Alkyl. For example, R eCan be C 1-3 Alkyl groups such as methyl or ethyl.

[0375] In some embodiments of Formula IIIC, R QB Yes-N(H)S(O) 2 (C 1-6 For example, R QB Can be -N(H)S(O) 2 (C 1-3 Alkyl), such as -N(H)S(O) 2 Me.

[0376] In some embodiments, the compound of Formula I is a compound of Formula IIID: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: m1 is 0, 1, or 2; R QB yes Among them, ring Q 2 Contains 0-2 additional ring heteroatoms (except NS(O) 2 The heterocyclic group is a 4-8 membered group, wherein the heteroatoms are independently selected from the group consisting of N, O and S(O). 0-2 , where ring Q 2 Optionally 1-4 independently selected R g replace; Ring E is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 alkyl.

[0377] In some embodiments of Formula IIID, R QB yes: m2 is 0, 1, 2 or 3; and R QB Optionally 1-4 independently selected R g replace.

[0378] In some embodiments of Formula IIID, R QB yes:

[0379] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R QB In L 2 The interposition.

[0380] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R QB In L 2 The counterpoint.

[0381] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, m1 is 0.

[0382] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, m1 is 1 or 2.

[0383] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, one occurrence of R QA is a halo. For example, one occurrence of RQA can be -F.

[0384] In some embodiments of Formula IIIA, IIIB, IIIC or HID, Ring E is cyclopropyl.

[0385] In some embodiments of Formula IIIA, IIIB, IIIC or HID, Ring E is cyclobutyl.

[0386] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 8c It's H.

[0387] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 8c It is C 1-3 Alkyl. For example, R 8c It may be methyl.

[0388] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 9 yes: In some embodiments, R 9d It's H.

[0389] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, The parts are:

[0390] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, The parts are: Each stereogenic center has the (S)-configuration.

[0391] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 3- to 12-membered heterocyclic group.

[0392] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 5-6 membered heterocyclic group.

[0393] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring C is optionally substituted by 1-3 independent R Ca Substituted tetrahydropyranyl.

[0394] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring C is selected from:

[0395] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, each R Ca Independently C 1-6 alkyl.

[0396] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 6 ring atoms.

[0397] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 4 , R 5 , R 6 and R 7 Each is H.

[0398] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, L 1 It is C(=O).

[0399] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 1 and R 2 It's H.

[0400] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 3 It is C 1-3 alkyl.

[0401] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 3 It's methyl.

[0402] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, R 1and R 2 is H; and R 3 It is C 1-3 Alkyl (eg, methyl).

[0403] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2-4 substituents each independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0404] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring A is phenyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0405] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring A is: Where R AA , R AB and R AC are independently hydrogen, halo, C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0406] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, Ring A is: Where R AA , R AB and R AC are independently halo or C 1-6 In some embodiments, R AA and R AC Independently C 1-6 Alkyl. For example, R AA and R AC Can be independently selected C 1-3 In some embodiments, R AB is a halo group, such as -F.

[0407] In some embodiments of Formula IIIA, IIIB, IIIC or IIID, L 2 yes:

[0408] In some embodiments, a compound of Formula IV or a pharmaceutically acceptable salt or solvate thereof is provided, comprising any one or more of the features detailed below.

[0409] In some embodiments, Q is selected from: C 3-15Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 independently selected R Q In some embodiments, Q is selected from: 5-10 membered heteroaryl and C 6-10 Aryl, each of which is optionally substituted by 1-6 independently selected R Q In some embodiments, Q is optionally replaced by 1-6 independently selected R Q In some embodiments, Q is optionally substituted by 1-6 independently selected R Q In some embodiments, Q is optionally substituted by 1-6 independently selected R Q In some embodiments, Q is optionally substituted by 1-2 independently selected R Q Substituted 9-membered heteroaryl.

[0410] In some embodiments, Q is Where: Q 1 Is NH or NR Q ;Q 2 and Q 3 are independently N, CH or CR Q ;Q 4 , Q 5 , Q 6 and Q 7 One of them is with L 2 bonded carbon atom; and Q 4 , Q 5 , Q 6 and Q 7 The other three are independently N, CH or CR Q In some embodiments, Q 1 Is NH or NR Q ;Q 2 and Q 3 are independently N, CH or CR Q ; Q 4 , Q 5 , Q 6 and Q 7 One of them is with L 2 bonded carbon atom; and Q 4 , Q 5 , Q 6 and Q 7 The other three are independently CH or CR Q In some embodiments, Q 1 Is NH or NR Q;Q 2 and Q 3 are independently N, CH or CR Q ;Q 4 , Q 5 , Q 6 and Q 7 One of them is with L 2 bonded carbon atom; and Q 4 , Q 5 , Q 6 and Q 7 The other three are independently CH or CR Q .

[0411] In some embodiments, Q 1 is NH. In some embodiments, Q 1 YesNR Q .

[0412] In some embodiments, Q 2 is N and Q 3 is N, CH or CR Q .

[0413] In some embodiments, Q 4 , Q 5 , Q 6 and Q 7 One of them is with L 2 Bonded carbon atom; Q 4 , Q 5 , Q 6 and Q 7 Two 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 ).

[0414] In some embodiments, there is one R Q In some embodiments, there are two R Q In some embodiments, there are three R Q In some embodiments, at least one R Q Attached to the 6-membered ring. In some embodiments, there are two R Q , and these two R Q At least one of is attached to the 6-membered ring.

[0415] In some embodiments, Q is Where: Q 1 Is NH or NR Q;Q 2 and Q 3 are independently N, CH or CR Q ; and n1 is 0 or 1.

[0416] In some embodiments, Q 1 is NH. In some embodiments, Q 1 YesNR Q .

[0417] In some embodiments, Q 2 is N and Q 3 is N, CH or CR Q .

[0418] In some embodiments, there is one R Q In some embodiments, there are two R Q In some embodiments, there are three R Q In some embodiments, at least one R Q Attached to the 6-membered ring. In some embodiments, there are two R Q , and these two R Q At least one of is attached to the 6-membered ring.

[0419] In some embodiments, Q is Where: Q 1 Is NH or NR Q ; and n1 is 0 or 1.

[0420] In some embodiments, Q 1 is NH. In some embodiments, Q 1 YesNR Q .

[0421] In some embodiments, there is one R Q In some embodiments, there are two R Q In some embodiments, there are two R Q , and these two R Q At least one of is attached to the 6-membered ring.

[0422] In some embodiments, Q is Where n1 is 0 or 1.

[0423] In some embodiments, Q is Where n1 is 0 or 1.

[0424] In some embodiments, n1 is 0. In some embodiments, n1 is 1.

[0425] In some embodiments, Q is

[0426] In some embodiments, Q is

[0427] In some embodiments, when at least one R Q (For example, R attached to ring N Q ), an R Q Selected from: (a) halo; (b) cyano; (c) OH; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (i) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (j) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (k) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; (l) optionally 1 to 6 independently selected R g Substituted 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) independently selected from: halo, cyano, OH, C 1-6 Alkyl and C 1-6 Alkoxy.

[0428] In some embodiments, when at least one R Q When an R Q (For example, R attached to ring N Q ) is selected from: (a) halo; (b) cyano; (c) OH; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkyl; and (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; And each remaining R Q When present is independently selected halo.

[0429] In some embodiments, when at least one R Q When an R Q (For example, R attached to ring N Q ) are independently selected C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R f Replace; and each remaining R Q (when present) is an independently selected halo. In some embodiments, when at least one R Q When an R Q (For example, R attached to ring N Q ) are independently selected C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R f Replace; and each remaining R Q (when present) is fluorine. In some embodiments, when at least one R Q When an R Q(For example, R attached to ring N Q ) are independently selected unsubstituted C 1-3 alkyl; and each remaining R Q (when present) is fluorine. In some embodiments, when at least one R Q When an R Q (For example, R attached to ring N Q ) is methyl; and each remaining R Q (when present) is fluorine.

[0430] In some embodiments, there are two R Q , an R Q (For example, R attached to ring N Q ) are independently selected C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R f Replace; and another R Q is halo. In some embodiments, there are two R Q , an R Q (For example, R attached to ring N Q ) are independently selected C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R f Replace; and another R Q is fluorine. In some embodiments, there are two R Q ; an R Q (For example, R attached to ring N Q ) are independently selected unsubstituted C 1-3 alkyl; and another R Q is fluorine. In some embodiments, there are two R Q ; an R Q (For example, R attached to ring N Q ) is methyl; and the other R Q It's fluorine.

[0431] In some embodiments, there is one R Q (For example, R attached to ring N Q ) and are independently selected C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R f In some embodiments, there is one R Q (For example, R attached to ring N Q ) and are independently selected C 1-3 Alkyl, which is optionally substituted by 1-6 independently selected R f In some embodiments, there is one R Q(For example, R attached to ring N Q ) and are independently selected unsubstituted C 1-3 In some embodiments, there is one R Q (For example, R attached to ring N Q ) and is a methyl group.

[0432] In some embodiments, Q is

[0433] In some embodiments, Q is optionally 1-6 independently selected R Q Substituted C 6-10 In some embodiments, Q is optionally substituted by 1-6 independently selected R Q In some embodiments, Q is optionally substituted by 1-2 independently selected R Q In some embodiments, Q is optionally substituted by 1-2 independently selected R Q Substituted phenyl.

[0434] In some embodiments, Q is: where Y 1 , Y 2 , Y 4 and Y 5 are independently N, CH or CR Q In some embodiments, Y 1 , Y 2 , Y 4 and Y 5 Each independently is CH or CR Q In some embodiments, Y 1 , Y 2 , Y 4 and Y 5 One or both of them are independently CH or CR Q ; and the remaining Y 1 , Y 2 , Y 4 and Y 5 It is CH.

[0435] In some embodiments, Q is where m1 is 0, 1, or 2.

[0436] In some embodiments, in L 2 The counterpoint R Q Selected from: (e)-C(=O)NR c R d or -S(O) 2 NR cR 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 .

[0437] In some embodiments, in L 2 The counterpoint R Q Yes-P(=O)R a R b .

[0438] In some embodiments, R a and R b C is independently selected 1-6 Alkyl, which is optionally substituted by 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 In some embodiments, R a and R b C is independently selected 1-6 Alkyl, which is optionally substituted by 1-2 each independently selected from C 1-6 Alkoxy, C 3-6 In some embodiments, R a and R b C is independently selected 1-3 alkyl, which is optionally substituted with 1-2 independently selected halo groups. a and R b is an independently selected unsubstituted C 1-3 In some embodiments, R a and R b Each is ethyl.

[0439] In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2.

[0440] In some embodiments, Q is In some embodiments, in L 2 The meta-R Q Yes - NR c R dIn some embodiments, each R c and R d Independently selected from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 In some embodiments, each R c and R d Independently selected from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 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 substituted by 1-6 groups independently selected from -OH, halo and C 1-6 In some embodiments, each R c and R d Independently selected from H and C 1-3 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 In some embodiments, R c and R d One of them is H, and R c and R d The other one is methyl.

[0441] In some embodiments, Q is

[0442] In some embodiments, R 1 is H. In some embodiments, R 2 is H. In some embodiments, R 3 It is C 1-6 Alkyl. For example, R 3 Can be C 1-3 In some embodiments, R 3 It is C 1-6 Alkyl, and R3 The attached carbon atom has the (S)-configuration.

[0443] In some embodiments, R 1 , R 2 and R 3 It's H.

[0444] In some embodiments, R 1 and R 2 is H; and R 3 It is C 1-6 In some embodiments, R 1 and R 2 is H; and R 3 In some embodiments, R 3 The attached carbon atom has the (S)-configuration.

[0445] In some embodiments, L 2 yes:

[0446] In some embodiments, Ring A is C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-4 substituents independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0447] In some embodiments, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2-4 substituents each independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0448] In some embodiments, Ring A is phenyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0449] In some embodiments, Ring A is: Where R AA , R AB and R AC are independently hydrogen, halo, C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0450] In some embodiments, Ring A is: Where R AA , R AB and R AC are independently halo or C 1-6In some embodiments, R AA and R AC Independently C 1-6 Alkyl (e.g., C 1-3 In some embodiments, R AB is a halo group (eg, -F).

[0451] In some embodiments, Ring A is pyridinyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0452] In some embodiments, L 1 It is C(=O).

[0453] In some embodiments, R 4 , R 5 and R 6 Each is H or halo. In some embodiments, R 4 , R 5 and R 6 Each is H or -F. For example, R 4 , R 5 and R 6 can each be H. As another non-limiting example, R 4 and R 5 can be H; and R 6 Can be -F.

[0454] In some embodiments, L 3 and L 4 In some embodiments, at least one of L is a bond. 3 and L 4 Both are bonds. In some embodiments, L 3 is a key; and L 4 It is C 1-2 In some embodiments, L 4 is a key; and L 3 It is C 1-2 Alkylene.

