Therapeutic compounds

Abstract

The present invention relates to compounds that are Nrf2 activators. These compounds have the structural formula IA as defined herein. The invention also relates to intermediate compounds and methods for preparing these compounds, to pharmaceutical compositions comprising these compounds, and to their use in the treatment of diseases or disorders associated with Nrf2 activation.

Description

[0001] The present invention is a divisional application of Chinese invention patent application No. 201980071533.X, filed on October 22, 2019, entitled “Therapeutic Compounds.”

[0002] introduction

[0003] The present invention relates to tetrahydroisoquinoline compounds. More specifically, the present invention relates to tetrahydroisoquinoline compounds that are Nrf2 activators. The present invention also relates to methods for preparing these compounds, to pharmaceutical compositions containing these compounds, and to their use in the treatment of diseases or disorders associated with Nrf2 activation and / or inhibition of Keap1-Nrf2 protein-protein interactions. Background Art

[0004] Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper (bZIP) transcription factor and a member of the Cap'n'Collar (CNC) transcription factor family. It is a key controller of the inducible cellular defense system, mediating the expression of over 100 genes associated with oxidative stress, including phase I and II detoxification enzymes and antioxidant proteins. These genes all contain antioxidant response elements (AREs) in their promoter regulatory regions, which are targets for Nrf2. Under basal conditions, Nrf2 levels are tightly regulated by the adaptor protein Keap1, a cytoplasmic actin-binding repressor that binds to Nrf2 and leads to proteasomal degradation via the Cul3-based E3 ubiquitin ligase complex. Under conditions of oxidative stress, Keap1 is inactivated, leading to increased levels of de novo Nrf2 synthesis. This Nrf2 translocates to the nucleus, binds to the AREs, and upregulates the expression of cytoprotective genes.

[0005] It has been shown that Nrf2 mRNA expression is significantly lower in COPD subjects than in control subjects, and Nrf2 mRNA is inversely correlated with the cumulative amount of cigarette smoked. Nrf2 protein is significantly lower in COPD subjects than in control subjects. CSE-induced apoptosis in A549 cells is increased in a time-dependent and concentration-dependent manner and is significantly enhanced by Nrf2 inhibition (Yamada, BMC Pulmonary Medicine, doi:10.1186 / s12890-016-0189-1). Therefore, elevated Nrf2 levels in the lungs of COPD patients should lead to a reduction in inflammatory processes that lead to deleterious structural modifications of the lung and slower disease progression. Nrf2 is also expected to play an active role in other respiratory diseases that exhibit an oxidative stress component (Cho, Toxicol Appl Pharmacol, doi: 10.1016 / j.taap.2009.07.024), such as acute, chronic, and severe asthma (Sussan, Am J Physiol Lung Cell Mol Physiol, doi: 10.1152 / ajplung.00398.2014), acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome (Yan, Free Radical Biol Med, doi: 10.1016 / j.freeradbiomed.2018.04.557; de la Vega Curr Pharmacol, doi: 10.1016 / j.freeradbiomed.2018.04.557; de la Vega Curr Pharmacol, doi: 10.1016 / j.freeradbiomed.2018.04.557). Rep [Current Pharmacology Reports], doi:10.1007 / s40495-016-0053-2), pulmonary fibrosis, including idiopathic pulmonary fibrosis (Kikuchi, Respir Res [Respir Res], doi:10.1186 / 1465-9921-11-31) and cystic fibrosis (Chen, PLoS One [Public Library of Science One], doi:10.1371 / journal.pone.0003367).

[0006] The cardioprotective properties of Nrf2 have been demonstrated in models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, and heart failure (Chen, Physiol Genomics, doi:10.1152 / physiolgenomics.00041.2017). The Nrf2 activator bardoxolone methyl recently completed a Phase II study in patients with pulmonary arterial hypertension (PAH) and is currently in a Phase III study based on significant improvement in 6-minute walk distance. Bardoxolone covalently binds to Keap1, but compounds that activate Nrf2 through other mechanisms of Keap1 binding also have potential for the treatment of PAH, particularly in patients with underlying connective tissue disorders (CTDs), such as scleroderma or lupus erythematosus. Oxidative stress is elevated in the diseased myocardium, leading to elevated levels of reactive oxygen species, which negatively impact cardiac function (Bolli, Circ, doi:10.1161 / circ.76.2.3111744). In a mouse model of pressure overload, Nrf2 activation inhibits myocardial oxidative stress, cardiac apoptosis, hypertrophy, fibrosis, and dysfunction (Wang, J Card Failure, doi:10.1016 / j.cardfail.2012.06.003) and protects against cardiac ischemia / reperfusion injury in rodent models (Zhang, J Mol Cell Cardiol, doi:10.1016 / j.yjmcc.2010.05.01). Furthermore, excessive oxidant production, which impairs the antioxidant defenses of the cardiovascular system, has been described in metabolic diseases such as obesity, metabolic syndrome, and diabetes, for which Nrf2 activation is also considered a promising therapeutic strategy (da Costa et al., Front Pharmacol. 2019 Apr 12;10:382). Furthermore, the Nrf2 activator sulforaphane reduces hepatic glucose production and improves glycemic control in patients with type 2 diabetes (Axelsson et al., Sci Transl Med. 2017 Jun 14;9(394). Therefore, it is expected that drugs that result in Nrf2 activation should be useful in many cardiovascular and metabolic diseases, including but not limited to atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmias, heart failure with reduced ejection fraction, diabetic cardiomyopathy, diabetic nephropathy, metabolic syndrome, obesity, diabetes (type 1 or type 2), and insulin resistance.

[0007] Subarachnoid hemorrhage (SAH) is a devastating condition associated with significant morbidity and mortality due to the lack of effective treatments. Early brain injury (EBI) and cerebral vasospasm (CVS) are two of the most important pathophysiological mechanisms underlying brain damage and poor prognosis in SAH patients (clinicaltrials.gov / ct2 / show / NCT0261474, SFX01 after subarachnoid hemorrhage (SAS)). Experimental evidence from SAH studies suggests that the Nrf2 / ARE pathway plays a protective role against EBI and CVS after SAH. Administration of sulforaphane (SFN) to rats after SAH enhances Nrf2-ARE pathway activity, attenuates basilar artery vasospasm, and inhibits the release of proinflammatory cytokines (Zhao, Brain Res., doi:10.1016 / j.brainres.2016.09.035). Intracerebral hemorrhage (ICH) accounts for 10%-15% of the 15 million strokes that occur annually worldwide. In vitro studies have shown that Nrf2 activators rapidly increase HO-1 expression in astrocytes and reduce their vulnerability to hemoglobin or heme. Systemic treatment with small-molecule Nrf2 activators increases HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators are consistently protective, improving barrier function and reducing edema, inflammation, neuronal loss, and neurological deficits (Chen-Roetling, Curr Pharm Des, doi:10.2174 / 1381612822666161027150616). Ischemic stroke induces reactive oxygen species, which trigger oxidative and inflammatory responses in the ischemic brain. To date, recombinant tissue plasminogen activator is the only available treatment for ischemic stroke. However, this treatment does not prevent oxidative stress and inflammation in the ischemic brain. D3T, a sulfur-containing dithiothione compound found in cruciferous vegetables, has been reported to induce antioxidant genes by activating Nrf2. D3T has been shown to attenuate cerebral infarction and reduce neurological deficits in stroke animals (Yen, J Immunol 2017, 198(Suppl 1)206.20). Furthermore, D3T reduced CNS-infiltrating inflammatory immune cells (including neutrophils and monocytes) in the ischemic brain. Furthermore, D3T-induced inhibition of inflammatory cytokine production was observed in wild-type cells but not in microglia lacking Nrf2. Furthermore, the protective effect of D3T on ischemic cerebral infarction reduction was abolished in stroke animals lacking Nrf2 and in stroke animals treated with an HO-1 inhibitor.These results suggest that D3T-mediated inhibition of ischemic brain inflammation is mediated through the Nrf2 / HO-1 pathway, and therefore targeting the Nrf2 / HO-1 pathway may be a promising therapeutic strategy to alleviate neuroinflammation in ischemic stroke.

[0008] Nrf2 is thought to play a key role in certain hemoglobinopathies, such as beta-thalassemia and sickle cell disease (SCD). SCD is a recessive genetic disorder caused by a single missense mutation, resulting in mutant beta-globin hemoglobin S (HbS). Under low oxygen concentrations, HbS polymerizes, causing deformed red blood cells to rupture easily, releasing free heme into the plasma. The resulting oxidative stress and inflammation lead to damage in multiple organs in the body. Ablation of Keap1 and constitutive activation of Nrf2 have been shown to lead to improved prognosis in SCD model mice (Zhu, Blood, doi: 10.1182 / blood-2017-10-810531; Keleku-Lukwete PNAS, doi: 10.1073 / pnas.1509158112). Nrf2 activation has been shown to slow the development of hemolytic anemia and organ dysfunction (Ghosh, JCI Insight, doi:10.1172 / jci.insight.81090), while loss of Nrf2 function exacerbates the pathophysiology of SCD in transgenic SCD mice (Zhu, Blood, doi.org / 10.1182 / blood-2017-10-810531). Global activation of Nrf2 with the known compound D3T reduces lethality in a heme-induced acute chest syndrome model in transgenic SCD mice (Ghosh, Brit. J. Heamtology, doi:10.1111 / bjh.15401). Furthermore, Nrf2 activators have been shown to regulate fetal hemoglobin (HbF) expression by directly binding to the γ-globin promoter and modifying chromatin structure in the β-globin locus. In sickle cell erythrocytes, Nrf2 provides unique benefits through HbF induction to inhibit hemoglobin S polymerization and protect against oxidative stress caused by chronic hemolysis (Zhu et al., Exp Biol Med (Maywood). 2019 Feb;244(2):171-182). Therefore, the development of small molecule activators of Nrf2 has the potential to improve the clinical severity of sickle cell disease and other diseases where increased HbF is beneficial, such as beta-thalassemia.

[0009] Nrf2 function is altered in many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Friedreich's ataxia (Dinkova-Kostova, FEBS [Federation of European Biochemical Societies], doi:10.1111 / febs.14379). Nrf2 activation mitigates multiple pathogenic processes associated with these neurodegenerative disorders by upregulating antioxidant defenses, suppressing inflammation, improving mitochondrial function, and maintaining protein homeostasis. Small-molecule pharmacological activators of Nrf2 have shown protective effects in various animal models of neurodegenerative diseases (Joshi, Neurobiol Aging, doi:10.1016 / j.neurobiolaging.2014.09.004; Alarcon-Aguilar, Neurobiol Aging, doi:10.1016 / j.neurobiolaging.2014.01.143) and in human cell cultures expressing mutant proteins. Tecfidera (dimethyl fumarate) activates Nrf2 (among other mechanisms) and is approved in the United States for the treatment of relapsing-remitting multiple sclerosis. The Nrf2 activator omaveloxolone (RTA-408) is currently in a Phase II clinical trial for the treatment of the inherited neurodegenerative disorder Friedreich's ataxia, and has achieved its primary endpoint of a change in the modified Friedreich's Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks of treatment. Therefore, targeting Nrf2 signaling may provide a therapeutic option to delay the onset, slow the progression, and improve the symptoms of neurodegenerative disorders.

[0010] Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints, characterized by periods of flare-ups and remissions. Sometimes multiple joints are affected, leading to permanent joint destruction and deformity. Nrf2 has been found to be activated in the joints of arthritic mice and RA patients. Nrf2 knockout mice have more severe cartilage damage and increased oxidative damage, and during antibody-induced arthritis, the expression of Nrf2 target genes is enhanced in Nrf2 wild-type but not knockout mice (Wruck, BMJ Annals of Rheumatic Diseases, doi:10.1136 / ard.2010.132720). Furthermore, in an animal model of rheumatoid arthritis using serum transferred from K / BxN transgenic mice to Nrf2(- / -) mice, Nrf2 deficiency accelerated the onset of arthritis, and the animals exhibited widespread disease affecting both the forepaws and hindpaws (Maicas, Antioxidants & Redox Signaling, doi: 10.1089 / ars.2010.3835).

[0011] Ulcerative colitis (UC) and Crohn's disease (CD) are chronic, relapsing-remitting inflammatory bowel diseases (IBD) caused by intestinal epithelial dysfunction. Damage to intestinal epithelial cells can disrupt the barrier function of the intestinal epithelium, promoting abnormal immune responses and inflammatory conditions. Therefore, an intact intestinal epithelium is crucial for a healthy intestine, and cytoprotective agents that can target intestinal epithelial cells would be beneficial for the treatment of UC and CD. CPUY192018, a small molecule inhibitor of the Keap1-Nrf2 protein-protein interaction (hence also called an Nrf2 activator), has been shown to have cytoprotective effects on both NCM460 cells and mouse colon in an experimental model of UC induced by dextran sulfate sodium (Lu, Scientific Reports, doi:10.1038 / srep26585). Nrf2 knockout mice have also been shown to have increased susceptibility to colitis-associated colorectal cancer (Khor, Cancer Prev Res (Phila), doi: 10.1158 / 1940-6207).

[0012] Fumaderm (a mixture of three salts of dimethyl fumarate (DMF) and monoethyl fumarate) was licensed in Germany in 1994 for the treatment of psoriasis. Monomethyl fumarate (MMF), the likely bioactive form of DMF, has been shown to increase total and nuclear Nrf2 levels in primary mouse keratinocytes and lead to enhanced mRNA expression of several Nrf2 downstream effectors such as heme oxygenase-1 and peroxidase-6. (Helwa, J Pharmacol. Exp. Ther., doi: 10.1124 / jpet.116.239715). Other skin disorders may benefit from treatment with Nrf2 activators, such as radiation-induced dermatitis / skin damage, atopic dermatitis, and wound healing (Wu et al., Mol Med Rep. 2019 Aug;20(2):1761-1771).

[0013] Activation of Nrf2 has been shown to have beneficial effects on both liver and kidney diseases. NAFLD (non-alcoholic fatty liver disease) is considered the leading cause of chronic liver disease worldwide. NAFLD represents a variety of diseases, some of which may progress to cirrhosis and hepatocellular carcinoma (HCC). Although all subtypes of NAFLD increase the risk of cardiovascular events and death, NASH (non-alcoholic steatohepatitis) is the predominant diagnosed subtype of NAFLD, which predisposes patients to cirrhosis and liver-related complications. Currently, drug treatments for NAFLD and NASH have been approved. However, knockout of Nrf2 in mice strongly predisposes to NASH stimulated by a methionine- and choline-deficient (MCD) diet (Chowdry, Free Radic Biol Med, doi:10.1016 / j.freeradbiomed.2009.11.007) or a high-fat (HF) diet (Okada, J Gastroenterol, doi:10.1007 / s00535-012-0659-z), and pharmacological activation of Nrf2 has been shown to reverse NASH in mouse models (Sharma, Cell Mol Gastroenterol Hepatol, doi:10.1016 / j.jcmgh.2017.11.016). Other liver diseases, such as toxin-induced liver disease, viral hepatitis, and cirrhosis, may benefit from treatment with Nrf2 activators. Oxidative stress molecules (such as reactive oxygen species) accumulate in the kidneys of animal models of acute kidney injury (AKI), where Nrf2 is transiently activated. Genetic or pharmacological enhancement of Nrf2 activity in the renal tubules significantly ameliorates AKI-related damage and prevents progression from AKI to chronic kidney disease (CKD) by reducing oxidative stress. However, a phase III clinical trial of the KEAP1 inhibitors CDDO-Me or bardoxolone methyl in patients with stage 4 CKD and type 2 diabetes mellitus (T2DM) was terminated due to cardiovascular events. Because recent basic research has accumulated positive results for KEAP1 inhibitors in intermediate stages of CKD, phase II trials have been reinitiated. Data from ongoing programs suggest that Nrf2 activators / KEAP1 inhibitors can improve glomerular filtration rate in patients with type 3 CKD and T2DM without safety concerns (Nezu, Am J Nephrol, doi:10.1159 / 000475890). Inflammation and oxidative stress have been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common chronic kidney disease with a relatively poor prognosis and unsatisfactory treatment options.CXA-10, which upregulates the Nrf2 pathway, is currently in clinical trials for focal segmental glomerulosclerosis (FIRSTx-A Study of Oral CXA-10 in Primary Focal Segmental Glomerulosclerosis (FSGS); clinicaltrials.gov / ct2 / show / NCT03422510). In a Phase II clinical trial, bardoxolone methyl led to significant improvements in kidney function after 12 weeks of treatment in patients with autosomal dominant polycystic kidney disease (ADPKD), type 1 diabetes-related CKD (T1D), IgA nephropathy (IgAN), or FSGS (https: / / www.reatapharma.com / press-releases / reata-announces-positive-phase-2-data-for-bardoxolone-methyl-in-patients-with-focal-segmental-glomerulosclerosis-and-in-patients-from-all-four-cohorts-of-phoenix / ). Alport syndrome is the second most common genetic cause of kidney failure, caused by a genetic defect in type IV collagen, a component of the glomerular basement membrane. Because bardoxolone methyl is believed to affect underlying pathological processes related to mitochondrial dysfunction, inflammation, and oxidative stress, it is currently being studied in these patients, suggesting that Nrf2 activators may be useful in this setting.

