Tetrahydroisoquinoline compounds as NRF2 activators

Abstract

The present invention relates to compounds that are Nrf2 activators. These compounds have the structural formula I defined herein. The present invention also relates to methods for preparing these compounds, to pharmaceutical compositions containing them, and to their use in treating diseases or disorders associated with Nrf2 activation.

Description

[0001] introduction

[0002] The present invention relates to tetrahydroisoquinoline compounds. More specifically, the present invention relates to tetrahydroisoquinoline compounds as Nrf2 activators. The present invention also relates to methods for preparing these compounds, to pharmaceutical compositions containing them, and to their use in treating diseases or disorders associated with Nrf2 activation and / or inhibition of Keap1-Nrf2 protein-protein interactions. Background Art

[0003] 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) family of transcription factors. It is a key player in the inducible cellular defense system, mediating the expression of more than 100 oxidative stress-related genes, 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 binding targets of Nrf2. Under basal conditions, the level of Nrf2 is strictly regulated by the adaptor protein Keap1, a repressor protein that binds to cytoplasmic actin, which binds to Nrf2 and causes proteasomal degradation through the Cul3-based E3 ubiquitin ligase complex. Under oxidative stress conditions, Keap1 is inactivated, resulting in increased levels of de novo synthesized Nrf2, which translocates to the nucleus, binds to the ARE, and leads to upregulation of cytoprotective gene expression.

[0004] It has been shown that the expression of Nrf2 mRNA in COPD subjects is significantly lower than that in control subjects and that Nrf2 mRNA is negatively correlated with pack year. Nrf2 protein in COPD subjects is significantly lower than that in control subjects. CSE-induced apoptosis of A549 cells increases in a time-dependent and concentration-dependent manner and is significantly increased by Nrf2 knockdown (Yamada, BMC Pulmonary Medicine, doi: 10.1186 / s12890-016-0189-1). Therefore, the increase in Nrf2 levels in the lungs of COPD patients should reduce the inflammatory process that causes harmful structural changes in the lungs and slow down disease progression. Nrf2 is also expected to show positive benefits 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; 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; de la Vega Curr Pharmacol, doi: 10.1016 / j. Rep [Current Pharmacology Reports], doi:10.1007 / s40495-016-0053-2), pulmonary fibrosis, including idiopathic pulmonary fibrosis (Kikuchi, Respir Res [Respiratory Research], doi:10.1186 / 1465-9921-11-31) and cystic fibrosis (Chen, PLoS One [Public Library of Science One], doi:10.1371 / journal.pone.0003367). In fact, the combination of cytoprotective effects of restoring redox and protein homeostasis, promoting resolution of inflammation and promoting lung repair by Nrf2 activators highlights their potential for treating COVID-19 (Cuadrado et al., Trends Pharmacol Sci [Advances in Pharmacology Research], doi:10.1016 / j.tips.2020.07.003).

[0005] 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). An Nrf2 activator (bardoxolonemethyl) has recently completed a phase II study in patients with pulmonary arterial hypertension (PAH), and a phase III study is ongoing based on significant improvements in 6-minute walk distance. Bardoxolone reacts covalently with Keap1, but compounds that activate Nrf2 through alternative mechanisms of Keap1 binding should also have promise as therapeutics in PAH, particularly in patients who also have underlying connective tissue disease (CTD) such as scleroderma or lupus erythematosus. Oxidative stress is elevated in the diseased myocardium, resulting in elevated levels of reactive oxygen species that negatively affect cardiac function (Bolli, Circ, doi: 10.1161 / circ.76.2.3111744). Nrf2 activation has been shown to inhibit myocardial oxidative stress, cardiac cell apoptosis, hypertrophy, fibrosis, and dysfunction in a mouse model of pressure overload (Wang, J Card Failure, doi: 10.1016 / j.cardfail.2012.06.003) and protect against myocardial ischemia / reperfusion injury in a rodent model (Zhang, J Mol Cell Cardiol, doi: 10.1016 / j.yjmcc.2010.05.01). Furthermore, excessive production of oxidants impairing the antioxidant defenses of the cardiovascular system has also been described in metabolic diseases such as obesity, metabolic syndrome, and diabetes, among others, where activation of Nrf2 is also considered a promising therapeutic strategy (da Costa, Front Pharmacol. doi: 10.3389 / fphar.2019.00382). Furthermore, the Nrf2 activator sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes (Axelsson, Sci Transl Med. doi: 10.1126 / scitranslmed.aah4477), and bardoxolone methyl has been shown to induce weight loss (proportional to baseline BMI) in patients with normal obesity while improving glycemic control (Chertow et al., JDiabetes Complications, doi: 10.1016 / j.jdiacomp.2018.09.005).Age-related mitochondrial dysfunction and oxidative damage are major causes of a variety of health problems, including sarcopenia and cardiovascular disease, and treatment of aged mice with the Nrf2 activator sulforaphane can restore Nrf2 activity, mitochondrial function, cardiac function, exercise capacity, glucose tolerance, and activation / differentiation of skeletal muscle satellite cells (Bose et al., Aging cell, doi: 10.1111 / acel.13261). Therefore, it is expected that drugs that cause Nrf2 activation should be useful for 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.

[0006] Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality due to the lack of effective therapies. Early brain injury (EBI) and cerebral vasospasm (CVS) are the two most important pathophysiological mechanisms of brain damage and poor prognosis in SAH patients (clinicaltrials.gov / ct2 / show / NCT0261474, SFX01 After Subarachnoid Haemorrhage). Evidence from experimental SAH studies suggests a protective role for the Nrf2 / ARE pathway in EBI and CVS after SAH. Administration of sulforaphane (SFN) to rats after SAH enhances the activity of the Nrf2-ARE pathway, reduces vasospasm of the basilar artery, and inhibits the release of proinflammatory cytokines (Zhao, Brain Res., doi:10.1016 / j.brainres.2016.09.035). Intracerebral hemorrhage (ICH) is the main event of 10%-15% of the 15 million strokes that occur each year worldwide. In vitro studies have shown that Nrf2 activators rapidly increase the expression of HO-1 in astrocytes and reduce their vulnerability to hemoglobin or heme. Systemic treatment with small molecule Nrf2 activators increases the expression of HO-1 in perivascular cells, especially astrocytes. When tested in mouse or rat ICH models, Nrf2 activators are always protective, thereby improving barrier function and reducing edema, inflammation, neuronal loss and neurological deficits (Chen-Roetling, Curr Pharm Des [Current Drug Design], doi: 10.2174 / 1381612822666161027150616). Ischemic stroke induces reactive oxygen species, which cause oxidative and inflammatory responses in the ischemic brain. To date, recombinant tissue plasminogen activator is the only available therapy for the treatment of ischemic stroke. However, this treatment did not prevent oxidative stress and inflammation in the ischemic brain. D3T is a sulfur-containing dithiolethione compound found in cruciferous vegetables and reported to induce antioxidant genes by activating Nrf2. D3T has been shown (Yen, J Immunol 2017, 198(1 Suppl) 206.20) to reduce cerebral infarction and improve neurological deficits in stroke animals. In addition, D3T reduced CNS-infiltrating inflammatory immune cells, including neutrophils and monocytes in the ischemic brain. In addition, D3T-induced inhibition of inflammatory cytokine production was observed in wild-type but not in microglia lacking Nrf2. In addition, the protective effect of D3T on reducing ischemic cerebral infarction was abolished in stroke animals lacking Nrf2 and in stroke animals administered HO-1 inhibitors.These results suggest that D3T-mediated suppression of inflammation in the ischemic brain is mediated through the Nrf2 / HO-1 pathway, and thus targeting the Nrf2 / HO-1 pathway may be a promising therapeutic strategy to improve neuroinflammation in ischemic stroke.

[0007] Nrf2 is thought to play a key role in some hemoglobinopathies, such as beta thalassemia and sickle cell disease (SCD). SCD is a recessive genetic disease caused by a single missense mutation that results in a mutation in beta globin hemoglobin S (HbS). Under low oxygen concentrations, HbS polymerizes, resulting in deformed red blood cells that are prone to rupture, releasing free heme into the plasma. The resulting oxidative stress and inflammation lead to damage to multiple organs in the body. Ablation of Keap1 and the resulting constitutive activation of Nrf2 have been shown to produce improved outcomes 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 progression of hemolytic anemia and organ dysfunction (Ghosh, JCI Insight, doi: 10.1172 / jci.insight.81090) and 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. Haematology, doi: 10.1111 / bjh.15401). In addition, Nrf2 activators have also 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 cells, Nrf2 provides unique benefits through HbF induction to inhibit hemoglobin S polymerization and prevent oxidative stress caused by chronic hemolysis (Zhu et al., Exp Biol Med [Journal of Experimental Medicine] doi:10.1177 / 1535370219825859). 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 β-thalassemia.

[0008] Nrf2 function is altered in many neurodegenerative diseases: Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Friedreich's ataxia (Dinkova-Kostova, FEBS, doi:10.1111 / febs.14379). Nrf2 activation mitigates multiple pathogenic processes associated with these neurodegenerative diseases by upregulating antioxidant defenses, suppressing inflammation, improving mitochondrial function, and maintaining protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in a variety of 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 trial for the treatment of the inherited neurodegenerative disease Friedrich's ataxia and has achieved the primary endpoint of change in the modified Friedrich's Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks of treatment. Targeting Nrf2 signaling may therefore provide a therapeutic option for delaying the onset, slowing the progression, and ameliorating the symptoms of neurodegenerative diseases. Nrf2 activators have also been suggested for the treatment of chronic pain and schizophrenia due to the role of oxidative stress and mitochondrial dysfunction in CNS diseases.

[0009] Rheumatoid arthritis (RA) is an autoimmune disease that can cause chronic inflammation of the joints and is characterized by the onset and remission of the disease. Sometimes multiple joints are affected, resulting in 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 more oxidative damage, and the expression of Nrf2 target genes during antibody-induced arthritis is enhanced in Nrf2 wild-type, but not in knockout mice (Wruck, BMJ Annals of Rheumatic Diseases, doi: 10.1136 / ard.2010.132720). Furthermore, in an animal model of rheumatoid arthritis by transferring serum from K / BxN transgenic mice to Nrf2(- / -) mice, the deficiency of Nrf2 accelerated the onset of arthritis, and the animals exhibited widespread disease affecting both the front and hind paws (Maicas, Antioxidants & Redox Signaling, doi:10.1089 / ars.2010.3835).

[0010] 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 may disrupt the barrier function of the intestinal epithelium, thereby promoting abnormal immune responses and inflammatory conditions. Therefore, an intact intestinal epithelium is essential for a healthy intestine, and cytoprotective agents that can target intestinal epithelial cells will be beneficial for the treatment of UC and CD. Antioxidant levels and oxidative stress biomarkers are often associated with disease severity in IBD, and many genome-wide association studies have linked IBD-associated single nucleotide polymorphisms (SNPs) to multiple genes involved in oxidative stress responses, many of which are regulated by Nrf2 (Khor et al., Nature, doi: 10.1038 / nature10209). CPUY192018, a small molecule inhibitor of Keap1-Nrf2 protein-protein interaction (and thus an Nrf2 activator), showed cytoprotective effects in an experimental model of UC induced by dextran sulfate sodium in both NCM460 cells and mouse colon (Lu, Scientific Reports, doi: 10.1038 / srep26585). Nrf2 knockout mice have also been shown to show increased susceptibility to colitis-associated colorectal cancer (Khor, Cancer Prev Res (Phila), doi: 10.1158 / 1940-6207).

[0011] Fumaderm is a mixture of dimethyl fumarate (DMF) and three monoethyl fumarate salts, approved in Germany in 1994 for the treatment of psoriasis. Monomethyl fumarate (MMF), a possible bioactive form of DMF, has been shown to increase total Nrf2 levels in primary mouse keratinocytes and enhance mRNA expression of several Nrf2 downstream effectors (such as heme oxygenase 1 and peroxiredoxin 6). (Helwa, J Pharmacol. Exp. Ther. [Journal of Pharmacology and Experimental Therapeutics], doi: 10.1124 / jpet.116.239715). Other skin diseases may benefit from the treatment of Nrf2 activators, such as radiation dermatitis / skin damage, atopic dermatitis and wound healing (Wu et al., Mol Med Rep. [Molecular Medicine Report] August 2019; 20 (2): 1761-1771).

[0012] Activation of Nrf2 has been shown to have beneficial effects in both liver and kidney diseases. NAFLD (non-alcoholic fatty liver disease) is recognized as the leading cause of chronic liver disease worldwide. NAFLD represents a spectrum 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 mortality, NASH (non-alcoholic steatohepatitis) is the predominant diagnosed subtype of NAFLD, which predisposes patients to cirrhosis and liver-related complications. There are currently approved drug treatments for NAFLD and NASH. However, Nrf2 knockout in mice is highly susceptible to NASH mimicked 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 may benefit from treatment with Nrf2 activators, such as toxin-induced liver disease, viral hepatitis, and cirrhosis. Oxidative stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models of acute kidney injury (AKI), in which Nrf2 is transiently and mildly activated. Genetic or pharmacological enhancement of Nrf2 activity in the renal tubules can significantly ameliorate AKI-related damage and prevent AKI from progressing 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 the occurrence of cardiovascular events. Since recent basic research has accumulated a positive effect of KEAP1 inhibitors in moderate stages of CKD, the phase II trial was restarted. Data from ongoing projects show that Nrf2 activators / KEAP1 inhibitors improve glomerular filtration rate in patients with stage 3 CKD and T2DM without safety issues (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). The PhII trial showed that bardoxolone methyl significantly improved renal function after 12 weeks in patients with autosomal dominant polycystic kidney disease (ADPKD), CKD associated with type 1 diabetes (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 and is caused by a genetic defect in type IV collagen, a component of the glomerular basement membrane. Because bardoxolone methyl is thought 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 disease.

[0013] 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 is able to eliminate ROS, carcinogens, and other DNA damaging agents, 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) in 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). Thus, activators of Nrf2 may play a role in preventing cancer.