[0455] In some embodiments, L 3 and L 4 Each independently is C 1-2 Alkylene.

[0456] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 (e.g., 1) independently selected C 1-6 Alkyl substituted C 3-8Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f In some embodiments, L 3 is a key; and L 4 is the key.

[0457] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 (e.g., 1) independently selected C 1-6 Alkyl substituted C 3-5 (For example, C 3 or C 4 ) cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 independently selected R f In some embodiments, L 3 is a key; and L 4 is the key.

[0458] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-2 (e.g., 1) independently selected C 1-6 Alkyl substituted C 3-4 Cycloalkyl ring.

[0459] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form:

[0460] In some embodiments, R 8a and R 8b Together with the carbon atoms to which they are attached, they form:

[0461] In some embodiments, R 9 yes: In some embodiments, R 9d Is H or C 1-6 Alkyl. For example, R 9d It can be H.

[0462] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are:

[0463] In some embodiments, L3 -C(R 8a R 8b )-L 4 -R 9 The parts are:

[0464] In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: In some embodiments, L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: Each stereogenic center has the (S)-configuration.

[0465] In some embodiments, R 9 is (IX-2), where L 3 -C(R 8a R 8b )-L 4 -R 9 The parts are: Where R 9d Is H or C 1-6 Alkyl. For example, R 9d It may be H. In some embodiments, Each stereogenic center of has the (S)-configuration.

[0466] In some embodiments, R 9 It is C(=O)OH.

[0467] In some embodiments, Ring C is optionally substituted with 1-3 independently selected R Ca In some embodiments, ring C is optionally substituted by 1-3 independently selected R Ca In some embodiments, Ring C is optionally substituted by 1-3 independently selected R Ca For example, ring C may be optionally substituted with 1 to 3 independent R Ca Substituted tetrahydropyranyl.

[0468] In some embodiments, Ring C is selected from: In some embodiments, Ring C is In some embodiments, Ring C is

[0469] In some embodiments, R Ca Independently C 1-6 alkyl.

[0470] In some embodiments, a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 6 ring atoms.

[0471] In some embodiments, a pair of R on the same ring atom Ca Together with the respective ring atoms to which they are attached they form a carbocyclic ring containing 3-5 ring atoms.

[0472] In some embodiments, the compound of Formula I is a compound of Formula IVA: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: Q 1 Is NH or NR Q ; Q 2 and Q 3 are independently N, CH or CR Q ; n1 is 0 or 1; Ring E is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R f Substituted C 1-6 alkyl.

[0473] In some embodiments of Formula IVA, Q 1 YesNR Q .

[0474] In some embodiments of Formula IVA, R attached to N Q Selected from: (a) halo; (b) cyano; (c) OH; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkyl; and (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy.

[0475] As a non-limiting example, R attached to N Q It can be unsubstituted C 1-3 alkyl.

[0476] In some embodiments of Formula IVA, Q 2 and Q 3 Each is independently N or CH. As a non-limiting example, Q 2 is N and Q 3 It can be CH.

[0477] In some embodiments of Formula IVA, n1 is 0. In some embodiments of Formula IVA, n1 is 1.

[0478] In some embodiments of Formula IVA, R attached to the 6-membered ring Q Selected from halo, cyano, OH, C 1-6 Alkyl and C 1-6 In some embodiments, R attached to the 6-membered ring Q It is a halo group.

[0479] In some embodiments of Formula IVA, L 2 In Q 1 Attachment of the alignment.

[0480] In some embodiments of Formula IVA, R attached to the 6-membered ring Q Attached to Q 3 The adjacent position.

[0481] In some embodiments, the compound of Formula I is a compound of Formula IVB: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, wherein: m1 is 0, 1, or 2; In L 2 The counterpoint R Q Yes-P(=O)R a R b ; Ring E is C 3-6 cycloalkyl; and R 8c is selected from H and optionally 1-3 independently selected R fSubstituted C 1-6 alkyl.

[0482] In some embodiments of Formula IVB, R a and R b C is independently selected 1-6 Alkyl, which is optionally substituted by 1-2 each independently selected from C 1-6 Alkoxy, C 3-6 In some embodiments, R a and R b is an independently selected unsubstituted C 1-3 alkyl.

[0483] In some embodiments of Formula IVB, m1 is 1 and is not in L 2 The counterpoint R Q In L 2 In some embodiments, in L 2 The meta-R Q Yes - NR c R d .

[0484] In some embodiments of Formula IVB, each R c and R d Independently selected from: H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), wherein the C 1-6 Alkyl and C(=O)(C 1-6 alkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 In some embodiments, R c and R d One of them is H, and R c and R d The other one is methyl.

[0485] In some embodiments of Formula IVA or IVB, Ring E is cyclopropyl.

[0486] In some embodiments of Formula IVA or IVB, Ring E is cyclobutyl.

[0487] In some embodiments of Formula IVA or IVB, R 8c It's H.

[0488] In some embodiments of Formula IVA or IVB, R 8c It is C 1-3 Alkyl. For example, R 8c It may be methyl.

[0489] In some embodiments of Formula IVA or IVB, R 9 yes: In some embodiments, R 9d It's H.

[0490] In some embodiments of Formula IVA or IVB, The parts are:

[0491] In some embodiments of Formula IVA or IVB, The parts are: Each stereogenic center has the (S)-configuration.

[0492] In some embodiments of Formula IVA or IVB, The parts are:

[0493] In some embodiments of Formula IVA or IVB, Part is

[0494] In some embodiments of Formula IVA or IVB, R 9 It is C(=O)OH.

[0495] In some embodiments of Formula IVA or IVB, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 3- to 12-membered heterocyclic group.

[0496] In some embodiments of Formula IVA or IVB, Ring C is optionally substituted with 1-3 independently selected R Ca Substituted 5-6 membered heterocyclic group.

[0497] In some embodiments of Formula IVA or IVB, Ring C is optionally substituted by 1-3 independent R Ca Substituted tetrahydropyranyl.

[0498] In some embodiments of Formula IVA or IVB, Ring C is selected from:

[0499] In some embodiments of Formula IVA or IVB, each R Ca Independently C 1-6 alkyl.

[0500] In some embodiments of Formula IVA or IVB, a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 6 ring atoms.

[0501] In some embodiments of Formula IVA or IVB, R4 , R 5 , R 6 and R 7 Each is H.

[0502] In some embodiments of Formula IVA or IVB, L 1 It is C(=O).

[0503] In some embodiments of Formula IVA or IVB, R 1 and R 2 It's H.

[0504] In some embodiments of Formula IVA or IVB, R 3 It is C 1-3 alkyl.

[0505] In some embodiments of Formula IVA or IVB, R 3 It's methyl.

[0506] In some embodiments of Formula IVA or IVB, R 1 and R 2 is H; and R 3 It is C 1-3 Alkyl (eg, methyl).

[0507] In some embodiments of Formula IVA or IVB, Ring A is phenyl or pyridinyl, each of which is optionally substituted with 2-4 substituents each independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0508] In some embodiments of Formula IVA or IVB, Ring A is phenyl, which is optionally substituted by 2-4 groups each independently selected from halo and C 1-6 The alkyl group is substituted with a substituent.

[0509] In some embodiments of Formula IVA or IVB, Ring A is: Where R AA , R AB and R AC are independently halo or C 1-6 In some embodiments, R AA and R AC Each independently is C 1-6 In some embodiments, R AA and R AC Independently selected from C 1-3 In some embodiments, R AB is a halo group, such as -F.

[0510] In some embodiments of Formula IVA or IVB, L 2 yes:

[0511] In some embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof is provided. Table 1

[0512] The compounds of formula I include pharmaceutically acceptable salts thereof. In addition, the 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 preparing and / or purifying compounds of formula I and / or separating enantiomers of compounds of formula I. Non-limiting examples of pharmaceutically acceptable salts of compounds of formula I include trifluoroacetate.

[0513] It is further understood that the compound of formula I or its salt can be isolated in the form of a solvate, and accordingly, any such solvate is included within the scope of the present disclosure. For example, the compound of formula I and its salt can exist in a non-solvated form as well as a solvated form with a pharmaceutically acceptable solvent (such as water, ethanol, etc.). Treatment methods and uses

[0514] In some embodiments, the disclosure features methods for treating a patient (e.g., a human) having a disease, disorder, or condition, wherein modulation of GLP-1R (e.g., inhibition or attenuation and / or elevation or unwanted 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 can include or further include treating one or more conditions, comorbidities, or sequelae associated with any one or more of the conditions described herein.

[0515] Provided herein are methods for treating a GLP-1-related disease, disorder or condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt, deuterated analog or solvate thereof (e.g., a compound of any one of Formulas II, III or IV, or a pharmaceutically acceptable salt, deuterated analog or solvate thereof) or a pharmaceutical composition.

[0516] In some embodiments, 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), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain with other medications, idiopathic intracranial hypertension, Wolfram's syndrome, gout, sugar cravings, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, vascular compliance restriction. damage, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract , glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0517] In some embodiments, the diseases, disorders, or conditions include, but are not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain caused by the use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes in the proximal tubules), adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic Cardiovascular disease, hyperglycemia, postprandial lipidosis, 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, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0518] In some embodiments, the diseases, disorders, or conditions include but are not limited to type 2 diabetes, early onset type 2 diabetes, obesity, idiopathic intracranial hypertension, Wolfram's syndrome, weight gain due to use of other medications, gout, excessive sugar cravings, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipidosis, 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.

[0519] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein induce one or more of the following: reduced blood glucose levels (e.g., reduced blood glucose levels), reduced blood hemoglobin A1c (HbA1c) levels, promotion of insulin synthesis, stimulation of insulin secretion, increase in beta cell mass, regulation of gastric acid secretion, regulation of gastric emptying, reduction in body mass index (BMI), and / or reduction in glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein may reduce blood glucose levels, reduce blood hemoglobin A1c (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase in beta cell mass, regulate gastric acid secretion, regulate gastric emptying, reduce body mass index (BMI), reduce glucagon production (e.g., levels), or any combination thereof. In certain embodiments, the compounds and pharmaceutical compositions and methods for treating patients described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein are methods for regulating glucose or insulin levels in a patient in need of such regulation, comprising administering to the patient an effective amount of a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) or a pharmaceutical composition.

[0520] In some embodiments, provided herein is a method for reducing the risk of major adverse cardiovascular events (MACE) in patients in need thereof (e.g., reducing by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80%), the method comprising administering to the patient an effective amount of a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof (e.g., a compound of any one of Formula II, III or IV, or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof) or a pharmaceutical composition. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult diagnosed with heart disease. In certain embodiments, the patient is an adult diagnosed with type 2 diabetes (T2D) and heart disease. In certain embodiments, the patient is an adult suffering from type 2 diabetes (T2D). In certain embodiments, the patient is an adult suffering from heart disease. In certain embodiments, the patient suffers from type 2 diabetes (T2D) and heart disease. Indications Obesity

[0521] In some embodiments, the condition, disease or disorder is obesity and the condition, disease or disorder related to obesity or relevant. The 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). The non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome (Cushingsyndrome), hypothyroidism, insulinoma, obesity type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome (Prader-Willisyndrome), Laurence-Moon-Biedl syndrome (Laurence-Moon-Biedl syndrome)) and drug-induced obesity (e.g., steroids, phenothiazines, insulin, sulfonylurea agents or beta-blocker-induced obesity).

[0522] In some embodiments, the disease, disease or disorder is related to obesity. Examples of such diseases, diseases or disorders include, but are not limited to, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic fatty liver disease (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient cerebral ischemic attack), bone or joint disease (e.g., knee osteoarthritis, hip osteoarthritis, deformed spondylitis, low back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick syndrome (Pickwickian syndrome)), menstrual disorders (e.g., abnormal menstrual cycle, abnormal menstrual volume and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, urinary incontinence and metabolic syndrome. In some embodiments, chemical compounds and pharmaceutical compositions described herein can be used to treat patients showing two symptoms of obesity and insulin deficiency. diabetes

[0523] In some embodiments, the condition, disease or disorder is diabetes. The non-limiting example of diabetes includes type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very late type 2 diabetes, type 2 diabetes treated with long-term insulin), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obesity diabetes, autoimmune diabetes and borderline diabetes. In some embodiments, the condition, disease or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylurea, very late type 2 diabetes, type 2 diabetes treated with long-term insulin).

[0524] Provided herein are methods for treating diabetes in a patient, the methods comprising (a) determining that the patient has type 2 diabetes, and (b) administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of Formula II, III, or IV or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) or a pharmaceutical composition as disclosed herein.

[0525] Provided herein are methods for treating type 2 diabetes in a patient, comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) or a pharmaceutical composition.

