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, which is a repressor protein that binds to cytoplasmic actin, 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, Exp Biol Med 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 "Alkylene" includes methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), 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" means 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 -CHF 2 、-CH 2 CF 3 , or perfluoroalkyl / alkoxy, such as -CF 3 , or -CF 2 CF 3 .

[0042] The term "heterocyclyl", "heterocyclic" or "heterocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring systems. Monocyclic heterocycles contain 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 heterocycles 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-oxathiolyl, dihydroisoxazolyl (e.g., 4,5-dihydroisoxazolyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, SO or SO 2 Oxidized sulfur heterocycles of the group. 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 radical is a saturated monocyclic 3 to 7-membered heterocyclic radical 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 technician, any heterocycle can be connected to another group via any suitable atom (such as via carbon or nitrogen atom). Suitably, the term "heterocyclic radical", "heterocyclic" or "heterocycle" refers to 4,5,6 or 7-membered monocycles as defined above.

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

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

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

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

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

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

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

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

[0051] The term "optionally substituted" refers to substituted groups, structures or molecules as well as unsubstituted groups, structures or molecules.

[0052] 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.

[0053] The phrase "compounds of the invention" refers to those compounds disclosed both generally and specifically herein.

[0054] Compounds of the present invention

[0055] In a first aspect, the present invention provides a compound having formula I

[0056]

[0057] in:

[0058] X 1 is nitrogen or a group -CR 6 ;

[0059] X 2 is nitrogen or a group -C*R 9 ;

[0060] R 1 Selected from C 1-4 Alkylene-R 11 , heterocyclyl and 8-10 membered bicyclic heteroaryl, wherein the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO 2 -R 13 , C 1-3 Alkylene-OR 14 and heteroaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 alkoxy and cyano; and wherein the 8-10 membered bicyclic heteroaryl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH and C 1-3 Alkoxy;

[0061] R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl;

[0062] R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl halides and cyano groups;

[0063] R 4 is hydrogen or C 1-4 alkyl;

[0064] R 5 -C(O)-C 1-4 Alkyl, -C(O)-C 3-7 cycloalkyl, -C(O)-heteroaryl or -C(O)-aryl, wherein the heteroaryl and aryl are optionally substituted with one or more substituents selected from the group consisting of: C 1-4 Alkyl, halo, hydroxy, C 1-3Alkoxy, CO 2 R 15 and cyano; or

[0065] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0066] comprising one or more -C(O)- moieties attached to the nitrogen atom;

[0067] optionally including one or more additional heteroatoms selected from oxygen, nitrogen and sulfur;

[0068] optionally fused to an aryl or heteroaryl ring;

[0069] Optionally attached to C 3-7 Cycloalkyl or 3 to 6 membered heterocyclyl ring; and

[0070] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0071] L 1 and L 2 independently selected from a bond and -CR 21 R 22 -, the premise is that if L 2 is a key, then X 1 and X 2 It can’t all be nitrogen;

[0072] R 6 and R 7 are independently selected from hydrogen, C 1-4 Alkyl, and C 3-7 Cycloalkyl; or

[0073] R 6 and R 7 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0074] R 8 C(=O)NR 8a R 8b or -C(=O)R 8c ;

[0075] R8a is hydrogen or C 1-6 alkyl;

[0076] R 8b For hydrogen, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-7 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;or

[0077] R 8a and R 8b Together with the nitrogen atom to which they are attached, they form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl ring, wherein the heterocyclyl ring optionally includes one or more additional heteroatoms selected from oxygen, nitrogen and sulfur, and is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0078] R 8c C 1-3 Alkyl or C 1-3 Haloalkyl;

[0079] R 9 Selected from hydrogen, C 1-4 Alkyl, hydroxyl, C 1-3 Alkoxy and halo;

[0080] R 10 Selected from hydrogen and C 1-4 Alkyl; or

[0081] R 9 and R 10 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; or

[0082] L 2 is a key and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, 6- or 7-membered cycloalkyl or heterocyclyl ring wherein:

[0083] The heterocyclyl ring includes 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0084] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally connected by a C 1-3 Alkylene bridge, or R 9 is a C that optionally connects C* to a carbon atom of the ring 1-3 Alkylene;

[0085] The cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 halogenated alkyl and deuterium; and

[0086] The cycloalkyl and heterocyclyl rings are optionally spiro-attached to C 3-7 Cycloalkyl;

[0087] R 11 Selected from -C(O)-R 24 、-SO 2 -R 25 、-NR 26 C(O)-R 27 、-NR 28 SO 2 -R 29 , heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are 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-R 30 , halogenated, OH, C 1-3 alkoxy, heterocyclyl and cyano; and the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 alkoxy, oxo, and cyano;

[0088] R 12 Selected from C 1-4Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and cyano groups;

[0089] R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and cyano groups;

[0090] R 17 Selected from hydrogen, C 1-4 Alkyl, C(O)C 1-3 Alkyl and C(O)NR 36 R 37 ;