[0014] Age-related macular degeneration (AMD) is the main cause of blindness in Western countries, and oxidative stress plays a major role in the pathogenesis and progression of AMD. It has been shown that Nrf2 activators can protect cells cultured for simulating the outer layer of the retina from oxidative stress, which indicates that early AMD patients have the potential to retain vision (Bellezza, Front Pharmacol. [Pharmacology Frontier] 2018; 9: 1280). In addition, Nrf2 activators can also be used for other eye conditions, such as Fox corneal endothelial dystrophy and uveitis.

[0015] Recently, Nrf-2 activators have also been shown to be beneficial in treating preeclampsia by inhibiting oxidative stress and endothelial cell apoptosis (Jiang et al., Oxid Med Cell Longev doi: 10.1155 / 2021 / 8839394).

[0016] Therefore, given the role of Nrf2 in multiple indications, there is a continuing need for drugs 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 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 present 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, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease, and non-alcoholic steatohepatitis.

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

[0025] In another aspect, the invention provides the use of a compound or a pharmaceutically acceptable salt in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0026] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, 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.

[0027] The present invention also provides a process for synthesizing a compound as defined herein, or a pharmaceutically acceptable salt 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 prevention as well as alleviation of established symptoms of a condition. "Treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset 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 treatment) or at least one clinical or subclinical symptom thereof; or (3) alleviating or relieving 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 to treat a disease, is sufficient to effect such treatment of the disease."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 and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific only to the straight chain type, and references to individual branched chain alkyl groups such as "isopropyl" are specific only to the branched form. 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 The term "alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene and butylene.

[0037] In this specification, the term "alkoxy" includes straight and branched chain alkyl groups singly bonded to oxygen. 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, cycloheptyl. Bicyclic rings may be fused or spiro-attached; 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" is used herein to refer 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" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring systems. Monocyclic heterocyclic rings contain about 3 to 12 (suitably 3 to 7) ring atoms, with 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclic rings contain 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. Bicyclic heterocyclic rings can be fused ring systems, spiro ring systems or bridged ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxirane, oxetane, tetrahydrofuranyl, dioxane and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiophene. (hexahydrothiepine). Other heterocycles include dihydro-oxathiolanyl (oxathiolyl), dihydroisoxazolyl (e.g. 4,5-dihydroisoxazolyl), dihydropyridinyl (e.g. 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl (oxathiazolyl), hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolyl (dioxolinyl), octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, sulfur-oxidized heterocycles containing SO or SO2 groups are also included. Examples include tetrahydrothiophene and thiomorpholinyl in the form of sulfoxides and sulfones, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclic groups with 1 or 2 oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclic groups are saturated monocyclic 3 to 7 membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by the skilled person, any heterocyclic ring may be connected to another group via any suitable atom (e.g., via a carbon or nitrogen atom). Suitably the term "heterocyclyl" refers to a 4, 5, 6 or 7 membered monocyclic ring as defined above.

[0043] The specification also uses composite terms to describe groups containing more than one functionality. Those skilled in the art will understand these terms. For example, C 1-4 Alkylene-C3-7 Cycloalkyl refers to 3-7 Cycloalkyl substituted C 1-4 Alkylene.

[0044] The term "optionally substituted" refers to substituted groups, structures or molecules as well as unsubstituted groups, structures or molecules.

[0045] 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.

[0046] The phrase "compounds of the invention" refers to those compounds disclosed both generally and specifically herein.

[0047] Compounds of the present invention

[0048] In a first aspect, the present invention provides a compound having formula I

[0049]

[0050] in:

[0051] R 1 C 1-4 Alkylene-R 4 ;

[0052] R 2 is selected from CO2H and tetrazolyl;

[0053] R 3 is selected from hydrogen and methyl;

[0054] X is CR 5 R 6 or O;

[0055] R 4 is 1,2,3-triazolyl, 1,2,4-triazolyl or pyrimidinyl, wherein the triazolyl or pyrimidinyl is:

[0056] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano; and

[0057] optionally fused to a cycloalkyl or heterocyclyl ring;

[0058] R 5 Selected from hydrogen, C 1-4 Alkyl, C3-7 Cycloalkyl and C 1-3 Haloalkyl;

[0059] R 6 Selected from hydrogen and C 1-4 Alkyl; or

[0060] R 5 and R 6 Together with the carbon atoms to which they are attached, they form a 3- or 4-membered cycloalkyl ring;

[0061] m is 0 or 1;

[0062] n is 1 or 2;

[0063] or a pharmaceutically acceptable salt thereof;

[0064] The prerequisite is that the compound having formula I is not one of the following compounds:

[0065] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0066] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0067] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0068] (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; or

[0069] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0070] Specific compounds of the present invention include, for example, compounds having Formula I or a pharmaceutically acceptable salt thereof, wherein, unless otherwise specified, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, n and m each have any meaning as defined above or in any one of paragraphs (1) to (54) below. For the avoidance of doubt, the scope of the present invention includes compounds of formula I or pharmaceutically acceptable salts thereof, wherein the definition of any substituent defined herein may be combined with the definition of any other substituent also defined herein: -

[0071] (1)R 1 C 1-4 Alkylene-R 4 ;

[0072] (2)R 1 CH2-R 4 ;

[0073] (3)R 1 CH2CH2-R 4 ;

[0074] (4)R 2 is CO2H;

[0075] (5)R 2 is a tetrazolyl group;

[0076] (6)R 3 is hydrogen;

[0077] (7)R 3 is methyl;

[0078] (8)R 4 is 1,2,3-triazolyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, and cyano;

[0079] (9)R 4 is 1,2,3-triazolyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl and C 1-4 Alkylene-C 3-7 Cycloalkyl;

[0080] (10)R 4 is 1,2,3-triazolyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl and C 1-3 Fluoroalkyl;

[0081] (11)R 4 is 1,2,3-triazolyl substituted by one or more substituents independently selected from the group consisting of methyl, difluoromethyl and trifluoromethyl;

[0082] (12)R 4 is 1,2,3-triazol-4-yl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, and cyano;

[0083] (13)R 4 is 1H-1,2,3-triazol-4-yl, optionally substituted with one or more substituents independently selected from the group consisting of methyl, difluoromethyl and trifluoromethyl;

[0084] (14)R 4 is 1-methyl-1H-1,2,3-triazol-4-yl, which is optionally substituted by: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy or cyano;

[0085] (15)R 4 is 1-methyl-1H-1,2,3-triazol-4-yl, which is optionally substituted by methyl, difluoromethyl or trifluoromethyl;

[0086] (16)R 4is 1,2,4-triazolyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, and cyano;

[0087] (17)R 4 is 1,2,4-triazolyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl and C 1-3 Fluoroalkyl;

[0088] (18)R 4 is 1,2,4-triazolyl substituted by one or more substituents independently selected from the group consisting of methyl, difluoromethyl and trifluoromethyl;

[0089] (19)R 4 is 4H-1,2,4-triazol-3-yl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano groups;

[0090] (20)R 4 is 4H-1,2,4-triazol-3-yl, optionally substituted with one or more substituents independently selected from the group consisting of methyl, difluoromethyl and trifluoromethyl;

[0091] (21)R 4 is 4-methyl-4H-1,2,4-triazol-3-yl, which is optionally substituted by: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy or cyano;

[0092] (22)R 4 is 4-methyl-4H-1,2,4-triazol-3-yl, which is optionally substituted by methyl, difluoromethyl or trifluoromethyl;

[0093] (23)R 4is pyrimidinyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, and cyano;

[0094] (24)R 4 is pyrimidinyl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl and C 1-3 Haloalkyl;

[0095] (25)R 4 is pyrimidinyl, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, difluoromethyl and trifluoromethyl;

[0096] (26)R 4 is pyrimidin-5-yl, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy or cyano;

[0097] (27)R 4 is pyrimidin-5-yl, which is optionally substituted by methyl, difluoromethyl or trifluoromethyl;

[0098] (28)R 4 is 1,2,3-triazolyl fused to a cycloalkyl or heterocyclyl ring;

[0099] (29)R 4 is 1,2,3-triazol-4-yl fused to a cycloalkyl or heterocyclyl ring;

[0100] (30)R 4 Select from one of the following groups:

[0101]

[0102] wherein the group is optionally C 1-4 Alkyl and C 1-3 Fluoroalkyl substitution;

[0103] (31)R 4 Select from one of the following groups:

[0104]

[0105] wherein the group is optionally substituted with methyl or difluoromethyl;

[0106] (32)R 4 Select from one of the following groups:

[0107]

[0108] wherein the group is optionally further C 1-4 Alkyl and C 1-3 Fluoroalkyl substitution;

[0109] (33)R 4 Select from one of the following groups:

[0110]

[0111] wherein the group is optionally further substituted with methyl, difluoromethyl or trifluoromethyl;

[0112] (34)R 4 Select from one of the following groups:

[0113]

[0114] (35)R 1 CH2-R 4 , and R 4 Select from one of the following groups:

[0115]

[0116] wherein the group is optionally C 1-4 Alkyl and C 1-3 Fluoroalkyl substitution;

[0117] (36)R 1 CH2-R 4 , and R 4 Select from one of the following groups:

[0118]

[0119] wherein the group is optionally further C 1-4 Alkyl and C 1-3 Fluoroalkyl substitution;

[0120] (37)R 1 CH2-R 4 , and R 4 Select from one of the following groups:

[0121]

[0122] wherein the group is optionally further substituted with methyl, difluoromethyl or trifluoromethyl;

[0123] (38)R 1 CH2-R 4 , and R 4 Select from one of the following groups:

[0124]

[0125] (39)R 1 CH2-R 4 , and R 4 Select from one of the following groups:

[0126]

[0127] (40) X is O;

[0128] (41)X is CR 5 R 6 ;

[0129] (42)R 5 is selected from hydrogen, methyl, cyclopropyl and C 1-3 Fluoroalkyl;

[0130] (43)R 5 is selected from hydrogen and methyl;

[0131] (44)R 5 is methyl;

[0132] (45)R 6 is selected from hydrogen and methyl;

[0133] (46)R 6 is hydrogen;

[0134] (47)R 5 is methyl and R 6 is hydrogen;

[0135] (48)R 5 and R 6 Together with the carbon atom to which they are attached, they form a cyclopropyl ring;

[0136] (49) n is 1 and X is CR 5 R 6 ;

[0137] (50)n is 1, X is CR 5 R 6 , R 5 is methyl and R 6 is hydrogen;

[0138] (51)n is 1, X is CR 5 R 6 And R 5 and R 6 Together with the carbon atom to which they are attached, they form a cyclopropyl ring;

[0139] (52) n is 2 and X is O;

[0140] (53) m is 0;

[0141] (54)m is 1.

[0142] Suitably, R 1 is as defined in any of paragraphs (1) to (3) or (35) to (39) above. In an embodiment, R 1 is as defined in paragraph (2) above. In an embodiment, R 1 is as defined in paragraph (39) above.

[0143] Suitably, R 2 is as defined in any of paragraphs (4) to (5) above. In an embodiment, R 2 is as defined in paragraph (4) above.

[0144] Suitably, R 3 is as defined in any of paragraphs (6) to (7) above. In an embodiment, R 3 is as defined in paragraph (7) above.

[0145] Suitably, R 4 is as defined in any of paragraphs (8) to (34) above. In an embodiment, R 4 is as defined in paragraphs (32) to (34) above. In an embodiment, R 4 is as defined in paragraph (34) above.

[0146] Suitably, X is as defined in any of paragraphs (40) to (41) above. In an embodiment, X is as defined in paragraph (41) above.

[0147] Suitably, R 5 is as defined in any of paragraphs (42) to (44) above. In an embodiment, R 5 is as defined in paragraph (44) above.

[0148] Suitably, R 6 is as defined in any of paragraphs (45) to (46) above. In an embodiment, R 6 is as defined in paragraph (46) above.

[0149] Suitably, R 5 and R 6 is as defined in any of paragraphs (47) to (48) above. In an embodiment, R 5 and R 6 is as defined in paragraph (48) above.

[0150] Suitably, n is as defined in any of paragraphs (49) to (52) above. In an embodiment, n is as defined in paragraph (49) above.

[0151] Suitably, m is as defined in any of paragraphs (53) to (54) above. In an embodiment, m is as defined in paragraph (54) above.

[0152] In another group of compounds, these compounds have one of the structural formulas IA to IK shown below (which are subformulas of formula I), or a pharmaceutically acceptable salt thereof:

[0153]

[0154] Where R 1 To R 6 , X and m are as defined above.

[0155] In embodiments, these compounds have the structural formula IA shown above, wherein R 1 is as defined in any of paragraphs (1) to (3) above; R 2 is as defined in any of paragraphs (4) to (5) above; R 3 is as defined in any of paragraphs (6) to (7) above; and X is as defined in any of paragraphs (40) to (41) above; provided that the compound of formula IA is not one of the following compounds:

[0156] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0157] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0158] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0159] (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; or

[0160] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0161] In another group of compounds, these compounds have the structural formula IA shown above, wherein R 1 is as defined in paragraph (2) above; 2 is as defined in paragraph (4) above; 3 is as defined in paragraph (7) above; and X is as defined in paragraph (41) above.

[0162] In embodiments, these compounds have the structural formula IB shown above, wherein R 1 is as defined in any of paragraphs (1) to (3) above; R 2 is as defined in any of paragraphs (4) to (5) above; R 3 is as defined in any of paragraphs (6) to (7) above; and X is as defined in any of paragraphs (40) to (41) above.

[0163] In another group of compounds, these compounds have the structural formula IB shown above, wherein R 1 is as defined in paragraph (2) above; 2 is as defined in paragraph (4) above; 3 is as defined in paragraph (7) above; and X is as defined in paragraph (41) above.

[0164] In embodiments, these compounds have the structural formula IC shown above, wherein R1 is as defined in any of paragraphs (1) to (3) above; R 2 is as defined in any of paragraphs (4) to (5) above; R 3 is as defined in any of paragraphs (6) to (7) above; and m is as defined in any of paragraphs (53) to (54) above.