[0526] Also provided herein is a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I as disclosed herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) or a pharmaceutical composition.

[0527] In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce HbA1c levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating patients with conditions, diseases or disorders described herein (e.g., type 2 diabetes) reduce BMI.

[0528] In some embodiments, a decrease in fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in fasting plasma glucose levels to about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment of type 2 diabetes.

[0529] In some embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a reduction in non-fasting plasma glucose levels to about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment of type 2 diabetes.

[0530] In some embodiments, a decrease in HbA1c levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in HbA1c levels to about or below 6.5%, about or below 6.0%, or about or below 5.0% indicates treatment of type 2 diabetes.

[0531] In some embodiments, a decrease in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes.

[0532] In some embodiments, a decrease in BMI of about 5% to about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 15% to about 80% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 25% to about 60% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes. In some embodiments, a decrease in BMI to about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes.

[0533] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmotic 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, slow wound healing, diabetic dyslipidemia, peripheral blood circulation disorders, cardiovascular risk factors. (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension and risk factors related to unmanaged cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive dysfunction.

[0534] Other non-limiting examples of disorders associated with diabetes include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic disorders in which activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0535] In some embodiments, the condition, disease or disorder is diabetes and obesity (diabetobias). In some embodiments, the compounds described herein may also be used to improve the therapeutic effectiveness of metformin. Disorders of metabolically important tissues

[0536] In some embodiments, the condition, disease or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include liver, fat, pancreas, kidney, and intestine.

[0537] In some embodiments, the condition, disease or disorder is fatty liver disease. Fatty liver disease includes, but is not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, hyperlipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipid malnutrition.

[0538] Non-alcoholic fatty liver disease (NAFLD) refers to a series of diseases that occur in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). It is believed that NAFLD is associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It may 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, mainly macrovesicular steatosis (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl: S186-90).

[0539] In some embodiments, the patient is a pediatric patient. As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into different subgroups, including: newborns (from birth to the first month of life); infants (1 month to two years old); children (two years old to 12 years old); and adolescents (12 to 21 years old (until but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Edition Philadelphia: WB Saunders 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 embodiments, a pediatric patient is from birth to the first 28 days of life, 29 days to less than two years of age, two years to less than 12 years of age, or 12 years to 21 years of age (up to but not including the 22nd birthday). In some embodiments, a pediatric patient is from birth to the first 28 days of life, 29 days to less than 1 year of age, one month to less than four months of age, three months to less than seven months of age, six months to less than 1 year of age, 1 year to less than 2 years of age, 2 years to less than 3 years of age, 2 years to less than seven years of age, 3 years to less than 5 years of age, 5 years to less than 10 years of age, 6 years to less than 13 years of age, 10 years to less than 15 years of age, or 15 years to less than 22 years of age. In some embodiments, the patient is an adult patient.

[0540] Other non-limiting examples of disorders of metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g., in the liver); fibrosis (e.g., in the liver); cirrhosis (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; skeletal disorders characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease ( disease, osteolytic metastasis in cancer patients, osteodystrophy in liver disease, and bone metabolism changes caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection of fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, weakness, sexual dysfunction (e.g., erectile dysfunction) and geriatric syndrome. 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 the decomposition reaction caused by surgical trauma. Cardiovascular and vascular disease

[0541] In some embodiments, the condition, disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart 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 prothrombotic states (exemplified by high fibrinogen or plasminogen activator inhibitors in the blood).

[0542] In some embodiments, the condition, disease or disorder is associated with a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy. Neurological disorders

[0543] In some embodiments, the condition, disease, or disorder is a neurological disorder (eg, a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of nervous system disorders include idiopathic intracranial hypertension (IIH), brain 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 chorea, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurotrauma, brain trauma, vascular amyloidosis, intracerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute disorganization disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, e.g., US20060275288 A1.

[0544] In some embodiments, the condition, disease or disorder is idiopathic intracranial hypertension. Idiopathic intracranial hypertension is characterized by increased intracranial pressure and papilledema. See, for example, Virdee et al. Ophthalmol Ther. 2020; 9(4): 767-781. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce cerebrospinal fluid secretion in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce intracranial pressure in patients with idiopathic intracranial hypertension. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms of patients with idiopathic intracranial hypertension. Symptoms of idiopathic intracranial hypertension can include severe headaches and visual impairment. In some embodiments, the patient with idiopathic intracranial hypertension is a female. In some embodiments, the patient with idiopathic intracranial hypertension is about 20 to about 30 years old. In some embodiments, the patient with idiopathic intracranial hypertension is obese.

[0545] In some embodiments, the condition, disease or disorder is Wolfram syndrome. Wolfram syndrome is caused by biallelic mutations in the Wolframin ER transmembrane glycoprotein (Wfs1) gene. See, for example, Seppa et al. Sci Rep 9, 15742 (2019). Wolfram syndrome may first appear as diabetes, followed by symptoms of optic atrophy, deafness, and neurodegeneration. Patients with Wolfram syndrome may have symptoms of ataxia, sleep apnea, dysphagia, hearing loss, and taste loss due to brainstem atrophy. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce neuroinflammation in patients with Wolfram syndrome. In some embodiments, neuroinflammation in the inferior olive nucleus of the patient is reduced. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce retinal ganglion cell death in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce axonal degeneration in patients with Wolfram syndrome. In some embodiments, the compounds and pharmaceutical compositions and methods described herein reduce one or more symptoms (eg, any of the symptoms described herein) in a patient suffering from Wolfram's syndrome.

[0546] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to improve behavioral responses to addictive drugs, reduce drug dependence, prevent relapse to drug abuse, and relieve anxiety caused by the absence of a given addictive substance. See, e.g., US20120021979 A1.

[0547] 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 protect dopamine neurons and motor function in Parkinson's disease. Insulin related

[0548] In some embodiments, 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, hypoglycemic conditions, insulin resistance syndrome, paresthesias 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 concomitant insulin-related coma endpoints.

[0549] 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. Autoimmune disorders

[0550] In some embodiments, 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, US20120148586A1. Stomach and intestinal disorders

[0551] In some embodiments, the condition, disease, or disorder is a gastric or intestinal related disorder. Non-limiting examples of such disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infections or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy- and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal 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). weight

[0552] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to make patients (e.g., patients in need) lose weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat or reduce food intake. In some embodiments, the patient's weight gain can be attributed to excessive food intake or an unbalanced diet, or can be weight gain from concomitant drugs (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.). In some embodiments, weight gain can be weight gain before reaching obesity, or it can be weight gain in obese patients. In some embodiments, weight gain can also be drug-induced weight gain or weight gain following cessation of smoking.

[0553] In some embodiments, weight gain is induced by the use of steroids or antipsychotics.

[0554] In some embodiments, the condition, disease, or disorder is an eating disorder, such as overeating, binge eating, bulimia, compulsive eating, or syndromic obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome. Inflammatory diseases

[0555] In some embodiments, the condition, disease or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, deforming spondylitis, deforming arthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colorectal disease), inflammation in metabolically important tissues (including liver, fat, pancreas, kidney and intestine), and pro-inflammatory states (e.g., elevated levels of pro-inflammatory cytokines or markers of inflammatory-like C-reactive protein in the blood). cancer

[0556] In some embodiments, the condition, disease or disorder 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), rectal cancer (e.g., gastric cancer), intestinal stromal tumors), colorectal cancer (eg, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (eg, non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (eg, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (eg, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), neurothecoma, liver cancer (eg, e.g., primary liver cancer, extrahepatic bile duct cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low malignant potential ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (eye) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer Cancers of the ovary (eg, ovarian, ovarian, and maxillary) include: ovarian, parathyroid, nasal, sinus, bone, (eg, osteosarcoma, Ewing's, uterine, and soft tissue sarcomas), angiofibroma, retinosarcoma, penile, testicular, solid tumors of childhood (eg, Wilms' tumor, childhood renal tumors), Kaposi's sarcoma, Kaposi's sarcoma due to AIDS, maxillary sinus, fibrohistiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (eg, acute myeloid, acute lymphoblastic). Hypothalamic-pituitary disorders

[0557] In some embodiments, the condition, disease or disorder is associated with the hypothalamus-pituitary-gonadal axis. For example, the condition, disease or disorder is associated with the hypothalamus-pituitary-ovarian axis. In another example, the condition, disease or disorder is associated with the hypothalamus-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis diseases include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0558] In some embodiments, the condition, disease, or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis. pulmonary disease

[0559] In some embodiments, the condition, disease or disorder is associated with a pulmonary disease. Pulmonary 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).

[0560] In some embodiments, the condition, disease, or disorder associated with diabetes is a pulmonary disease. Combination therapy

[0561] In some embodiments, the present disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[0562] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0563] In some embodiments, the methods described herein include administering a compound described herein in combination with one or more of the following: dietary therapy (e.g., dietary monitoring, dietary therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., ) and dietary changes.

[0564] In some embodiments, a compound of X as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, may be administered in combination with one or more additional therapeutic agents.

[0565] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, diabetes therapeutics, diabetic complications therapeutics, hyperlipidemia therapeutics, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapeutics, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis therapeutics, vitamins, anti-dementia drugs, erectile dysfunction drugs, urinary frequency or incontinence therapeutics, NAFLD therapeutics, NASH therapeutics, dysuria therapeutics, and antiemetics.

[0566] 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, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., velneperit), peptide YY or its analogs, cannabinoid receptor antagonists (e.g., rimonabant), serotonin 6 receptor antagonists (e.g., serotonin 6 receptor antagonists), ... serotonin 6 receptor antagonists (e.g., serotonin 6 receptor antagonists), serotonin 6 receptor antagonists (e.g., serotonin 6 receptor antagonists), serotonin 6 receptor antagonists (e.g., serotonin 6 receptor antagonists), serotonin 6 receptor antagonists (e.g., serotonin 6 receptor antagonists), serotonin 6 receptor antagonists (e.g abant), taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylase inhibitors, opioid receptor antagonists (e.g., GSK-1521498, naltrexone), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors (e.g., described in WO 2020 / 234726, WO 2020 / 044266, and U.S. Pat. No. 8,859,577), stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g.,JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozine tabonate, remogliflozin etabonate or ertugliflozin), SGLT-1 inhibitors, MCR-4 agonists, monoamine reuptake inhibitors, melanocyte-stimulating hormone analogs, 5HT2c agonists, galanin antagonists, anorectic agents (such as bombesin agonists), thyromimetic agents, dehydroepiandrosterone or its analogs, human agouti-related protein (AGRP) inhibitors, neuromedin U agonists, NFK inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, D RF-11605, gemfibrozil, fenofibrate, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-21 9994), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin), GPR119 agonists (e.g., compounds described in PSN-821, MBX-2982, APD597, WO 2010 / 140092, WO 2010 / 128425, WO 2010 / 128414, WO 2010 / 106457), glucokinase activators (e.g.,piragliatin, AZD-1656, AZD6370, TTP-355, TTP-399, TTP547, ARRY403, MK-0599, TAK-329, AZD5658 or described in WO 2010 / 103437, WO 2010 / 103438, WO 2010 / 013161, WO 2007 / 122482, WO 2006 / 112549, WO 2007 / 028135, WO 2008 / 047821, WO 2008 / 050821, WO 2008 / 136428 and WO 2008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance-modifying drugs, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxytocin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; using Escherichia coli (Escherichia coli) or yeast gene synthesis of human FGF21 preparations; fragments or derivatives of FGF21), anorectics (e.g., P-57), human proinsulin peptide (HIP), melanocortin receptor 4 agonists (e.g., setmelanotide), melanin concentrating hormone receptor 1 antagonists, serotonergic agents (e.g., sibutramine, lorcaserin), farnesoid X receptor (FXR) agonists (e.g., obeticholic acid, tropifexor, cilofexor, LY2562175, Met409, TERN-101, EDP305, described in WO 2020 / 234726 and WO 2020 / 044266), phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, biotin, MAS receptor modulators, glucagon receptor agonists, CCKa agonists (e.g., compounds described in WO 2005 / 116034 and U.S. Publication No. 2005 / 0287100), and AMP-activated protein kinase (AMPK) activators. ,