[0014] Oxidative stress plays a key role in the development and progression of cancer (Gorrini, Nat Rev Drug Discov., doi:10.1038 / nrd4002). Due to its importance in maintaining redox cellular homeostasis, Nrf2 is considered a cytoprotective transcription factor and tumor suppressor. At low steady-state levels, Nrf2 eliminates ROS, carcinogens, and other DNA-damaging substances, thereby inhibiting tumor development and metastasis (Milkovic et al. Redox Biol., doi:10.1016 / j.redox.2017.04.013). Evgen is currently evaluating SFX-01 (sulforaphane-cyclodextrin complex) for the treatment and evaluation of metastatic breast cancer (STEM), including ER+ / HER- metastatic breast cancer (clinicaltrials.gov / ct2 / show / NCT02970682). Bardoxolone derivatives have been shown to prevent vinyl carbamate-induced lung cancer in A / J mice (Liby, Cancer Res. doi: 10.1158 / 0008-5472). Therefore, activators of Nrf2 may play a role in preventing cancer.

[0015] Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries, and oxidative stress plays a major role in the pathogenesis and progression of AMD. Studies have shown that Nrf2 activators can protect cells in the outer layer of the retina from oxidative stress, suggesting that vision can be preserved in patients with early AMD (Bellezza, Front Pharmacol. 2018;9:1280). Furthermore, Nrf2 activators may be useful in other ocular conditions, such as Fuchs' corneal endothelial dystrophy and uveitis.

[0016] Therefore, given the role of Nrf2 in multiple indications, there remains a need for agents that can activate Nrf2. Summary of the Invention

[0017] In one aspect, the invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0019] In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0020] In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[0021] In another aspect, the present invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[0022] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by Nrf2 activation, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0023] Examples of diseases or disorders mediated by Nrf2 activation include chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease, and non-alcoholic steatohepatitis.

[0024] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0025] In another aspect, the present invention provides use of a compound or a pharmaceutically acceptable salt in the preparation of a medicament for treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease, or nonalcoholic steatohepatitis.

[0026] In another aspect, the present invention provides a method of treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0027] The present invention also provides methods for synthesizing the compounds as defined herein, or pharmaceutically acceptable salts thereof.

[0028] In another aspect, the present invention provides a compound obtainable by, or by, or directly by a synthetic process as defined herein, or a pharmaceutically acceptable salt thereof.

[0029] In another aspect, the invention provides novel intermediates as defined herein suitable for use in any of the synthetic methods set out herein.

[0030] Preferred, suitable and optional features of any particular aspect of the invention are also preferred, suitable and optional features of any other aspect. DETAILED DESCRIPTION

[0031] definition

[0032] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0033] It should be understood that references to "treating" or "treatment" include preventing as well as alleviating established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or condition that develops in a person who may have or be susceptible to the condition, disorder, or condition but does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) palliating or alleviating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0034] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to affect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0035] In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups such as "propyl" are specific only to the straight-chain version, and references to individual branched-chain alkyl groups such as "isopropyl" are specific only to the branched version. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0036] In this specification, the term "alkylene" includes straight-chain and branched divalent alkyl groups. For example, "C 1-4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene and butene.

[0037] In this specification, the term "alkoxy" includes straight and branched chain alkyl groups connected to an oxygen single bond. For example, "C 1-4 "Alkoxy" includes methoxy, ethoxy, isopropoxy and tert-butoxy.

[0038] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

[0039] "Cycloalkyl" refers to a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bicyclic rings can be fused or spiro-connected; examples of bicyclic cycloalkyls include bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, spiro[2.4]heptane, bicyclo[4.1.0]heptane, and bicyclo[2.2.1]heptane.

[0040] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0041] The term "haloalkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include fluoroalkyl groups, such as -CHF2, -CH2CF3, or perfluoroalkyl / alkoxy groups, such as -CF3 or -CF2CF3.

[0042] The term "heterocyclyl", "heterocyclic" or "heterocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring systems. Monocyclic heterocycles contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. One or more bicyclic heterocycles can be fused, spiro or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetane, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl and the like. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiazolinone. Other heterocycles include dihydro-oxathiols, dihydroisoxazolyls (e.g., 4,5-dihydroisoxazolyls), dihydropyridyls (e.g., 1,2-dihydropyridyls or 1,6-dihydropyridyls), tetrahydro-oxazolyls, tetrahydro-oxadiazolyls, tetrahydro-dioxazolyls, tetrahydro-oxathiazolyls, hexahydrotriazinyls, tetrahydro-oxazinyls, morpholinyls, thiomorpholinyls, tetrahydropyrimidinyls, dioxolinyls, octahydrobenzofuranyls, octahydrobenzimidazolyls, and octahydrobenzothiazolyls. Sulfur-containing heterocycles also include sulfur-oxidized heterocycles containing SO or SO groups. Examples include tetrahydrothiophene and thiomorpholinyls in the sulfoxide and sulfone forms, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​of heterocyclic radicals with 1 or 2 oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidyl.Specific heterocyclic radicals are saturated monocyclic 3 to 7 membered heterocyclic radicals comprising 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulphur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidyl, homopiperidinyl, piperazinyl or homopiperazinyl.As will be appreciated by the skilled artisan, any heterocycle can be connected to another group via any suitable atom (such as via carbon or nitrogen atom). Suitably, the term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a 4, 5, 6 or 7 membered monocyclic ring as defined above.

[0043] The term "heteroaryl" or "heteroaromatic" means an aromatic monocyclic, bicyclic or polycyclic ring incorporating one or more (e.g., 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more typically from 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic ring, such as a bicyclic structure formed by a fused five-membered and six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring includes at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in a heteroaryl group (including any amino group substituent of the ring) will be less than 5. Suitably, the term "heteroaryl" or "heteroaromatic" refers to a 5 or 6 membered monocyclic heteroaryl ring as defined above.

[0044] Non-limiting examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, Cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolane, 2,2-dioxa-1,3-dihydro-2-benzothiophenyl, 4,5,6,7-tetrahydrobenzofuranyl, indolyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7-tetrahydrobenzo[d]isoquinolyl, oxazolyl, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0045] Non-limiting examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0046] Non-limiting examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0047] Specific non-limiting examples of bicyclic heteroaryl groups comprising a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0048] Specific non-limiting examples of bicyclic heteroaryl groups comprising two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0049] Specific non-limiting examples of bicyclic heteroaryl groups comprising a five-membered ring fused to a five-membered ring include, but are not limited to, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0050] The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In this embodiment, aryl is phenyl or naphthyl, particularly phenyl.

[0051] The term "carboxylic acid mimicking group" refers to an alternative structure or isostere of a carboxylic acid group that generally retains the characteristics of the carboxylic acid group required for biological activity, but changes the physicochemical properties of the resulting compound, such as acidity or lipophilicity. Such carboxylic acid mimicking groups are known to those skilled in the art of pharmaceutical chemistry. Examples of carboxylic acid mimicking groups include, but are not limited to, tetrazole, 3-trifluoromethyl-1,2,4-triazole, hydroxamic acid, hydroxamate, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfonylurea, acylurea, thiazolidinedione, oxazolidinedione, oxadiazole-5 (4H)-one, thiadiazole-5 (4H)-one, oxadiazole-2-oxide, oxadiazole-5 (4H)-thione, isoxazole, tetracarboxylic acid, cyclopentane-1,3-dione and cyclopentane-1,2-dione.

[0052] The term "optionally substituted" refers to substituted groups, structures or molecules as well as unsubstituted groups, structures or molecules.

[0053] When optional substituents are selected from "one or more" groups, it is to be understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0054] The phrase "compounds of the invention" refers to those compounds disclosed both generally and specifically herein.

[0055] Compounds of the present invention

[0056] In a first aspect, the present invention provides a compound having formula I

[0057]

[0058] in:

[0059] R 1 Selected from C 1-4 Alkylene-R 11 , heterocyclyl and 8-10 membered bicyclic heteroaryl, wherein the heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of: C 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 、C 1-3 Alkylene-OR 14 , and optionally one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 wherein the 8-10 membered bicyclic heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH and C 1-3 Substitution of alkoxy groups;

[0060] R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl;

[0061] R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 alkyl halides and cyano groups;

[0062] R 4 is hydrogen or C 1-4 alkyl;

[0063] R5 Yes-C(O)-C 1-4 alkyl, -C(O)-heteroaryl or -C(O)-aryl, wherein the heteroaryl and aryl are optionally substituted by one or more selected from C 1-4 Alkyl, halogen, hydroxyl, C 1-3 Alkoxy, CO2R 15 and substituted with a cyano substituent; or

[0064] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring wherein:

[0065] The heterocyclyl ring comprises one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or optionally spiro-attached to a C 3-7 a cycloalkyl group; and

[0066] The heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO2R 20 Substituents substituted;

[0067] L 1 and L 2 independently selected from a bond and -CR 21 R 22 -;

[0068] R 6 and R 7 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 cycloalkyl; or

[0069] R 6 and R 7 together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0070] R 8 Selected from CO2R 23 、C(O)NHSO2C 1-3Alkyl, tetrazolyl, 3-trifluoromethyl-1,2,4-triazol-5-yl, and carboxylic acid mimicking groups selected from hydroxamic acid, hydroxamate, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfonylurea, acylurea, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-one, oxadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetracarboxylic acid, cyclopentane-1,3-dione, and cyclopentane-1,2-dione;

[0071] R 9 Selected from hydrogen, C 1-4 Alkyl, hydroxyl, C 1-3 alkoxy and halide;

[0072] R 10 Selected from hydrogen and C 1-4 alkyl; or

[0073] R 9 and R 10 together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; or

[0074] L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocyclyl ring wherein:

[0075] The heterocyclic group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0076] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally joined by a C 1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 an alkylene group; and

[0077] The cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Substitution with haloalkyl and deuterium substituents;

[0078] R 11 Selected from -C(O)-R 24 、-SO2-R 25 、-NR 26 C(O)-R 27 、-NR 28 SO2-R 29, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substituted with alkoxy, heterocyclyl and cyano; and the heterocyclyl group is optionally substituted with one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substitution of alkoxy, oxo, and cyano substituents;

[0079] R 12 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0080] R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0081] R 17 Selected from hydrogen, C 1-4 Alkyl, C(O)C 1-3 Alkyl and C(O)NR 36 R 37 ;

[0082] R 18 、R 19 and R 20 Independently selected from C 1-4 Alkyl, OH, C 1-3 Alkoxy and NR 38 R 39 ;

[0083] R 24Selected from C 1-4 Alkyl, NR 40 R 41 OR 42 ;

[0084] R 25 Selected from C 1-4 Alkyl and NR 43 R 44 ;

[0085] R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 45 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0086] R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 46 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0087] R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ;

[0088] R 40 Selected from hydrogen and C 1-4 alkyl;

[0089] R 41 Selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 alkoxy, aryl and heteroaryl; or

[0090] R 40 and R 41Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 3-7 Substitution of cycloalkyl and cyano groups;

[0091] R 45 and R 46 Independently selected from hydroxyl, C 1-3 Alkoxy and C 3-7 cycloalkyl; and

[0092] R 14 、R 15 、R 16 、R 21 、R 22 、R 23 、R 26 、R 28 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 42 、R 43 、R 44 、R 47 and R 48 are each independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl;

[0093] or a pharmaceutically acceptable salt thereof.

[0094] Specific compounds of the present invention include, for example, compounds having Formula I or pharmaceutically acceptable salts thereof, wherein, unless otherwise specified, R 1 、R 2 、R 3 、R 4 、R 5 , L 1 , L 2 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 17 、R 18 、R 19、R 20 、R 24 、R 25 、R 27 、R 29 、R 30 、R 40 and R 41 each has any meaning defined in paragraphs (1) to (86) above or below:-

[0095] (1)R 1 It is C 1-4 Alkylene-R 11 ;

[0096] (2)R 1 It is CH2-R 11 ;

[0097] (3)R 1 It is CH2CH2-R 11 ;

[0098] (4)R 1 is CH(Me)-R 11 ;

[0099] (5)R 1 is a heterocyclyl group optionally substituted by one or more substituents independently selected from the group consisting of: C 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 , and the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0100] (6)R 1 is a heterocyclyl group optionally substituted by one or more substituents independently selected from the group consisting of: C 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 , and the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl and C 3-7 Substitution of cycloalkyl groups;

[0101] (7)R 1 is piperidinyl or pyrrolidinyl, each optionally substituted with one or more substituents independently selected from: -C(O)-R 12、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 , and the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0102] (8)R 1 is pyrrolidinyl optionally substituted with one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 , and the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 cycloalkyl substitution;

[0103] (9)R 1 One selected from the following groups:

[0104]

[0105] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected from -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl group is optionally substituted by a C 1-4 Alkyl or C 3-7 cycloalkyl substitution;

[0106] (10)R 1 is an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of: C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH and C 1-3 alkoxy;

[0107] (11)R 1 is an 8-membered bicyclic heteroaryl group optionally substituted by one or more substituents independently selected from the group consisting of: C 1-4 Alkyl, OH and C 1-3 alkoxy;

[0108] (12)R 1is 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl or 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl, each of which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH and C 1-3 Substitution of alkoxy groups;

[0109] (13)R 1 One selected from the following groups:

[0110]

[0111] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, heterocycloalkyl and cyano groups;

[0112] (14)R 1 One selected from the following groups:

[0113]

[0114] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 、C 1-3 Substitution of alkoxy and cyano groups;

[0115] (15)R 1 One selected from the following groups:

[0116]

[0117]

[0118] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected C 1-4 Alkyl, C1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, heterocycloalkyl and cyano groups;

[0119] (16)R 1 One selected from the following groups:

[0120]

[0121] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected C 1-4 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0122] (17)R 1 yes:

[0123]

[0124] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein the group is optionally substituted by one or more independently selected from C 1-4 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0125] (18)R 1 yes:

[0126]

[0127] (19)R 2 is selected from hydrogen, fluorine and chlorine;

[0128] (20)R 2 is hydrogen or fluorine;

[0129] (21)R 3 Selected from hydrogen, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 alkyl halides and cyano groups;

[0130] (22)R 3 is selected from hydrogen, chlorine, bromine, methoxy, methyl, trifluoromethyl and cyano;

[0131] (23)R 3 selected from hydrogen and chlorine;

[0132] (24)R 3 It is chlorine;

[0133] (25)R 4 It is hydrogen;

[0134] (26)R 5 Yes-C(O)-C 1-4 Alkyl or -C(O)-aryl, wherein the aryl group is optionally substituted by one or more selected from C 1-4 Alkyl, halogen, hydroxyl, C 1-3 Alkoxy, CO2R 15 and cyano substituents;

[0135] (27)R 4 is hydrogen and R 5 Yes-C(O)-C 1-4 Alkyl or -C(O)-aryl, wherein the aryl group is optionally substituted by one or more selected from C 1-4 Alkyl, halogen, hydroxyl, C 1-3 Alkoxy, CO2R 15 and cyano substituents;

[0136] (28)R 4 is hydrogen and R 5 Yes-C(O)-C 1-4 Alkyl or -C(O)-aryl, wherein the aryl group is optionally substituted by one or more radicals selected from halo, hydroxy and CO2R 15 Substituents substituted;

[0137] (29)R 4 is hydrogen and R 5 is -C(O)-aryl, wherein the aryl group is optionally substituted by one or more selected from fluorine, hydroxy and CO2R 15 a phenyl group substituted with a substituent;

[0138] (30)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring wherein:

[0139] The heterocyclyl ring comprises one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or optionally spiro-attached to a C 3-7 a cycloalkyl group; and

[0140] The heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R18 、S(O)R 19 and SO2R 20 Substituents substituted;

[0141] (31)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl or heterocyclyl ring wherein:

[0142] The heterocyclyl ring comprises a -C(O)- moiety attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or is optionally spiro-attached to a C 3-7 a cycloalkyl group; and

[0143] The heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0144] (32)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl ring, which is optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0145] (33)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl ring, which is optionally substituted by one or more independently selected from C 1-4 Substitution of alkyl, halide and OH groups;

[0146] (34)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a pyrazolyl ring, which is optionally substituted by one or more independently selected from C 1-4 Substitution of alkyl, halide and OH groups;

[0147] (35)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl ring comprises a -C(O)- moiety attached to the nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or optionally to a C 3-7 The cycloalkyl group is spiro-connected; and the heterocyclyl ring is optionally substituted by one or more independently selected C 1-4 Substitution of alkyl, halide and OH groups;

[0148] (36)R 4 and R 5together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the heterocyclyl ring comprises a -C(O)- moiety attached to the nitrogen atom and is optionally fused to a phenyl or heteroaryl ring, or is optionally spiro-attached to a cyclopropyl group; and the heterocyclyl ring is optionally substituted with one or more substituents independently selected from methyl, fluoro and OH;

[0149] (37)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following:

[0150]

[0151] wherein the saturated ring of the heterocyclic portion is optionally fused with C 3-7 The cycloalkyl group is spiro-linked, and wherein the heterocyclic portion is optionally substituted by one or more independently selected C 1-4 Substitution of alkyl, halide and OH groups;

[0152] (38)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following:

[0153]

[0154] wherein the saturated ring of the heterocyclic moiety is optionally spiro-attached to a cyclopropyl group, and wherein the heterocyclic moiety is optionally substituted with one or more substituents independently selected from methyl, fluoro and OH;

[0155] (39)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form the following heterocyclic moiety:

[0156]

[0157] wherein the heterocyclic moiety is optionally spiro-attached to a cyclopropyl group and is optionally substituted with one or more substituents independently selected from methyl and fluoro;