[0165] In another group of compounds, these compounds have the structural formula IC shown above, wherein R 1 is as defined in paragraph (2) above; 2 is as defined in paragraph (4) above; 3 is as defined in paragraph (7) above; and m is as defined in paragraph (54) above.

[0166] In the embodiments, the compounds have the structural formula ID shown above, wherein R 1 is as defined in any of paragraphs (1) to (3) above; R 2 is as defined in any of paragraphs (4) to (5) above; R 3 is as defined in any of paragraphs (6) to (7) above; R 5 is as defined in any of paragraphs (42) to (44) above, R 6 is as defined in any of paragraphs (45) to (46) above; or R 5 and R 6 is as defined in any of paragraphs (47) to (48) above; and m is as defined in any of paragraphs (53) to (54) above; provided that the compound of formula ID is not one of the following compounds:

[0167] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0168] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0169] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0170] (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; or

[0171] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0172] In another group of compounds, these compounds have the structural formula ID shown above, wherein R 1 is as defined in paragraph (2) above; 2 is as defined in paragraph (4) above; 3 is as defined in paragraph (7) above; 5 is as defined in paragraph (44) above, R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and m is as defined in paragraph (54) above.

[0173] In embodiments, these compounds have the structural formula IE shown above, wherein R 1 is as defined in any of paragraphs (1) to (3) above; R 3 is as defined in any of paragraphs (6) to (7) above; R 5 is as defined in any of paragraphs (42) to (44) above, R 6 is as defined in any of paragraphs (45) to (46) above; or R 5 and R 6 is as defined in any of paragraphs (47) to (48) above; provided that the compound of formula IE is not one of the following compounds:

[0174] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0175] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0176] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0177] (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; or

[0178] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0179] In another group of compounds, these compounds have the structural formula IE shown above, wherein R 1 is as defined in paragraph (2) above; 3 is as defined in paragraph (7) above; 5 is as defined in paragraph (44) above, R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above.

[0180] In embodiments, these compounds have the structural formula IF as shown above, wherein R2 is as defined in any of paragraphs (4) to (5) above; R 3 is as defined in any of paragraphs (6) to (7) above; R 4 is as defined in any of paragraphs (8) to (34) above; R 5 is as defined in any of paragraphs (42) to (44) above, R 6 is as defined in any of paragraphs (45) to (46) above; or R 5 and R 6 is as defined in any of paragraphs (47) to (48) above; and m is as defined in any of paragraphs (53) to (54) above; provided that the compound of formula IF is not one of the following compounds:

[0181] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0182] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0183] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0184] (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; or

[0185] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0186] In another group of compounds, these compounds have the structural formula IF as shown above, wherein R 2 is as defined in paragraph (4) above; 3 is as defined in paragraph (7) above; 4 is as defined in paragraph (34) above; R 5 is as defined in paragraph (44) above, R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and m is as defined in paragraph (54) above.

[0187] In embodiments, these compounds have the structural formula IG as shown above, wherein R 3 is as defined in any of paragraphs (6) to (7) above; R 4 is as defined in any of paragraphs (8) to (34) above; R 5 is as defined in any of paragraphs (42) to (44) above, R 6 is as defined in any of paragraphs (45) to (46) above; or R 5 and R 6 is as defined in any of paragraphs (47) to (48) above; provided that the compound of formula IG is not one of the following compounds:

[0188] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0189] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0190] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0191] (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; or

[0192] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0193] In another group of compounds, these compounds have the structural formula IG shown above, wherein R 3 is as defined in paragraph (7) above; 4 is as defined in paragraph (34) above; R 5 is as defined in paragraph (44) above, R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above.

[0194] In embodiments, these compounds have the structural formula IH as shown above, wherein R 4 is as defined in any of paragraphs (8) to (34) above; R 5 is as defined in any of paragraphs (42) to (44) above, R 6 is as defined in any of paragraphs (45) to (46) above; or R 5 and R 6 is as defined in any of paragraphs (47) to (48) above; and m is as defined in any of paragraphs (53) to (54) above; provided that the compound of formula IH is not one of the following compounds:

[0195] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0196] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0197] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0198] (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; or

[0199] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0200] In another group of compounds, these compounds have the structural formula IH as shown above, wherein R 4 is as defined in paragraph (34) above; R 5 is as defined in paragraph (44) above, R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and m is as defined in paragraph (54) above.

[0201] In embodiments, these compounds have the structural formula IJ shown above, wherein R 4is as defined in any of paragraphs (8) to (34) above; and m is as defined in any of paragraphs (53) to (54) above.

[0202] In another group of compounds, these compounds have the structural formula IJ as shown above, wherein R 4 is as defined in any of paragraphs (32) to (34) above, for example paragraph (34); and m is as defined in paragraph (54) above.

[0203] In embodiments, these compounds have the structural formula IK shown above, wherein R 2 is as defined in any of paragraphs (4) to (5) above; R 4 is as defined in any of paragraphs (8) to (34) above; and m is as defined in any of paragraphs (53) to (54) above; provided that the compound of formula IK is not one of the following compounds:

[0204] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0205] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0206] (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]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or

[0207] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0208] In another group of compounds, these compounds have the structural formula IK shown above, wherein R 2 is as defined in paragraph (4) above; 4 is as defined in paragraph (34) above; and m is as defined in paragraph (54) above.

[0209] In another group of compounds, these compounds have the structural formula IL shown below (which is a subformula of formula I), or a pharmaceutically acceptable salt thereof:

[0210]

[0211] Where R 5 and R 6 is as defined above and R 7 and R 8 Independently selected from: hydrogen, C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano; or R 7 and R 8 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring; provided that the compound of formula IL is not one of the following:

[0212] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0213] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0214] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0215] (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; or

[0216] (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

[0217] In embodiments, these compounds have the structural formula IL shown above, wherein R 5 is as defined in any of paragraphs (42) to (44) above, R 6 is as defined in any of paragraphs (45) to (46) above; or R 5 and R 6 is as defined in any of paragraphs (47) to (48) above; and R 7 and R 8 Independently selected from: hydrogen, C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl and C 1-2 Alkylene-C 3-7 Cycloalkyl; or R 7 and R 8 Together with the atoms to which they are attached they form a 6-membered heterocyclyl ring.

[0218] In another group of compounds, these compounds have the structural formula IL shown above, wherein R 5 is as defined in paragraph (44) above, R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and R 7 and R 8 are independently selected from: methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl and CH2-cyclopropyl; or R 7 and R 8 Together with the atoms to which they are attached they form a 6-membered heterocyclyl ring.

[0219] In another group of compounds, these compounds have the structural formula IL shown above, wherein R 5 is as defined in paragraph (44) above, R6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; 7 is methyl; and R 8 is hydrogen, methyl, or difluoromethyl.

[0220] Specific compounds of the present invention include any of the following:

[0221] 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one;

[0222] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0223] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0224] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0225] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0226] (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or

[0227] (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0228] or a pharmaceutically acceptable salt thereof.

[0229] In an embodiment, the compound having Formula I is selected from the following compounds:

[0230] 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one;

[0231] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0232] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0233] (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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;

[0234] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0235] (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; and

[0236] (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

[0237] or a pharmaceutically acceptable salt thereof.

[0238] The various functional groups and substituents that make up the compounds of the 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, such as less than 700, or less than 650.

[0239] Suitable or preferred features of any compound of the invention may also be suitable features of any other aspect.

[0240] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases providing physiologically acceptable cations (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine).

[0241] Compounds with the same molecular formula but different properties or order of bonding of their atoms or arrangement of their atoms in space are called "isomers". Isomers whose atoms are different in spatial arrangement are called "stereoisomers". 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 in which the molecule rotates the plane of polarized light. Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0242] The compounds of the present invention typically 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 thereof 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 [Higher Organic Chemistry]", 4th edition, J. March, John Wiley and Sons Publishing Company (John Wiley and Sons), New York (New York), 2001), for example, by synthesis from optically active starting 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.

[0243] The present invention also encompasses compounds of the present invention as defined herein that contain 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; and O may be in any isotopic form, including 16 O and 18 O; etc.

[0244] It should also be understood that certain compounds of the invention can exist in solvated as well as unsolvated forms, such as hydrated forms. It should be understood that the invention encompasses all such solvated forms that have Nrf2 activating activity.

[0245] It is also to be understood that certain compounds of the invention may exhibit polymorphism and that the invention encompasses all such forms that possess Nrf2 activating activity.

[0246] Compound of the present invention can exist with many different tautomeric forms, and mention that compound of the present invention comprises all such forms.For the avoidance of doubt, compound can exist with one in several tautomeric forms, and only clearly describe or show one situation, all other forms are still included in compound of the present invention.The example of tautomeric form comprises ketone, enol and enolate form, for example, in following tautomer pair: ketone / enol (shown hereinafter), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso group / oxime, thioketone / enethiol and nitro / acid nitro.

[0247]

[0248] 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 example of N-oxides is the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amines with oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids), see, for example, Advanced Organic Chemistry [Higher Organic Chemistry], edited by Jerry March, 4th edition, Wiley International Science Company (Wiley Interscience), page. More specifically, N-oxides can be prepared by LW Deady's procedure (Syn. Comm. [Synthesis 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).

[0249] 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 change 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 in vivo cleavable ester derivatives that can be formed at carboxyl or hydroxyl groups in the compounds of the present invention and in vivo cleavable amide derivatives that can be formed at carboxyl or amino groups in the compounds of the present invention.

[0250] Thus, the present invention 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. Thus, the present invention includes those compounds of formula I produced by organic synthesis means and also includes such 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.

[0251] Suitable pharmaceutically acceptable prodrugs of the compounds having Formula I are those that are based on sound medical judgment as pharmaceutically acceptable prodrugs suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0252] Various forms of prodrugs have been described, for example, in the following documents:

[0253] a) Methods in Enzymology [ Enzymatic methods ], No. 42 Volume, pp. 309-396, edited by K. Widder et al., (Academic Press, 1985);

[0254] b) Design of Pro-drugs, edited by H.Bundgaard (Elsevier, 1985);

[0255] c) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Pro-drugs", edited by H.Bundgaard, p.113-191 (1991);

[0256] d) H.Bundgaard, Advanced Drug Delivery Reviews[Advanced Drug Delivery Reviews], 8 ,1-38(1992);

[0257] e) H.Bundgaard et al., Journal of Pharmaceutical Sciences [Journal of Pharmaceutical Sciences], 77 ,285(1988);

[0258] f) N. Kakeya et al., Chem.Pharm.Bull. [Chemistry and Pharmacy Bulletin], 32 ,692(1984);

[0259] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Vol. 14; and

[0260] h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0261] The in vivo effects of compounds of formula I may be exerted in part through one or more metabolites that are 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).

[0262] It will also be appreciated 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) that enable them to bind to moieties of solid supports (such as, for example, biotin-containing moieties) and targeting ligands (such as antibodies or antibody fragments).

[0263] synthesis

[0264] In the descriptions of synthetic methods set forth below and in the referenced synthetic methods for preparing starting materials, it is to be 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.

[0265] Those skilled in the art of organic synthesis will appreciate that the functionality present on the various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0266] 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 shown within the ordinary skill of an organic chemist.

[0267] 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 substituents to prevent their undesirable reactions. A skilled chemist will understand when such protection is required and how such protecting groups can be placed in suitable positions and subsequently removed.

[0268] For examples of protecting groups, see one of the many general texts on the subject, such as "Protecting groups in Organic Synthesis (3rd edition), John Wiley & Sons, New York (1999), T. Greene & P. ​​Wuts. Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist, suitable for removing the protecting group in question, such method being selected so as to effect removal of the protecting group with minimal perturbation of groups elsewhere in the molecule.

[0269] 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.

[0270] For example, the suitable protecting group of amino or alkylamino is, for example, acyl, for example, alkanoyl such as acetyl, alkoxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl, for example, benzyloxycarbonyl, or aroyl, for example, benzoyl. The deprotection conditions of the above-mentioned protecting group must vary with the selection of the protecting group. Therefore, for example, acyl such as alkanoyl or alkoxycarbonyl or aroyl can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (for example, lithium hydroxide or sodium hydroxide). Alternatively, acyl such as tert-butoxycarbonyl can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl such as benzyloxycarbonyl can be removed, for example, by hydrogenation over a catalyst such as palladium carbon, or by treatment with a Lewis acid such as BF3.OEt2. 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.

[0271] Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways in a manner that is already well known. 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 order 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 the allocation described herein, and in some cases may be suitable for allocations 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).

[0272] General Method A

[0273]

[0274] In a typical synthesis procedure, phthalimide, when used as a protecting group, is removed using a typical reagent (e.g., hydrazine), and the amine is reacted with a suitable reagent to install the desired lactam. The third step involves installing the desired ether by conventional methods such as alkylation using an alkyl halide or activated alcohol (e.g., mesylate, triflate) or a Mitsunobu reaction using reagents such as DBAD or DEAD and a suitable phosphine. The Boc protecting group is then typically removed by treatment with HCl. In the fifth step, the cycloalkyl acid group can be activated to react with the amine of the tetrahydroisoquinoline (THIQ) backbone. Typical amide coupling agents such as HATU or CDI are used for acid activation.

[0275] General Method B

[0276]

[0277] In another typical procedure, the order of steps can be changed compared to general method A. Again by conventional methods as described in general method A above, the desired ether is installed in the first step. The phthalimide is removed in the second step and the amine is reacted with a suitable reagent to install the desired lactam. The Boc protecting group is then removed and the cycloalkylamide moiety can then be introduced in the fifth step.

[0278] The THIQ skeleton can be constructed according to the pathway outlined in Scheme 1:

[0279]

[0280] Scheme 1: a) SOCl2, EtOAc; b) ammonium acetate, CH3NO2, AcOH; c) LiAlH4, THF; d) DIPEA, DCM; e) NCS, DMF; f) P2O5, cyclopentane; g) NaBH(OAc)3, AcOH, DCM; h) BBr3, DCM; i) chiral SFC chromatography.

[0281] R 2 Compounds that are -COOH can be converted to tetrazolyls by reaction of the appropriate nitrile with an azide as shown in Scheme 2.