[0567] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, as 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 E. 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 a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., described in, for example, WO any glucagon analogue described in 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, glimepiride, tolbutamide, glyburide, gliclazide, acetohexamide, glyburide, glybuzole, glyburide, glipizide), thiazolidinedione agents (e.g., rosiglitazone, lobeglitazone, troglitazone, basiglitazone, rivoglitazone, lobeglitazone, or pioglitazone), glitazar (e.g., aleglitazar, chiglitazar, saroglitazar, muraglitazar, tesaglitazar), SGLT2 inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, THR1474, TS-071, ISIS388626, LX4211, repagliflozin, empagliflozin, canagliflozin, ipragliflozin, topagliflozin, sergliflozin edocarbonate, repagliflozin edocarbonate, erpagliflozin, described in WO 2010 / 023594), GPR40 agonists (e.g., FFAR1 / FFA1 agonists, e.g., fasiglifam), alpha glucosidase inhibitors (e.g., adiposin, camiglibose, pradimicin-Q, salbostatin, voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as prandial glucose regulators (sometimes referred to as "short-acting secretagogues"), e.g., meglitinides (e.g.,nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, abiglutide, tasiglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, Gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, anagliptin (SK-0403), teneligliptin, omarigliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0568] In some embodiments, the one or more additional therapeutic agents include those useful, for example, in the treatment of NAFL and NASH. Non-limiting examples include FXR agonists (e.g., obeticholic acid), PF-05221304, PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid-bile conjugates (e.g., aramchol), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), caspase inhibitors (e.g., emricasan), MAPK5 inhibitors (e.g., GS-4997), galectin 3 inhibitors (e.g., GR-MD-02), fibroblast growth factor 21 (FGF21) (e.g., BMS-986036), niacin analogs (e.g., ARJ 3037MO), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976 and compounds described in WO 2009 / 144554, WO 2003 / 072197, WO 2009 / 144555 and WO 2008 / 065508), ketohexose kinase (KHK) inhibitors (compounds described in WO 2020 / 234726), apoptosis signal regulating kinase 1 (ASK1) inhibitors, ileal bile acid transporter (IBAT) inhibitors, dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), diacylglycerol acyltransferase 2 (DGAT2) inhibitors (e.g., compounds described in WO 2020 / 234726), 2020 / 234726 and compounds in U.S. Publication No. 20180051012), CB1 receptor antagonists, anti-CB1R antibodies, glycyrrhizin, schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinedione (e.g., troglitazone, rosiglitazone, pioglitazone, balaglitazone, rivoglitazone, lobeglitazone), metformin, cysteamine, sulfonylurea, alpha glucosidase inhibitors, meglitinide, vitamin E, tetrahydrolipstatin, milk thistle protein, antiviral agents and antioxidants.

[0569] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, to treat diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their increasers (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), PKC inhibitors (e.g., ruboxistaurin 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-regulating kinase-1 (ASK-1) inhibitors.

[0570] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents useful, for example, for the treatment of hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 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-benzoxazepin-3-yl]ethyl

[0013] acyl] piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), plant sterols (e.g., soysterols, gamma oryzanol, γ-oryzanol), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and omega-3 fatty acid preparations (e.g., omega-3-fatty acid ethyl ester 90).

[0571] In some embodiments, the one or more additional therapeutic agents include those therapeutic agents that can be used, for example, as antihypertensive agents. Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, zofenopril, fbsinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium), (e.g., potassium), eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).Other non-limiting examples of antihypertensive agents include diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, m-ethylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, acid, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamterene, amiloride, spironolactone), alpha-adrenergic blockers, beta-adrenergic blockers, calcium channel blockers (e.g., diltiazem ), verapamil, nifedipine and amlodipine), vasodilators (e.g., hydralazine), renin inhibitors, AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), dual ET / AII antagonists (e.g., compounds disclosed in WO 2000 / 01389), neutral endopeptidase (NEP) inhibitors, If channel blocker ivabradin, and vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates).

[0572] 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., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichlorothiazide, hydrochlorothiazide, hydrofluthiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).

[0573] 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 immunoenhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering methods (e.g., interferons, interleukins (IL), such as IL-1, IL-2, IL-12), and colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin).

[0574] In some embodiments, the one or more additional therapeutic agents include those that can be used as, for example, anti-embolic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., argatroban, dabigatran, boroarginine derivatives, boropeptides, heparin, hirudin, and melagatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, described in WO02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO 2005 / 058823, and WO 2005 / 113504), thrombolytics (e.g., anistreplase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase, factor VIla inhibitors, PAI-1 inhibitors, α2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, eicosapentaenoic acid ethyl, beraprost sodium, and sarpogrelate hydrochloride).

[0575] 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 risedronate disodium. Suitable examples of vitamins include vitamin B1 and vitamin B12. Suitable examples of erectile dysfunction drugs include apomorphine and sildenafil citrate. Suitable examples of agents for treating frequent urination or urinary incontinence include flavorxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Suitable examples of agents for treating dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

[0576] Other exemplary additional therapeutic agents include agents that regulate hepatic glucose homeostasis (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat complications of chronic hyperglycemia such as aldose reductase inhibitors (e.g., epalrestat and ranirestat), agents used to treat complications associated with microangiopathy, anti-dyslipidemic agents such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin, pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, itavastatin, ZD-4522), HMG-CoA synthase inhibitors, cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine, questran, colestipol and colesevelam), cholesterol absorption inhibitors (e.g., plant sterols, sterols, such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), diacylglycerol acyltransferase 1 (DGAT1) inhibitors (e.g., AZD7687, LCQ908, compounds described in WO 2009 / 016462, WO 2010 / 086820), monoacylglycerol O-acyltransferase inhibitors, α-amylase inhibitors (e.g., amylase inhibitors, tadalafil, AL-3688), α-glucosidase hydrolase inhibitors, SIRT-1 activators, c-Jun N-terminal kinase (JNK) inhibitors, VPAC2 receptor agonists, TGR5 receptor modulators (e.g., compounds described in), GPBAR1 receptor modulators, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, carnitine palmitoyltransferase inhibitors, mineralocorticoid receptor inhibitors, inhibitors of TORC2, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators , GPR105 modulators, Kv1.3 modulators, retinol binding protein 4 modulators, somatostatin receptor modulators, PDHK2 modulators, PDHK4 modulators, MAP4K4 inhibitors, IL1 family modulators (e.g., ILIβ modulators), ACAT inhibitors, MTP inhibitors (e.g., diriotapide, mitratapide and implitapide), lipoxygenase inhibitors, PCSK9 modulators (e.g.,alizumab and eloumab), RXRα modulators, cysteamine, cystamine, RNA antisense constructs that inhibit protein tyrosine phosphatase PTPRU, vitamin B complex, penetratin protein, protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., trodusquemine, hyrtiosal extract, and compounds described in Zhang et al. Drug Discovery Today. 2007, 12(9-10):373-381), ezetimibe, betaine, pentoxifylline, αδ-9 desaturase, BCKDK inhibitors, branched-chain α-ketoacid dehydrogenase kinase (BCBK) inhibitors, PNPLA3 inhibitors, FGF19 analogs, SCD1 inhibitors, bile acid binding resins, nicotinic acid ( acid (niacin) and its analogs, 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 blockers (e.g., labetalol)), adrenergic receptor agonists (including alpha-2 agonists (e.g., clonidine)), angiotensin converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers (such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzthiazepines (e.g., phenoxyethanol). For example, diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., eplerenone, spironolactone), centrally acting adrenergic drugs (such as central alpha agonists (e.g., clonidine)), diuretics (e.g., furosemide, torsemide, bumetanide, ethuronic acid), thiazide-type diuretics (e.g., chlorothiazide, hydrochlorothiazide, benzthiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, polythiazide, trichloromethiazide, indapamide), benzopyrrolone-type diuretics (e.g., chlorthalidone, metolazone), quinazoline-type diuretics (e.g., quinethazolone), potassium-sparing diuretics (e.g., triamterene and amiloride), thyroid receptor agonists (e.g., described in WO 2020 / 117987), hemostatic modulators (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), nonsteroidal anti-inflammatory drugs (NSAIDS), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE inhibitors (e.g., cilostazol (Pletal), dipyridamole), purinergic receptor antagonists (e.g., P2Y1 and P2Y12), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban, eptifibatide, and abciximab), (abcixima)), adenosine reuptake inhibitors (e.g., dipyridamole), noradrenergic agents (e.g., phentermine), serotonergic agents (e.g., sibutramine, lorcaserin), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modulators, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission modulators (such as selective serotonin reuptake inhibitors (SSRI) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARI), norepinephrine-serotonin reuptake inhibitors (SNRI) and monoamine oxidase inhibitors (MAOI) (e.g., toloxatone and amifampicin)), described in WO 2007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, 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 2008 / 001931), SGLT1 inhibitors, adiponectin or its agonist, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia improving agents (such as cyclooxygenase inhibitors (e.g., indomethacin)), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, agents for improving fat metabolism (e.g.,eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6 and oncostatin M, metabolic modifying proteins or peptides (such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3)), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE 5 inhibitors, glycation inhibitors (e.g., ALT-711), drugs that promote nerve regeneration (e.g., Y-128, VX853, neurotrophic peptides), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., K, +channel openers, mexiletine, propafenone, metoprolol, atenolol, carvedilol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, ditiazem, and verapamil), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), alpha2 receptor agonists (e.g., , clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepines), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depleting therapies (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies), drugs that affect T cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri), drugs that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), ), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolate), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, siglitazar, saroglitazar, moglitazar, tesaglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, eicosapentaenoic acid ethyl, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0577] In some embodiments, the one or more additional therapeutic agents include therapeutic agents that can be used, for example, for antiemetics. As used herein, an "antiemetic" agent refers to any agent that resists (e.g., reduces or eliminates) nausea or vomiting (vomiting). It should be understood that when referring to the therapeutically effective amount of an antiemetic, the amount administered is the amount required to offset (e.g., reduce or eliminate) nausea or vomiting (vomiting). Without wishing to be bound by theory, it is believed that the administration of one or more antiemetics in combination with a compound of formula (I) described herein can allow the administration of a higher dose of a compound of formula (I), for example, because the patient may be able to take in food normally and therefore respond faster to treatment.

[0578] Non-limiting examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (neurokinin substance 1P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[0579] For example, the antiemetic may be selected from neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0580] 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, bemisetron, zatisetron, batapride, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]one-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL72222, tropane-3,5-dimethylbenzoic acid, 3-(4-allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleic acid, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netupitant), quetiapine, qamosetron, ramosteron, licarsetron, risperidone, ziprasidone and zatosetron.

[0581] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemisetron, zatisetron, batanopride, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, tropane-3,5-dimethylbenzoate, 3-(4-allyl-piperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazapine.

[0582] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron, hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemisetron, and zatosetron.

[0583] In certain embodiments, the 5HT-3 receptor antagonist is granisetron, dolasetron, and ondansetron.

[0584] In certain embodiments, the 5HT-3 receptor antagonist is granisetron.

[0585] In certain embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0586] In some embodiments, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0587] In some embodiments, the antiemetic is an anticholinergic agent (an acetylcholine receptor inhibitor). Non-limiting examples of anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, trihexy-5 (benzhexol hydrochloride), benztropine (benztropine mesylate), anketan (biperiden hydrochloride), disipal (orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and carmatelin (procyclidine hydrochloride).

[0588] In some embodiments, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, and trimethobenzamide (Tigan).

[0589] In some embodiments, the antiemetic is a NK1 receptor antagonist (eg, a neurokinin substance 1P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include: aprepitant, casopitant, elopitant, fosaprepitant, maropitant, netupitant, lolapitant, and viltepitant.

[0590] 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 (bensulfonopitant ammonium / chloride), LY 303870 (Lanepitant), 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 k. TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazaoctano[2,1-g][1,7]naphthyridine-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.

[0591] 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., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metoprazine); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimeramide, and amisulpride.

[0592] In some embodiments, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabidiol (THC), a cannabinoid agonist such as WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol and Nabilone (Cesamet).

[0593] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / antipsychotics (e.g., dexrazine, haloperidol, and prochlorperazine); ); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphoric acid; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0594] In some embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contact with or administration of the compounds and pharmaceutical compositions (e.g., about an hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 month before).

[0595] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about the same time as the contact or administration of the compound and pharmaceutical composition. For example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient simultaneously in the same dosage form. For another example, the additional therapeutic agent or regimen and the compound and pharmaceutical composition are provided to the patient in separate dosage forms in parallel. Pharmaceutical compositions and modes of administration

[0596] When used as a drug, the compound of Formula I (including its pharmaceutically acceptable salt or solvate) can be applied in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field, and can be applied by various routes, depending on whether local treatment or systemic treatment and the area to be treated are desired. Application can be topical (including transdermal, epidermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or blowing into powder or aerosol, including by a nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once a day or twice a day (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0597] Also provided herein is a pharmaceutical composition, the pharmaceutical composition containing a combination of a compound of Formula I or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof as an active ingredient and one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using a compound of Formula I or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof. In some embodiments, the composition is suitable for topical administration. In the manufacture of the composition provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient or encapsulated in such a carrier, the carrier being in the form of, for example, a capsule, a sachet (sachet), paper or other container. When an excipient is used as a diluent, it can be a solid, semisolid or liquid material, and the material serves as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, 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 a tablet or capsule.