[0158] (40)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form the following heterocyclic moiety:

[0159]

[0160] wherein the heterocyclic moiety is optionally spiro-connected to a cyclopropyl group and is optionally C 1-3 Alkyl substituted, wherein the cyclopropyl and / or C 1-3 The alkyl group is attached to the heterocycle at the alpha position or to the carbonyl group at the beta position;

[0161] (41)L 1 and L 2 are independently selected from a bond and -CH2-;

[0162] (42)L 1 is a key and L 2 It is -CH2-;

[0163] (43)L 1 is CH2- and L 2 It is a key;

[0164] (44)L 1 and L 2 All are keys;

[0165] (45)R 6 and R 7 independently selected from hydrogen and C 1-4 alkyl;

[0166] (46)R 6 and R 7 independently selected from hydrogen and methyl;

[0167] (47)R 6 and R 7 together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0168] (48)R 8 Selected from CO2R 23 、C(O)NHSO2C 1-3 Alkyl, tetrazolyl and 3-trifluoromethyl-1,2,4-triazol-5-yl;

[0169] (49)R 8 Selected from CO2R 23 、C(O)NHSO2C 1-3 Alkyl and tetrazolyl groups;

[0170] (50)R 8 is selected from CO2H, C(O)NHSO2Me and tetrazolyl;

[0171] (51)R 8 It is CO2H;

[0172] (52)R 9 Selected from hydrogen, C 1-4 Alkyl, C 1-3 alkoxy and halide;

[0173] (53)R 9 is selected from the group consisting of hydrogen, methyl, methoxy and fluorine;

[0174] (54)R9 Selected from C 1-4 Alkyl, C 1-3 alkoxy and halide;

[0175] (55)R 9 selected from methyl, methoxy and fluoro;

[0176] (56)R 9 is hydrogen or C 1-4 alkyl;

[0177] (57)R 9 is hydrogen or methyl;

[0178] (58)R 9 It is a methyl group;

[0179] (59)R 10 is selected from hydrogen and methyl;

[0180] (60)R 9 and R 10 together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0181] (61)L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, or 6-membered cycloalkyl or heterocyclyl ring wherein:

[0182] The heterocyclic group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0183] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally joined by a C 1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 an alkylene group; and

[0184] The cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy and deuterium substituents;

[0185] (62)L 1 and L 2 are all bonds, and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, or 6-membered cycloalkyl or heterocyclyl ring wherein:

[0186] The heterocyclic group contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0187] The cycloalkyl ring optionally contains a carbon-carbon double bond and is optionally joined by a C 1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 an alkylene group; and

[0188] The cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy and deuterium substituents;

[0189] (63)L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, or 6-membered cycloalkyl ring, wherein the cycloalkyl ring is optionally composed of a C 1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 Alkylene groups, the cycloalkyl ring is optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy and deuterium substituents;

[0190] (64)L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached, they form a cyclohexyl ring, wherein the cyclohexyl ring optionally contains a carbon-carbon double bond and is optionally connected by a C 1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 Alkylene group, the cyclohexyl ring is optionally replaced by one or more independently selected C 1-4 Substitution with alkyl, halide, OH and deuterium substituents;

[0191] (65)R 11 Selected from -C(O)-R 24 、-NR 26 C(O)-R 27 and heteroaryl, wherein the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, heterocyclic and cyano groups;

[0192] (66)R 11 Yes-C(O)-R 24 And R 24 Selected from NR 40 R 41 OR 42 ;

[0193] (67)R 11 Yes-NR 26 C(O)-R 27 And R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl and C 3-7 Substitution of cycloalkyl groups;

[0194] (68)R 11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 heteroaryl substituted with a substituent of an alkoxy group, a heterocyclic group, or a cyano group;

[0195] (69)R 11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 、C 1-3 heteroaryl substituted with alkoxy and cyano substituents;

[0196] (70)R 11 is optionally substituted by one or more independently selected from methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, cyano, oxetanyl, CH2-R 30 and CH2CH2-R 30 a heteroaryl group substituted with a substituent of

[0197] (71)R 11 is pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted by one or more independently selected from C1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, heterocyclic and cyano groups;

[0198] (72)R 11 is a heteroaryl group selected from:

[0199]

[0200] Each heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, heterocycloalkyl and cyano groups;

[0201] (73)R 11 is oxazolyl, isoxazolyl or 1,2,3-triazolyl, each of which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, heterocycloalkyl and cyano groups;

[0202] (74)R 11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 1,2,3-triazolyl substituted with alkoxy, heterocycloalkyl and cyano substituents;

[0203] (75)R 11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 heterocyclic groups substituted with alkoxy, oxo and cyano substituents;

[0204] (76)R11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Heterocyclic groups substituted with haloalkyl, halo, OH and oxo substituents;

[0205] (77)R 11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 dihydroisoxazolyl or dihydropyridinyl substituted with haloalkyl, halo, OH and oxo;

[0206] (78)R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl and heteroaryl, wherein the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl and C 1-3 Substitution of haloalkyl groups;

[0207] (79)R 29 is methyl, ethyl or cyclopropyl;

[0208] (80)R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0209] (81)R 30 is selected from hydroxy, methoxy, cyclopropyl and cyano;

[0210] (82)R 40 is selected from hydrogen and methyl;

[0211] (83)R 41 is selected from hydrogen, methyl, cyclopropyl, methoxy and phenyl;

[0212] (84)R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 3-7 Substitution of cycloalkyl and cyano groups;

[0213] (85)R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 5-membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more independently selected from C 1-4 Substitution of alkyl, halide and OH groups;

[0214] (86)R 40 and R 41 Together with the nitrogen atom to which they are attached they form a 5-membered heterocyclyl ring, wherein said heterocyclyl ring is optionally substituted with one or more substituents independently selected from methyl, fluoro and OH.

[0215] Suitably, R 1 is as defined in any of paragraphs (1) to (18) above. In one embodiment, R 1 is as defined in paragraph (2) above. In another embodiment, R 1 is as defined in paragraphs (7) to (9) above. In another embodiment, R 1 is as defined in any of paragraphs (13) to (18) above. In another embodiment, R 1 is as defined in paragraphs (16) to (18) above.

[0216] Suitably, R 2 is as defined in any of paragraphs (19) to (20) above. In one embodiment, R 2 is as defined in paragraph (20) above.

[0217] Suitably, R 3 is as defined in any of paragraphs (21) to (24) above. In another embodiment, R 3 is as defined in paragraphs (23) to (24) above.

[0218] Suitably, R 4 is as defined in paragraph (25) above.

[0219] Suitably, R 5 is as defined in paragraph (26) above.

[0220] Suitably, R 4 and R 5 is as defined in any of paragraphs (27) to (29) above. In another embodiment, R 4 and R 5 is as defined in paragraph (29) above. In one embodiment, R 4 and R 5 is as defined in paragraphs (30) to (40) above. In another embodiment, R 4 and R 5 is as defined in paragraphs (37) to (40) above. In another embodiment, R 4 and R 5 is as defined in paragraph (34) above. In another embodiment, R4 and R 5 is as defined in paragraph (40) above.

[0221] Appropriately, L 1 and L 2 is as defined in any of paragraphs (41) to (44) above. In another embodiment, L 1 and L 2 is as defined in paragraph (44) above.

[0222] Suitably, R 6 and R 7 is as defined in any of paragraphs (45) to (47) above. In another embodiment, R 6 and R 7 is as defined in paragraph (46) above.

[0223] Suitably, R 8 is as defined in any of paragraphs (48) to (51) above. In another embodiment, R 8 is as defined in paragraphs (50) to (51) above. In one embodiment, R 8 is as defined in paragraph (51) above.

[0224] Suitably, R 9 is as defined in any of paragraphs (52) to (58) above. In another embodiment, R 9 is as defined in paragraphs (57) to (58) above. In one embodiment, R 9 is as defined in paragraph (58) above.

[0225] Suitably, R 10 is as defined in paragraph (59) above.

[0226] Suitably, R 9 and R 10 is as defined in paragraph (60) above.

[0227] Appropriately, L 2 、R 7 and R 10 is as defined in any of paragraphs (61) to (64) above. In another embodiment, L 2 、R 7 and R 10 is as defined in paragraph (64) above.

[0228] Suitably, R 11 is as defined in any of paragraphs (65) to (77) above. In another embodiment, R11 is as defined in paragraphs (72) to (74) above. In another embodiment, R 11 is as defined in paragraphs (73) to (74) above. In another embodiment, R 1 is as defined in paragraph (2) above, and R 11 is as defined in paragraphs (72) to (74) above.

[0229] Suitably, R 29 is as defined in paragraphs (78) to (79) above. In one embodiment, R 29 is as defined in paragraph (79) above.

[0230] Suitably, R 30 is as defined in paragraphs (80) to (81) above. In one embodiment, R 30 is as defined in paragraph (81) above.

[0231] Suitably, R 40 is as defined in paragraph (82) above.

[0232] Suitably, R 41 is as defined in paragraph (83) above.

[0233] Suitably, R 40 and R 41 is as defined in any of paragraphs (84) to (86) above. In another embodiment, R 40 and R 41 is as defined in paragraph (86) above.

[0234] In another group of compounds, these compounds have the structural formula IA shown below:

[0235]

[0236] Among them L 1 and L 2 and R 1 to R 10 As defined above.

[0237] In another group of compounds, these compounds have the above structural formula IA, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 4 and R 5is as defined in any of paragraphs (37) to (40) above; 1 and L 2 is as defined in any of paragraphs (41) to (44) above; R 6 and R 7 is as defined in any of paragraphs (45) to (47) above; R 8 is as defined in any of paragraphs (48) to (51) above; R 9 is as defined in any of paragraphs (52) to (58) above; and R 10 is as defined in paragraph (59) above.

[0238] In another group of compounds, these compounds have the structural formula IB shown below:

[0239]

[0240] where R 1 to R 6 , R 8 and R 9 As defined above.

[0241] In another group of compounds, these compounds have the above structural formula IB, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 4 and R 5 is as defined in any of paragraphs (37) to (40) above; R 6 is hydrogen or methyl; R 8 is as defined in any of paragraphs (48) to (51) above; and R 9 is as defined in any of paragraphs (52) to (58) above.

[0242] In another group of compounds, these compounds have the above structural formula IB, wherein R 1 is as defined in any of paragraphs (13) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 4 and R 5 is as defined in any of paragraphs (37) to (40) above; R 6 is hydrogen or methyl; R 8is as defined in any of paragraphs (50) to (51) above; and R 9 is as defined in any of paragraphs (57) to (58) above.

[0243] In another group of compounds, these compounds have the structural formula IC shown below:

[0244]

[0245] where R 1 to R 6 and R 9 As defined above.

[0246] In another group of compounds, these compounds have the above structural formula IC, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 4 and R 5 is as defined in any of paragraphs (37) to (40) above; R 6 is hydrogen or methyl; and R 9 is as defined in any of paragraphs (57) to (58) above.

[0247] In another group of compounds, these compounds have the structural formula ID shown below:

[0248]

[0249] where R 1 to R 3 , R 6 and R 9 As defined above.

[0250] In another group of compounds, these compounds have the above structural formula ID, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 6 is hydrogen or methyl; and R 9 is as defined in any of paragraphs (57) to (58) above.

[0251] In another group of compounds, these compounds have the above structural formula ID, wherein R 1is as defined in any of paragraphs (9) and (13) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 6 is hydrogen; and R 9 is as defined in paragraph (58) above.

[0252] In another group of compounds, these compounds have the structural formula IE shown below:

[0253]

[0254] where R 1 to R 6 , R 8 and R 9 As defined above.

[0255] In another group of compounds, these compounds have the above structural formula IE, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (21) to (24) above; R 4 and R 5 is as defined in any of paragraphs (37) to (40) above; R 6 is hydrogen or methyl; R 8 is as defined in any of paragraphs (48) to (51) above; and R 9 is as defined in any of paragraphs (52) to (58) above.

[0256] In another group of compounds, these compounds have the above structural formula IE, wherein R 1 is as defined in any of paragraphs (13) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 4 and R 5 is as defined in any of paragraphs (37) to (40) above; R 6 is hydrogen or methyl; R 8 is as defined in any of paragraphs (50) to (51) above; and R 9 is as defined in any of paragraphs (57) to (58) above.

[0257] In another group of compounds, these compounds have the structural formula IF shown below:

[0258]

[0259] where R 1 to R 6 and R 9 As defined above.

[0260] In another group of compounds, these compounds have the above structural formula IF, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 4 and R 5 is as defined in any of paragraphs (37) to (40) above; R 6 is hydrogen or methyl; and R 9 is as defined in any of paragraphs (57) to (58) above.

[0261] In another group of compounds, these compounds have the structural formula IG shown below:

[0262]

[0263] where R 1 to R 3 , R 6 and R 9 As defined above.

[0264] In another group of compounds, these compounds have the above structural formula IG, wherein R 1 is as defined in any of paragraphs (7) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (21) to (24) above; R 6 is hydrogen or methyl; and R 9 is as defined in any of paragraphs (57) to (58) above.

[0265] In another group of compounds, these compounds have the above structural formula IG, wherein R 1 is as defined in any of paragraphs (9) and (13) to (18) above; R 2 is as defined in paragraph (20) above; R 3 is as defined in any of paragraphs (23) to (24) above; R 6is hydrogen; and R 9 is as defined in paragraph (58) above.

[0266] Specific compounds of the present invention include any of the following:

[0267] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazole-3-carboxamide)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0268] (1S,2R)-2-((S)-8-(2-(Benzo[d]oxazole-2-carboxamide)ethoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0269] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0270] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0271] (1S,2R)-2-((S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0272] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0273] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0274] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0275] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0276] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0277] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0278] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0279] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5,7-dichloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0280] (1S,2R)-2-((S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0281] (1S,2R)-2-((S)-1-((1-oxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0282] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0283] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0284] (1S,2R)-2-((S)-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0285] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0286] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(2-methylthiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0287] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0288] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0289] (1S,2R)-2-((S)-5-bromo-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0290] (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0291] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0292] (1S,2R)-2-((S)-5-bromo-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0293] (1S,2R)-2-((S)-5-bromo-8-((2-ethyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0294] (1S,2R)-2-((1S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((1-oxo-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0295] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0296] (1S,2R)-2-((S)-5-Bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0297] (1S,2R)-2-((S)-5-bromo-8-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0298] (1S,2R)-2-((S)-5-bromo-8-(imidazo[1,2-a]pyridin-7-ylmethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0299] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0300] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0301] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0302] (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0303] (1S,2R)-2-((S)-5-bromo-8-((7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0304] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0305] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0306] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0307] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0308] (1S,2R)-2-((S)-5-bromo-8-((4-ethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0309] (1S,2R)-2-((S)-5-bromo-8-((5-cyano-1-ethyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0310] (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0311] (1S,2R)-2-((1S)-5-bromo-8-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0312] (1S,2R)-2-((1S)-5-bromo-8-(1-(1-isopropyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0313] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0314] (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0315] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0316] (1S,2R)-2-((S)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-8-((1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0317] (1S,2R)-2-((S)-5-chloro-8-((1-(2,2-difluoroethyl)-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0318] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0319] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0320] (1S,2R)-2-((S)-5-chloro-8-((1-ethyl-1H-pyrazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0321] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0322] (1S,2R)-2-((S)-5-chloro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0323] (1S,2R)-2-((S)-5-fluoro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0324] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methyl-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0325] (1S,2R)-2-((S)-5-cyano-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0326] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxy-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0327] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0328] (1S,2R)-2-((S)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0329] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0330] (1S,2R)-2-((S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0331] (1S,2R)-2-((S)-5-bromo-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0332] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0333] (1S,2R)-2-((S)-8-(Benzo[d]isothiazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0334] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0335] (1S,2R)-2-((S)-5-chloro-8-((5-methylisothiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0336] (1S,2R)-2-((S)-5-chloro-8-(isothiazol-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0337] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid

[0338] (1S,2R)-2-((1S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0339] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0340] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0341] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0342] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0343] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0344] (R)-4-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-4-oxobutanoic acid;

[0345] 1-(((S)-2-((1R,2S)-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one;

[0346] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0347] (1S,2R)-2-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0348] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((4-methyl-1H-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0349] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrimidin-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0350] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid;

[0351] (1R,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid;

[0352] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0353] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0354] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0355] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0356] (1S,2R)-2-((S)-5-chloro-8-(imidazo[1,2-a]pyrimidin-2-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0357] (1S,2R)-2-((S)-5-chloro-8-(isoxazolo[5,4-b]pyridin-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0358] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0359] (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0360] 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

[0361] 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-carboxylic acid;

[0362] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-indazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0363] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0364] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0365] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluorocyclopentane-1-carboxylic acid;

[0366] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0367] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0368] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0369] (1R,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-fluorocyclohexane-1-carboxylic acid;

[0370] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0371] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0372] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0373] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0374] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0375] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0376] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0377] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0378] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0379] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0380] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0381] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclohexane-1-carboxylic acid;

[0382] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclopentane-1-carboxylic acid;

[0383] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0384] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0385] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0386] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0387] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0388] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0389] (1S,2R)-2-((S)-5-chloro-8-((4-chloro-5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0390] (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0391] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0392] (1S,2R)-2-((S)-5-chloro-8-((5-(2-methoxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0393] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0394] (1S,2R)-2-((S)-5-chloro-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0395] (1S,2R)-2-((S)-5-chloro-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0396] (1S,2R)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0397] (1S,2S)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0398] (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0399] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0400] (1S,2R)-2-((S)-5-chloro-8-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0401] (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0402] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0403] (1S,2R)-2-((S)-8-((2,5-bis(difluoromethyl)-2H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0404] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-carboxylic acid;