[0282]

[0283] Scheme 2: a) HATU, DIPEA, NH4Cl, DMF; b) POCl3, imidazole, pyrimidine; c) n Bu3SnN3, xylene.

[0284] The compounds of the present invention (wherein the group -NR 4 R 5 represents pyrrolidone) can be prepared from an intermediate (where -NR 4 R 5 represents a phthalimide group) is prepared by removing the phthalimide group with hydrazine and then converting the resulting primary amine into the pyrrolidone by reaction with an appropriate lactone or ω-haloester.

[0285]

[0286] Scheme 3: a) N2H4, EtOH; b) 4-bromobutyric acid methyl ester, Et3N, PhMe.

[0287] Pharmaceutical composition

[0288] The compounds of the present invention are usually but not necessarily formulated into pharmaceutical compositions before being administered to a patient. Therefore, according to another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound of the present invention as defined above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0289] The pharmaceutical composition of the present invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound of the present invention can be extracted and then administered to the patient, for example, in the form of a powder or syrup. Alternatively, the pharmaceutical composition of the present invention can be prepared and packaged in unit dosage form, wherein each physically discrete unit comprises a safe and effective amount of the compound of the present invention. When prepared in unit dosage form, the pharmaceutical composition of the present invention typically contains 1 mg to 1000 mg.

[0290] The compositions of the present invention may 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), transdermally (e.g., via a transdermal patch), by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), by insufflation (e.g., as a fine powder) or parenterally (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0291] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle that participates in imparting form or consistency to a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed so as to avoid interactions that would significantly reduce the efficacy of the compounds of the invention when administered to a patient and interactions that would render the pharmaceutical composition pharmaceutically unacceptable. In addition, each excipient must be of sufficiently high purity to make it pharmaceutically acceptable.

[0292] Suitable pharmaceutically acceptable excipients will change according to the selected specific dosage form. In addition, suitable pharmaceutically acceptable excipients can be selected for the specific functions that they can provide in the composition. For example, some pharmaceutically acceptable excipients can be selected for the ability that they can promote the production of uniform dosage forms. Some pharmaceutically acceptable excipients can be selected for the ability that they can promote the production of stable dosage forms. Some pharmaceutically acceptable excipients can be selected for the ability that they can promote to carry or transport one or more compounds of the present invention to another organ or another part of the body once they are applied to the patient. Some pharmaceutically acceptable excipients can be selected for the ability that they enhance patient compliance.

[0293] 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, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art will appreciate that certain pharmaceutically acceptable excipients can provide more than one function and can provide alternative functions, depending on how much excipient is present in the formulation and what other ingredients are present in the formulation.

[0294] Those skilled in the art have the knowledge and skills enabling them to select the appropriate pharmaceutically acceptable excipients in appropriate amounts for the present invention. In addition, those skilled in the art can utilize many resources which describe pharmaceutically acceptable excipients and can be used to select the appropriate pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (American Pharmaceutical Association and Pharmaceutical Press).

[0295] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing).

[0296] The amount of the active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host to be treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g (more suitably from 0.5 mg to 100 mg, such as 1 mg to 30 mg) of the active agent admixed with a suitable and convenient amount of excipients (which can vary from about 5% to about 98% by weight of the total composition).

[0297] In accordance with well-known medical principles, for therapeutic or prophylactic purposes, the dosage size of the compound of formula I will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0298] 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 routes are adopted, a lower dose will be applied. Therefore, for example, for intravenous or intraperitoneal administration, a dose of, for example, 0.1 mg / kg body weight to 30 mg / kg body weight will be usually used. Similarly, for administration by inhalation, a dose of, for example, 0.05 mg / kg body weight to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of this invention.

[0299] Route of administration

[0300] 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).

[0301] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., 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, e.g., 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 depot, e.g., subcutaneous or intramuscular.

[0302] In preferred embodiments, the compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, is administered orally or via inhalation.

[0303] Therapeutic uses and applications

[0304] 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.

[0305] 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.

[0306] 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.

[0307] In another aspect, the 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.

[0308] 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 present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0309] 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, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, 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 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, chronic pain, schizophrenia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, uveitis, or preeclampsia.

[0310] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) can be used to treat chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0311] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, 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 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, chronic pain, schizophrenia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, uveitis, or preeclampsia.

[0312] In another aspect, the invention provides a compound as defined herein, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0313] In another aspect, the present invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament 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, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary hypertension, subarachnoid hemorrhage, cerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis Rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation 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, chronic pain, schizophrenia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, uveitis, or preeclampsia.

[0314] In another aspect, the invention provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0315] In another aspect, the present invention provides a method of treating the following diseases: 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, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, 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 dermatitis, atopic dermatitis Inflammation, 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, chronic pain, schizophrenia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchsian corneal endothelial dystrophy, uveitis or preeclampsia, 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 or pharmaceutical composition thereof.

[0316] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, asthma, pulmonary hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] Combination therapy

[0321] The compounds of the 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 vary depending on the disease or condition to be treated and its severity.

[0322] Combination therapy is commonly used to treat certain medical conditions.

[0323] According to a particular aspect of the invention there is provided a combination useful for the treatment of a disease or condition in which Nrf2 activation is implicated, the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0324] According to this aspect of the invention, there is provided a combination suitable for preventing or treating the following diseases: 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, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, 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 skin In the present invention, the present invention is preferably used in combination with a compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0325] 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.

[0326] Herein, where the term "combination" is used, it is understood that this refers to simultaneous administration, separate administration 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. In the case of sequential administration or separate administration, delaying the administration of the second component should not result in a loss of the beneficial effects of the combination.

[0327] 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.

[0328] The one or more additional therapeutic agents may comprise additional compounds of the invention. Thus, in an embodiment, a pharmaceutical composition is provided comprising two compounds of the invention or pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable diluent or carrier.

[0329] According to a particular aspect of the invention, there is provided a combination suitable for preventing or treating: allergic, inflammatory or autoimmune diseases (e.g. asthma or COPD); cardiovascular or metabolic diseases (e.g. diabetes); neurodegenerative diseases; chronic kidney or liver disease; sickle cell disease; pulmonary hypertension; cancer; or to aid in transplantation.

[0330] 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, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0331] Examples of other therapeutic agents that can be used as part of a 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:

[0332] (i) β2-adrenergic receptor agonists (which may be racemates or single enantiomers), including salmeterol, salbutamol, formoterol, salmethoxazole, fenoterol, carmoterol, etanterol, namoterol, clenbuterol, pirbuterol, fulbuterol, reproterol, bambuterol, indacaterol, terbutaline, vilanterol, olodaterol, and salts thereof;

[0333] (ii) anticholinergic drugs that are muscarinic receptor antagonists, including ipratropium bromide (e.g., as the bromide, CAS 22254-24-6, sold under the name Atrotrop), oxitropium bromide and tiotropium bromide (e.g., as the bromide, CAS 136310-93-5, sold under the name Severola), revatropate, LAS-34273, aclidinium bromide, glycopyrronium, umeclidinium, and salts thereof;

[0334] (iii) Corticosteroid anti-inflammatory agents. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, fluticasone furoate, beclomethasone esters (e.g., 17-propionate or 17,21-dipropionate), budesonide, flunisolide, mometasone esters (e.g., mometasone furoate), triamcinolone acetonide, roflenide, ciclesonide, buticort propionate, RPR-106541, and ST-126;

[0335] (iv) anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include sodium cromoglycate, sodium nedocromil, 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;

[0336] (v) vasodilators and antiproliferative agents (e.g., prostaglandins and PDE5 inhibitors), including epoprostenol (Flolan), treprostinil (Remodulin), iloprost (Ventavis), treprostinil (Tyvaso), bosentan (Tracleer), ambrisentan (Letairis), sildenafil (Revatio), and tadalafil (Adcirca);

[0337] (vi) antidiabetic drugs, including insulin, biguanides (such as metformin), sulfonylureas (such as glimepiride), glinides (such as repaglinide), thiazolidinediones (such as pioglitazone), dipeptidyl peptidase IV inhibitors (such as sitagliptin), incretin mimetics / GLP-1 analogs (such as liraglutide, exenatide, dulaglutide), sodium glucose cotransporter 2 (SGLT2) inhibitors (such as canagliflozin, dapagliflozin and empagliflozin) and α-glucosidase inhibitors (such as acarbose);

[0338] (vii) hydroxyurea and other drugs 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, BAY 41-2271); and

[0339] (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.

[0340] The above-mentioned combinations may conveniently be presented for use 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.

[0341] 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 separate compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0342] 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 relevant publication references).

[0343] Examples

[0344] General procedure:

[0345] Methods for preparing the compounds of the invention are shown in the following examples. Starting materials are prepared according to procedures known in the art or as shown herein, or are commercially available. Commercial reagents are used without further purification. When reaction temperature is not included, the reaction is carried out at an ambient temperature of typically 18°C-27°C.

[0346] The compounds described in this invention are 1In the case of H NMR spectroscopy characterization, spectra were recorded on a 500 MHz Bruker, 400 MHz Bruker, 250 MHz Bruker, 300 MHz JEOL or 400 MHz JEOL instrument. When temperature was not included, spectra were recorded at ambient temperature. Chemical shift values ​​are expressed in parts per million (ppm). In the case of complex NMR spectra due to the presence of interconverting isomers, approximate partial integrals of the signals are reported or only the characterization of the major isomer is reported. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, b = broad, t = triplet, q = quartet, m = multiplet, d = doublet.

[0347] Analytical LCMS

[0348] Where 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 this invention exhibit slowly interconverting stereoisomers, multiple retention times are reported.

[0349]

[0350]

[0351] Preparative Chiral SFC

[0352] Preparative chiral SFC was performed using a variation of the method outlined below.

[0353] Method 1:

[0354] Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with stacked injection module). Column: Diacel Chiralpak IA / IB / IC, YMC amylose / cellulose C (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 and modifier selected from Me2NH, formic acid, as specified. Gradient / isocratic as specified

[0355] abbreviation:

[0356]

[0357] Synthesis of intermediates

[0358] Intermediate 1: (E)-1-Fluoro-2-methoxy-4-(2-nitrovinyl)benzene

[0359]

[0360] A solution of 4-fluoro-3-methoxybenzaldehyde (57g, 370mmol; CAS: 128495-46-5), ammonium acetate (14.25g, 185mmol) and nitromethane (100.14mL, 1850mmol) in acetic acid (150mL) was heated at 100°C for 5 hours. The reaction mixture was cooled to room temperature overnight. The resulting solid was collected by filtration, washed with ether, and the solid was dried in vacuo. The solid was suspended in DCM (1L) and washed with water. The organic layer was filtered to remove the precipitate, dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound (42g, 200mmol, 54%). The precipitate was dissolved in 2-MeTHF, and the organic layer was washed with water, brine, dried (Na2SO4) and evaporated to obtain another product (11g, 55.2mmol, 15% yield) as a yellow solid. The acetic acid mother liquor was evaporated and diluted with IMS. The resulting solid was collected by filtration and washed with IMS to provide another batch of product (1.5 g).These batches were combined to give the title compound (54.5 g, 74%) which was used without further purification. 1 H NMR (300MHz, CDCl3) δ7.95(d,1H),7.52(d,1H),7.16-7.08(m,3H),3.95(s,3H).

[0361] Intermediate 2: 2-(4-fluoro-3-methoxyphenyl)ethane-1-amine

[0362]

[0363] Sulfuric acid (8.92 mL, 167 mmol) was added dropwise under nitrogen to a stirred solution of lithium aluminum hydride in THF (2M; 12.7 g, 335 mmol) pre-cooled in an ice-salt bath. The mixture was stirred for 15 min until all gas evolution subsided. A solution of Intermediate 1 (22 g, 112 mmol) in 2-MeTHF (660 mL) was added dropwise, ensuring that the temperature remained <20°C. The cooling bath was removed and the mixture was heated to reflux for 5 min, then cooled in an ice-salt bath. IPA (57 mL) was added dropwise, followed by sodium hydroxide (2M, 39 mL). MgSO4 was added and the mixture was stirred for 30 min, then filtered through Filter. Wash the filter cake with 2-MeTHF / IPA about 98:2 (about 1.5 L), then with 10% MeOH in DCM (about 1.5 L). Concentrate the filtrate in vacuo to give the title compound (18.8 g, 99%), which is used without further purification. 1H NMR (400MHz, CDCl3) δ7.02-6.97(m,1H),6.80(dd,1H),6.74-6.68(m,1H),3.89-3.88(s,3H),2.96(t,2H),2.71(t,2H),1.24-1.18(m,2H).

[0364] Intermediate 3: 2-(1,3-dioxoisoindolin-2-yl)-N-(4-fluoro-3-methoxyphenethyl)acetamide

[0365]

[0366] To a solution of intermediate 2 (49.3 g, 291 mmol) and DIPEA (101.5 mL, 583 mmol) in DCM (250 mL) cooled in an ice-salt bath under nitrogen was added a solution of intermediate 1 (65.2 g, 291 mmol) in DCM (1.25 L). The mixture was stirred and heated from 0 ° C to room temperature in 2 h. The resulting precipitate was separated by filtration and washed thoroughly with DCM. The solid was dried in vacuo to give the title compound (83 g, 80%), which was used without further purification. 1 H NMR (400MHz, CDCl3) δ7.89-7.86(m,2H),7.77-7.74(m,2H),6.90(dd,1H),6.78(dd,1 H),6.66(ddd,1H),5.75(s,1H),4.29(s,2H),3.88(s,3H),3.52(q,2H),2.79(t,2H).

[0367] Intermediate 4: N-(2-chloro-4-fluoro-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl Amide

[0368]

[0369] A mixture of intermediate 3 (82.6 g, 232 mmol) and NCS (34.05 g, 255 mmol) in DMF (780 mL) was heated to 50 ° C and stirred at 50 ° C for 1 h, then cooled and concentrated in vacuo. Water (about 2 L) was added to the resulting residue and the resulting precipitate was stirred for 1 h. The solid was isolated by filtration, washed with water, Et2O, air-dried and dried in vacuo to give the title compound (85.8 g, 94%), which was used without further purification. LCMS (Method 2): 1.43 min, 391.3 [M+H] + .