[0598] Further provided herein is a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof as an active ingredient can be prepared by uniformly mixing the compound of formula I or a pharmaceutically acceptable salt thereof, a deuterated analog or a solvate thereof with a drug carrier according to conventional drug 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.

[0599] 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.

[0600] Methods of formulating 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.

[0601] In some embodiments, the compound or pharmaceutical composition can 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-tocopheryl 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; buffer substances, such as phosphate, tris, glycine, sorbic acid, potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; 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 hydroxyalkylcyclodextrin (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of compounds described herein. A dosage form or composition containing a chemical entity as described herein in the range of 0.005% to 100% and the remainder being supplemented by a non-toxic excipient can be prepared. The composition under consideration can contain 0.001%-100% of the chemical entity provided herein, in one embodiment 0.1%-95%, in another embodiment 75%-85%, in another embodiment 20%-80%. The actual method of preparing such dosage forms is known or will be clear to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0602] In some embodiments, the compounds and pharmaceutical compositions described herein or their pharmaceutical compositions can be administered to patients in need by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intranasal, intratracheal, intestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, transdermal, transdural, rectal, respiratory system (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, permeable trachea, ureter, urethra and vagina. In some embodiments, the route of administration is oral or parenteral (eg, intratumoral).

[0603] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition thereof, may be formulated for parenteral administration, for example, for injection via an intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal route. For example, such compositions may be prepared as injectables, as liquid solutions or suspensions; solid forms suitable for preparing solutions or suspensions after adding liquids prior to injection may also be prepared; and the formulations may also be emulsified. In view of the present disclosure, the preparation of such formulations will be known to those skilled in the art. In some embodiments, a device is used for parenteral administration. For example, such devices may include needle syringes, microneedle syringes, needle-free syringes, and infusion techniques.

[0604] In some embodiments, pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it can be easily injected. In some embodiments, the form should be stable under manufacturing and storage conditions and must be preserved against the contaminating effects of microorganisms such as bacteria and fungi.

[0605] In some embodiments, carrier can also be solvent or dispersion medium, and described solvent or dispersion medium contain water, ethanol, polyol (for example, glycerine, propylene glycol and liquid polyethylene glycol etc.), its suitable mixture and vegetable oil.In some embodiments, for example, by using coating (such as lecithin), by maintaining required particle size in the case of dispersion, and by using surfactant, suitable fluidity can be maintained.In some embodiments, the effect of preventing microorganism can be reached by various antibacterial and antifungal agents (for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal etc.).In some embodiments, include isotonic agent, for example sugar or sodium chloride.In some embodiments, by using the medicament (for example, aluminum monostearate and gelatin) of delayed absorption in composition, the absorption of injectable composition can be prolonged.

[0606] In some embodiments, sterile injectable solutions are prepared in the following manner: the desired amount of compound of formula I or its pharmaceutically acceptable salt, deuterated analog or solvate (e.g., compound of any one of formula II, III or IV or its pharmaceutically acceptable salt, deuterated analog or solvate) is incorporated into an appropriate solvent with various other ingredients listed above, followed by filtration sterilization. In some embodiments, dispersions are prepared in the following manner: various sterile active ingredients are incorporated into sterile vehicles, and the vehicle contains basic dispersion medium and other ingredients required from those ingredients listed above. In some embodiments, sterile powders are used to prepare sterile injectable solutions. In some embodiments, the preparation method is vacuum drying and freeze drying technology, which produces active ingredients plus any additional desired ingredients from its previously sterile filtered solution.

[0607] In some embodiments, pharmacologically acceptable excipients that can 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: cocoa butter glycerides, synthetic polymers such as polyvinyl pyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaoxybenzoate, sodium propylparaoxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, polyethylene glycol cetearyl ether, cocoyl capryloyl caprate, caprylocaprate), isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0608] In some embodiments, suppositories can be prepared by mixing a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition as described herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, a suppository wax, and 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, compositions for rectal administration are in the form of enemas.

[0609] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition thereof, can be formulated for local delivery to the digestive or gastrointestinal (GI) tract via oral administration (e.g., solid or liquid dosage form).

[0610] 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, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate and / or the following: a) a filler or extender such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) a binder such as, for example, carboxymethyl cellulose, alginate, gelatin, , polyvinyl pyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retardants such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) 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 include a buffer. In some embodiments, similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0611] In some embodiments, the pharmaceutical composition will take the form of a unit dosage form such as a pill or tablet, and thus, the composition may contain a diluent such as lactose, sucrose, dicalcium phosphate, etc., lubricants such as magnesium stearate, etc., and binders such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc., together with a compound of Formula I as provided herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof); In some embodiments, a powder, a spherical granulation (marume), a solution, or a suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) as another solid dosage form is encapsulated in a capsule (gelatin or cellulose matrix capsule). In some embodiments, also contemplated are physically separated unit dosage forms of one or more compounds as provided herein and pharmaceutical compositions or additional active agents; for example, capsules (or tablets in capsules) with granules of each drug; two-layer tablets; two-chamber gel caps, etc. In some embodiments, enteric-coated or delayed-release oral dosage forms are also contemplated.

[0612] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants or preservatives that are particularly useful for preventing the growth or activity of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[0613] In some embodiments, excipients are sterile and generally do not contain undesirable substances. For example, these compositions can be sterilized by conventional well-known sterilization techniques. In some embodiments, for various oral dosage form excipients, such as tablets and capsules, sterilization is not required. For example, United States Pharmacopeia / National Formulary (United States Pharmacopeia / National Formulary, USP / NF) standards can be sufficient.

[0614] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), or a pharmaceutical composition thereof, is formulated for ocular administration. In some embodiments, an ocular composition may include, but is not limited to, any one or more of the following: viscogen (e.g., carboxymethylcellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorine complex; Allergan, Inc.)).

[0615] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) or a pharmaceutical composition thereof may be formulated for topical application to the skin or mucosa (e.g., percutaneous or transdermal). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are semisolid preparations typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semisolid emulsions, often oil-in-water or water-in-oil. For example, cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. For example, an oil phase, sometimes also referred to as an "internal" phase, generally includes paraffin fats and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not required, the volume of the aqueous phase generally exceeds the oil phase, and generally contains a moisturizer. In some embodiments, the emulsifier in the cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. In some embodiments, like other carriers or vehicles, the ointment base should be inert, stable, nonirritating and nonsensitizing.

[0616] In any of the foregoing embodiments, the pharmaceutical composition as described herein may comprise one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly (D, L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-loaded lipid bilayers.

[0617] In some embodiments, the dosage of a compound of Formula I or a pharmaceutically acceptable salt thereof, a deuterated analog, or a solvate thereof (e.g., a compound of any one of Formulas II, III, or IV or a pharmaceutically acceptable salt thereof, a deuterated analog, or a solvate thereof) is determined based on a variety of factors, including, but not limited to, the type, age, weight, sex, medical condition of the patient; the severity of the patient's medical condition; route of administration; and the activity of the compound or its pharmaceutically acceptable salt, deuterated analog, or solvate thereof. In some embodiments, the appropriate dosage for a particular situation can be determined by a medical technician. In some embodiments, the total daily dose can be divided into multiple portions and administered in multiple portions throughout the day or administered in a manner that provides continuous delivery.

[0618] In some embodiments, the compound of Formula I or its pharmaceutically acceptable salt, deuterated analog or solvate (e.g., a compound of any one of Formula II, III or IV or its pharmaceutically acceptable salt, deuterated analog or solvate) is administered at a dosage 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 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 dosage is a therapeutically effective amount.

[0619] In some embodiments, a compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is administered at 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 150 mg / Kg; about 0.0002 mg / Kg to about 200 mg / Kg; about 0.0002 mg / Kg to about 300 mg / Kg; about 0.0002 mg / Kg to about 500 mg / Kg; about 0.0002 mg / Kg to about 250 mg / Kg; about 0.0002 mg / Kg to about 30 ... 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; 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 In some embodiments, the compound of Formula I as described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formula II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is administered at a dose of about 100 mg / Kg.

[0620] In some embodiments, the foregoing doses of a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) can be administered daily (e.g., in a single dose or 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).

[0621] In some embodiments, the administration period of a compound of Formula I described herein, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formula II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the period of time during which administration is discontinued 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 embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is administered to a patient for a period of time, followed by a separate period of time during which administration of the compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is ceased. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is administered for a first time period and a second time period after the first time period, wherein administration is stopped during the second time period, followed by a third time period in which administration of a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is initiated, and then a fourth time period in which administration is stopped after the third time period. For example, after a time period of administration of a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any one of Formulas II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof), administration is then repeatedly stopped for a determined or undetermined time period. In some embodiments, the administration 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 embodiments, the period of time over which administration is discontinued 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.

[0622] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulae II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is orally administered to a patient one or more times per day (e.g., once per day, twice per day, three times per day, four times per day, or in a single daily dose).

[0623] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulae II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is administered to a patient by parenteral administration once or more per day (e.g., 1 to 4 times per day, twice per day, three times per day, four times per day, or a single daily dose).

[0624] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof (e.g., a compound of any of Formulae II, III, or IV, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof) is administered to a patient weekly by parenteral administration. Patient selection

[0625] In some embodiments, the methods described herein further comprise the step of identifying a patient (eg, subject) in need of such treatment (eg, by blood assays, body mass index, or other routine methods known in the art).

[0626] In some embodiments, the methods described herein further comprise the step of identifying a patient (eg, a patient) suffering from a disease, disorder, or condition (eg, a GLP-1 related disease, disorder, or condition) as provided herein.

[0627] In some embodiments, the methods described herein further include the following steps: identifying a patient (e.g., a patient) with type 2 diabetes. In some embodiments, determining whether a patient has type 2 diabetes includes performing an assay to determine the level of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is about 6.5% to about 24.0%. In some embodiments, the level of HbA1c is greater than or about 6.5%. In some embodiments, the level of HbA1c is greater than or about 8.0%. In some embodiments, the level of HbA1c is greater than or about 10.0%. In some embodiments, the level of HbA1c is greater than or about 12.0%. In some embodiments, the level of HbA1c is greater than or about 14.0%. In some embodiments, the level of HbA1c is greater than or about 16.0%. In some embodiments, the level of HbA1c is greater than or about 18.0%. In some embodiments, the level of HbA1c is greater than or about 20.0%. In some embodiments, the level of HbA1c is greater than or about 22.0%. In some embodiments, the level of HbA1c is greater than or about 24.0%.

[0628] In some embodiments, the level of fasting plasma glucose is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the level of fasting plasma glucose is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the level of fasting plasma glucose is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0629] In some embodiments, the level of non-fasting plasma glucose is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[0630] In some embodiments, determining whether the patient has type 2 diabetes further comprises determining the patient's BMI. In some embodiments, the patient's BMI is greater than or about 22 kg / m 2 Up to or greater than 100kg / m 2 In some embodiments, the patient's BMI is greater than or about 30 kg / m 2 to greater than or about 90kg / m 2 In some embodiments, the patient's BMI is greater than or about 40 kg / m 2 Up to or greater than 80kg / m2 In some embodiments, the patient's BMI is greater than or about 50 kg / m 2 Up to or greater than 70kg / m 2 .

[0631] In some embodiments, the additional factors (e.g., risk factors) used to determine whether a patient suffers from type 2 diabetes further include the patient's age and race. In some embodiments, the patient's age is greater than or about 10 years old. In some embodiments, the patient's age is greater than or about 15 years old. In some embodiments, the patient's age is greater than or about 20 years old. In some embodiments, the patient's age is greater than or about 25 years old. In some embodiments, the patient's age is greater than or about 30 years old. In some embodiments, the patient's age is greater than or about 35 years old. In some embodiments, the patient's age is greater than or about 40 years old. In some embodiments, the patient's age is greater than or about 42 years old. In some embodiments, the patient's age is greater than or about 44 years old. In some embodiments, the patient's age is greater than or about 46 years old. In some embodiments, the patient's age is greater than or about 48 years old. In some embodiments, the patient's age is greater than or about 50 years old. In some embodiments, the patient's age is greater than or about 52 years old. In some embodiments, the patient's age is greater than or about 54 years old. In some embodiments, the patient's age is greater than or about 56 years old. In some embodiments, the age of the patient is greater than or about 58 years old. In some embodiments, the age of the patient is greater than or about 60 years old. In some embodiments, the age of the patient is greater than or about 62 years old. In some embodiments, the age of the patient is greater than or about 64 years old. In some embodiments, the age of the patient is greater than or about 66 years old. In some embodiments, the age of the patient is greater than or about 68 years old. In some embodiments, the age of the patient is greater than or about 70 years old. In some embodiments, the age of the patient is greater than or about 72 years old. In some embodiments, the age of the patient is greater than or about 74 years old. In some embodiments, the age of the patient is greater than or about 76 years old. In some embodiments, the age of the patient is greater than or about 78 years old. In some embodiments, the age of the patient is greater than or about 80 years old. In some embodiments, the age of the patient is greater than or about 85 years old. In some embodiments, the age of the patient is greater than or about 90 years old. In some embodiments, the age of the patient is greater than or about 95 years old. In some embodiments, the patient's race can be African American, American Indian or Alaska Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander. Synthesis of compounds

[0632] Compounds can be prepared using methods disclosed herein and conventional modifications thereof, which will be clear from the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be completed as described in the following examples. If available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers. Universal synthesis

[0100] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, unless otherwise stated, other method conditions may also be used given certain method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.). Optimum reaction conditions may vary with the reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0101] In addition, as will be clear to those skilled in the art, conventional blocking groups may be necessary to prevent some functional groups from experiencing undesirable reactions. Suitable blocking groups for various functional groups and suitable conditions for protecting and deprotecting some functional groups are well known in the art. For example, many blocking groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, the 3rd edition, Wiley, New York and the references cited therein.