[0405] (R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid;

[0406] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,4-d2;

[0407] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0408] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0409] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0410] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0411] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0412] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0413] (1S,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0414] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0415] 1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2-((1R,2S)-2-methyl-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one;

[0416] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((4,4-dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0417] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0418] (1S,2R)-2-((S)-5-chloro-8-((5-methyl-4-(trifluoromethyl)isoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0419] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0420] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0421] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)-5-methylisoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0422] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0423] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0424] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0425] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0426] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0427] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0428] (1S,2R)-2-((1S)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0429] (1S,2R)-2-((S)-5-chloro-8-((6,7-difluorobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0430] (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0431] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0432] (1S,2R)-2-((S)-5-chloro-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0433] (1S,2S)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0434] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0435] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4-(trifluoromethyl)pyrimidin-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0436] (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0437] (1S,2R)-2-((S)-5-chloro-8-((1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0438] (1S,2R)-1-methyl-2-((S)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0439] (1S,2R)-2-((S)-5-chloro-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0440] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0441] (1S,2R)-2-((S)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0442] (1S,2R)-2-((S)-5-fluoro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0443] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0444] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0445] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0446] (1S,2R)-2-((S)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0447] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0448] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0449] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0450] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0451] (1S,2R)-2-((S)-5-chloro-8-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0452] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0453] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0454] (1S,2R)-1-methyl-2-((S)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0455] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0456] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0457] (1S,2R)-2-((S)-8-((1,5-bis(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0458] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0459] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0460] (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0461] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0462] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0463] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0464] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0465] (1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid;

[0466] 5-(((S)-2-((1R,2S)-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one;

[0467] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0468] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)thiazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0469] (1S,2R)-2-((S)-5-chloro-8-((5-methylthiazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0470] (1S,2R)-2-((S)-5-chloro-8-((2-methyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0471] (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid;

[0472] (1S,3S,4R,6R)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid;

[0473] (1S,2R)-2-((1S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0474] (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,5-d2;

[0475] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0476] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0477] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0478] (1S,2R)-2-((1S)-5-chloro-8-((1-methyl-1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0479] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluoro-1-methylcyclohexane-1-carboxylic acid;

[0480] (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid;

[0481] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4-d;

[0482] (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0483] (1S,2R,5S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0484] (1S,2R,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0485] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0486] (2S,3R)-3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-2-carboxylic acid;

[0487] (1R,2R,6S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0488] (1R,2R,6R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0489] (1S,2S,3R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid; and

[0490] (1S,2S,3S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[0491] or a pharmaceutically acceptable salt thereof.

[0492] In one embodiment, the compound of Formula I is selected from the following compounds:

[0493] (1S,2R)-2-((S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0494] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0495] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0496] (1S,2R)-2-((S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0497] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0498] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0499] (1S,2R)-2-((S)-5-bromo-8-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0500] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0501] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0502] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0503] (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0504] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0505] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0506] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0507] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0508] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0509] (1S,2R)-2-((S)-5-chloro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0510] (1S,2R)-2-((S)-5-cyano-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0511] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0512] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0513] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0514] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0515] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0516] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0517] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0518] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid;

[0519] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0520] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0521] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0522] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0523] (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0524] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0525] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0526] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0527] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0528] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0529] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0530] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0531] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0532] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0533] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0534] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0535] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0536] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0537] (1S,2R)-2-((S)-5-chloro-8-((5-(2-methoxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0538] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0539] (1S,2R)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0540] (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0541] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0542] (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0543] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0544] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,4-d2;

[0545] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0546] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0547] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0548] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0549] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0550] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0551] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((4,4-dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0552] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0553] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0554] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0555] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)-5-methylisoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0556] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0557] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0558] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0559] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0560] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0561] (1S,2R)-2-((1S)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0562] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0563] (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0564] (1S,2R)-1-methyl-2-((S)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0565] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0566] (1S,2R)-2-((S)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0567] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0568] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0569] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0570] (1S,2R)-2-((S)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0571] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0572] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0573] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0574] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0575] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0576] (1S,2R)-1-methyl-2-((S)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0577] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0578] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0579] (1S,2R)-2-((S)-8-((1,5-bis(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0580] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0581] (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0582] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0583] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0584] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0585] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0586] (1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid;

[0587] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0588] (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid;

[0589] (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,5-d2;

[0590] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0591] (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid; and

[0592] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4-d;

[0593] or a pharmaceutically acceptable salt thereof.

[0594] In one embodiment, the compound of Formula I is selected from the following compounds:

[0595] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0596] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0597] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0598] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0599] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0600] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0601] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0602] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,4-d2;

[0603] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0604] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0605] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0606] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0607] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0608] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0609] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0610] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0611] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0612] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0613] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0614] (1S,2R)-2-((S)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0615] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0616] (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0617] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0618] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0619] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0620] (1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid;

[0621] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0622] (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid;

[0623] (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,5-d2;

[0624] (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid; and

[0625] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4-d;

[0626] or a pharmaceutically acceptable salt thereof.

[0627] In one embodiment, the compound of Formula I is selected from the following compounds:

[0628] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0629] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0630] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0631] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,4-d2;

[0632] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0633] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0634] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0635] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0636] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0637] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; and

[0638] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4-d;

[0639] or a pharmaceutically acceptable salt thereof.

[0640] The various functional groups and substituents comprising the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, eg, less than 700, or less than 650.

[0641] Suitable or preferred features of any compound of the invention may also be suitable features of any other aspect.

[0642] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, with, for example, an acid addition salt of an inorganic or organic acid, the acid being, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts or salts formed with an organic base that provides a physiologically acceptable cation, for example, a salt formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0643] Compounds with the same molecular formula but different properties or orders of their atomic bonding or the arrangement of their atoms in space are called "isomers". The term "stereoisomer" refers to isomers whose atoms are different in spatial arrangement. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when the asymmetric center is bonded to four different groups, there may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described and designated as right-handed or left-handed (i.e., as (+) or (-)-isomers, respectively) by the R- and S-sequencing rules of Cahn and Prelog or by the way that molecules rotate the plane of polarized light. Chiral compounds can exist as individual enantiomers or their mixtures. A mixture comprising equal proportions of enantiomers is called a "racemic mixture".

[0644] The compounds of the present invention generally have one or more asymmetric centers; therefore, such compounds can be generated as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual enantiomers, diastereomers, and racemic mixtures or other mixtures thereof. Methods for stereochemical determination and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active raw materials or by splitting racemic forms. Some compounds of the present invention may have geometric isomer centers (E- and Z-isomers). It should be understood that the present invention encompasses all optical, diastereomers, and geometric isomers and mixtures thereof with Nrf2 activating activity.

[0645] The present invention also encompasses compounds of the present invention as defined herein that include one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; etc.

[0646] It will also be understood that certain compounds of the present invention may exist in solvated as well as unsolvated forms, such as hydrated forms, and it will be understood that the present invention encompasses all such solvated forms that possess Nrf2 activating activity.

[0647] It is also understood that certain compounds of the present invention may exhibit polymorphism, and that the present invention encompasses all such forms that possess Nrf2 activating activity.

[0648] Compound of the present invention can exist with many different tautomeric forms, and mentions that compound of the present invention comprises all such forms.For the avoidance of doubt, when compound can exist with one of several tautomeric forms, and only have one to be specifically described or when showing, compound of the present invention still comprises every other form.The example of tautomeric form comprises ketone, enol and enolate form, for example, in following tautomer pair: ketone / enol (shown hereinafter), imines / enamine, amides / imino alcohol, amidine / amidine, nitroso-group / oxime, thioketone / enethiol and nitro / acid nitro.

[0649]

[0650] The compounds of the present invention comprising amine functional groups can also form N-oxides. The compounds with formula I comprising amine functional groups mentioned herein also include N-oxides. When the compound comprises several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. The specific examples of N-oxides are tertiary amines of nitrogen-containing heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry [higher organic chemistry], edited by Jerry March, 4th edition, Wiley International Science Company (Wiley Interscience), pp. 1977. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. [synthetic communication] 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

[0651] The compounds of the present invention can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include ester derivatives that can be formed in vivo at carboxyl groups or hydroxyl groups in the compounds of the present invention and amide derivatives that can be formed in vivo at carboxyl groups or amino groups in the compounds of the present invention.

[0652] The present invention therefore includes those compounds of formula I as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of their prodrugs. The present invention therefore includes those compounds of formula I produced by organic synthesis and also those compounds produced in the human or animal body by metabolism of precursor compounds, i.e. compounds of formula I which may be synthetically produced compounds or metabolically produced compounds.

[0653] Suitable pharmaceutically acceptable prodrugs of the compounds of Formula I are those that are, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0654] Various forms of prodrugs have been described, for example, in the following documents:

[0655] a) Methods in Enzymology, Vol. Volume 42, pages 309-396, edited by K. Widder et al. (Academic Press, 1985);

[0656] b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

[0657] c) A Textbook of Drug Design and Development, eds. Krogsgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” pp. 113-191 (1991);

[0658] d)H.Bundgaard, Advanced Drug Delivery Reviews [Advanced Drug Delivery Reviews] , 8 ,1-38(1992);

[0659] e) H.Bundgaard et al., Journal of Pharmaceutical Sciences , 77 ,285(1988);

[0660] f) N. Kakeya et al., Chem.Pharm.Bull. [ Bulletin of Chemistry and Pharmacy ], 32 ,692(1984);

[0661] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; and

[0662] h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0663] Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which have a carboxyl group) are, for example, esters thereof which are cleavable in vivo. An in vivo cleavable ester of a compound of formula I comprising a carboxyl group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters of a carboxyl group include C 1-6 Alkyl esters such as methyl, ethyl and tert-butyl C 1-6 Alkoxymethyl esters such as methoxymethyl ester, C 1-6 Alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthaloyl ester, C 3-8 Cycloalkylcarbonyloxy-C 1-6 Alkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolanyl methyl esters such as 5-methyl-2-oxo-1,3-dioxolan-4-yl methyl ester and C 1-6 Alkoxycarbonyloxy-C 1-6 Alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

[0664] Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which have hydroxyl groups) are, for example, esters or ethers thereof that can be cleaved in vivo. Esters or ethers that can be cleaved in vivo of compounds of formula I that contain hydroxyl groups are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include inorganic esters such as phosphates (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include: C 1-10 Alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1-10 Alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C 1-6 )2-carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1-4 Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0665] Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which have a carboxyl group) are, for example, amides which may be cleaved in vivo, for example from amines (such as ammonia, C 1-4 Alkylamines such as methylamine, (C 1-4 Alkyl) 2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C 1-4 Alkoxy-C2-4 Alkylamines such as 2-methoxyethylamine, phenyl-C 1-4 Amides formed from alkylamines such as benzylamine and amino acids such as glycine) or their esters.

[0666] Suitable pharmaceutically acceptable prodrugs of compounds of formula I (which have an amino group) are, for example, amide derivatives thereof which are cleavable in vivo. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, C 1-10 Amides formed with alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 alkyl)piperazin-1-ylmethyl.

[0667] The in vivo effects of compounds of Formula I may be exerted in part through one or more metabolites formed in the human or animal body following administration of a compound of Formula I. As described above, the in vivo effects of compounds of Formula I may also be exerted by way of metabolic precursor compounds (prodrugs).

[0668] It will also be understood that compounds of Formula I may also be covalently linked (at any suitable position) to other groups, such as, for example, solubilizing moieties (e.g., PEG polymers), moieties that enable them to bind to solid supports (such as, for example, biotin-containing moieties) and targeting ligands (such as antibodies or antibody fragments).

[0669] synthesis

[0670] In the descriptions of synthetic methods described below and in the referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, experimental durations, and work-up procedures, can be selected by one skilled in the art.

[0671] Those skilled in the art of organic synthesis will understand that the functionality present on the various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0672] The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variations and in the accompanying examples. Alternatively, the necessary starting materials can be obtained by procedures similar to those described in the ordinary skill of organic chemists.

[0673] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined below, or during the synthesis of certain starting materials, it may be necessary to protect certain substituent groups to prevent their undesirable reactions. A skilled chemist will understand when such protection is necessary and how these protecting groups can be placed in the appropriate positions and subsequently removed.

[0674] For examples of protecting groups, see one of the many general texts on the subject, such as "Protecting groups in Organic Synthesis" (3rd ed.), John Wiley & Sons, NY (1999), T. Greene and P. Wuts. Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist, suitable for the removal of the protecting group in question, the method being selected so as to effect removal of the protecting group with minimal perturbation of groups elsewhere in the molecule.

[0675] Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy groups, it may be necessary to protect this group in some of the reactions mentioned herein.

[0676] For example, the suitable protecting group of amino or alkylamino group is such as acyl group, for example alkanoyl group such as acetyl, alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, arylmethoxycarbonyl group, for example benzyloxycarbonyl, or aroyl group, for example benzoyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, can remove acyl group such as alkanoyl or alkoxycarbonyl group or aroyl group by being hydrolyzed with suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide etc. Alternatively, can remove acyl group such as tert-butoxycarbonyl group for example by processing with suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and can for example by through catalyst such as the hydrogenation of palladium carbon, or by using Lewis acid such as BF3.OEt2 process and remove arylmethoxycarbonyl group such as benzyloxycarbonyl group. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0677] Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways in a known manner. Compounds of formula I can be prepared by the methods given below, by the methods given in the experiments, or by similar methods. The described pathways are merely illustrative of some methods for synthesizing compounds of formula I, and those skilled in the art will appreciate that the sequence of reaction steps is not limited to those described. It will also be appreciated that the allocation of nucleophiles and electrophiles is not limited to that described herein, and in some cases may be suitable for an allocation to be reversed. Different approaches to synthetic chemistry strategies are described in "Organic Synthesis: The Disconnection Approach," 2nd edition, S. Warren and P. Wyatt (2008).

[0678] General Method A

[0679]

[0680] In a typical synthetic procedure, when phthalimide is used as a protecting group, it is removed using typical reagents such as hydrazine, and the amine is reacted with an appropriate reagent to install the desired substituent NR 4 R 5 The third step involves installation of the desired ether by conventional methods, such as alkylation with an alkyl halide or activated alcohol (e.g., mesylate, triflate) or Mitsunobu reaction using reagents such as DBAD or DEAD and an appropriate phosphine. The Boc protecting group is then typically removed by treatment with HCl. 1 C(R 6 )(R 7 )L 2 C(R 8 )(R 9 )R 10 The group can be introduced from the bis-acid derivatives of suitable replacement and protection; Ideally, one of the acid groups is activated to react with the amine of tetrahydroisoquinoline (THIQ) scaffold, and the other acid group is suitably protected, such as benzyl or dimethoxybenzyl ester, or protected by the ring-opening of suitable cyclic anhydride, or by reacting with acyl chlorides. Typical amide coupling agents (such as HATU) are used to realize acid activation. In the final step, by suitable methods (such as hydrolysis, hydrogenolysis, strong acid (such as HCl or TFA or Lewis acid (such as BBr ))) remove protecting group from carboxylic acid.

[0681] General Method B

[0682]

[0683] In another typical procedure, the order of the steps can be changed compared to General Method A. The first two steps are carried out as described for General Method A. In the third step, the Boc protecting group (CO2) is then removed, typically by treatment with HCl. t Bu) is removed. L can then be introduced in the fourth step as described in General Method A 1 C(R 6 )(R 7 )L 2 C(R 8 )(R 9 )R 10 The desired ether is then installed by conventional methods, such as alkylation with an alkyl halide or an activated alcohol (such as a mesylate, a triflate), or the Mitsunobu reaction using reagents such as DBAD or DEAD and an appropriate phosphine. In the final step, the protecting group is removed from the carboxylic acid by an appropriate method (such as hydrolysis, hydrogenolysis, a strong acid (such as HCl or TFA or a Lewis acid (such as BBr )).

[0684] General Method C

[0685]

[0686] In another typical procedure, the order of the steps can be altered compared to General Methods A and B. In the first step, the desired ether is installed again by the conventional methods described above in General Methods A and B. In the second step, the phthalimide protecting group is removed and the amine is reacted with an appropriate reagent to install the desired substituent NR 4 R 5 The Boc protecting group is then removed and L can then be introduced in the fifth step. 1 C(R 6 )(R 7 )L 2 C(R 8 )(R 9 )R 10 The final step involves removal of the formic acid protecting group as described in the general procedure above.

[0687] The R 3 It is the THIQ bracket of bromine

[0688]

[0689] Scheme 1: a) SOCl2, EtOAc; b) 2-(3-methoxyphenyl)ethan-1-amine, Et3N, DCM; c) NBS, DMF; d) P2O5, MeCN; e) Phenylruthenium(II) chloride dimer, (1S,2S)-(+)-N-p-toluenesulfonyl-1,2-diphenylethylene-diamine, Et3N, HCO2H, MeCN; f) HCl, THF; g) BBr3, DCM; h) Boc2O, DCM.

[0690] R 8 The compound having -COOH can be converted to R in Formula 1 by reacting an appropriate nitrile with an azide by a well-known method. 8 Other groups (such as tetrazole) are defined as shown in Scheme 2.