[0370] Intermediate 5: 2-((5-chloro-7-fluoro-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline-1, 3-Dione

[0371]

[0372] A suspension of sulfolane (794 mL, 8330 mmol) and intermediate 4 (30.0 g, 76.8 mmol) was heated to 90 °C, whereupon the solid dissolved. Phosphorus pentoxide (65.4 g, 461 mmol; CAS: 1314-56-3) was added in one portion and the mixture was stirred at 90-100 °C for 1 h. The mixture was cooled to about 30 °C and poured onto stirred water (3 L). The solution was neutralized to pH 7.5 with Na2CO3, and the mixture was filtered. The precipitate was diluted in DCM (500 mL) and the organics were washed with water, brine, dried over MgSO4 and concentrated in vacuo to give the title compound (27.0 g, 68.8 mmol, 90% yield). LCMS (Method 2): 1.64 min, 373.2 [M+H] + .

[0373] Intermediate 6: 2-((5-chloro-7-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindole Indole-1,3-dione

[0374]

[0375] A stirred suspension of intermediate 5 (50.3 g, 135 mmol) in DCM (600 mL) was cooled in an ice bath under argon. Acetic acid (15.5 mL, 270 mmol) and sodium triacetoxyborohydride (57.2 g, 270 mmol) were added thereto in portions over 30 min. The mixture was stirred for 18 hours and warmed to room temperature. Additional acetic acid (3.09 mL, 54.0 mmol) and sodium triacetoxyborohydride (11.4 g, 54.0 mmol) were then added to the mixture and stirring continued for 2.5 h. The mixture was diluted with DCM and neutralized with saturated sodium bicarbonate solution. It was extracted with additional DCM, and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (48.8 g, 77%). LCMS (Method 1): 0.96 min, 375.0 [M+H] + .

[0376] Intermediate 7: 2-((5-chloro-7-fluoro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline- 1,3-Diketone hydrobromide

[0377]

[0378] To a stirred solution of intermediate 6 (37.0 g, 98.7 mmol) in DCM (500 mL) cooled in an ice bath under nitrogen was added boron tribromide in DCM (1 M; 395 mL, 395 mmol; CAS: 10294-33-4), and the reaction mixture was allowed to warm to room temperature and stirred for 72 h. The liquid was quenched by adding it dropwise onto ice water (1.0 L) and a solid was precipitated. Ice water was added to the remaining residue in the reaction flask, the mixture was sonicated for 0.5 h and a solid was precipitated. The two suspensions were filtered and the collected solids were combined, washed with water, azeotroped with methanol and dried in vacuo to provide the title compound (43.0 g, 99%). LCMS (Method 1): 0.92 min, 361.0 [M+H] + .

[0379] Intermediate 8: (S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-hydroxy-3,4- tert-Butyl dihydroisoquinoline-2(1H)-carboxylate

[0380]

[0381] To a suspension of intermediate 7 (43.0 g, 97.4 mmol) in DCM (900 mL) was added DIPEA (67.5 mL, 389 mmol) in portions under nitrogen followed by di-tert-butyl dicarbonate (19.1 g, 87.6 mmol; CAS: 24424-99-5) and the resulting mixture was stirred until no further gas evolution was observed. The reaction mixture was diluted with water, extracted with DCM and the combined organics were washed with water (x 4), brine, dried (MgSO4) and concentrated in vacuo. The residue was refluxed in MeCN (900 mL) for 2 hours, cooled and separated by filtration to give a beige solid which was air dried for 18 h to give 34 g of racemic material. The racemates were separated by SFC (Method 1: YMC Amylose-C 20x250mm, 5um 20 / 80 EtOH (0.1% DEA) / CO2, 100ml / min, 120 bar, 40°C, DAD 230nm) to give the title compound (first eluting enantiomer; 15.9g, 35% yield). The absolute stereochemistry was confirmed by small molecule X-ray crystallography of the carboxylic acid final compound generated from enantiomer 2. LCMS (Method 2): 1.50min, 459.2[MH] - . 1H NMR(400MHz; DMSO-d6)δ7.95-7.80(m,4H),7.42-7.37(m,1H),5.60-5.45(m,1H),4.19-3 .75(m,3H),3.45-3.35(m,1H),2.83-2.79(m,1H),2.63-2.53(m,1H),1.03-0.95(m,9H).

[0382] Intermediate 9: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclohexane-carboxylic acid; (1R)-1-phenyl Ethylamine

[0383]

[0384] A solution of (2,4-dimethoxyphenyl)methanol (43.6 g, 259 mmol, CAS: 7314-44-5) in toluene (80 ml) was added dropwise to a suspension of cis-1,2-cyclohexanedicarboxylic anhydride (20.0 g, 130 mmol, CAS: 13149-00-3) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (46.3 g, 143 mmol, CAS: 56-54-2) in toluene (150 ml) at -5°C. The solution was then transferred to a refrigerator and allowed to stand for 4 days. The reaction mixture was warmed to room temperature, washed with 1 M aqueous HCl (200 mL) until the pH of the wash was 1, and the organics were washed with water, brine (100 mL), filtered through a phase separator and concentrated in vacuo. The residue was diluted with toluene (100 mL) and (1R)-1-phenylethylamine (16.5 mL, 130 mmol; CAS 3886-69-9) was added. The mixture was seeded with some crystals of solid material from the previous batch and stirred at room temperature for 24 h. The resulting solid was collected, washed with toluene, triturated with Et2O, and the solid was further sonicated in Et2O, filtered and dried in vacuo to give the title compound (45.9 g, 80%). LCMS (Method 1): 1.44 min, 345.0 [M+Na] + .

[0385] Intermediate 10: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclohexane-1-carboxylic acid

[0386]

[0387] Intermediate 9 (45.9 g, 103 mmol) was partitioned between citric acid (10% aqueous solution; 300 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo and dried in vacuo to give the title compound (33.7 g, assumed quantitative) which was used without further purification. 1 HNMR(400MHz, CDCl3)δ7.22-7.20(m,1H),6.46-6.43(m,2H),5.15-5.04(q,2H),3.80(s,3H ),3.79(s,3H),2.89-2.81(m,2H),2.08-2.00(m,2H),1.81-1.73(m,2H),1.58-1.38(m,4H).

[0388] Intermediate 11: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclohexane-1-carboxylic acid

[0389]

[0390] To a stirred solution of intermediate 10 (20.4 g, 63.1 mmol) in anhydrous THF (150 mL) cooled to -25 °C under argon was added LDA (2 M in THF / hexanes; 158 mL, 158 mmol) dropwise. The mixture was stirred at -25 °C for 30 min, then iodomethane (11.8 mL, 189 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature over 4 h. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc, and the combined organics were washed with 10% aqueous citric acid, the aqueous layer was further extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (23.6 g, assumed quantitative). LCMS (Method 1): 1.60 min, 359.1 [M+Na] + .

[0391] Intermediate 12: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-(2,4-dimethoxybenzyl)(1S, 2R)-1-Methylcyclohexane-1,2-dicarboxylate

[0392]

[0393] To a stirred solution of intermediate 11 (21.2 g, 63.1 mmol) in DMF (112 mL) was added HATU (31.2 g, 82.1 mmol; CAS: 148893-10-1) at room temperature under argon and the reaction mixture was stirred for 5 min. DIPEA (12.1 mL, 69.5 mmol) was added to the mixture and the mixture was stirred at room temperature for 18 h. The mixture was diluted with water, extracted with EtOAc and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification on Rf+ (330 g silica gel column Puriflash HC, 0-50% EtOAc in cyclohexane) gave the title compound (25.0 g, 87%). LCMS (Method 1): 1.70 min, 477.2 [M+Na] + .

[0394] Intermediate 13: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclopentane-carboxylic acid; (1R)-1- Phenylethylamine

[0395]

[0396] To a stirred suspension of (3aR,6aS)-4,5,6,6a-tetrahydro-3aH-cyclopenta-[c]furan-1,3-dione (14.8 g, 106 mmol, CAS: 35878-28-5) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidine-2-yl]methanol (37.7 g, 117 mmol, CAS: 56-54-2) in toluene (100 mL) was added dropwise (2,4-dimethoxyphenyl)methanol (35.5 g, 211 mmol) in toluene (70 mL) at -5°C. The solution was then transferred to a refrigerator and allowed to stand for 4 days. The solution was warmed to room temperature, washed with 1M aqueous HCl (400 mL) until pH 1 and the organic layer was washed with water, brine, filtered through a phase separator and concentrated in vacuo. The residue was diluted with toluene (90 mL) and (1R)-1-phenylethylamine (13.4 mL, 106 mmol; CAS 3886-69-9) was added and the reaction mixture was stirred at room temperature for 24 h. The resulting solid was collected, washed with toluene, triturated with Et2O, and the solid was further sonicated in Et2O, filtered and dried in vacuo to give the title compound (34.0 g, 75%). LCMS (Method 1): 1.34 min, 331.0 [M+Na] + .

[0397] Intermediate 14: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclopentane-1-carboxylic acid

[0398]

[0399] Intermediate 13 (34.0 g, 79.1 mmol) was partitioned between 10% aqueous citric acid (300 mL) and EtOAc (300 mL). The aqueous layer was further extracted with EtOAc and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (24.9 g, assumed quantitative) which was used without further purification. LCMS (Method 1): 1.33 min, 331.0 [M+Na] + .

[0400] Intermediate 15: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclopentane-1-carboxylic acid

[0401]

[0402] To a stirred solution of diisopropylamine (0.57 mL, 4.05 mmol; CAS: 108-18-9) in anhydrous THF (3.6 mL) at -78°C under argon was added n-butyllithium (2.5 M in THF; 1.6 mL, 4.05 mmol) and the reaction mixture was stirred at -78°C for 15 min. Intermediate 14 (500 mg, 1.62 mmol) in anhydrous THF (3.6 mL) was added dropwise and the reaction mixture was stirred at -78°C for 15 min. Iodomethane (0.3 mL, 4.86 mmol) was then added and the reaction mixture was stirred at -78°C for 15 min and then warmed to 0°C within 1 h. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (50 mL) and 10% citric acid solution and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (561 mg, assumed quantitative) which was used without further purification. LCMS (Method 1): 1.47 min, 345.0 [M+Na] + .

[0403] Intermediate 16: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-(2,4-dimethoxybenzyl)(1S, 2R)-1-Methylcyclopentane-1,2-dicarboxylic acid

[0404]

[0405] To a stirred solution of intermediate 15 (561 mg, 1.74 mmol) in DMF (1.5 mL) was added HATU (728 g, 1.91 mmol) and the resulting mixture was stirred at room temperature under argon for 5 min. DIPEA (0.33 mL, 1.91 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (40 g silica column Puriflash HC, 0-50% EtOAc in isohexane) afforded the title compound (307 mg, 40%). LCMS (Method 1): 1.62 min, 463.1 [M+Na] + .

[0406] Synthesis Example

[0407] Example 1: 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy 7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazolyl-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline- 1-yl)methyl)-5-azaspiro[2.4]heptan-6-one

[0408]

[0409] Step a.

[0410] To a stirred solution of intermediate 8 (3.65 g, 7.92 mmol) in DMF (14 mL) was added 4-(chloromethyl)-5-(difluoromethyl)-1-methyl-triazole (1.87 g, 10.3 mmol; CAS: 2138555-23-2) and cesium carbonate (7.74 g, 23.8 mmol) at room temperature under nitrogen and the reaction mixture was stirred at room temperature for 18 h. Water was added and the mixture was extracted with EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (120 g silica gel column Puriflash HC, 100% DCM, then 0-30% EtOAc in DCM) gave (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (4.07 g, 85%). LCMS (Method 1): 1.78 min, 628.1 [M+Na] + .

[0411] Step b.

[0412] To a stirred solution of the above intermediate (4.07 g, 6.72 mmol) in EtOH (34 mL) was added hydrazine monohydrate (1.26 mL, 16.8 mmol; CAS: 7803-57-8) and the resulting mixture was heated at 75 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered and the filtrate was concentrated and dried in vacuo to give (S)-tert-butyl 1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.04 g, 95%). LCMS (Method 1): 1.12 min, 476.2 [M+H] + .

[0413] Step c.

[0414] To a stirred solution of the above intermediate (3.04 g, 6.39 mmol) in toluene (26 mL) was added 2-[1-(bromomethyl)cyclopropyl]methyl acetate (1.46 g, 7.03 mmol; CAS: 855473-50-6) and triethylamine (1.34 mL, 9.58 mmol) was heated to reflux for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was distributed between DCM and brine. The organic phase was separated and the aqueous phase was further extracted with DCM (x 2). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (80 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.06 g, 84%). LCMS (Method 1): 1.66 min, 592.2 [M+Na] + .

[0415] Step d.

[0416] A solution of the above intermediate (3.06 g, 5.37 mmol) in HCl in dioxane (4 M; 26.8 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, azeotroped with chloroform and dried in vacuo to give (S)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (2.93 g, quantitative). LCMS (Method 1): 0.98 min, 470.1 [M+H] + .

[0417] Step e.

[0418] To a stirred solution of the above intermediate (6.93 g, 13.7 mmol) and intermediate 12 (9.33 g, 20.5 mmol) in DMF (16 mL) was added DIPEA (4.74 mL, 27.4 mmol), and the resulting mixture was stirred at room temperature under argon for 5 days. To a stirred solution of the above intermediate (2.72 g, 5.37 mmol) and intermediate 12 (3.66 g, 8.05 mmol) in DMF (6.3 mL) was added DIPEA (1.86 mL, 10.74 mmol), and the resulting mixture was stirred at room temperature under argon for 4 days. The two reaction mixtures were combined, diluted with EtOAc and saturated sodium bicarbonate solution and the mixture was extracted with EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (300 g silica gel column Puriflash HC, 0-100% EtOAc in cyclohexane) gave 2,4-dimethoxybenzyl (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (4.1 g, 27%). LCMS (Method 2): 3.39 min, 788.5 [M+H] + Fractions containing impure product were combined, concentrated in vacuo and purified by HPLC at Teledyne ISCO Flash column chromatography on Rf+ (200 g silica gel column Puriflash HC, 0-100% EtOAc in cyclohexane) further purified to provide another batch of product (7.06 g, 8.96 mmol). LCMS (Method 2): 3.40 min, 788.6 [M+H] + The two batches were combined to give 2,4-dimethoxybenzyl (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclo-hexane-1-carboxylate (11.16 g, 14.158 mmol, 55%) which was used without further purification.