[0102] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, if desired, such compounds may be prepared or separated into pure stereoisomers, i.e., as individual enantiomers or diastereomers or as a mixture enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective agents well known in the art. Alternatively, the racemic mixture of such compounds may be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0103] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or their obvious modifications. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), EMKA-Chemie Gmbh & Co. KG (Eching, Germany) or Millipore Sigma (Burlington, Massachusetts, USA). Other starting materials can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0104] Scheme 1 illustrates a general method that can be used to synthesize compounds described herein, wherein Ring A, Ring B, Ring C, Q, X, Y, L 1 , L 2 , R 1 , R 2 and R 3 Each of wherein is independently as defined herein, and LG is a leaving group such as alkoxy, hydroxy, halo (eg, Cl, Br or I), and the like. Scheme I

[0633] Referring to Scheme 1, compounds I-1 and I-2 are reacted under standard coupling conditions (such as when L 1 Amide bond forming conditions when the amine is -C(=O)-, such as coupling in the presence of a carboxyl activating agent such as HATU (e.g., in a polar aprotic solvent such as DMF), provide compounds of Formula I. After the reaction is complete, the compound of Formula I can be recovered by conventional techniques (such as neutralization, extraction, precipitation, chromatography, filtration, etc.).

[0634] Scheme II illustrates a general method that can be used to synthesize compounds I-2, wherein Ring B and Ring C are independently as defined herein, L3 is a bond, and R8a and R8b together with the carbon atom to which they are attached form an optionally substituted C 3-15 Cycloalkyl (e.g., cyclopropyl), the C 3-15 The cycloalkyl group is represented as ring D' in Scheme II, and the dashed curve Lx represents C 2-14 Alkylene, the C 2-14 The alkylene group may be optionally substituted as defined herein (e.g., optionally with C 1-6 Alkyl substituted, the C 1-6 The alkyl group is optionally substituted with 1 to 3 R f Replacement), R 50 is an alkyl group which may be optionally substituted, and LG is a leaving group such as alkoxy, hydroxy, halo (eg, Cl, Br or I), and the like. Solution II

[0635] Referring to Scheme II, compound II-1 is reacted with a suitable coupling partner (such as a compound having the formula (ring C)-Y 1 A reagent (wherein ring C is as defined in formula I; and Y 1 is B(OH) 2 or a boronate ester such as BPin)) is subjected to a metal-catalyzed cross-coupling reaction (e.g., using Pd(dppf)ClCH in the presence of potassium carbonate). 2 Cl 2 Suzuki coupling) to provide compound I-2. Optionally, when ring C is a saturated heterocyclic group, II-1 can be combined with a compound of formula (ring C)-Y 1 Wherein ring C is a partially saturated heterocyclic group, followed by optional hydrogenation (e.g., with palladium on carbon) to give I-2. As a non-limiting example, when ring C is tetrahydropyran-4-yl, II-1 can be coupled with (ring-C)-Y 1 (For example, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of the formula: ) coupling.

[0636] As shown in Scheme II, certain compounds of Formula I-2 can be prepared from compound II-2. For example, reaction of II-2 with II-3 (e.g., in the presence of NaH in DMF) provides II-4, which is then reacted under standard conditions (e.g., with H 2O / LiOH in THF) hydrolyzes the ester group to give compound II-5. Amide coupling of II-5 with NHMePh under standard conditions (e.g., HATU and Hunig's base) provides II-6. Then, reaction of II-6 with reagent II-6b under basic conditions (e.g., KHMDS, DMPU) provides II-7. As a non-limiting example, II-6b can be The ring D' in the corresponding products are II-7 is treated with a hydroxylamine source (e.g., NH 2 OH.HCl) followed by reaction with a phosgene equivalent (e.g., CDI (e.g., at 80°C in the presence of DBU and DMSO)) to provide compound II-8. Hydrolysis of the amide group in compound II-8 (e.g., at 125°C with CH 3 OCH 2 CH 2 OH) to provide compound II-9. Compound II-9 can be used in Scheme 1 as compound I-2.

[0637] In certain embodiments, the method outlined in Scheme II for installing on Ring B Part of the process can be carried out according to Scheme IIA shown below, wherein ring A, ring B, ring C, ring D', Q, X, Y, L 1 , L 2 , R 1 , R 2 and R 3 Each of is independently as defined herein. Scheme IIA

[0638] Scheme III illustrates a general method that can be used to synthesize exemplary compounds of Formula I-1 (e.g., Compound III-7), which can be used in Scheme I to provide compounds of Formula I, wherein Ring A, Q, X, Y, L 1 , L 2 , R 1 , R 2 and R 3 Each of wherein is independently as defined herein, and X is a leaving group such as a halo (eg, Cl, Br, or I), and PG is a protecting group. Scheme III

[0639] In Scheme III, reaction between III-1 and III-2 (e.g., in the presence of a polar aprotic solvent such as DMA) provides compound III-3, which is then treated with an acid (e.g., MeSO 3 H, THF, 60°C) and subsequent reprotection of the secondary amino group (e.g., with Boc 2 (2) provides compound III-4, wherein PG is a nitrogen protecting group, such as a carbamate protecting group (like Boc). Compound III-4 is then coupled with compound III-5 (wherein X is a halide (e.g., -Br or -I) or a pseudohalide (e.g., -OTf)) under typical Ullman coupling conditions known in the art, for example, to provide compound III-6. As a non-limiting example, the coupling can be carried out in CuI, K 2 CO 3 and The nitrogen protecting group (ie, PG) on III-6 is then removed (eg, under acidic conditions such as HCl in dioxane) to provide compound III-7.

[0640] Appropriate starting materials and reagents for the steps outlined in any of Schemes I, II or III can be purchased or prepared by methods known to those skilled in the art. After completion of each reaction, each intermediate or final compound can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modifications to obtain compounds of the present disclosure are within the skill of the art.

[0641] In certain embodiments, when it is desired to control stereochemistry, appropriate control of reaction conditions and selection of substituents of reagents can at least partially determine or maintain the formation of various stereoisomers. In some embodiments, various substituents (e.g., ring A, ring B, ring C, Q, X, Y, L, etc.) of various compounds of Schemes I, II, or III are 1 , L 2 , R 1 , R 2 and R 3 ) are each independently as defined herein. However, any of the various compounds of Schemes I, II or III is derivatized prior to the reaction step, and / or the resulting reaction products are further derivatized to provide various compounds of Formula I.

[0642] It will be clear to one of ordinary skill in the art that in the synthetic sequences detailed in Schemes I, II or III above, the reactive groups (such as NH 2, NH and OH) can be protected with appropriate protecting groups, followed by a deprotection step at an appropriate stage of the synthesis. A person of ordinary skill in the art can also conceive of variations of the foregoing method to synthesize other compounds of formula I. For example, by exchanging III-2 with other electrophilic reagents, compounds with other L 3 -C(R 8a R 8b )-L 4 -R 9 For another example, by replacing III-1 with other appropriate reagents, compounds with other L 2 Part of the compound.

[0643] The compounds provided in Table 1 can be prepared according to the methods shown in Schemes I, II and III. Example

[0644] The following examples are included to show the specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the technology disclosed in the following examples represents a technology that works well in the practice of the present disclosure, and therefore can be considered to constitute the specific mode of its practice. However, according to the present disclosure, it will be appreciated by those skilled in the art that many changes can be made in the disclosed specific embodiments and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0645] Abbreviations (as used herein):

[0646] General Information: All evaporations or concentrations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates with spots visualized using UV light (214 and 254 nm). Purification was performed by column and flash chromatography using silica gel (100-200 mesh). Solvent systems are reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. 1 H chemical shifts are reported as δ values ​​in ppm with deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration. LCMS spectra were obtained on a SHIMADZULC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series 6110 or 6120 mass spectrometer by electrospray ionization, and unless otherwise indicated. Example 1 3-(1-{2-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-6-(oxan-4-yl)-1H-indol-3-yl}cyclopropyl)-2,5-dihydro-1,2,4-oxadiazol-5-one (Compound 28) Step A 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester

[0647] To methyl 6-bromo-1H-indole-2-carboxylate (5 g, 19.69 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.96 g, 23.62 mmol) and K 2 CO 3 (8.15 g, 59.06 mmol) in dioxane (80 mL) and H 2 O (8 mL) was added to the mixture with Pd(dppf)Cl 2 .CH 2 Cl 2 (0.8 g, 0.98 mmol). After being gassed with nitrogen three times. The resulting mixture was stirred at 90 ° C under nitrogen for 3 h. After cooling, the mixture was filtered and concentrated to dryness under vacuum. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent 0-25% EtOAc / PE gradient) to give 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester (3.58 g, yield 70.8%). LC-MS: m / z: 258.4 (M+H) + . Step B 6-(Tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester

[0648] A mixture of methyl 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.48 g, 13.54 mmol) and 5% Pd / C (348 mg) in MeOH (35 mL) was degassed and washed with H 2The reaction mixture was stirred at room temperature under H 2 Stir under balloon for 2 h. The mixture was filtered and concentrated to give methyl 6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.43 g, yield 98.0%). LC-MS: m / z: 260.1 (M+H) + . Step C 3-bromo-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester

[0649] To methyl 6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (3.33 g, 12.86 mmol) was added in CH 3 CN (30 mL) and CH 2 Cl 2 NBS (1.6 g, 9.0 mmol) was added to the solution in 4% paraformaldehyde (20 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was washed with H 2 O (300 mL) and diluted with CH 2 Cl 2 (50 mL x 3) extraction. The organic layer was washed with brine and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate to give crude 3-bromo-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester (3.9 g, yield 90.7%). LC-MS: m / z: 338.1 (M+H) + . Step D 3-(Cyanomethyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester

[0650] To methyl 3-bromo-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (300 mg, 0.89 mmol) in DMSO (6 mL) and H 2 To a solution in 2% CO (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (346 mg, 1.77 mmol), KF (154 mg, 2.66 mmol) and Pd(dppf)Cl 2(65 mg, 0.09 mmol). After being gassed with nitrogen three times. The resulting mixture was stirred at 130 ° C under nitrogen for 3 h. After cooling, the mixture was concentrated and purified by flash silica gel chromatography (silica flash column, eluent 0-20% EtOAc / PE gradient) to give 3-(cyanomethyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester (290 mg, yield 65.1%). LC-MS: m / z 299.3 (M+H) + . Step E 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester

[0651] A mixture of methyl 3-(cyanomethyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (100 mg, 0.34 mmol), vinyldiphenylsulfonium trifluoromethanesulfonate (146 mg, 0.40 mmol) and DBU (153 mg, 1.01 mmol) in DMSO (1 mL) was stirred at room temperature under nitrogen for 2 h. The mixture was treated with H 2 O (30 mL), extracted with EtOAc (10 mL x 3). The organic layer was washed with brine and washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate. The residue was purified by preparative TLC (20% EtOAc / PE) to give methyl 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (38 mg, 35.0% yield). LC-MS: m / z 325.2 (M+H) + . Step F 3-(1-Cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid

[0652] Methyl 3-(cyanocyclopropyl)-6-(3,4,5,6-tetrahydro-2H-pyran-4-yl)benzo[b]thiophene-2-carboxylate (38 mg, 0.12 mmol) and LiOH (9.8 mg, 0.23 mmol) were dissolved in THF (1 mL) and H 2 The mixture was stirred at room temperature for 6 h in 2% CO (0.2 mL). The mixture was diluted with water (30 mL), acidified to pH = 5.0 with 1 M HCl aqueous solution, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2) and purified by anhydrous Na 2 SO4 Dry, filter, and concentrate to give 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (37 mg, crude). LC-MS: m / z 311.3 (M+H) + . Step G (S) -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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carbonitrile