[0691]

[0692] Scheme 2: a) HATU, DIPEA, NH4Cl, DMF; b) POCl3, imidazole, pyridine; c) n Bu3SnN3, xylene.

[0693] R 3 The positional changes can be conveniently prepared from compounds of the present invention or intermediates thereof, wherein R 3 is bromine and is prepared according to chemical methods well known in the art, as shown in Schemes 3 and 4. 3 The compounds of the present invention wherein R is H or Cl can be prepared by the method outlined in Scheme 3. 3 It is prepared as an intermediate of Br.

[0694]

[0695] Scheme 3: a) H2, 10% Pd / C, THF, EtOH; b) BBr3, DCM; c) Boc2O, DCM; d) NCS, DMF.

[0696] As shown in Scheme 4, bromine R 3 Fluorinated and trifluoro derivatives can be prepared by converting the substituents to suitable borate esters or boronic acids. Bromine can be converted to an alkyl group by reacting it with a suitable alkyl borate ester and a suitable palladium catalyst; for example, when the alkyl group is methyl, the suitable borate ester is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, and the suitable palladium catalyst is Pd(dppf)Cl2. 3 Compounds which are cyano groups can be prepared from bromo derivatives by treatment with a cyanating agent such as Zn(CN)2 and a palladium catalyst such as Pd(PPh3)4.

[0697]

[0698] Scheme 4: a) dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine, X-phos Pd, boronic acid; b) CF3SO3Ag, ; c) bis(pinacol)diboron, Pd(dppf)Cl2; d) potassium trimethoxy(trifluoromethyl)borate, Cu(OAc)2; e) Pd(dppf)Cl2, alkyl borane; f) Zn(CN)2, Pd(PPh3)4.

[0699] According to Scheme 5, the NR- 4 R 5 Compounds of the invention which represent indolinones.

[0700]

[0701] Scheme 5: a) NaBH4, MeOH; b) TFA, Et3SiH.

[0702] According to the route outlined in Scheme 6, compounds of the present invention (wherein the group -NR 4 R 5 Represents pyrrolidone) can be prepared in the following manner: from an intermediate (wherein -NR 4 R 5 represents a phthalimide group) by removing the phthalimide group with hydrazine and then converting the resulting primary amine into a pyrrolidone or into an indolinone by reaction with an appropriate lactone or ω-haloester.

[0703]

[0704] Scheme 6: a) N2H4, EtOH; b) methyl 4-bromobutyrate, Et3N, PhMe.

[0705] where R 2 The compounds of the present invention wherein R is a halogen substituent can be prepared from intermediates or intermediates wherein R 2 Examples of the present invention that are hydrogen are prepared by treatment with a suitable halogenating agent such as N-chlorosuccinimide as shown in Scheme 7.

[0706]

[0707] Scheme 7: a) NCS, DCM / DMF.

[0708] Pharmaceutical composition

[0709] Prior to administration to a patient, the compound of the invention is typically, but not necessarily, formulated into a pharmaceutical composition. Therefore, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0710] The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound of this invention can be extracted and then administered to a patient, for example, together with a powder or syrup. Additionally, the pharmaceutical compositions of the present invention can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of the compound of this invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0711] The compositions of the present invention can be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), transdermal administration (e.g., via a transdermal patch), administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), administration by insufflation (e.g., as a fine powder) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0712] As used herein, a "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle that contributes to the form or consistency of a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed, thereby avoiding interactions that could significantly reduce the efficacy of the compound of the invention when administered to a patient and that would render the pharmaceutical composition unpharmaceutically acceptable. In addition, each excipient must be of sufficiently high purity to be pharmaceutically acceptable.

[0713] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. Additionally, suitable pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected because they have the ability to promote the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be selected because they have the ability to produce stable dosage forms. Certain pharmaceutically acceptable excipients may be selected because they are easy to carry or transport one or more compounds of the present invention once they are administered to a patient from one organ or part of the body to another organ or part of the body. Certain pharmaceutically acceptable excipients may be selected because they have the ability to enhance patient compliance.

[0714] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, flavor masking agents, coloring agents, anti-caking agents, wetting agents, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants and buffers. As will be appreciated by those skilled in the art, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions, depending on how many excipients are present in the formulation and what other ingredients are present in the formulation.

[0715] Those skilled in the art have the knowledge and skills that enable them to select the suitable pharmaceutically acceptable excipient of appropriate amount to be used for the present invention.In addition, the technical staff can obtain the resources of many descriptions pharmaceutically acceptable excipients, and these resources can be used for selecting suitable pharmaceutically acceptable excipients.Example comprises Remington's Pharmaceutical Sciences [Lemington's pharmaceutical science] (Mark Publishing Company (Mack Publishing Company)), The Handbook of Pharmaceutical Additives [pharmaceutical additive handbook] (Gower Publishing Company (Gower Publishing Limited)) and The Handbook of Pharmaceutical Excipients [pharmaceutical excipient handbook] (American Pharmaceutical Association and Pharmaceutical Press (American Pharmaceutical Association and the Pharmaceutical Press)).

[0716] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0717] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 0.5 mg to 0.5 g (more suitably from 0.5 to 100 mg, e.g., from 1 to 30 mg) of active agent compounded with an appropriate and convenient amount of excipient (the amount of the excipient may vary from 5% to 98% by weight of the total composition).

[0718] According to well-known medical principles, for therapeutic or prophylactic purposes, the size of the dose of the compound of formula I will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0719] When using the compounds of this invention for treatment or prevention purposes, it is usually applied so that if divided doses are needed, a daily dose of, for example, 0.1 mg / kg to 75 mg / kg body weight is accepted. Generally speaking, when parenteral route is adopted, a lower dosage will be applied. Therefore, for example, for intravenous or intraperitoneal administration, a dosage of, for example, 0.1 mg / kg to 30 mg / kg body weight will be usually used. Similarly, for administration by inhalation, a dosage of, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration can also be suitable, particularly in tablet form. Typically, a unit dosage form will comprise approximately 0.5 mg to 0.5 g of the compounds of this invention.

[0720] Route of administration

[0721] The compounds of the invention or pharmaceutical compositions comprising the active compounds may be administered to the subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the site of desired action).

[0722] Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or reservoir, e.g., subcutaneous or intramuscular.

[0723] In a preferred embodiment, the compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as defined herein is administered orally or via inhalation.

[0724] Therapeutic uses and applications

[0725] The compounds of the present invention are activators of Nrf2. Therefore, they are potentially useful therapeutic agents for treating diseases or conditions mediated by Nrf2 activation.

[0726] Thus, in one aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0727] In another aspect, the invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[0728] In another aspect, the present invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[0729] In another aspect, the present invention relates to a method of treating a disease or disorder mediated by Nrf2 activation, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0730] Examples of specific diseases or conditions that can be treated using compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, any of the following: chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, Rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, or uveitis.

[0731] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) may be used to treat chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0732] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, rheumatoid arthritis inflammation, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, or uveitis.

[0733] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0734] In another aspect, the present invention provides the use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, rheumatoid arthritis inflammation, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, or uveitis.

[0735] In another aspect, the present invention provides use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease, or non-alcoholic steatohepatitis.

[0736] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, A method for treating non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy or uveitis, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0737] In another aspect, the present invention provides a method of treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0738] In another aspect, the present invention provides a method for activating Nrf2 in vitro, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0739] In another aspect, the present invention provides a method for activating Nrf2 in vivo, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0740] In another aspect, the present invention provides a method of activating Nrf2 in vitro and / or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0741] Combination therapy

[0742] The compounds of the present invention may be administered alone as a monotherapy or may be administered in combination with one or more additional therapeutic agents. The choice of one or more additional therapeutic agents will of course depend on the disease or condition to be treated and its severity.

[0743] Combination therapy is commonly used to treat certain medical conditions.

[0744] According to a particular aspect of the present invention there is provided a combination useful in the treatment of a disease or condition involving Nrf2 activation, the combination comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0745] According to this aspect of the invention, there is provided a composition suitable for preventing or treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatosis, The invention also provides a method for treating a patient suffering from leukemia, atopic dermatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy or uveitis, the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0746] In another aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0747] Herein, where the term "combination" is used, it is understood that this refers to simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, a delay in administering the second component should not result in a loss of the beneficial effects of the combination.

[0748] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, in association with a pharmaceutically acceptable diluent or carrier.

[0749] The one or more additional therapeutic agents may comprise an additional compound of the invention.Thus, in one embodiment, a pharmaceutical composition is provided comprising two compounds of the invention or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable diluent or carrier.

[0750] According to a particular aspect of the invention, there is provided a combination suitable for preventing or treating allergic, inflammatory or autoimmune diseases (such as asthma or COPD); cardiovascular or metabolic diseases (such as diabetes); neurodegenerative diseases; chronic kidney or liver disease; sickle cell anemia; pulmonary hypertension; cancer; or for use in assisting transplantation.

[0751] According to a particular aspect of the invention there is provided a combination suitable for the prevention or treatment of chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0752] Examples of additional therapeutic agents that can be used as part of combination therapy with the compounds of the invention (e.g., as one of two or more active agents, as part of a dual or triple combination) include, but are not limited to, the following:

[0753] (i) β2-adrenergic receptor agonists (which may be racemates or single enantiomers), including salmeterol, salbutamol, formoterol, salmethamine, fenoterol, carmoterol, etidinol, nanterol, clenbuterol, bilaterol, flunabutol, phloroglucinol, bambuterol, indacaterol, terbutaline, vilanterol, olopataterol and their salts;

[0754] (ii) anticholinergics that act as antagonists at muscarinic receptors, including ipratropium bromide (e.g., bromide, CAS 22254-24-6, sold under the trade name Atrovent), oxitropium and tiotropium bromide (e.g., bromide, CAS 136310-93-5, sold under the trade name Spiriva), revatropate, LAS-34273, aclidinium, glycopyrronium, umeclidinium, and their salts;

[0755] (iii) Corticosteroid anti-inflammatory drugs. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, fluticasone furoate, beclomethasone esters (e.g., 17-propionate or 17,21-dipropionate), budesonide, flunisolone, mometasone esters (e.g., mometasone furoate), methotrexate, rofluphenazine, ciclesonide, butyl butyrate, RPR-106541, and ST-126;

[0756] (iv) anti-inflammatory drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include sodium cromoglycate, sodium nedocromycin, phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, JAK inhibitors, Pi3K inhibitors, leukotriene synthesis inhibitors (e.g., montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists, and adenosine receptor agonists or antagonists (e.g., adenosine 2a agonists), cytokine antagonists (e.g., chemokine antagonists, such as CCR3 antagonists), or cytokine synthesis inhibitors or 5-lipoxygenase inhibitors;

[0757] (v) vasodilators and antiproliferative drugs (e.g., prostaglandins and PDE5 inhibitors), including ipasutinib (Flolan), treprostinil (Remodulin), iloprost (Ventavis), treprostinil (Tyvaso), bosentan (Tracleer), ambrisentan (Letairis), sildenafil (Revatio), and tadalafil (Adcirca); (vi) antidiabetic drugs, including insulin, biguanides (e.g., metformin), sulfonylureas (e.g., glimepiride), meglitinides (such as repaglinide), thiazolidinediones (such as pioglitazone), dipeptidyl peptidase IV inhibitors (such as sitagliptin), incretins / GLP-1 analogs (such as liraglutide, exenatide, dulaglutide), sodium glucose co-transporter 2 (SGLT2) inhibitors (such as canagliflozin, dapagliflozin, and empagliflozin), and alpha-glucosidase inhibitors (such as acarbose);

[0758] (vii) hydroxyurea and other drugs that can be used to treat sickle cell disease, such as L-glutamine, NCX1443, GBT440 (voxelotor), pan-selectin antagonists (GMI-1070, rivipansel), humanized anti-P-selectin antibodies (SelG1, crinalizumab), P-selectin aptamers, sevuparin, Regadenoson, Ticagrelor, N-acetyl-cysteine ​​(NAC), phosphodiesterase 9 inhibitors (e.g., PF-04447943, IMR-687, BAY 73-6691, BAY41-2271); and

[0759] (viii) ASK1 inhibitors such as selonsertib, FXR agonists such as obeticholic acid, GS-9674, Px-102, ACC inhibitors such as GS-0976, and PPARα / δ agonists such as Elafibranor.

[0760] The above-mentioned combinations may conveniently be presented in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

[0761] Such combined / combination therapy may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0762] These combination therapies employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within an approved dosage range and / or dosage (as described in the publication reference).

[0763] The following numbered statements 1-33 are not claims, but describe various aspects and embodiments of the present invention:

[0764] 1. A compound having formula I

[0765]

[0766] in:

[0767] R 1 Selected from C 1-4 Alkylene-R 11 , heterocyclyl and 8-10 membered bicyclic heteroaryl; wherein the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 、C 1-3Alkylene-OR 14 , and optionally one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 wherein the 8-10 membered bicyclic heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH and C 1-3 Substitution of alkoxy groups;

[0768] R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl;

[0769] R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 alkyl halides and cyano groups;

[0770] R 4 is hydrogen or C 1-4 alkyl;

[0771] R 5 Yes-C(O)-C 1-4 alkyl, -C(O)-heteroaryl or -C(O)-aryl, wherein the heteroaryl and aryl are optionally substituted by one or more selected from C 1-4 Alkyl, halogen, hydroxyl, C 1-3 Alkoxy, CO2R 15 and substituted with a cyano substituent; or

[0772] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring wherein:

[0773] The heterocyclyl ring comprises one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or optionally spiro-attached to a C 3-7 a cycloalkyl group; and

[0774] The heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO2R 20Substituents substituted;

[0775] L 1 and L 2 independently selected from a bond and -CR 21 R 22 -;

[0776] R 6 and R 7 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 cycloalkyl; or

[0777] R 6 and R 7 together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0778] R 8 Selected from CO2R 23 、C(O)NHSO2C 1-3 Alkyl, tetrazolyl, 3-trifluoromethyl-1,2,4-triazol-5-yl, and carboxylic acid mimicking groups selected from hydroxamic acid, hydroxamate, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfonylurea, acylurea, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-one, oxadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetracarboxylic acid, cyclopentane-1,3-dione, and cyclopentane-1,2-dione;

[0779] R 9 Selected from hydrogen, C 1-4 Alkyl, hydroxyl, C 1-3 alkoxy and halide;

[0780] R 10 Selected from hydrogen and C 1-4 alkyl; or

[0781] R 9 and R 10 together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; or

[0782] L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocyclyl ring wherein:

[0783] The heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0784] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally joined by a C1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 an alkylene group; and

[0785] The cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Substitution with haloalkyl and deuterium substituents;

[0786] R 11 Selected from -C(O)-R 24 、-SO2-R 25 、-NR 26 C(O)-R 27 、-NR 28 SO2-R 29 , heterocyclyl, aryl and heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substituted with alkoxy, heterocyclyl and cyano; and the heterocyclyl group is optionally substituted with one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substitution of alkoxy, oxo, and cyano substituents;

[0787] R 12 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0788] R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are optionally substituted by one or more independently selected from C1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0789] R 17 Selected from hydrogen, C 1-4 Alkyl, C(O)C 1-3 Alkyl and C(O)NR 36 R 37 ;

[0790] R 18 、R 19 and R 20 Independently selected from C 1-4 Alkyl, OH, C 1-3 Alkoxy and NR 38 R 39 ;

[0791] R 24 Selected from C 1-4 Alkyl, NR 40 R 41 and OR 42 ;

[0792] R 25 Selected from C 1-4 Alkyl and NR 43 R 44 ;

[0793] R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 45 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0794] R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 46 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups;

[0795] R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ;

[0796] R 40 Selected from hydrogen and C 1-4 alkyl;

[0797] R 41 Selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 alkoxy, aryl and heteroaryl; or

[0798] R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 3-7 Substitution of cycloalkyl and cyano groups;

[0799] R 45 and R 46 Independently selected from hydroxyl, C 1-3 Alkoxy and C 3-7 cycloalkyl; and

[0800] R 14 、R 15 、R 16 、R 21 、R 22 、R 23 、R 26 、R 28 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 42 、R 43 、R 44 、R 47 and R 48 are each independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl;

[0801] or a pharmaceutically acceptable salt thereof.

[0802] 2. The compound according to claim 1, wherein the compound has the structural formula IA shown below

[0803]

[0804] Among them L 1 and L 2 and R 1 to R 10 As defined in statement 1.

[0805] 3. The compound according to statement 1 or statement 2, wherein L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached they form a 4-, 5- or 6-membered cycloalkyl ring.

[0806] 4. The compound according to claim 1, wherein the compound has the structural formula IB shown below

[0807]

[0808] where R 1 to R 6 、R 8 and R 9 As defined in statement 1, and the cyclohexyl ring is optionally replaced by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 substituted with alkoxy and deuterium, and the cyclohexyl ring is optionally connected by a C 1-3 Alkylene group bridge, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 Alkylene group.

[0809] 5. A compound according to any one of statements 1 to 4, wherein R 8 It is CO2R 23 And R 23 It's hydrogen.

[0810] 6. A compound according to any one of statements 1 to 5, wherein R 9 is hydrogen or C 1-4 alkyl.

[0811] 7. A compound according to any one of statements 1 to 6, wherein R 9 is hydrogen or methyl.

[0812] 8. A compound according to any one of statements 1 to 7, wherein R 1 It is C 1-4 Alkylene-R11 .

[0813] 9. A compound according to statement 8, wherein R 1 It is CH2-R 11 .