[0419] Step f.

[0420] To a stirred solution of the above intermediate (11.16 g, 14.16 mmol) in DCM (68 mL) was added triethylsilane (2.26 mL, 14.16 mmol), followed by TFA (1.09 mL, 14.16 mmol) and the resulting mixture was stirred at room temperature for 2 h. Additional TFA (0.28 mL, 3.54 mmol) was added and the mixture was stirred for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was dried in vacuo for 18 hours. The residue was taken up in DCM, filtered and the filtrate was purified by chromatography on a Teledyne ISCO Purification by flash column chromatography on Rf+ (300 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) followed by purification by ISCO Purification by flash column chromatography on Rf+ (120 g silica column Puriflash HC, 0%-50% methyl acetate in DCM) and then on Teledyne ISCO Flash chromatography on Rf+ (300 g silica column Puriflash HC, 1%-10% MeOH in DCM) gave (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid as a solid (4.4 g). Fractions containing impure product were combined, concentrated in vacuo and further purified by flash column chromatography to provide additional product (1.26 g). The two batches were combined to give (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid (5.66 g, 63%). LCMS (Method 4): 4.68 min, 638.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.20(d,1H),6.82(t,1H),5.48(dd,1H),5.40(d,1H),5.23(d,1H),4. 16(s,3H),4.06(dd,1H),4.00-3.89(m,1H),3.83(m,1H),3.24(d,1H),3.13(d,1H),3.08(d d,1H),2.99(m,1H),2.67(m,1H),2.57(dd,1H),2.47-2.36(m,2H),2.07(d,1H),1.85-1.72 (m,2H),1.70-1.43(m,3H),1.41-1.23(m,1H),1.12(s,3H),1.03(m,1H),0.69-0.50(m,4H).

[0421] Step g.

[0422] To a stirred solution of the above intermediate (315 mg, 0.49 mmol), HATU (206 mg, 0.54 mmol; CAS: 148893-10-1) and ammonium chloride (29 mg, 0.54 mmol) in DMF (1.6 mL) was added DIPEA (0.17 mL, 0.99 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO column. Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-5% MeOH in DCM) gave (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide (270 mg, 86%). LCMS (Method 2): 2.53 min, 637.4 [M+H] + .

[0423] Step h.

[0424] To a stirred solution of the above intermediate (240 mg, 0.38 mmol) in DCM (2.5 mL) was added trifluoroacetic anhydride (0.16 mL, 1.13 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified by ISCO Flash column chromatography on Rf+ (25 g silica column Puriflash HC, 15 um, 0-5% MeOH in DCM) gave (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carbonitrile (197 mg, 84%). LCMS (Method 1): 1.56 min, 619.3 [M+H] + .

[0425] Step i.

[0426] To a stirred solution of the above intermediate (145 mg, 0.23 mmol) was added tributyltin(IV)azide (0.41 mL, 1.5 mmol; CAS: 17846-68-3) along with α,α,α-trifluorotoluene (4.0 mL) and the resulting mixture was heated at 180°C for 19 h under microwave irradiation. In a separate tube, to a stirred solution of the above intermediate (25 mg, 0.04 mmol) was added tributyltin(IV)azide (0.09 mL, 0.32 mmol; CAS: 17846-68-3) along with α,α,α-trifluorotoluene (0.8 mL) and the resulting mixture was heated at 180°C for 19 h under microwave irradiation. The reaction mixtures were combined, concentrated in vacuo and purified by chromatography on a Teledyne ISCO Purification by flash chromatography on Rf+ (40 g silica column Puriflash HC, 0-5% MeOH in DCM) followed by purification by Teledyne ISCO Flash chromatography on Rf+ (12 g silica gel column Puriflash HC, 15 um, 0-100% EtOAc in cyclohexane). The fractions containing the product were combined and concentrated in vacuo, the residue was dissolved in MeCN / water (1:1) and freeze-dried to provide the title compound (51 mg, 33%). LCMS (Method 3): 4.54 min, 662.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ15.53(bs,1H),7.53(d,1H),7.18(t,1H),5.40-5.28(m,2H) ,5.20(m,1H),4.09-3.96(m,4H),3.90(dd,1H),3.56(m,1H),3.18(m,1H),2.92(d,1H ),2.88-2.78(m,2H),2.75(m,1H),2.68(d,1H),2.30-2.10(m,2H),2.02(d,1H),1.93 -1.76(m,2H),1.75-1.61(m,2H),1.61-1.37(m,3H),1.30(s,3H),0.73-0.24(m,4H).

[0427] Example 2: (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane- 1-Formic acid

[0428]

[0429] Step a.

[0430] To a suspension of sodium hydride (60%, dispersed in mineral oil; 1.33 g, 33.3 mmol; CAS: 7646-69-7) in DMF (10 mL) cooled to 0°C was added methyl 2-hydroxyacetate (2.14 mL, 27.8 mmol; CAS: 96-35-5) dropwise and the resulting mixture was stirred at room temperature under argon for 0.5 h. 2-(2-bromoethoxy)tetrahydropyran (4.61 mL, 30.5 mmol; CAS: 17739-45-6) was added and the resulting mixture was warmed to room temperature and stirred for 4 h. Water was added, the mixture was extracted with EtOAc and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (120 g silica column Puriflash HC / Biotage SNAP, 0-50% EtOAc in cyclohexane) gave methyl 2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)acetate (2.14 g, 35%). 1 H NMR(400MHz; CDCl3)δ4.64(dd,1H),4.20-4.19(m,2H),3.93-3.83(m,2H),3 .78-3.75(m,5H),3.68-3.62(m,1H),3.54-3.48(m,1H),1.90-1.50(m,6H).

[0431] Step b.

[0432] To a stirred solution of the above intermediate (2.14 g, 9.81 mmol) in MeOH (20 mL) was added pyridinium p-toluenesulfonate (49 mg, 0.20 mmol; CAS: 24057-28-1) and the resulting mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) gave methyl 2-(2-hydroxyethoxy)acetate (1.12 g, 85%). 1 H NMR (400MHz; CDCl3) δ4.16(s,2H),3.78-3.74(m,5H),3.71-3.68(m,2H),2.71(t,1H).

[0433] Step c.

[0434] To a stirred solution of the above intermediate (1.12 g, 8.4 mmol), imidazole (0.85 g, 12.5 mmol) and triphenylphosphine (2.85 g, 10.9 mmol) in Et2O (4.2 mL) and MeCN (2.1 mL) cooled in an ice bath was added iodine (2.97 g, 11.7 mmol) and the resulting mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with EtOAc, filtered, and the filtrate was washed with aqueous sodium sulfite and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (80 g silica column Puriflash HC, 0-50% EtOAc in cyclohexane) gave methyl 2-(2-iodoethoxy)acetate (1.39 g, 68%). 1 H NMR (400MHz; CDCl3) δ4.16(s,2H),3.83(t,2H),3.77(s,3H),3.30(t,2H).

[0435] Step d.

[0436] To a stirred solution of (S)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (290 mg, 0.61 mmol; Example 1, step b) in toluene (2.5 mL) was added the above intermediate (193 mg, 0.79 mmol) and triethylamine (0.13 mL, 0.910 mmol) and the reaction mixture was heated at 120° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine and extracted with DCM. The combined organics were washed with brine, dried over Na2SO4, concentrated and purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (229 mg, 67%). LCMS (Method 1): 1.56 min, 582.2 [M+Na] + .

[0437] Step e.

[0438] A solution of hydrochloric acid (4M in dioxane; 2.04 mL, 8.18 mmol) was added to the above intermediate (229 mg, 0.410 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and azeotroped with toluene to give (S)-4-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)morpholin-3-one hydrochloride (219 mg, quantitative). LCMS (Method 1): 0.85 min, 460.1 [M+H] + .

[0439] Step f.

[0440] To a stirred solution of the above intermediate (203 mg, 0.41 mmol) and intermediate 12 (279 mg, 0.61 mmol) in DMF (10 mL) was added DIPEA (0.14 mL, 0.82 mmol), and the reaction mixture was stirred at room temperature under argon for 6 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (173 mg, 54%). LCMS (Method 1): 1.70 min, 778.3 [M+H] + .

[0441] Step g.

[0442] To a stirred solution of the above intermediate (173 mg, 0.22 mmol) in DCM (2 mL) was added triethylsilane (0.04 mL, 0.22 mmol) followed by TFA (0.02 mL, 0.22 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (12 g silica gel column Puriflash HC, 15 um, 0-5% MeOH in DCM) was used for purification. The fractions containing the desired product were combined and concentrated in vacuo, and the residue was taken up in MeCN / water (1:1) and freeze-dried to provide the title compound (94.3 mg, 67%). LCMS (Method 3): 4.45 min, 628.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.88(bs,1H),7.54(d,1H),7.34(t,1H),5.52(dd,1H),5 .44(d,1H),5.25(d,1H),4.31(dd,1H),4.14(s,3H),3.98(d,1H),3.90(m,1H),3.8 4-3.70(m,2H),3.69-3.50(m,2H),3.26(m,1H),2.98-2.86(m,2H),2.84-2.83(m, 2H),2.62(m,1H),2.19(m,1H),1.68-1.49(m,3H),1.47-1.19(m,4H),1.10(s,3H).

[0443] Example 3: (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) 1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- 1-Methylcyclohexane-1-carboxylic acid

[0444]

[0445] Step a.

[0446] To a stirred solution of (R)-4-methyldihydrofuran-2(3H)-one (13.4 g, 134 mmol, CAS: 65284-00-6) in EtOH (250 mL) was added trimethyl iodosilane (38.1 mL, 268 mmol) at -20 °C. The solution was stirred for 30 min at -20 °C. Triethyl orthoformate (22.3 mL, 134 mmol) was then added and the reaction was stirred at reflux for 18 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 5% EtOAc in heptane) to obtain (R)-4-iodo-3-methylbutyric acid ethyl ester (24.3 g, 71%). 1 H NMR (300MHz, CDCl3) δ4.15(q,2H),3.32-3.23(m,2H),2.46(dd,1H),2.24(dd,1H),2.07-1.99(m,1H),1.30-1.25(t,3H),1.06(d,3H).

[0447] Step b.

[0448] To a stirred solution of (S)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (145 mg, 0.30 mmol; Example 1, step b) in toluene (1.3 mL) was added the above intermediate (101 mg, 0.40 mmol) and triethylamine (0.06 mL, 0.46 mmol) and the reaction mixture was heated at 120° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, extracted with DCM and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (89 mg, 52%). LCMS (Method 1): 1.63 min, 580.2 [M+Na] + .

[0449] Step c.

[0450] Hydrochloric acid (4M in dioxane; 0.8 mL, 3.2 mmol) was added to the above intermediate (89 mg, 0.16 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (R)-1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-4-methylpyrrolidin-2-one hydrochloride (83 mg, quantitative). LCMS (Method 1): 0.93 min, 458.1 [M+H] + .

[0451] Step d.

[0452] To a stirred solution of the above intermediate (79 mg, 0.16 mmol) in DMF (0.5 mL) was added intermediate 12 (109 mg, 0.24 mmol) and DIPEA (0.06 mL, 0.32 mmol), and the resulting mixture was stirred at room temperature under argon for 6 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (12 g silica Puriflash HC, 0-100% EtOAc in cyclohexane) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (44 mg, 36%). LCMS (Method 1): 1.75 min, 776.3 [M+H] + .

[0453] Step e.

[0454] To a stirred solution of the above intermediate (44 mg, 0.060 mmol) in DCM (0.5 mL) was added triethylsilane (0.01 mL, 0.06 mmol) followed by TFA (0.004 mL, 0.06 mmol) and the reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. Flash column chromatography on Rf+ (12 g silica gel column Puriflash HC, 15 um, 0-5% MeOH in DCM) was performed for purification. Fractions containing the desired product were combined and concentrated in vacuo. The residue was taken up in acetonitrile / water (1:1) and freeze-dried to provide the title compound (26 mg, 71%). LCMS (Method 3): 4.61 min, 626.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.97(bs,1H),7.52(d,1H),7.35(t,1H),5.48-5 .38(m,2H),5.21(d,1H),4.14(s,3H),3.98-3.80(m,2H),3.56(m,1H),3. 02(m,1H),2.95-2.71(m,4H),2.70-2.57(m,1H),2.37-2.22(m,2H),2.16 (m,1H),1.73-1.50(m,4H),1.48-1.15(m,4H),1.08(s,3H),0.98(d,3H).

[0455] Example 4: (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methane 1,2,3,4-tetrahydroisoquinoline-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)- 2-Carboxylic acid)-1-methylcyclopentane-1-carboxylic acid

[0456]

[0457] Step a.

[0458] To a stirred solution of methyl 2-(pyridin-2-yl)acetate (5.0 g, 33.1 mmol, CAS: 1658-42-0) in MeCN (83 mL) was added 4-acetamidobenzenesulfonyl azide (7.95 g, 33.1 mmol, CAS: 2158-14-7) and the reaction mixture was cooled to 0 ° C under argon. DBU (3.97 mL, 33.1 mmol) was added dropwise over 10 min. The reaction mixture was warmed to room temperature and stirred for 3 h. Saturated ammonium chloride solution was added and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography on Interchim 4125 (120 g silica column Puriflash HP, 0-15% EtOAc in DCM) gave [1,2,3]triazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (5.48 g, 89%). 1 H NMR (400MHz, CDCl3) δ8.86-8.83(m,1H),8.31-8.28(m,1H),7.56(ddd,1H),7.19-7.15(m,1H),4.06(s,3H).