[0653] To a solution of 3-(1-cyanocyclopropyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (37 mg, 0.12 mmol) in DMF (2 mL) was added (S)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (65 mg, 0.12 mmol) (HCl salt, preparation described in WO 2021155841A1), HATU (54 mg, 0.14 mmol) and DIPEA (46 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was then diluted with brine (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash silica gel chromatography (12 g Silica flash column, eluent 0-10% MeOH / CH 2 Cl 2 Gradient, 50 mL / min) to give (S)-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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carbonitrile (66 mg, 65.3% yield). LC-MS: m / z 843.4 (M+H) +Step H (S,Z)-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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-N'-hydroxycyclopropane-1-carboximidamide

[0654] To a solution of (S)-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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carbonitrile (66 mg, 0.078 mmol) in EtOH (1 mL) was added DIPEA (30 mg, 0.234 mmol) and NH 2 OH.HCl (16.3 mg, 0.234 mmol). The resulting mixture was stirred at 70°C for 6 h. After cooling, the mixture was diluted with brine (30 ml) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash silica gel chromatography (12 g Silica flash column, eluent 0-5% MeOH / CH 2 Cl 2 Gradient, 50 mL / min) to give the title compound (S,Z)-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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-N'-hydroxycyclopropane-1-carboximidamide (36 mg, yield 57.6%). LC-MS: m / z 876.2 (M+H) + . Step I 3-(1-{2-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-6-(oxan-4-yl)-1H-indol-3-yl}cyclopropyl)-2,5-dihydro-1,2,4-oxadiazol-5-one (Compound 28)

[0655] To a solution of (S,Z)-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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-N'-hydroxycyclopropane-1-carboximidamide (36 mg, 0.041 mmol) in dioxane (1 mL) was added CDI (20 mg, 0.123 mmol). The resulting mixture was stirred at 60 °C for 16 h. After cooling, the reaction mixture was concentrated. The residue was purified by preparative HPLC (column: Pursuit XRs C1819*250mm*10μm; mobile phase A: water (0.1% formic acid), mobile phase B: CH 3 CN; flow rate: 20 mL / min; gradient: 57% B to 67% B, retention time: 9.2-10.3 min) to give 3-(1-{2-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-6-(oxan-4-yl)-1H-indol-3-yl}cyclopropyl)-2,5-dihydro-1,2,4-oxadiazol-5-one (12.0 mg, yield 32.3%). LC-MS: m / z 902.9 (M+H) + . 1H NMR (400MHz, DMSO-d6): δ11.88(br s,1H),11.47(s,1H),7.67-7.78(m,1H),7.52(d,J=8.0Hz,1H),7.33-7.44(m,1H),7.2 0-7.32(m,2H),7.08-7.19(m,2H),6.97-7.07(m,2H),6.81-6.96(m,2H),5.56-5.70(m ,1H),3.84-4.02(m,3H),3.39-3.51(m,3H),2.61-2.91(m,6H),2.20(s,6H),1.86-1.9 8(m,4H),1.64-1.78(m,4H),1.43-1.58(m,2H),1.17-1.36(m,5H),0.93-1.05(m,6H). 19 FNMR (377MHz, DMSO-d6): δ-122.07. Example 2 3-(1-{6-[(4S)-3-{3-[4-(diethylphosphoryl)-3-(methylamino)phenyl]-2-oxo-2,3-dihydro-1H-imidazol-1-yl}-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carbonyl]-3-(oxan-4-yl)pyrrolo[1,2-b]pyridazin-7-yl}cyclopropyl)-4,5-dihydro-1,2,4-oxadiazol-5-one (Compound 26) Step A1-Amino-1H-pyrrole-3-carboxylic acid methyl ester

[0656] At 0°C, NaH (60% wt, dispersed in paraffin liquid) (2.50 g, 104 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid methyl ester (10.0 g, 80.0 mmol) in DMF (300 mL) under stirring. After stirring at 0°C for 20 min. Then (aminooxy) diphenylphosphine oxide (28.0 g, 120.0 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 16 h. The mixture was poured into ice water (300 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate. The residue was purified by flash silica gel chromatography (220 g Silica flash column, eluent 0-10% MeOH / CH 2 Cl 2 Gradient, at 100 mL / min) to give 1-amino-1H-pyrrole-3-carboxylic acid methyl ester (8.8 g, yield 78.6%). LC-MS: m / z 141.0 (M+H) + . Step B Methyl 3-bromopyrrolo[1,2-b]pyridazine-6-carboxylate

[0657] To a mixture of 1-amino-1H-pyrrole-3-carboxylic acid methyl ester (8.8 g, 62.85 mmol) and 2-bromomalonaldehyde (18.98 g, 125.71 mmol) in dioxane (50 mL) was added H 3 PO 4 (8.5 mL). The resulting mixture was stirred at 45 °C for 16 h. After cooling, the reaction mixture was passed through saturated NaHCO 3 The aqueous solution was basified and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate. The residue was purified by flash silica gel chromatography (120 g Purification by silica flash column, eluting with 0-10% EtOAc / PE gradient at 40 mL / min) gave methyl 3-bromopyrrolo[1,2-b]pyridazine-6-carboxylate (601 mg, 3.8% yield). LC-MS: m / z 255.0 (M+H) + . Step C 3-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester

[0658] To methyl 3-bromopyrrolo[1,2-b]pyridazine-6-carboxylate (600 mg, 2.36 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (992 mg, 4.72 mmol) in dioxane (5 mL) and H 2 O (1 mL) was added to the mixture with Pd(dppf)Cl 2 (173 mg, 0.236 mmol) and K 2 CO 3(978 mg, 7.09 mmol). The reaction mixture was aerated with nitrogen three times and then stirred at 90 ° C for 16 h. After cooling, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter, and concentrate. The residue was purified by flash silica gel chromatography (4 g Silica flash column, eluting with 0-25% EtOAc / PE gradient at 50 mL / min) to afford methyl 3-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylate (427 mg, 70.1% yield). LC-MS: m / z 259.1 (M+H) + . Step D 3-(Tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester

[0659] A mixture of methyl 3-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylate (470 mg, 1.82 mmol) and 10% Pd / C (388 mg) in EtOAc / MeOH (5 mL / 5 mL) was stirred at room temperature under H 2 Stirred under balloon for 3 h. The mixture was filtered and the residue was concentrated to obtain methyl 3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylate (395 mg, yield 83.4%). LC-MS: m / z 261.1 (M+H) + . Step E 7-(Cyanomethyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester

[0660] Under stirring, 3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester (350 mg, 1.35 mmol), 2-bromoacetonitrile (178 mg, 1.48 mmol), FeSO 4 .7H 2 O (187 mg, 0.67 mmol) and NaI (202 mg, 1.35 mmol) in DMSO (7 mL) and H 2 To the ice-water cooled mixture of 2% HO (1 mL) was added 30% HO. 2 O 2(0.4 g). After addition, the mixture was stirred at room temperature for 16 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash silica gel chromatography (4 g Silica flash column, eluting with 0-25% EtOAc / PE gradient at 50 mL / min) to afford methyl 7-(cyanomethyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylate (100 mg, 24.9% yield). LC-MS: m / z 300.0 (M+H) + . Step F 7-(1-cyanocyclopropyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester

[0661] DBU (154 mg, 1.00 mmol) was added to a mixture of 7-(cyanomethyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester (100 mg, 0.33 mmol) and vinyl diphenylsulfonium trifluoromethanesulfonate (145 mg, 0.40 mmol) in DMSO (3 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was purified by anhydrous Na 2 SO 4 Dry, filter and concentrate. The residue was purified by flash silica gel chromatography (4 g Silica flash column, eluting with 0-25% EtOAc / PE gradient at 50 mL / min) to afford methyl 7-(1-cyanocyclopropyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylate (95 mg, 87.4% yield). LC-MS: m / z 326.5 (M+H) + . Step G 7-(1-Cyanocyclopropyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid

[0662] Methyl 7-(1-cyanocyclopropyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylate (95 mg, 0.292 mmol) and LiOH (123 mg, 2.923 mmol) were mixed in THF / MeOH / H 2 The mixture was stirred at 50 °C for 6 h in 2% CO (5 mL / 1 mL / 1 mL). After cooling, the mixture was diluted with water (50 mL) and extracted with EtOAc (25 mL x 2). The aqueous phase was acidified to pH = 4 by 1 M HCl aqueous solution and washed with CH 2 Cl 2 (30 mL x 3) extraction. The combined organic layers were washed with anhydrous Na 2 SO 4 Dried and then concentrated to obtain 7-(1-cyanocyclopropyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid (80 mg, yield 88.0%). LC-MS: m / z 312.1 (M+H) + . Step H (S)-1-(6-(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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazin-7-yl)cyclopropane-1-carbonitrile

[0663] To a mixture of 7-(1-cyanocyclopropyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazine-6-carboxylic acid (80 mg, 0.258 mmol) and (S)-1-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (167 mg, 0.284 mmol) (HCl salt, preparation described in WO 2021155841A1) in DMF (3 mL) was added DIPEA (133 mg, 1.032 mmol) and HATU (147 mg, 0.387 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine, purified by Na 2 SO 4The residue was concentrated by preparative TLC (5% MeOH / CH 2 Cl 2 ) was purified to obtain (S)-1-(6-(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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazin-7-yl)cyclopropane-1-carbonitrile (305 mg, crude product). LC-MS: m / z 844.2 (M+H) + . Step I (S,Z)-1-(6-(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-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-b]pyridazin-7-yl)-N'-hydroxycyclopropane-1-carboximidamide

[0664] To (S)-1-(6-(3-(3-(4-(diethylphosphoryl)-3-(methylamino)phenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphe...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, in: X is C and Y is N, or Y is C and X is N, and the dashed line represents an optional bond, so that the moiety yes wherein bond y is attached to Y and bond x is attached to X; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; or the part-L 3 -C(R 8a R 8b )-L 4 -R 9 is C(=O)OH and optionally 1-4 independently selected from R f Phenyl substituted with another substituent; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H, optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl, and C(=O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups, C 3-15 Cycloalkyl and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; L 2 Selected from Where aa represents the point of attachment to Q; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Q is selected from C 1-10 Alkyl; C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, wherein Q is replaced by -P(=O)R a R b and optionally substituted by 1-6 independently selected from R Q Another substituent of ; Each R Q Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (i) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (j) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (k) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; (l) optionally 1 to 6 independently selected R g Substituted 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; or Q is C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 each independently selected from R QA and R QB Substituents are substituted; If either or both of (aa) or (bb) apply: (aa)Q is covered by at least one R QB replace; or (bb) Q is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Q contains an endocyclic S(O) 2 Group; each R QA Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (i) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (j) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; and (k) optionally 1 to 6 independently selected R g Substituted C 3-8 Cycloalkyl; Each R QB Independently selected from: (a)-L a -S(O) 2 -L b -R e ;and (b) a 4-12 membered heterocyclic group or a 7-10 membered bicyclic heteroaryl group, each of which contains an endocyclic S(O) 2 A group wherein the heterocyclic group or heteroaryl group is optionally substituted by 1 to 6 independently selected R g replace; L a Selected from -N(H)-, -N(R c )- and -(CR h R h ) q1 -; L b Selected from -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 -; q1 and q2 are independently 0, 1, 2, 3 or 4; The condition is that when L a Yes-(CR h R h ) q1 - and q1 is 0, then -L b -R e Not unsubstituted C 1-3 alkyl; R a and R b Independently selected from optionally 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6 Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted 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 atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R c and R d Independently selected 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), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; L e Yes key, NR c or O; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms connecting them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