[0814] 10. A compound according to any one of statements 1 to 9, wherein R 11 Selected from -C(O)-R 24 、-NR 26 C(O)-R 27 , heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substituted with alkoxy, heterocyclyl and cyano; and the heterocyclyl group is optionally substituted with one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substituents of alkoxy, oxo and cyano are substituted.

[0815] 11. A compound according to any one of statements 1 to 10, wherein R 11 is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substituents of the alkoxy group, the heterocyclic group and the cyano group include heteroaryl groups substituted with the alkoxy group.

[0816] 12. A compound according to any one of statements 1 to 11, wherein R 11 is optionally substituted by one or more independently selected from methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, cyano, oxetanyl, CH2-R 30 and C2H4-R 30 A substituent is substituted with a heteroaryl group.

[0817] 13. A compound according to any one of statements 1 to 12, wherein R 11is pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 The substituents of the alkoxy group, heterocyclic group and cyano group are substituted.

[0818] 14. A compound according to any one of statements 1 to 12, wherein R 11 is a heteroaryl group selected from:

[0819]

[0820] Each heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 The substituents of the alkoxy group, heterocyclic group and cyano group are substituted.

[0821] 15. A compound according to any one of statements 1 to 7, wherein R 1 One selected from the following groups:

[0822]

[0823]

[0824] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected C 1-4 Alkyl, C 1-3 Halogenated alkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 The substituents of the alkoxy group, heterocyclic group and cyano group are substituted.

[0825] 16. A compound according to any one of statements 1 to 7, wherein R 1 is a heterocyclyl group optionally substituted by one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3Alkylene-OR 14 , and the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 The substituents of the alkoxy group and the cyano group are substituted.

[0826] 17. A compound according to any one of statements 1 to 7, wherein R 1 is piperidinyl or pyrrolidinyl, each optionally substituted with one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 , and the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 The substituents of the alkoxy group and the cyano group are substituted.

[0827] 18. A compound according to statement 17, wherein R 1 is pyrrolidinyl optionally substituted with one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 , and the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

[0828] 19. A compound according to any one of statements 1 to 7, wherein R 1 One selected from the following groups:

[0829]

[0830] in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected from -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl group is optionally substituted by a C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

[0831] 20. A compound according to any one of statements 1 to 19, wherein R 2 It is hydrogen or fluorine.

[0832] 21. A compound according to any one of statements 1 to 20, wherein R 3 It is hydrogen or chlorine.

[0833] 22. A compound according to any one of statements 1 to 21, wherein R 4 is hydrogen and R 5 Yes-C(O)-C 1-4 Alkyl or -C(O)-aryl, wherein the aryl is optionally substituted with one or more selected from C 1-4 Alkyl, halogen, hydroxyl, C 1-3 Alkoxy, CO2R 15 and substituted with a cyano substituent.

[0834] 23. A compound according to any one of statements 1 to 21, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl or heterocyclyl ring, wherein the heterocyclyl comprises a -C(O)- moiety attached to the nitrogen atom and is optionally fused to the aryl or heteroaryl ring, or optionally to a C 3-7 The cycloalkyl group is spiro-connected, and wherein the heteroaryl and heterocyclyl are optionally substituted by one or more independently selected C 1-4 Alkyl, halogen, OH, C 1-3 The substituents of the alkoxy group and the cyano group are substituted.

[0835] 24. A compound according to statement 23, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl ring, which is optionally substituted by one or more independently selected from C 1-4 Alkyl, halo and OH substituents.

[0836] 25. The compound according to statement 24, wherein the 5-membered heteroaryl ring is pyrazolyl.

[0837] 26. A compound according to statement 23, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl comprises a -C(O)- moiety attached to the nitrogen atom and is optionally fused to an aryl ring, or optionally to a C 3-7 The cycloalkyl group is spiro-linked, and wherein the heterocyclic group is optionally substituted by one or more independently selected C 1-4 Alkyl, halo and OH substituents.

[0838] 27. A compound according to any one of statements 1 to 21, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following:

[0839]

[0840] wherein the saturated ring of the heterocyclic portion is optionally fused with C 3-7 The cycloalkyl group is spiro-linked, and wherein the heterocyclic portion is optionally substituted by one or more independently selected C 1-4 Alkyl, halo and OH substituents.

[0841] 28. The compound according to statement 1, which is selected from any one of the following:

[0842] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazole-3-carboxamide)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0843] (1S,2R)-2-((S)-8-(2-(Benzo[d]oxazole-2-carboxamide)ethoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0844] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0845] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0846] (1S,2R)-2-((S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0847] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0848] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0849] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0850] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0851] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0852] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0853] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0854] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5,7-dichloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0855] (1S,2R)-2-((S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0856] (1S,2R)-2-((S)-1-((1-oxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0857] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0858] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0859] (1S,2R)-2-((S)-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0860] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0861] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(2-methylthiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0862] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0863] (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0864] (1S,2R)-2-((S)-5-bromo-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0865] (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0866] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0867] (1S,2R)-2-((S)-5-bromo-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0868] (1S,2R)-2-((S)-5-bromo-8-((2-ethyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0869] (1S,2R)-2-((1S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((1-oxo-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0870] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0871] (1S,2R)-2-((S)-5-Bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0872] (1S,2R)-2-((S)-5-bromo-8-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0873] (1S,2R)-2-((S)-5-bromo-8-(imidazo[1,2-a]pyridin-7-ylmethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0874] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0875] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0876] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0877] (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0878] (1S,2R)-2-((S)-5-bromo-8-((7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0879] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0880] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0881] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0882] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0883] (1S,2R)-2-((S)-5-bromo-8-((4-ethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0884] (1S,2R)-2-((S)-5-bromo-8-((5-cyano-1-ethyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0885] (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0886] (1S,2R)-2-((1S)-5-bromo-8-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0887] (1S,2R)-2-((1S)-5-bromo-8-(1-(1-isopropyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0888] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0889] (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0890] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0891] (1S,2R)-2-((S)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-8-((1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0892] (1S,2R)-2-((S)-5-chloro-8-((1-(2,2-difluoroethyl)-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0893] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0894] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0895] (1S,2R)-2-((S)-5-chloro-8-((1-ethyl-1H-pyrazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0896] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0897] (1S,2R)-2-((S)-5-chloro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0898] (1S,2R)-2-((S)-5-fluoro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0899] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methyl-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0900] (1S,2R)-2-((S)-5-cyano-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0901] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxy-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0902] (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0903] (1S,2R)-2-((S)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0904] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0905] (1S,2R)-2-((S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0906] (1S,2R)-2-((S)-5-bromo-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0907] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0908] (1S,2R)-2-((S)-8-(Benzo[d]isothiazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0909] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0910] (1S,2R)-2-((S)-5-chloro-8-((5-methylisothiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0911] (1S,2R)-2-((S)-5-chloro-8-(isothiazol-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0912] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0913] (1S,2R)-2-((1S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0914] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0915] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0916] (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0917] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0918] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0919] (R)-4-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-4-oxobutanoic acid;

[0920] 1-(((S)-2-((1R,2S)-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one;

[0921] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0922] (1S,2R)-2-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0923] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((4-methyl-1H-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0924] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrimidin-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0925] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid;

[0926] (1R,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid;

[0927] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0928] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0929] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0930] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0931] (1S,2R)-2-((S)-5-chloro-8-(imidazo[1,2-a]pyrimidin-2-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0932] (1S,2R)-2-((S)-5-chloro-8-(isoxazolo[5,4-b]pyridin-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0933] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0934] (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0935] 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid;

[0936] 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-carboxylic acid;

[0937] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-indazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0938] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0939] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0940] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluorocyclopentane-1-carboxylic acid;

[0941] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0942] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0943] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[0944] (1R,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-fluorocyclohexane-1-carboxylic acid;

[0945] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0946] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0947] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0948] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0949] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0950] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0951] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0952] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0953] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0954] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0955] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0956] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclohexane-1-carboxylic acid;

[0957] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclopentane-1-carboxylic acid;

[0958] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0959] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0960] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0961] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0962] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0963] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0964] (1S,2R)-2-((S)-5-chloro-8-((4-chloro-5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0965] (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0966] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0967] (1S,2R)-2-((S)-5-chloro-8-((5-(2-methoxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0968] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0969] (1S,2R)-2-((S)-5-chloro-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0970] (1S,2R)-2-((S)-5-chloro-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0971] (1S,2R)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0972] (1S,2S)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0973] (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0974] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0975] (1S,2R)-2-((S)-5-chloro-8-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0976] (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0977] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0978] (1S,2R)-2-((S)-8-((2,5-bis(difluoromethyl)-2H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0979] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-carboxylic acid;

[0980] (R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid;

[0981] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,4-d2;

[0982] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0983] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0984] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0985] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0986] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0987] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0988] (1S,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0989] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0990] 1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2-((1R,2S)-2-methyl-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one;

[0991] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((4,4-dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0992] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[0993] (1S,2R)-2-((S)-5-chloro-8-((5-methyl-4-(trifluoromethyl)isoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0994] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0995] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0996] (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)-5-methylisoxazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0997] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0998] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0999] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1000] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1001] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1002] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1003] (1S,2R)-2-((1S)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1004] (1S,2R)-2-((S)-5-chloro-8-((6,7-difluorobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1005] (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1006] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1007] (1S,2R)-2-((S)-5-chloro-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1008] (1S,2S)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1009] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1010] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4-(trifluoromethyl)pyrimidin-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1011] (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1012] (1S,2R)-2-((S)-5-chloro-8-((1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1013] (1S,2R)-1-methyl-2-((S)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[1014] (1S,2R)-2-((S)-5-chloro-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1015] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1016] (1S,2R)-2-((S)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1017] (1S,2R)-2-((S)-5-fluoro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1018] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1019] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

[1020] (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1021] (1S,2R)-2-((S)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1022] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1023] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1024] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1025] (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1026] (1S,2R)-2-((S)-5-chloro-8-(((S)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1027] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1028] (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1029] (1S,2R)-1-methyl-2-((S)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[1030] (1S,2R)-2-((S)-5-bromo-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1031] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1032] (1S,2R)-2-((S)-8-((1,5-bis(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1033] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1034] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1035] (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1036] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

[1037] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1038] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1039] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1040] (1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid;

[1041] 5-(((S)-2-((1R,2S)-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one;

[1042] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1043] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)thiazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1044] (1S,2R)-2-((S)-5-chloro-8-((5-methylthiazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1045] (1S,2R)-2-((S)-5-chloro-8-((2-methyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1046] (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid;

[1047] (1S,3S,4R,6R)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid;

[1048] (1S,2R)-2-((1S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1049] (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4,5-d2;

[1050] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1051] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1052] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1053] (1S,2R)-2-((1S)-5-chloro-8-((1-methyl-1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[1054] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluoro-1-methylcyclohexane-1-carboxylic acid;

[1055] (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid;

[1056] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid-4-d;

[1057] (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1058] (1S,2R,5S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1059] (1S,2R,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1060] (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1061] (2S,3R)-3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-2-carboxylic acid;

[1062] (1R,2R,6S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1063] (1R,2R,6R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1064] (1S,2S,3R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid; and

[1065] (1S,2S,3S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]hept-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid;

[1066] or a pharmaceutically acceptable salt thereof.

[1067] 29. A pharmaceutical composition comprising a compound according to any one of statements 1 to 28 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[1068] 30. A compound according to any one of statements 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to statement 29, for use in therapy.

[1069] 31. A compound according to any one of statements 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to statement 29, for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[1070] 32. A compound according to any one of statements 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to statement 29, for use in the treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, rheumatoid arthritis arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, or uveitis.

[1071] 33. A method of treating a disease or disorder selected from the group consisting of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopy Dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs corneal endothelial dystrophy and uveitis, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of statements 1 to 28, or a pharmaceutically acceptable salt thereof.

[1072] Examples

[1073] General procedure:

[1074] Methods for preparing the compounds of the present invention are shown in the following examples. Starting materials are prepared according to procedures known in the art or as described herein, or are commercially available. Commercial reagents can be used without further purification. When the reaction temperature is not included, the reaction is carried out at an ambient temperature of generally 18°C ​​to 27°C.

[1075] The compounds described in this invention are 1In the case of H NMR spectroscopy, spectra were recorded on a 500 MHz Bruker, 400 MHz Bruker, 250 MHz Bruker, 300 MHz JEOL, or 400 MHz JEOL instrument. Spectra were recorded at ambient temperature when temperature was not included. Chemical shift values ​​are expressed in parts per million (ppm). In cases where NMR spectra were complicated by the presence of tautomers, approximate partial integrations of the signals were reported, or only the characteristics of the major isomer were reported. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, b = broad, t = triplet, q = quartet, m = multiplet, d = doublet.

[1076] Analytical LCMS

[1077] When the compounds described in this invention were characterized by LCMS data, retention times and molecular weights were determined using the methods listed in the table below. Where compounds of the invention exhibited slowly interconverting stereoisomers, multiple retention times were reported.

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084] Preparative HPLC

[1085] Preparative HPLC was performed using a variety of preparative systems with variable wavelength UV detection or the Mass Directed AutoPrep (MDAP) systems listed in the table below. Collection was triggered by UV, MS, or a combination of both. UV detection was typically performed at a selected wavelength of 210 nm, 230 nm, or 280 nm. Mass spectra were recorded on a mass spectrometer using alternating positive and negative electrospray ionization.

[1086]

[1087]

[1088] Preparative Chiral SFC

[1089] Preparative chiral SFC was performed using one of the methods outlined below.

[1090] Method 1:

[1091] Waters Tha Prep 100 preparative SFC system (P200 CO pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module). Columns: Diacel Chiralpak IA / IB / IC, YMC amylose / cellulose C (5 μm, 20-21.2 x 250 mm), maintained at 40°C. Conditions: Supercritical fluid CO and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, modifier selected from MeNH, formic acid (as specified). Specified gradient / isocratic.

[1092] Method 2:

[1093] Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module). Column: Phenomenex Lux Cellulose-4 (5 μm, 20-21.2 x 250 mm), maintained at 40°C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF; modifier selected from Me2NH, formic acid (as specified). Specified gradient / isocratic.

[1094] Method 3:

[1095] Waters Thaler Prep100 preparative SFC system (P200 CO₂ pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module). Columns: YMC Amylose-C / Amylose-SA / Cellulose-C / Cellulose-SB / Cellulose-SC (5 μm, 20 x 250 mm), maintained at 40°C. Conditions: Supercritical fluid CO₂ and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, and formic acid. Specified gradient / isocratic.

[1096] Method 3a:

[1097] Waters ThaR Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module). Columns: YMC Amylose-C / Amylose-SA / Cellulose-C / Cellulose-SB / Cellulose-SC (5 μm, 20 x 250 mm), maintained at 40°C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, and Me2NH. Specified gradient / isocratic.

[1098] Method 4:

[1099] Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module). Column: Phenomenex Lux Cellulose-3 (5 μm, 20-21.2 x 250 mm), maintained at 40°C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF; modifier selected from Me2NH, formic acid (as specified). Specified gradient / isocratic.

[1100] abbreviation:

[1101]

[1102]

[1103] Synthesis of intermediates

[1104] Intermediate 1: 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride

[1105]

[1106] To a stirred suspension of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (555 g, 2.71 mol; CAS: 4702-13-0) in EtOAc (958 mL) at room temperature was added thionyl chloride (1039 mL, 14.24 mol). The mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo to give the title compound (605 g, 99%), which was used without further purification. 1H NMR (300MHz, CDCl3) δ7.96-7.87(m,2H),7.85-7.74(m,2H),4.81(d,2H).

[1107] Intermediate 2: 2-(1,3-dioxoisoindolin-2-yl)-N-(3-methoxyphenethyl)acetamide

[1108]

[1109] To a stirred solution of 2-(3-methoxyphenyl)ethan-1-amine (160 g, 1.06 mol, CAS: 2039-67-0) and triethylamine (248 mL, 2.04 mol) in DCM (2.4 L) at 5° C. was added a solution of intermediate 1 (232 g, 1.04 mol) in DCM (1.2 L). The reaction mixture was stirred at room temperature for 18 hours, then hydrochloric acid (2 M; 2.4 L) was added and the mixture was stirred for 1 hour. The mixture was filtered and the precipitate was washed with water and then dried in vacuo. The residue was dissolved in DCM (10.0 L) and washed with saturated aqueous NaHCO 3 solution, and the organics were dried over MgSO 4 , filtered and concentrated in vacuo to give a white solid (267 g). The first separated organic layer was washed with water, saturated aqueous NaHCO 3 solution, and the organics were dried over MgSO 4 , filtered and concentrated in vacuo to give another portion of white solid (61.4 g). The isolated solids were combined to give the title compound as a white solid (328 g, 82%) which was used without further purification. LCMS (Method 7): 1.68 min, 339.1 [M+H] + .

[1110] Intermediate 3: N-(2-bromo-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide

[1111]

[1112] To a stirred solution of intermediate 2 (328 g, 970 mmol) in DMF (3.2 L) was added NBS (173 g, 970 mmol) in portions over 0.5 h. The reaction mixture was heated at 40 ° C, then cooled to room temperature and allowed to stand at room temperature for 18 hours. The reaction mixture was poured into water (5.0 L) and the resulting precipitate was collected by filtration and washed with water. The residue was diluted with DCM, the aqueous phase was separated, and the combined organics were concentrated in vacuo to give the title compound (314 g, 76%), which was used without further purification. 1H NMR(300MHz, CDCl3)δ7.90-7.73(m,4H),7.37(dd,1H),6.78(d,1H),6.64(td,1H ),5.80(s,1H),4.31(d,2H),3.79-3.75(m,3H),3.59-3.54(m,2H),2.94(dd,2H).