[0459] Step b.

[0460] To a stirred solution of the above intermediate (2.0 g, 11.3 mmol) in EtOH (455 mL) was added Pd / C (10%; 1.20 g, 11.3 mmol), and the reaction mixture was degassed and backfilled with hydrogen (x 3). The reaction mixture was stirred under hydrogen atmosphere at atmospheric pressure for 3 h. The mixture was stirred by Filtration and concentration in vacuo provided methyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (1.98 g, 99%). 1 H NMR (400MHz, CDCl3) δ: 4.41 (t, 2H), 3.94 (s, 3H), 3.11 (t, 2H), 2.13-2.06 (m, 2H), 1.98-1.91 (m, 2H).

[0461] Step c.

[0462] To a stirred suspension of the above intermediate (1.96 g, 11.1 mmol) in THF (88 mL) was added lithium borohydride (2 M in THF; 10.0 mL, 19.9 mmol) dropwise over 10 min. The reaction was stirred at room temperature under argon for 20 h. The reaction mixture was cooled to 0 ° C and diluted with 10% citric acid (33 mL) and then extracted with DCM. The combined organics were washed with water and concentrated in vacuo. The crude product was purified by Interchim Flash column chromatography on a 4100 (80 g silica column Puriflash HP, 0-30% EtOAc in DCM) gave (4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (620 mg, 35%). 1 H NMR (400MHz, CDCl3) δ4.76(s,2H),4.38(t,2H),2.92-2.88(m,3H),2.17-2.10(m,2H),2.05-1.95(m,2H).

[0463] Step d.

[0464] Thionyl chloride (0.59 mL, 8.1 mmol) was added to the above intermediate (620 mg, 4.1 mmol). Chloroform (6.5 mL) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene (x 2) and concentrated in vacuo to provide 3-(chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine (702 mg, assumed quantitative) which was used without further purification. LCMS (Method 1): 0.90 min, 171.9 [M+H] + .

[0465] Step e.

[0466] To a stirred solution of intermediate 8 (434 mg, 0.94 mmol) in DMF (3 mL) was added the above intermediate (210 mg, 1.22 mmol) and cesium carbonate (920 mg, 2.82 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with water, extracted with EtOAc and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in DCM) gave (S)-tert-butyl 5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (425 mg, 76%). LCMS (Method 1): 1.76 min, 596.2 [M+H] + .

[0467] Step f.

[0468] To a stirred solution of the above intermediate (425 mg, 0.71 mmol) in EtOH (3.6 mL) was added hydrazine monohydrate (0.13 mL, 1.78 mmol; CAS: 7803-57-8) and the reaction mixture was heated at 75 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered and the filtrate concentrated in vacuo to give (S)-tert-butyl 1-(aminomethyl)-5-chloro-7-fluoro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (298 mg, 85%). LCMS (Method 1): 1.07 min, 466.2 [M+H] + .

[0469] Step g.

[0470] To a stirred solution of the above intermediate (298 mg, 0.64 mmol) in toluene (3 mL) was added methyl 2-[1-(bromomethyl)cyclopropyl]acetate (146 mg, 0.70 mmol; CAS: 855473-50-6) and triethylamine (0.13 mL, 0.96 mmol) and the mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, extracted with DCM and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (40 g silica column Puriflash HC, 0-90% EtOAc in DCM) gave (S)-tert-butyl 5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (321 mg, 90%). LCMS (Method 1): 1.66 min, 582.3 [M+Na] + .

[0471] Step h.

[0472] Hydrochloric acid (4M in dioxane; 2.9 mL, 11.5 mmol) was added to the above intermediate (321 mg, 0.57 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (S)-5-((5-chloro-7-fluoro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (294 mg, 98%). LCMS (Method 1): 1.01 min, 460.2 [M+H] + .

[0473] Step i.

[0474] To a stirred solution of the above intermediate (135 mg, 0.27 mmol) and intermediate 16 (204 mg, 0.47 mmol) in DMF (0.4 mL) was added DIPEA (0.1 mL, 0.60 mmol) and the reaction mixture was stirred at room temperature under argon for 18 h. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residues were purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in DCM) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-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-carboxylate (154 mg, 74%). LCMS (Method 1): 1.68 min, 764.4 [M+H] + .

[0475] Step j.

[0476] To a stirred solution of the above intermediate (154 mg, 0.20 mmol) in DCM (2.0 mL) at 0 ° C, triethylsilane (0.14 mL, 0.89 mmol) was added, followed by TFA (0.03 mL, 0.45 mmol) and the resulting mixture was stirred at room temperature for 1 h 15. Additional triethylsilane (0.04 mL, 0.22 mmol) and TFA (0.02 mL, 0.22 mmol) were added and stirring was continued at room temperature for another 45 min. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (x 2). The residue was purified by HPLC by heating at RT. Flash column chromatography on 4125 (40 g 15 μm silica column Puriflash HP, 0-5% MeOH in DCM) gave the title compound (57 mg, 43%). LCMS (Method 3): 4.33 min, 614.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.11(d,1H),5.60(dd,1H),5.23(m,1H),5.15(m,1H), 4.42(m,1H),4.31(m,1H),4.01(dd,1H),3.84(m,2H),3.35(d,1H),3.13-3.0 1(m,2H),2.94(m,1H),2.87-2.65(m,5H),2.55(m,1H),2.34(d,1H),2.21-2 .00(m,4H),1.98-1.65(m,4H),1.44(m,1H),1.28(s,3H),0.66-0.50(m,4H).

[0477] Example 5: (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)- 7-Fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methyl Cyclohexane-1-carboxylic acid

[0478]

[0479] Step a.

[0480] To a stirred solution of intermediate 8 (300 mg, 0.65 mmol) in DMF (1.2 mL) was added 3-(chloromethyl)-4,5-dimethyl-1,2,4-triazole (123 mg, 0.85 mmol; CAS: 881845-16-5) and cesium carbonate (636 mg, 1.95 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 4 h. Additional 3-(chloromethyl)-4,5-dimethyl-1,2,4-triazole (19 mg, 0.13 mmol) and cesium carbonate (106 mg, 0.33 mmol) were added and the resulting mixture was stirred for an additional 1 h. The reaction mixture was diluted with water, extracted with EtOAc, and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was prepared by HPLC-MS / MS at Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-5% MeOH in DCM) gave (S)-tert-butyl 5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (331 mg, 89%). LCMS (Method 1): 1.47 min, 570.2 [M+H] + .

[0481] Step b.

[0482] To a stirred solution of the above intermediate (331 mg, 0.58 mmol) in EtOH (3 mL) was added hydrazine monohydrate (0.11 mL, 1.45 mmol; CAS: 7803-57-8) and the resulting mixture was heated at 75 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered and the filtrate concentrated in vacuo to give (S)-tert-butyl 1-(aminomethyl)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (229 mg, 90%). LCMS (Method 1): 1.00 min, 440.1 [M+H] + .

[0483] Step c.

[0484] To a stirred solution of the above intermediate (229 mg, 0.52 mmol) in toluene (2.1 mL) was added methyl 2-[1-(bromomethyl)cyclopropyl]acetate (119 mg, 0.57 mmol; CAS: 855473-50-6) and triethylamine (0.11 mL, 0.780 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, extracted with DCM, and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The product was purified by HPLC at Teledyne ISCO Flash column chromatography on Rf+ (25 g silica Puriflash HC, 0-5% MeOH in DCM) gave (S)-tert-butyl 5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (95 mg, 34%). LCMS (Method 1): 1.36 min, 534.2 [M+H] + .

[0485] Step d.

[0486] Hydrochloric acid (4M in dioxane; 0.89 mL, 3.56 mmol) was added to the above intermediate (95 mg, 0.18 mmol) and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (S)-5-((5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (110 mg, assumed quantitative). LCMS (Method 2): 1.90 min, 434.3 [M+H] + .

[0487] Step e.

[0488] To a stirred solution of the above intermediate (84 mg, 0.18 mmol) and intermediate 12 (121 mg, 0.27 mmol) in DMF (0.5 mL) was added DIPEA (0.06 mL, 0.36 mmol) and the resulting mixture was stirred at room temperature under argon for 3 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica Puriflash HC, 0-5% MeOH in DCM) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (72 mg, 54%). LCMS (Method 1): 1.51 min, 752.3 [M+H] + .

[0489] Step f.

[0490] To a stirred solution of the above intermediate (72 mg, 0.10 mmol) in DCM (0.9 mL) was added triethylsilane (0.02 mL, 0.10 mmol) followed by TFA (0.01 mL, 0.10 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel column Puriflash HC, 15 um, 0-5% MeOH in DCM) was used for purification. Fractions containing the desired product were combined and concentrated in vacuo. The residue was taken up in MeCN / water (1:1) and freeze-dried to provide the title compound (24 mg, 41%). LCMS (Method 3): 3.78 min, 602.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.84(bs,1H),7.55(d,1H),5.61(dd,1H),5.38-5.26(m ,2H),4.03-3.88(m,2H),3.57(m,1H),3.51(s,3H),3.06(d,1H),3.00(m,1H),2. 87(dd,1H),2.80(dd,1H),2.72-2.59(m,2H),2.40-2.24(m,4H),2.21(d,1H),2. 07(d,1H),1.72-1.48(m,3H),1.47-1.17(m,4H),1.11(s,3H),0.63-0.43(m,4H).

[0491] Example 6: (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane 1-Hydroxy-1-oxo-1-ol

[0492]

[0493] Step a.

[0494] To a stirred solution of intermediate 8 (300 mg, 0.65 mmol) in DMF (1.2 mL) was added 4-(chloromethyl)-1-methyl-triazole (111 mg, 0.85 mmol; CAS: 269726-46-7) and cesium carbonate (636 mg, 1.95 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with water, extracted with EtOAc and the combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave (S)-tert-butyl 5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (332 mg, 92%). LCMS (Method 1): 1.68 min, 578.2 [M+Na] + .

[0495] Step b.

[0496] To a stirred solution of the above intermediate (332 mg, 0.60 mmol) in ethanol (3 mL) was added hydrazine monohydrate (0.11 mL, 1.49 mmol; CAS: 7803-57-8) and the resulting mixture was heated at 75 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered and the filtrate concentrated in vacuo to give (S)-tert-butyl 1-(aminomethyl)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3triazol-4-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (264 mg, assumed quantitative). LCMS (Method 1): 1.05 min, 426.1 [M+H] + .

[0497] Step c.

[0498] To a stirred solution of the above intermediate (254 mg, 0.60 mmol) in toluene (2.4 mL) was added methyl 2-[1-(bromomethyl)cyclopropyl]acetate (136 mg, 0.66 mmol; CAS: 855473-50-6) and triethylamine (0.12 mL, 0.89 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, extracted with DCM and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave (S)-tert-butyl 5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (199 mg, 64%). LCMS (Method 1): 1.54 min, 542.2 [M+Na] + .

[0499] Step d.

[0500] Hydrochloric acid (4M in dioxane; 1.9 mL, 7.65 mmol) was added to the above intermediate (199 mg, 0.38 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (S)-5-((5-chloro-7-fluoro-8-((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 hydrochloride (217 mg, assumed quantitative). LCMS (Method 1): 0.90 min, 420.1 [M+H] + .

[0501] Step e.

[0502] To a stirred solution of the above intermediate (175 mg, 0.38 mmol) and intermediate 12 (261 mg, 0.58 mmol) in DMF (0.5 mL) was added DIPEA (0.13 mL, 0.77 mmol), and the reaction mixture was stirred at room temperature under argon for 3 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel Puriflash HC, 0-100% EtOAc in cyclohexane) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (177 mg, 63%). LCMS (Method 1): 1.66 min, 738.3 [M+H] + .

[0503] Step f.

[0504] To a stirred solution of the above intermediate (177 mg, 0.24 mmol) in DCM (2.2 mL) was added triethylsilane (0.04 mL, 0.24 mmol) followed by TFA (0.02 mL, 0.24 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by chromatography on a Teledyne ISCO Flash column chromatography on Rf+ (25 g silica gel column Puriflash HC, 15 um, 0-5% MeOH in DCM) was used for purification. Fractions containing the desired product were combined and concentrated in vacuo to give the title compound (94 mg, 67%). 44 mg of the product was dissolved in MeCN / water (1:1) and freeze-dried to provide the title compound (37 mg, 25%). LCMS (Method 3): 4.26 min, 588.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.91(bs,1H),8.18(s,1H),7.50(d,1H),5.68(dd,1H) ,5.30(m,1H),5.22(m,1H),4.03(s,3H),4.00-3.88(m,2H),3.57(m,1H),3.28(d ,1H),3.05-2.95(m,2H),2.84-2.71(m,2H),2.64(m,1H),2.35-2.16(m,2H),2.1 0(d,1H),1.73-1.48(m,3H),1.47-1.19(m,4H),1.10(s,3H),0.65-0.44(m,4H).

[0505] Example 7: (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane 1-Hydroxy-1-oxo-1-ol

[0506]

[0507] Step a.

[0508] A mixture of 2,2-dimethylpropanoic acid azidomethyl ester (2.36 g, 15 mmol; CAS: 872700-68-0) and 2-butyn-1-ol (1.05 g, 15 mmol; CAS: 764-01-2) was heated in a sealed vial at 110°C under argon for 12 h. The mixture was cooled to room temperature and purified by flash column chromatography (silica, 0-80% EtOAc in cyclohexane) to give (4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)methyl pivalate (1.5 g, 44%). LCMS (Method 1): 1.05 min, 228.1 [M+H] + .

[0509] Step b.

[0510] To a stirred suspension of intermediate 8 (5 g, 10.9 mmol) in EtOH (100 mL) was added hydrazine monohydrate (2.03 mL, 27.12 mmol; CAS: 7803-57-8) and the resulting mixture was heated at 85 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered and the filtrate concentrated in vacuo to give (S)-tert-butyl 1-(aminomethyl)-5-chloro-7-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.7 g, 95%). LCMS (Method 2): 2.17 min, 331.2 [M+H] +

[0511] Step c.