2. The compound according to claim 1, wherein the moiety yes Where bond y is attached to Y, and bond x is attached to X.

3. The compound according to claim 1, wherein the moiety yes Where bond y is attached to Y, and bond x is attached to X.

4. A compound of formula II: or a pharmaceutically acceptable salt or solvate thereof, in: Q 1 , Q 2 , Q 3 , Q 4 and Q 5 is defined as (AA) or (BB) below: (AA) Q 1 and Q 5 Independently selected from N, CH and CR QC ; Q 2 , Q 3 and Q 4 Independently selected from N, CH, CR QC and CR QD , provided that Q 2 , Q 3 and Q 4 At least one of them is CR QD ; Each is a single bond or a double bond, provided that it contains Q 1 -Q 5 The ring is aromatic; (BB) Q 1 is the key; Q 2 , Q 3 , Q 4 and Q 5 Independently selected from O, S, N, NH, NR c , CH, CR QC and CR QD , provided that Q 2 , Q 3 , Q 4 and Q 5 At least one of them is CR QD ; Each is a single bond or a double bond, provided that it contains Q 1 -Q 5 The ring is aromatic; R QD is P(=O)R a R b , where R a and R b Independently selected from optionally 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6 Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted 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 atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R QC Independently selected from (a) halo; (b) cyano; (c) OH; (d) -NR c R d ; (e) C(=O)NR c R d ; (f) S(=O) 0-2 R e (g) optionally 1-6 independently selected R f Substituted C 1-6 (h) optionally substituted by 1-6 groups independently selected from hydroxy, halo and C 1-6 Alkoxy substituents substituted C 1-6 (i) optionally substituted by one or more independently selected from C 1-6 Alkyl and C(=O)(C 1-6 alkyl) substituent; (j) optionally substituted by 1 to 3 independently selected C(═O)(C 1-6 Alkyl) substituted C 6-10 Aryl; and (k) optionally 1-6 independently selected R g substituted 5-10 membered heteroaryl; or a pair of R on adjacent carbon atoms QC Together with the atoms to which they are attached, they form a ring containing 5-8 ring atoms, wherein 0-2 ring atoms are heteroatoms each independently selected from O, N and S, wherein the ring is optionally substituted with 1-2 independently selected R h Group substitution; L 2 Selected from Where aa represents the 1 -Q 5 The attachment point of the ring; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-7 cycloalkyl, 5-7 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 Alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H; optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(═O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups; 3-15 Cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; Each R c and R d Independently selected from H, C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e It is H, C 1-6 Alkyl or C 1-6 Haloalkyl; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, NR c R d and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each R h independently selected from halo, cyano, C 1-6 Alkyl, C 1-6 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

5. A compound of formula III: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, in: Ring D is selected from C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 each independently selected from R QA and R QB Substituents are substituted; If either or both of (aa) or (bb) apply: (aa) Ring D is surrounded by at least one R QB replace; or (bb) Ring D is a 4-12 membered heterocyclyl or a 7-10 membered bicyclic heteroaryl, wherein Ring D contains an endocyclic S(O) 2 Group; Each R QA Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR a R b ; (e)-C(=O)NR c R d ; (f) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (h) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (i) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (j) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; and (k) optionally 1 to 6 independently selected R g Substituted C 3-8 Cycloalkyl; Each R QB Independently selected from (a)-L a -S(O) 2 -L b -R e ;and (b) a 4-12 membered heterocyclic group or a 7-10 membered bicyclic heteroaryl group, each of which contains an endocyclic S(O) 2 A group wherein the heterocyclic group or heteroaryl group is optionally substituted by 1 to 6 independently selected R g replace; L a Selected from -N(H)-, -N(R c )- and -(CR h R h ) q1 -; L b Selected from -O-, -N(H)-, -N(R c )- and -(CR h R h ) q2 -; q1 and q2 are independently 0, 1, 2, 3 or 4; The condition is that when L a Yes-(CR h R h ) q1 - and q1 is 0, then -L b -R e Not unsubstituted C 1-3 alkyl; L 2 Selected from where aa represents the point of attachment to ring D; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H; optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(═O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups; 3-15 Cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; Each R a and R b Independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl) and C(=O)O(C 1-6 alkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl) and C(=O)O(C 1-6 alkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; Each R c and R d Independently selected 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), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1-6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Alkyl halide, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms connecting them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

6. A compound of formula IV: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, in: Ring A is C 6-10 Aryl, C 5-10 cycloalkyl, 5-10 membered heterocyclyl or 5-10 membered heteroaryl, each of which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl; R 1 , R 2 and R 3 are each independently selected from H and are optionally substituted by 1-6 each independently selected from halo, -OH and C 1-6 Alkoxy substituents substituted C 1-6 alkyl; L 1 Selected from -C(=O)-, -CH 2 -、-CH(C 1-6 alkyl)- and -S(=O) 2 ; Ring B is selected from Where bb represents the 1 Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; L 3 is key or C 1-3 Alkylene; L 4 is key or C 1-5 Alkylene; R 8a and R 8b independently selected from H and optionally substituted by one or more independently selected from halo and C 3-15 Substituents of cycloalkyl substituted C 1-6 Alkyl; or R 8a and R 8b Together with the carbon atoms to which they are attached, they form optionally 1-3 independently selected C 1-6 Alkyl substituted C 3-15 Cycloalkyl ring, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 6 independently selected R f replace; 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): R 9a Is H or C 1-6 alkyl; R 9b It is H, C 1-6 Alkyl, C(=O)(C 1-6 Alkyl), S(O) 0-2 (C 1-6 alkyl) or cyano; R 9c , R 9d , R 9e , R 9f and R 9g are each independently selected from H; optionally 1-6 independently selected halo and C 1-6 Alkoxy substituted C 1-6 Alkyl; and C(═O)(C 1-6 alkyl); Ring C is selected from 3-12 membered heterocyclic groups; 3-10 Cycloalkyl; and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R Ca replace; Each R Ca independently selected from halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and NR c R d ; or a pair of R on the same or different ring atoms Ca Together with the one or more ring atoms to which they are attached, they form a carbocyclic ring containing 3 to 8 ring atoms; L 2 Selected from Where aa represents the point of attachment to Q; n1 is an integer from 1 to 3; L 2A is key or C 1-10 Alkylene; R La Selected from H, C 1-6 Alkyl and C(=O)(C 1-6 alkyl); R Lb and R Lc Each of which is independently selected from H and C 1-6 alkyl; Q is selected from C 1-10 Alkyl; C 3-15 Cycloalkyl; 3-12 membered heterocyclyl; 5-10 membered heteroaryl; and C 6-10 Aryl, each of which is optionally substituted by 1-6 independently selected R Q replace; Each R Q Independently selected from (a) halo; (b) cyano; (c) OH or oxo; (d)-NR c R d ; (e)-C(=O)NR c R d or -S(O) 2 NR c R d ; (f)-S(=O) 0-2 R e ; (g) optionally 1 to 6 independently selected R f Substituted C 1-6 alkyl; (h) optionally 1 to 6 independently selected R f Substituted C 1-6 Alkoxy; (i) optionally 1 to 6 independently selected R g substituted 3-12 membered heterocyclic group; (j) optionally 1 to 6 independently selected R g Substituted C 6-10 Aryl; (k) optionally 1 to 6 independently selected R g substituted 5-10 membered heteroaryl; (l) optionally 1 to 6 independently selected R g Substituted 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 optionally 1-6 each independently selected from C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and halo 1-6 Alkyl; optionally 1-3 each independently selected from C 1-3 Alkyl and halo substituents substituted 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 atom to which they are attached, they form a ring containing 5-8 ring atoms, of which 0-2 ring atoms (excluding the one attached to R a and R b wherein the ring is optionally substituted with 1-3 independently selected C 1-6 Alkyl substitution; Each R c and R d Independently selected 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), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl), wherein the C 1-6 Alkyl, C(=O)(C 1-6 alkyl), C(=O)(C 3-6 Cycloalkyl), C(=O)O(C 1-6 Alkyl), S(O) 1-2 (C 1-6 Alkyl) and S(O) 1-2 (C 3-6 cycloalkyl) are each optionally substituted by 1 to 6 independently selected from -OH, halo and C 1-6 Substitution of alkoxy groups; R e is H, or R e Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, NH 2 NH(C 1-3 Alkyl), N(C 1-3 alkyl) 2 , C 1-3 Alkoxy and C 1-3 Haloalkoxy; L e Yes key, NR c or O; Each R f are independently selected from halo, -OH, NR c R d , C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted by 1 to 4 groups independently selected from -OH, C 1-6 3-12 membered heterocyclic group substituted with alkyl and 3-12 membered heterocyclic group substituent; Each R g Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR c R d , cyano, halo, C 3-6 Cycloalkyl and optionally one or more independently selected from C 1-6 Alkyl and C(=O)C 1-6 a 3- to 12-membered heterocyclic group substituted by a substituent of the alkyl group; and Each occurrence of R h Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and halo; or A pair of R on the same or different carbon atoms h Together with one or more carbon atoms connecting them, they form C 3-6 Cycloalkyl or 4-8 membered heterocyclic group, each of which is optionally substituted by 1-3 substituents independently selected from the following: halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy.

7. The compound according to any one of claims 1 to 6, wherein ring A is C 6-10 Aryl, which is optionally substituted by 1-5 substituents each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 3-6 Cycloalkyl.

8. The compound according to any one of claims 1 to 7, wherein ring A is phenyl, which is optionally substituted by 1 to 3 substituents each independently selected from fluoro, methyl and cyclopropyl.

9. A compound according to any one of claims 1 to 8, wherein R 1 and R 2 It's H.

10. A compound according to any one of claims 1 to 9, wherein R 3 It is C 1-6 alkyl.

11. A compound according to any one of claims 1 to 10, wherein R 3 It's methyl.

12. A compound according to any one of claims 1 to 11, wherein L 1 It is -C(=O)-.

13. The compound according to any one of claims 1 to 12, wherein Ring B is:

14. The compound according to any one of claims 1 to 12, wherein Ring B is:

15. The compound according to any one of claims 1 to 12, wherein Ring B is:

16. The compound according to any one of claims 1 to 12, wherein Ring B is:

17. A compound according to any one of claims 1 to 16, wherein R 4 , R 5 , R 6 and R 7 It's H.

18. A compound according to any one of claims 1 to 17, wherein L 3 is the key.

19. A compound according to any one of claims 1 to 18, wherein R 8a and R 8b Together with the carbon atoms to which they are attached, they form C 3-15 Cycloalkyl.

20. A compound according to any one of claims 1 to 19, wherein R 8a and R 8b Together with the carbon atoms to which they are attached they form a cyclopropyl group.

21. A compound according to any one of claims 1 to 20, wherein R 9 yes 22. A compound according to any one of claims 1 to 21, wherein R 9d It's H.

23. The compound according to any one of claims 1 to 22, wherein Ring C is a 3-12 membered heterocyclyl.

24. The compound according to any one of claims 1-23, wherein Ring C is tetrahydropyranyl.

25. A compound according to any one of claims 1 to 24, wherein L 2 yes where aa represents the point of attachment to Q.

26. A compound according to any one of claims 1 to 25, wherein L 2A is the key.

27. A compound of formula IIE: or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, in: Ring B is selected from: Where bb represents the point of attachment to -C(O)- and xx represents the point of attachment to X b Attachment point; R 4 , R 5 , R 6 and R 7 are independently selected from H, halo and C 1-6 alkyl; R AA , R AB and R AC are independently hydrogen, halo, C 1-3 Alkyl or C 3-6 Cycloalkyl; R 3 Is H or C 1-3 alkyl; R QC is H or a halide; R QD Selected from: (a) H; (b) -NH 2 ; (c)-NH(C 1-3 (d) halo; (e) C optionally substituted by 1-3 independently selected halo 1-3 and (f) C optionally substituted by 1-3 independently selected halo groups 1-3 alkyl; R a and R b Each independently selected from: C 1-4 Alkyl and C 3-6 Cycloalkyl; or R a and R b Together with the phosphorus atom to which they are attached, they form a ring containing 5-8 ring atoms, wherein 0-1 ring atoms (except the one attached to R a and R b ) are heteroatoms independently selected from the group consisting of O, S and N; R 8c Is H or C 1-3 alkyl; X B is CH or N; and Each R Cb Independently selected from H and C 1-3 alkyl.

28. A compound according to Table 1, or a pharmaceutically acceptable salt, deuterated analog or solvate thereof.

29. A pharmaceutical composition comprising a compound according to any preceding claim, or a pharmaceutically acceptable salt, deuterated analogue or solvate thereof, and a pharmaceutically acceptable excipient.

30. A method for treating a GLP-1 related disease, disorder or condition, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt, deuterated analog or solvate thereof, or a pharmaceutical composition according to claim 29.

31. The method of claim 30, wherein 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), atypical diabetes of the young (YOAD), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes of adults (LADA), obesity (including hypothalamic obesity and monogenic obesity), weight gain due to the use of other medications, idiopathic intracranial hypertension, Wolfram's syndrome, gout, sugar cravings, 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 arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, vascular compliance restriction, damage, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataract, renal insufficiency sclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, polycystic ovary syndrome (PCOS), or any combination thereof.

32. A method of treating type 2 diabetes in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a compound according to any one of claims 1-28, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition according to claim 29.

33. A method for regulating insulin levels in a patient in need of such regulation, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-28, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition according to claim 29.

34. A method for regulating glucose levels in a patient in need of such regulation, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-28, or a pharmaceutically acceptable salt, deuterated analog, or solvate thereof, or a pharmaceutical composition according to claim 29.

35. The method of any one of claims 30-34, further comprising administering an additional therapy or therapeutic agent to the patient.

36. The method of claim 35, wherein the additional therapy or therapeutic agent is selected from an anti-diabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an antiemetic, an agent treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

Images