[1113] Intermediate 4: 2-((5-bromo-8-methoxy-3,4-dioxoisoindolin-1-yl)methyl)isoindolin-1,3- diketone

[1114]

[1115] Phosphorus pentoxide (630 g, 4.44 mol) was added to a suspension of intermediate 3 (312 g, 748 mmol) in MeCN (5.0 L). The reaction mixture was heated at 60 ° C for 4 hours, cooled to room temperature, and allowed to stand at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated to a volume of 500 mL in vacuo. The filtered solid was dissolved in water (4.0 L) and combined with the organic layer. The combined mixture was heated at 40 ° C for 1 hour, cooled to room temperature, and saturated NaHCO3 aqueous solution was added to the stirred mixture to adjust to pH 8. The precipitated solid was collected by filtration and washed with water (1.0 L). The residue was dried in vacuo at 40 ° C to give the title compound (293 g, 92%), which was used without further purification. LCMS (method 7): 2.34 min, 401.1 [M+H] + .

[1116] Intermediate 5: (S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-methoxy-3,4-dihydro Isoquinoline-2(1H)-carbaldehyde

[1117]

[1118] Under argon, a solution of chlorophenylruthenium (II) dimer (3.78 g, 7.6 mmol, CAS: 37366-09-9) and (1S, 2S)-(+)-N-tosyl-1,2-diphenylethylenediamine (6.78 g, 18.5 mmol, CAS: 167316-27-0) in MeCN (300 mL) was stirred at room temperature for 1 hour. MeCN (2.1 L) and DCM (300 mL) were added thereto, followed by intermediate 4 (205 g, 457 mmol) and MeCN (1.4 L). A solution of formic acid and triethylamine (1: 1; 760 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature under argon for 72 hours. The reaction mixture was diluted with water (2.0 L) and NaHCO was added thereto to adjust to pH 8.0. The mixture was diluted with DCM (3.0 L) and the organics were washed with water, dried over MgSO4 and filtered. The organics were passed through a plug of silica gel, eluted with 66% EtOAc in DCM, and the combined organics were concentrated in vacuo to give the title compound (215 g, 99%), which was used without further purification. LCMS (Method 4): 0.91 min, 431.1 [M+H] + .

[1119] Intermediate 6: (S)-2-((5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline- 1,3-diketone

[1120]

[1121] To a suspension of intermediate 5 (215 g, 451 mmol) in THF (1.5 L) was added HCl (2 M aqueous solution; 2.14 L, 4.33 mol), and the mixture was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature, and saturated NaHCO3 aqueous solution was slowly added to adjust to pH 8. The mixture was extracted with DCM (2x2.0 L), and the combined organics were dried over MgSO4 and filtered. The solution was concentrated in vacuo, and the residue was recrystallized twice from MeCN (1.0 L + 250 mL). The resulting precipitate was filtered and dried in vacuo to give the title compound (113 g, 59%), which was used without further purification. LCMS (method 7a): 2.30 min, 401.1 [M + H] + ; 1H NMR(300MHz, CDCl3)δ7.86(dt,2H),7.76-7.69(m,2H),7.43(d,1H),6.64(d,1H),4.53(dd,1H),4.1 2-3.92(m,2H),3.91-3.81(m,3H),3.64(s,0H),3.43-3.32(m,1H),3.06(qd,1H),2.56-2.82(m,2H).

[1122] Intermediate 7: (S)-2-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1, 3-diketone

[1123]

[1124] To a solution of intermediate 6 (141 g, 351 mmol) in DCM (2.5 L) was added boron tribromide (1 M in DCM; 1.34 L, 1.44 mol) dropwise at 0 ° C over 1 hour, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to 0 ° C, MeOH (150 mL) was slowly added, and the mixture was stirred for 1.5 hours. The precipitate obtained was separated by filtration, washed with DCM, and dried in vacuo at 50 ° C to give the title compound (intermediate 7-HBr) (129 g, 71%). Hydrochloric acid (2 M aqueous solution; 3.0 L) was added to the combined organic matter, and the mixture was stirred for 1 hour. The precipitate obtained was separated by filtration and dried in vacuo at 50 ° C to give the title compound (intermediate 7-HCl) (44.1 g, 27%). The acidic aqueous phase was separated and adjusted to pH 8 by adding Na2CO3 and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (3.67 g, 2%) which was used without further purification. LCMS (Method 9a): 1.87 min, 389.1 [M+H] + .

[1125] Intermediate 8: tert-Butyl (S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-3,4- Dihydroisoquinoline-2(1H)-carboxylate

[1126]

[1127] To the stirred suspension of intermediate 7-HBr (129g, 251mmol) in DCM (1L), triethylamine (89mL, 636mmol) and di-tert-butyl dicarbonate (41.5g, 190mmol) were added. Other di-tert-butyl dicarbonate (7.3g, 33.5mmol) was added, and the mixture was stirred for 2 hours. The final part (3.37g, 15.45mmol) of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and the mixture was extracted with DCM. The organic matter merged was dried over MgSO4, filtered and concentrated in a vacuum to obtain title compound (145g, assuming it to be quantitative), which can be used without further purification. LCMS (method 9a): 2.54min, 487.1[MH] - .

[1128] Intermediate 9: (S)-2-((8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dihydroisoquinolin-1-yl)methyl ketone

[1129]

[1130] To a solution of intermediate 6 (250 mg, 0.62 mmol) in THF (6 mL) and EtOH (6 mL) was added Pd / C (10%; 25 mg). The mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 48 hours. Another portion of Pd / C (10%; 10 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 72 hours. The mixture was then passed through The mixture was filtered through a pad of 4% paraffin wax and washed with EtOH (10 mL) and MeOH (10 mL). The filtrate was concentrated in vacuo. Purification by flash column chromatography (19% EtOAc in DCM with 1% 7M NH3 in MeOH to 16% EtOAc in DCM with 4% 7M NH3 in MeOH) gave the title compound (153 mg, 76%). LCMS (Method 4): 0.76 min, 323.23 [M+H] + .

[1131] Intermediate 10: (S)-2-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-diol ketone

[1132]

[1133] To a solution of intermediate 9 (200 mg, 0.62 mmol) in DCM (2 mL) was added boron tribromide (1 M in DCM; 3.1 mL, 3.1 mmol) at -10 ° C under argon. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0 ° C and MeOH (1 mL) was added. The mixture was warmed to room temperature, concentrated in vacuo, and the residue was stirred in saturated NaHCO3 aqueous solution (10 mL) and EtOAc (10 mL) for 15 minutes. The layers were separated and the aqueous phase was extracted with EtOAc (15 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (130 mg, 68%), which was used without further purification. LCMS (Method 4): 0.66 min, 309.19 [M+H] + .

[1134] Intermediate 11: tert-Butyl (S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-3,4-dihydro Isoquinoline-2(1H)-carboxylate

[1135]

[1136] To a solution of intermediate 10 (3.4 g, 11.03 mmol) in DCM (400 mL) was added di-tert-butyl dicarbonate (2.9 g, 13.23 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 aqueous solution (150 mL) was added and the mixture was stirred for 15 minutes. The layers were separated and the organic layer was washed with water (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was diluted with a 1: 1 mixture of IPA and heptane (50 mL), and the mixture was stirred for 1 hour. The solid was filtered and washed with pentane (50 mL) to give the title compound (3.8 g, 85%), which was used without further purification. LCMS (method 4): 0.82 min, 407.4 [MH] - .

[1137] Intermediate 12: tert-Butyl (S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-3,4- Dihydroisoquinoline-2(1H)-carboxylate

[1138]

[1139] Method 1: To a solution of intermediate 11 (77.72 g, 188 mmol) in DMF (1.50 L) was added N-chlorosuccinimide (27.5 g, 206 mmol). The mixture was heated at 50 ° C for 72 hours and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with water (x2), brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was combined with another batch of crude material (70.97 mmol), dissolved in DCM (750 mL) and allowed to crystallize. The resulting precipitate was collected by filtration, washed with DCM and dried in vacuo to give the title compound (80 g, 65%), which was used without further purification. LCMS (Method 9a): 2.57 min, 441.2 [MH] - .

[1140] Method 2: To a suspension of intermediate 55-HBr (57.3 g, 135.2 mmol) in DCM (1000 mL) was added DIPEA (59.7 mL, 343 mmol) followed by di-tert-butyl dicarbonate (22.1 g, 101 mmol; CAS: 24424-99-5). The reaction mixture was stirred at room temperature for 66 hours. An additional portion of di-tert-butyl dicarbonate (3.56 g, 16.31 mmol) was added and the mixture was stirred for 2 hours, followed by the addition of di-tert-butyl dicarbonate (1.6 g, 7.33 mmol) and the mixture was stirred for an additional hour. The reaction mixture was washed with water and the organics were separated, dried (MgSO4) and filtered. The organics were concentrated in vacuo (to approximately 500 mL) and the mixture was allowed to stand at room temperature for 18 hours. The precipitate was isolated by filtration, washed with Et2O and dried in vacuo (50°C) to give the title compound (43.3 g, 72%). LCMS (method 9a): 2.33 min, 441.1 [MH] - . 1 H NMR (300 MHz, CDCl 3 ) d 7.91-7.85 (m, 2H), 7.74 (dq, 2H), 7.23-7.18 (m, 1H), 6.80-6.76 (m, 1H), 5.49-5.78 (1H), 4.08 (dd, 1H), 3.83-4.00 (1H), 3.22-3.54 (1H), 2.87-3.04 (1H), 2.61-2.84 (1H), 1.20 (s, 4H), 1.03 (d, 5H). The organics were concentrated in vacuo and combined with the crude material from the following experiment (Method 3) for further purification.

[1141] Method 3: To a suspension of intermediate 55-HCl (49.3 g, 130 mmol) in DCM (1.0 L) was added DIPEA (57.36 mL, 329 mmol) followed by di-tert-butyl dicarbonate (22.49 g, 103.05 mmol; CAS: 24424-99-5). The reaction mixture was allowed to stir at room temperature for 66 hours. An additional portion of di-tert-butyl dicarbonate (0.46 g, 2.12 mmol) was added and the mixture was stirred for 2 hours, followed by the addition of di-tert-butyl dicarbonate (0.5 g, 2.29 mmol) and the mixture was stirred for an additional hour. The reaction mixture was washed with water and the organics were separated, dried (MgSO4) and filtered. The organics were concentrated in vacuo (to approximately 500 mL) and the mixture was allowed to stand at room temperature for 18 hours. The precipitate was isolated by filtration, washed with Et2O and dried in vacuo (50°C) to give the title compound (26.95 g, 46%). LCMS (method 9a): 2.38 min, 441.1 [MH] - The organics were concentrated in vacuo and combined with the concentrated organics from Method 2 and further purified by flash column chromatography (silica; 40% EtOAc in heptane) to give another batch of the title compound (32.4 g, 72.7 mmol). LCMS (Method 9): 2.56 min, 441.1 [MH]-.

[1142] Intermediate 13: tert-Butyl (1S)-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)-3,4- Dihydroisoquinoline-2(1H)-carboxylate

[1143]

[1144] To a stirred suspension of intermediate 11 (400 mg, 0.98 mmol) in MeOH (8 mL) was added NaBH4 (148 mg, 3.9 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 72 h, then quenched with saturated NH4Cl aqueous solution (about 15 mL) and acidified by adding 10% citric acid aqueous solution. The product was collected by filtration, washed with water and dried in vacuo. The residue was azeotroped with MeCN to give the title compound (343 mg, 85%), which was used without further purification. LCMS (Method 5): 1.86, 1.99 min, 409.1 [MH] + .

[1145] Intermediate 14: (S)-2-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindolin-1-one

[1146]

[1147] To a solution of intermediate 13 (50 mg, 0.122 mmol) in TFA (1 mL) was added triethylsilane (0.03 mL, 0.18 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was distributed between DCM (2 mL) and a saturated NaHCO aqueous solution (5 mL). The layers were separated and the water layer was washed with DCM (10 mL). The combined organics were dried over NaSO, filtered and concentrated in vacuo to give the title compound (30 mg, 84%), which was used without further purification. 1 H NMR (400MHz, CDCl3) δ7.88(m,1H),7.61-7.41(m,3H),7.06(t,1H),6.77(d,1H),6.62(d,1H),4.83( d,1H),4.52(d,1H),4.41(d,1H),3.90(d,1H),3.58(dd,1H),3.22-3.03(m,2H),2.83-2.61(m,2H).

[1148] Intermediate 15: tert-Butyl (1S)-5-bromo-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)- 3,4-Dihydroisoquinoline-2(1H)-carboxylate

[1149]

[1150] Under a nitrogen atmosphere, NaBH4 (0.53 g, 14.1 mmol) and MeOH (15 mL) were added to a stirred solution of intermediate 8 (4.58 g, 9.4 mmol) in anhydrous THF (130 mL) cooled in an ice / brine bath. The solution was warmed to room temperature and stirred for 30 minutes. A second portion of NaBH4 (0.53 g, 14.1 mmol) was added and stirring continued for 45 minutes. Another portion of NaBH4 (0.36 g, 9.4 mmol) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water, acidified to pH 3-4 with 10% citric acid, and extracted with EtOAc. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (4.4 g, 97%), which was used without further purification. LCMS (Method 2): 1.46 min, 511.2 / 513.2 [M+Na] + .

[1151] Intermediate 16: (S)-2-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1- ketone

[1152]

[1153] To a stirred solution of intermediate 15 (4.44 g, 9.07 mmol) in TFA (50 mL, 652 mmol) was added triethylsilane (2.5 mL, 15.65 mmol). The mixture was stirred at room temperature for 90 minutes and then diluted with DCM (200 mL). Saturated aqueous NaHCO3 solution was carefully added, followed by ammonia (30-33 wt% in water; 100 mL). The aqueous layer was extracted with DCM, and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. MeCN (40 mL) and DCM (10 mL) were added to the residue, and the resulting suspension was sonicated for 5 minutes. The solid was collected by filtration, rinsed with MeCN / DCM (4:1; 10 mL), and concentrated in vacuo to give the title compound (1.92 g, 56%). LCMS (method 2): 0.86 min, 373.1 / 375.1 [M+H] + .

[1154] Intermediate 17: tert-Butyl (1S)-5-chloro-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)- 3,4-Dihydroisoquinoline-2(1H)-carboxylate

[1155]

[1156] To a stirred solution of intermediate 12 (2.18 g, 4.92 mmol) in anhydrous THF (72 mL) at 0 ° C under argon, NaBH (0.28 g, 7.38 mmol) was added, followed by anhydrous MeOH (8 mL). The mixture was stirred at 0 ° C for 5 minutes, warmed to room temperature, and stirred for 75 minutes. Another portion of NaBH (0.28 g, 7.38 mmol) was added, and the mixture was stirred at room temperature for another 2 hours. Another NaBH (0.19 g, 4.92 mmol) was added, and the mixture was stirred at room temperature for another 19 hours. The mixture was quenched with saturated NaHCO aqueous solution (120 mL), then acidified to pH 5 with 10% citric acid aqueous solution (220 mL). The mixture was extracted into EtOAc (3 × 100 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (2.18 g, assumed quantitative) which was used without further purification. LCMS (Method 2): 1.44 min, 467.2 / 469.2 [M+Na] + .

[1157] Intermediate 18: (S)-2-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1- ketone

[1158]

[1159] To a stirred solution of intermediate 17 (1.98 g, 4.45 mmol) in TFA (33.6 mL, 436.2 mmol) was added triethylsilane (1.07 mL, 6.68 mmol) under argon, and the resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with DCM (300 mL), and saturated NaHCO aqueous solution (440 mL) was carefully added under stirring to reach a pH of 8-9. The aqueous layer was further extracted with DCM (2 × 300 mL), and the combined organic matter was dried over Na SO , filtered, and concentrated in vacuo. The residue was ground with diethyl ether (30 mL), and the solid was collected by filtration, washed with diethyl ether (× 3), and dried in vacuo at 40° C. Purification by flash column chromatography (Puriflash 40 g, 0-5% MeOH in DCM) gave the title compound (420 mg, 35%). LCMS (method 1): 0.79 min, m / z 329.1 [M+H] + .

[1160] Intermediate 19: tert-Butyl (S)-1-(aminomethyl)-5-bromo-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1161]

[1162] To a stirred suspension of intermediate 8 (3.41 g, 7 mmol) in EtOH (100 mL) was added hydrazine hydrate (1.7 mL, 34.95 mmol), and the resulting red mixture was heated at 65 ° C for 7 hours to form a colorless precipitate. The mixture was cooled to room temperature, and the precipitated solid was removed by filtration and the solid was washed with EtOH (20 mL). The filtrate was concentrated in vacuo to give the title compound (3.24 g, assumed to be quantitative), which was used without further purification. LCMS (Method 2): 1.01 min, 357.1 [M+H] + .