[0512] To a stirred solution of the above intermediate (3.4 g, 10.8 mmol) in toluene (75 mL) was added 1-(bromomethyl) cyclopropaneacetic acid methyl ester (2.6 g, 12.3 mmol; CAS: 855473-50-6) and triethylamine (2.6 mL, 18.5 mmol) in toluene (75 mL) and heated under reflux for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was distributed between EtOAc and water. The organic phase was separated and the aqueous layer was further extracted with DCM. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0-50% EtOAc in DCM) to give (S)-tert-butyl 5-chloro-7-fluoro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.6 g, 60%). LCMS (Method 1) 1.61 min, 447.1 [M+Na]+

[0513] Step d.

[0514] To a suspension of the above intermediate (1 g, 2.4 mmol) in 1,4-dioxane (2 mL) was added HCl in dioxane (4 M; 5.6 mL, 23.5 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was filtered and the solid was azeotroped with MeOH and then MeOH / toluene to give (S)-5-((5-chloro-7-fluoro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (0.85 g, quantitative). LCMS (Method 1): 0.83 min, 324.9 [M+H] + .

[0515] Step e.

[0516] To a stirred solution of the above intermediate (0.85 g, 2.35 mmol) and intermediate 12 (1.6 g, 3.53 mmol) in DMF (6 mL) was added DIPEA (1 mL, 5.88 mmol), and the resulting mixture was stirred at room temperature for 24 h. Additional portions of intermediate 12 (1 g, 2.2 mmol) and DIPEA (1 mL, 5.88 mmol) were added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc and saturated citric acid solution, and the mixture was extracted with EtOAc. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four TM Flash column chromatography on 40 g silica gel column Puriflash HC, 0-100% EtOAc in cyclohexane) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (0.59 g, 39%). LCMS (Method 1): 1.68 min, 643.2 [M+H] +

[0517] Step f.

[0518] To a solution of the above intermediate (0.58 g, 0.9 mmol), (4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)methyl pivalate (0.23 g, 0.99 mmol, Example 7, step a) and triphenylphosphine (0.31 g, 1.17 mmol) in THF (5 mL) was added DEAD (0.21 mL, 1.35 mmol) dropwise. The mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four TM Purification by flash column chromatography on a 40 g silica column (Puriflash HC, 50 μM, 0-50% EtOAc in cyclohexane) followed by purification by chromatography on a Biotage Isolera Four TM The product was further purified by flash column chromatography on 40 g silica column Puriflash HC, 50 μM, 0-40% EtOAc in cyclohexane to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (0.56 g, 73%). LCMS (Method 1) 1.93 min, 852.3 [M+H] + .

[0519] Step g.

[0520] To a solution of the above intermediate (0.55 g, 0.65 mmol) in DCM (3.6 mL) was added triethylsilane (0.52 mL, 3.23 mmol), followed by TFA (0.2 mL, 2.6 mmol), and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water and DCM and the phases were separated. The organics were washed with water, filtered through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four TMFlash column chromatography on 40 g silica gel column Puriflash HC, 50 μM, 0-5% MeOH in DCM) gave (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid (0.35 g, 77%). LCMS (Method 1): 1.70 min, 702.3 [M+H] + .

[0521] Step h.

[0522] To a solution of the above intermediate (0.35 g, 0.49 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (82.4 mg, 1.97 mmol) in water (0.5 mL) and the resulting solution was stirred at room temperature for 1 h. Ammonia (30-33 wt % in water; 0.5 mL) was added and the mixture was stirred at room temperature for 18 h. The solution was diluted with EtOAc and water and then acidified to pH 5 by dropwise addition of HCl (1 M). The mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on a Biotage Isolera Four TM Flash column chromatography on (40 g silica gel column Puriflash HC, 15 μm, 5%-80% EtOAc in cyclohexane) to give the title compound (60 mg, 21%). LCMS (Method 3) 4.27 min, 588.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ14.78(bs,1H),11.92(bs,1H),7.52(d,1H),5.79(dd,1H),5. 28(dd,1H),5.18(dd,1H),4.03-3.90(m,2H),3.58(m,1H),3.18(d,1H),3.01(m,1H), 2.90(dd,1H),2.80(dd,1H),2.67(m,1H),2.55(d,1H),2.36-2.23(m,4H),2.19(d,1H ),2.09(d,1H),1.72-1.47(m,3H),1.46-1.15(m,4H),1.11(s,3H),0.63-0.42(m,4H).

[0523] Biological assays

[0524] KEAP1 Kelch fluorescence polarization (FP) assay

[0525] Inhibition of Kelch domain-NRF2 interaction was determined using a fluorescence polarization-based competition assay in a black 384-well microplate. Compounds were tested at a starting concentration of 10 μM and serially diluted 1:3 on a Biomek FX robot to generate a 12-point dose response curve. Each well contained 2 nM FITC-labeled NRF2 peptide (FITC-LDEETGEFL-NH2) and 25 nM human KEAP1 (N-terminus, residues 321-609) enzyme in a final volume of 20 μL of assay buffer (50 mM Tris-HCl pH 8.0, 100 mM NaCl, 5 mM MgCl2, 0.005% Tween-20, 0.005% BSA, 0.5% DMSO) in the presence of different concentrations of test compounds. Unlabeled peptide (LDEETGEFL-NH2) at 50 μM (negative control) and 0.5% DMSO (positive control) were used to determine the assay window.

[0526] After 1 hour at room temperature, fluorescence polarization (excitation 470 nm / emission 530 nm) was measured using an Envision absorbance plate reader. 50 Values ​​were determined by fitting the data to a four-parameter logistic fit using XLfit or XE Runner in ActivityBase. The assay limit was such that compounds below 10 nM could not be distinguished. IC values ​​of example compounds 50 The values ​​are shown in Table 1 (NT = not tested).

[0527] Table 1

[0528]

[0529] Beas2B NQO1 mRNA cell-based assay

[0530] NRF2-mediated upregulation of the gene NAD(P)H:quinone receptor oxidoreductase 1 (NQO1) was measured using the following assay:

[0531] BEAS-2B cells (ATCC CRL-9609) were plated at 20,000 cells / well in 96-well clear plates in 75 μL of cell culture medium and incubated overnight (37°C, 5% CO2). On day 2, 25 μL of compound or control was added to the cells for 24 h. On day 3, the culture medium was aspirated from the plates and analyzed using Cells-to-CT. TM 1-Step Method The kit (Ambion A25603) was used according to the manufacturer's instructions to perform expression analysis directly from cultured cells without RNA purification.

[0532] Briefly, cells were washed with ice-cold PBS and 22.5 μL of room temperature DNase / Lysis solution was added to the cells and incubated at room temperature for 5 minutes. To stop the reaction, 2.25 μL of stop solution was added to the cell lysate. The samples were diluted 1:5 with nuclease-free water and then 2.5 μL was transferred to a PCR plate. Real-time PCR was performed using a C-1000 thermal cycler (Bio-Rad) using human β-actin as an internal control. 1-step RT-PCR master mix (Ambion Cells-to-CT TM 1-Step Method cDNA was amplified using primers specific for NQO1 using the TaqMan Gene Expression Assays (Applied Biosystems, Inc., USA). The primer / probe set used to amplify cDNA was obtained from TaqMan Gene Expression Assays (Applied Biosystems). The relative mRNA level of the target gene NQO1 was calculated using the comparative CT (ΔΔCT) relative quantification method as described in the Applied Biosystems Chemistry Guide. Data are presented as an increase in target gene mRNA compared to vehicle (0.1% DMSO) control and EC values ​​were determined by fitting the data to a four-parameter logistic fit using XLfit or XERunner in ActivityBase. 50 EC values ​​of example compounds 50 The values ​​are shown in Table 2 (NT = not tested).

[0533] Table 2

[0534]

[0535] PK / PD Methods

[0536] Test articles were administered orally or intravenously to male Wistar Han rats (Charles River labs) at the indicated dose concentrations. Intravenous doses were administered via slow push injection into the tail vein. Oral formulations were administered into the stomach via gastric gavage. Actual dosing times were recorded.

[0537] At the indicated time points, 2 x 0.25 mL blood samples were collected via the tail vein into K2EDTA blood collection tubes. The collected blood samples were then centrifuged to obtain plasma or poured into 1.5 mL PCR RNAlater tubes containing 650 μL RNAlater.

[0538] Blood samples were placed on wet ice immediately after collection. 0.25 mL blood samples in K2EDTA were centrifuged as quickly as possible (+4°C, 1500 g, 10 min), and the resulting plasma was stored in appropriately labeled polypropylene tubes in a refrigerator set to maintain a temperature of -80°C until plasma pharmacokinetics were determined. Another 0.25 mL blood sample in a 1.5 mL PCR RNAlater tube containing 650 μL RNAlater was stored in a refrigerator at 4°C until blood pharmacodynamics were determined.

[0539] As soon as possible after the last sample collection, each animal was sacrificed by intraperitoneal injection of Na pentobarbital anesthetic overdose and death was confirmed by cervical dislocation.

[0540] The lungs of each animal were removed and divided into 4 pieces immediately after extraction. The first two lung segments (labeled as left and right) were placed in 5 mL RNAlater tissue protection tubes containing 5 mL RNAlater stabilization reagent and stored at 4°C to stabilize RNA (PD analysis). The remaining two lung segments (labeled as left and right) were weighed and quickly frozen by immersion in liquid nitrogen in polypropylene tubes (PK analysis).

[0541] The liver was also collected from each animal. Six representative slices (similar in size to the lung slices) from different regions (no thicker than 0.5 cm) were collected. Four slices (no thicker than 0.5 cm) were placed in two separate (two slices per tube) 5 mL RNAlater tissue protection tubes containing 5 mL RNAlater stabilizing reagent (tissue segments were completely immersed in RNAlater solution) and stored at 4°C (PD analysis). The remaining two slices were weighed and flash frozen by immersion in liquid nitrogen in separate polypropylene tubes (maximum 0.5 g per tube, PK analysis).

[0542] In some studies, the heart, spleen, and brain were also collected from each animal. These tissues were cut into four equal-sized pieces and two pieces were placed in a single 5 mL RNA later tissue protection tube containing 5 mL RNAlater stabilization reagent and stored at 4°C. The remaining two pieces were weighed and placed individually in polypropylene tubes and quickly frozen by immersion in liquid nitrogen.

[0543] Store research sample tubes containing RNAlater RNA Stabilization Reagent at approximately +4°C to allow the RNA Stabilization Reagent to perfuse the tissue. Store snap-frozen sections in a freezer set to maintain a temperature of -80°C.

[0544] PK study samples were quantified using a method based on protein precipitation and LC-MS / MS analysis. Before analysis, thawed tissue samples were weighed and homogenized at 4°C using an Omni-Prep Bead Ruptor (Omni Inc, Kennesaw, Georgia) after adding HPLC-grade water. Blood plasma and tissue homogenate samples were extracted by protein precipitation using an internal standard of acetonitrile acidified with 0.1% formic acid. Samples were mixed and centrifuged at 4000rpm for 30 minutes at 4°C to remove precipitated protein, and the supernatant was appropriately diluted with HPLC-grade water in 96-well plates. Using Waters Xevo TQ-S (Waters, Elstree, UK), a calibration curve matched with a control matrix and quality control standards, representative aliquots of blood plasma and tissue homogenate were measured by LC-MS / MS for the test items. Standards were prepared by mixing aliquots of control plasma and tissue homogenate with test articles, and extracted as described for the experimental samples.

[0545] RNA extraction and real-time PCR analysis of NQO1 gene expression in in vivo PD studies were performed as described below.

[0546] Total RNA was isolated using the RNeasy plus mini RNA isolation kit (Qiagen) or Mouse RiboPure TM -Blood RNA isolation kit (ThermoFisher Scientific) according to the manufacturer's instructions and quantified using an Agilent RNA 6000Nano instrument. Real-time PCR was performed using a C-1000 thermal cycler (Bio-Rad) using rat β-actin as an internal control. cDNA was amplified using primers specific for NQO1 / Nqo1 using a universal mastermix (Applied Biosystems). Primer / probe sets used to amplify cDNA were obtained from TaqMan Gene Expression Assays (Applied Biosystems). Relative mRNA levels of the target gene NQO1 were calculated using the comparative CT (ΔΔCT) relative quantification method as described in the Applied Biosystems Chemistry Guide. Data are presented as the increase in target gene mRNA compared to vehicle control treated for each tissue type.

Claims

1. A compound according to formula I, or a pharmaceutically acceptable salt thereof: in: R 1 CH2-R 4 ; R 2 is selected from CO2H and tetrazolyl; R 3 is selected from hydrogen and methyl; X is CR 5 R 6 or O; R 4 Select from one of the following groups: R 5 is methyl and R 6 is hydrogen; or R 5 and R 6 Together with the carbon atom to which they are attached, they form a cyclopropyl ring; m is 0 or 1; and n is 1 or 2; The prerequisite is that the compound having formula I is not one of the following compounds: (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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; or (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]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid.

2. The compound according to claim 1, wherein The compound has one of the structural formulas IA to IK shown below: Where R 1 To R 6 , X and m are as defined in claim 1.

3. The compound according to claim 1 or 2, wherein R 2 is CO2H.

4. The compound according to claim 1 or 2, wherein R 3 It is methyl.

5. The compound according to claim 1 or 2, wherein X is CR 5 R 6 .

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

7. The compound according to claim 1, which is selected from: 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptane-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; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; and (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

15. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease or disorder mediated by Nrf2 activation.

16. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 in the preparation of a medicament for treating the following diseases: chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury with or without multiple organ dysfunction syndrome / acute respiratory distress syndrome, pulmonary fibrosis, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac remodeling, arrhythmia, cardiac hypertrophy, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, 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 dermatitis, atopic dermatitis, nonalcoholic fatty liver disease, toxin-induced liver disease, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, IgA nephropathy, Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, chronic pain, schizophrenia, lung cancer, breast cancer, colon cancer, age-related macular degeneration, Fuchs' corneal endothelial dystrophy, or uveitis.

Images