[1163] Intermediate 20: tert-Butyl (S)-5-bromo-8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)hydroxy-3,4-diol Hydroisoquinoline-2(1H)-carboxylate

[1164]

[1165] A stirred solution of methyl 4-bromobutyrate (1.52 g, 8.4 mmol; CAS: 4897-84-1), intermediate 19 (3.24 g, 7 mmol) and triethylamine (1.47 mL, 10.55 mmol) in toluene (70 mL) was heated at reflux for 18 hours. A second portion of methyl 4-bromobutyrate (250 mg, 1.38 mmol) was added and the mixture was heated at reflux for an additional 5 hours. The mixture was cooled to room temperature, diluted with EtOAc and washed with 10% aqueous citric acid, water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by chromatography on a Teledyne ISCO column. Purification by flash column chromatography on Rf+ (100 g silica gel column, Biotage SNAP, 0-100% EtOAc in DCM, then 0-100% MeOH in DCM) gave the title compound (1.41 g, 47%). LCMS (Method 2): 1.48 min, 447.2 [M+Na] + .

[1166] Intermediate 21: (S)-1-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one

[1167]

[1168] A stirred solution of intermediate 20 (826 mg, 1.94 mmol) in DCM (60 mL) was treated with TFA (3 mL, 39.2 mmol) and the resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with DCM (50 mL) and water (50 mL) and basified to pH 8 by adding saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (593 mg, 94%), which was used without further purification. LCMS (Method 2): 0.74 min, 325.1 [M+H] + Using bromine isotopes.

[1169] Intermediate 22: tert-Butyl (S)-1-(aminomethyl)-5-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[1170]

[1171] Method 1: To a solution of intermediate 12 (2.35 g, 5.31 mmol) in EtOH (50 mL) was added hydrazine hydrate (1.29 mL, 26.5 mmol) and the mixture was heated at reflux for 24 hours. The reaction was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo. The product was purified by HPLC (Teledyne ISCO) Purification by flash column chromatography on Rf+ (120 g silica gel column Puriflash HC / Biotage SNAP, 0-30% EtOAc in MeOH) gave the title compound (1.49 g, 90%). LCMS (Method 2): 1.01 min, 313.0 [M+H] + .

[1172] Method 2: To a stirred suspension of intermediate 12 (40.0 g, 90.3 mmol) in EtOH (150 mL) was added hydrazine monohydrate (16.9 mL, 226 mmol; CAS: 7803-57-8), and the resulting mixture was heated to 75° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with additional IMS and filtered. The filter cake was washed with cold EtOH, and the combined filtrate was concentrated in vacuo to about 400 mL. The solution was allowed to stand for 18 hours, then filtered to remove the precipitate, and the precipitate was washed with cold EtOH. The filtrate was concentrated in vacuo, and EtOH (100 mL) and MeCN (100 mL) were added to the residue. The suspension was filtered and concentrated in vacuo to give the title compound (24.5 g, 82% yield).

[1173] Intermediate 23: tert-Butyl (S)-5-chloro-8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)hydroxy-3,4-diol Hydroisoquinoline-2(1H)-carboxylate

[1174]

[1175] To a solution of intermediate 22 (1.65 g, 5.28 mmol) in toluene (40 mL) was added methyl 4-bromobutyrate (1.24 g, 6.86 mmol; CAS: 4897-84-1) and triethylamine (1.1 mL, 7.93 mmol). The reaction was heated at reflux for 24 hours. Then, additional portions of methyl 4-bromobutyrate (1.24 g, 6.86 mmol) and triethylamine (1.1 mL, 7.93 mmol) in toluene (1 mL) were added and the reaction was heated to reflux for an additional 6.5 hours. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed successively with brine (20 mL), water (20 mL), dried over MgSO and concentrated in vacuo. The product was purified by chromatography on a Teledyne ISCO column. Purification by flash column chromatography on Rf+ (200 g silica gel column Puriflash HC / Biotage SNAP, 0-100% EtOAc in cyclohexane) gave the title compound (1.29 g, 64%). LCMS (Method 2): 1.43 min, 403 [M+Na] + .

[1176] Intermediate 24: (S)-1-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one

[1177]

[1178] To the stirring mixture of intermediate 23 (203mg, 0.530mmol) in anhydrous DCM (8mL) was added TFA (0.82mL, 10.66mmol) under argon, and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (5mL), and the pH was adjusted to 8-9 by adding saturated NaHCO3 aqueous solution (about 8mL). The water layer was extracted with DCM (3x10mL). The combined organic matter was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound (173mg, assumed to be quantitative), which can be used without further purification. LCMS (method 2): 0.75min, 281.1[M+H] + .

[1179] Intermediate 25: (1R,2S)-2-((Benzyloxy)carbonyl)cyclohexane-1-carboxylic acid

[1180]

[1181] To a suspension of cis-1,2-cyclohexanedicarboxylic anhydride (10 g, 65.0 mmol, CAS: 13149-00-3) and quinidine (23 g, 71.4 mmol) in toluene (200 mL) was added benzyl alcohol (21 g, 195 mmol) dropwise at -10°C under argon over 30 minutes. The reaction mixture was then stored in a refrigerator at 0°C for 5 days. After warming to room temperature, the mixture was diluted with EtOAc (150 mL) and toluene (150 mL). The solution was washed with aqueous HCl (1 M; 2 x 200 mL) and then brine (200 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to approximately 350 mL, and a solution of (R)-α-methylbenzylamine (7.86 g, 65 mmol) in toluene (75 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes, then seeded with small crystals of the pure ammonium salt (prepared by taking a small aliquot of the solution and concentrating to dryness) and stirred for an additional 18 hours. The solid was then collected by filtration and washed with toluene (50 mL) and then dried in vacuo. The solid was then partitioned between EtOAc (250 mL) and a 1M aqueous HCl solution (200 mL). The EtOAc layer was collected, washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (10 g, 58%, >99% ee). Chiral HPLC (Chiralpak IA 4.6x250 mm, 90:10 hep / IPA + 0.1% TFA, flow rate 1 ml / min); Rt = 6.2 min. LCMS (Method 4): 0.51 min, 236.3 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ7.38-7.26(m,5H),5.20-5.04(m,2H),2.92-2.85(m,2H),2.09-1.99(m,2H),1.85-1.75(m,2H),1.61-1.35(m,4H).

[1182] Intermediate 26: (1S,2R)-benzyl 2-(chlorocarbonyl)cyclohexane-1-carboxylate

[1183]

[1184] To a solution of intermediate 25 (0.50 g, 1.90 mmol) in DCM (5 mL) was added oxalyl chloride (0.82 mL, 9.53 mmol). The reaction mixture was stirred at room temperature for 3 hours, then the reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (2 x 20 mL) in vacuo to give the title compound (0.57 g, 100%) which was used without further purification. 1 HNMR (400MHz, CDCl3) δ7.42-7.20(m,5H),5.19-5.08(m,2H),3.22-3.00(m,2H),2.17-2.01(m,2H),1.92-1.77(2H,m),1.60-1.37(m,4H).

[1185] Intermediate 27: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclohexane-carboxylic acid; (1R)-1- Phenylethylamine

[1186]

[1187] A solution of (2,4-dimethoxyphenyl)methanol (32.7 g, 195 mmol, CAS: 7314-44-5) in toluene (50 ml) was added dropwise to a suspension of cis-1,2-cyclohexanedicarboxylic anhydride (10.0 g, 64.9 mmol, CAS: 13149-00-3) and (S)-(6-methoxy-4-quinolinyl)-[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (23.2 g, 71.4 mmol, CAS: 56-54-2) in toluene (150 ml) at -5°C over 1 hour. The solution was then transferred to a refrigerator and left for 12 days. The reaction mixture was washed with 1M aqueous HCl (200 mL), brine (100 mL), and the organic layer was dried over MgSO4 and filtered. A portion of the filtrate (about 2 mL) was concentrated in vacuo, and ether (2 mL) was added to the residue, followed by (1R)-1-phenylethylamine (1 drop; CAS 3886-69-9). The resulting solid was collected by grinding. (1R)-1-phenylethylamine (8.4 mL, 64.9 mmol) was added to the remaining filtrate under stirring. The solid collected from the previous grinding was added to the solution and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration, washed with ether (200 mL) and dried to give the title compound (16.4 g, 57%), which was used without further purification. 1 H NMR (300 MHz, MeOD) δ 7.42-7.20 (m, 6H), 6.49-6.44 (m, 2H), 5.11-4.90 (m, 2H), 4.32 (q, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.76-2.65 (m, 2H), 2.13-1.33 (m, 11H). The above reaction was repeated using 10 g of cis-1,2-cyclohexanedicarboxylic anhydride to obtain 20.6 g of the title compound (68%).

[1188] Intermediate 28: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclohexane-1-carboxylic acid

[1189]

[1190] Intermediate 27 (16.4 g, 36.98 mmol) was partitioned between citric acid (10% aqueous solution; 80 mL) and EtOAc (400 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (11.5 g, 99%) which was used without further purification. 1H NMR(300MHz,MeOD)δ7.17(d,1H),6.51-6.44(m,2H),5.02(dd,2H),3.78(s,3H),3.76 (s,3H),2.81-2.79(m,2H),2.01-1.99(m,2H),1.75-1.71(m,2H),1.47-1.41(m,4H).

[1191] Intermediate 29: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclohexane-1-carboxylic acid

[1192]

[1193] To a stirred solution of intermed...

Claims

1. A compound having the formula: in: R is hydrogen or -C(O)O t Bu(Boc); R 1 Selected from C 1-4 Alkylene-R 11 , heterocyclyl and 8-10 membered bicyclic heteroaryl; wherein the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 , C 1-3 Alkylene-OR 14 , and optionally one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 wherein the 8-10 membered bicyclic heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH and C 1-3 Substitution of alkoxy groups; R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl; R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl halides and cyano groups; R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring wherein: The heterocyclyl ring comprises one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or optionally spiro-attached to a C 3-7 a cycloalkyl group; and The heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO2R 20 Substituents are substituted; R 11 Selected from -C(O)-R 24 、-SO2-R 25 、-NR 26 C(O)-R 27 、-NR 28 SO2-R 29 , heterocyclyl, aryl and heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substituted with alkoxy, heterocyclyl and cyano substituents; and the heterocyclyl group is optionally substituted with one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, oxo and cyano groups; R 12 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 17 Selected from hydrogen, C 1-4 Alkyl, C(O)C 1-3 Alkyl and C(O)NR 36 R 37 ; R 18 , R 19 and R 20 Independently selected from C 1-4 Alkyl, OH, C 1-3 Alkoxy and NR 38 R 39 ; R 24 Selected from C 1-4 Alkyl, NR 40 R 41 OR 42 ; R 25 Selected from C 1-4 Alkyl and NR 43 R 44 ; R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 45 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 46 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ; R 40 Selected from hydrogen and C 1-4 alkyl; R 41 Selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, aryl and heteroaryl; or R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 3-7 Substitution of cycloalkyl and cyano groups; R 45 and R 46 Independently selected from hydroxyl, C 1-3 Alkoxy and C 3-7 cycloalkyl; and R 14 , R 16 , R 26 , R 28 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 42 , R 43 , R 44 , R 47 and R 48 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl.

2. The compound according to claim 1, wherein R 1 It is C 1-4 Alkylene-R 11 , optionally wherein R 1 It is CH2-R 11 .

3. The compound according to claim 1 or 2, wherein R 11 : (A) is selected from -C(O)-R 24 、-NR 26 C(O)-R 27 , heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substituted with alkoxy, heterocyclyl and cyano substituents; and the heterocyclyl group is optionally substituted with one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, oxo and cyano groups; (B) is optionally one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 heteroaryl substituted with a substituent of an alkoxy group, a heterocyclic group, and a cyano group; (C) is optionally substituted by one or more independently selected from methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, cyano, oxetanyl, CH2-R 30 and C2H4-R 30 A heteroaryl group substituted with a substituent; (D) is pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Alkoxy, heterocyclic and cyano are substituted by substituents; or (E) is a heteroaryl group selected from the group consisting of: Each heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 The substituents of the alkoxy group, the heterocyclic group and the cyano group are substituted.

4. The compound according to claim 1, wherein R 1 : (A) is a heterocyclic group optionally substituted by one or more substituents independently selected from the following: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; (B) is piperidinyl or pyrrolidinyl, each optionally substituted by one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; (C) is pyrrolidinyl optionally substituted by one or more substituents independently selected from the group consisting of: -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution; or (D) is one selected from the following groups: in represents the point of attachment of the group to the oxygen atom of the rest of the compound, and wherein each group is optionally substituted by one or more independently selected from -C(O)-R 12 、SO2-R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl group is optionally substituted by a C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

5. A compound according to any one of claims 1 to 4, wherein R 2 It is hydrogen or fluorine.

6. A compound according to any one of claims 1 to 5, wherein R 3 It is hydrogen or chlorine.

7. A compound according to any one of claims 1 to 6, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form: (A) a 5-membered heteroaryl or heterocyclyl ring, wherein the heterocyclyl comprises a -C(O)- moiety attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or optionally to a C 3-7 The cycloalkyl group is spiro-connected, and wherein the heteroaryl and heterocyclyl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; (B) a 5-membered heteroaryl ring, which is optionally substituted by one or more independently selected from C 1-4 Substitution of alkyl, halide and OH groups; (C) a pyrazolyl ring, which is optionally substituted by one or more independently selected from C 1-4 Substitution of alkyl, halide and OH groups; (D) a 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl comprises a -C(O)- moiety attached to a nitrogen atom and is optionally fused to an aryl ring, or optionally to a C 3-7 The cycloalkyl group is spiro-connected, and wherein the heterocyclic group is optionally substituted by one or more independently selected from C 1-4 Alkyl, halo and OH are substituted by substituents; or (E) a heterocyclic moiety selected from the group consisting of: The saturated ring of the heterocyclic moiety is optionally connected to C 3-7 The cycloalkyl group is spiro-connected, and wherein the heterocyclic portion is optionally substituted by one or more independently selected from C 1-4 Alkyl, halide and OH substituents are substituted.

8. The compound according to claim 1, which is: or a salt thereof.

9. The compound according to claim 1, which is:

10. The compound according to claim 1, which is: or a salt thereof.

11. The compound according to claim 1, which is:

12. The compound according to claim 1, which is: or a salt thereof.

13. The compound according to claim 1, which is:

14. A method for synthesizing a compound of formula IA using a compound according to claim 1 or a salt thereof: in: R 1 Selected from C 1-4 Alkylene-R 11 , heterocyclyl and 8-10 membered bicyclic heteroaryl; wherein the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 , C 1-3 Alkylene-OR 14 , and optionally one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH, C 1-3 wherein the 8-10 membered bicyclic heteroaryl is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, OH and C 1-3 Substitution of alkoxy groups; R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl; R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl halides and cyano groups; R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring wherein: The heterocyclyl ring comprises one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or is optionally spiro-attached to a C 3-7 a cycloalkyl group; and The heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO2R 20 Substituents are substituted; L 1 and L 2 independently selected from a bond and -CR 21 R 22 -; R 6 and R 7 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl; or R 6 and R 7 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5- or 6-membered cycloalkyl ring; R 8 Selected from CO2R 23 、C(O)NHSO2C 1-3 Alkyl, tetrazolyl, 3-trifluoromethyl-1,2,4-triazol-5-yl and carboxylic acid mimetic groups selected from hydroxamic acid, hydroxamate, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfonylurea, acylurea, thiazolidinedione, oxazolidinedione, oxadiazole-5(4H)-one, thiadiazole-5(4H)-one, oxadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetracarboxylic acid, cyclopentane-1,3-dione and cyclopentane-1,2-dione; R 9 Selected from hydrogen, C 1-4 Alkyl, hydroxyl, C 1-3 Alkoxy and halide; R 10 Selected from hydrogen and C 1-4 Alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached, form a 3-, 4-, 5- or 6-membered cycloalkyl ring; or L 2 is a key, and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocyclyl ring wherein: The heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally connected by a C 1-3 Alkylene group bridging, or R 9 Optionally, C* is connected to a carbon atom of the ring. 1-3 an alkylene group; and The cycloalkyl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 1-3 Substitution of haloalkyl and deuterium substituents; R 11 Selected from -C(O)-R 24 、-SO2-R 25 、-NR 26 C(O)-R 27 、-NR 28 SO2-R 29 , heterocyclyl, aryl and heteroaryl; wherein the aryl and heteroaryl groups are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 substituted with alkoxy, heterocyclyl and cyano substituents; and the heterocyclyl group is optionally substituted with one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogen, OH, C 1-3 Substitution of alkoxy, oxo and cyano groups; R 12 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 17 Selected from hydrogen, C 1-4 Alkyl, C(O)C 1-3 Alkyl and C(O)NR 36 R 37 ; R 18 , R 19 and R 20 Independently selected from C 1-4 Alkyl, OH, C 1-3 Alkoxy and NR 38 R 39 ; R 24 Selected from C 1-4 Alkyl, NR 40 R 41 OR 42 ; R 25 Selected from C 1-4 Alkyl and NR 43 R 44 ; R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 45 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 46 , halogen, OH, C 1-3 Substitution of alkoxy and cyano groups; R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ; R 40 Selected from hydrogen and C 1-4 alkyl; R 41 Selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, aryl and heteroaryl; or R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted by one or more independently selected from C 1-4 Alkyl, halogen, OH, C 1-3 Alkoxy, C 3-7 Substitution of cycloalkyl and cyano groups; R 45 and R 46 Independently selected from hydroxyl, C 1-3 Alkoxy and C 3-7 cycloalkyl; and R 14 , R 16 , R 21 , R 22 , R 23 , R 26 , R 28 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 42 , R 43 , R 44 , R 47 and R 48 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl.

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