[0091] R 18 , R 19 and R 20 Independently selected from C 1-4 Alkyl, OH, C 1-3 Alkoxy and NR 38 R 39 ;

[0092] R 24 Selected from C 1-4 Alkyl, NR 40 R 41 OR 42 ;

[0093] R 25 Selected from C 1-4 Alkyl and NR 43 R 44 ;

[0094] R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C1-4 Alkylene-R 45 , halogenated, OH, C 1-3 Alkoxy and cyano groups;

[0095] R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted 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-R 46 , halogenated, OH, C 1-3 Alkoxy and cyano groups;

[0096] R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ;

[0097] R 40 Selected from hydrogen and C 1-4 alkyl;

[0098] R 41 Selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 alkoxy, aryl and heteroaryl; or

[0099] R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0100] R 45 and R 46 Independently selected from hydroxyl, C 1-3 Alkoxy and C 3-7 Cycloalkyl; and

[0101] R 14 , R 15 , R 16 , R 21 , R 22 , R 23 , R 26, R 28 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 42 , R 43 , R 44 , R 47 and R 48 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl;

[0102] or a pharmaceutically acceptable salt thereof.

[0103] Specific compounds of the present invention include, for example, compounds having Formula I or a pharmaceutically acceptable salt thereof, wherein, unless otherwise indicated, R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , X 1 , X 2 , R 6 , R 7 , R 8 , R 8a , R 8b , R 8c , R 9 , R 10 , R 11 , R 12 , R 13 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25 , R 27 , R 29 , R 30 , R 40 and R 41 Each has any meaning as defined above or in any of paragraphs (1) to (111) below. For the avoidance of doubt, the scope of the present invention includes compounds having formula I or pharmaceutically acceptable salts thereof, wherein the definition of any substituent as defined herein may be combined with the definition of any other substituent also defined herein:-

[0104] (1)R 1 C 1-4Alkylene-R 11 ;

[0105] (2)R 1 CH 2 -R 11 ;

[0106] (3)R 1 CH 2 CH 2 -R 11 ;

[0107] (4)R 1 CH 2 CH 2 CH 2 -R 11 ;

[0108] (5)R 1 CH(Me)-R 11 ;

[0109] (6)R 1 is a heterocyclic group, optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano groups;

[0110] (7)R 1 is a heterocyclic group, optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl and C 3-7 Cycloalkyl;

[0111] (8)R 1 is piperidinyl or pyrrolidinyl, each of which is optionally substituted by one or more substituents independently selected from the following: -C(O)-R 12 、SO 2 -R 13, heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano groups;

[0112] (9)R 1 is pyrrolidinyl, which is optionally substituted by one or more substituents independently selected from the following: -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution;

[0113] (10)R 1 Select from one of the following groups:

[0114]

[0115] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution;

[0116] (11)R 1 is an 8-10 membered bicyclic heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH and C 1-3 Alkoxy;

[0117] (12)R 1 is an 8-membered bicyclic heteroaryl group, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, OH and C 1-3 Alkoxy;

[0118] (13)R 1 Select from one of the following groups:

[0119]

[0120] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocycloalkyl and cyano;

[0121] (14)R 1 Select from one of the following groups:

[0122]

[0123] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , C 1-3 Alkoxy and cyano groups;

[0124] (15)R 1 Select from one of the following groups:

[0125]

[0126] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH and C 1-3 Alkoxy;

[0127] (16)R 1 yes:

[0128]

[0129] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein the group is optionally substituted with one or more substituents independently selected from: C1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl and C 1-4 Alkylene-R 30 ;

[0130] (17)R 1 yes:

[0131]

[0132] (18)R 2 is selected from hydrogen, fluorine and chlorine;

[0133] (19)R 2 is hydrogen or fluorine;

[0134] (20)R 3 Selected from hydrogen, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl halides and cyano groups;

[0135] (21)R 3 is selected from the group consisting of hydrogen, chlorine, bromine, methoxy, methyl, trifluoromethyl and cyano;

[0136] (22)R 3 is selected from hydrogen and chlorine;

[0137] (23)R 3 for chlorine;

[0138] (24)R 4 is hydrogen;

[0139] (25)R 5 -C(O)-C 1-4 Alkyl, -C(O)-C 3-7 cycloalkyl, or -C(O)-aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of: C 1-4 Alkyl, halo, hydroxy, C 1-3 Alkoxy, CO 2 R 15 and cyano;

[0140] (26)R 4 is hydrogen and R 5 -C(O)-C 1-4 alkyl or -C(O)-aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of: C 1-4 Alkyl, halo, hydroxy, C 1-3 Alkoxy, CO 2 R 15 and cyano;

[0141] (27)R 4 is hydrogen and R 5 -C(O)-C 1-4 alkyl;

[0142] (28)R 4 and R 5 Together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0143] comprising one or more -C(O)- moieties attached to the nitrogen atom;

[0144] optionally including one or more additional heteroatoms selected from oxygen, nitrogen and sulfur;

[0145] optionally fused to an aryl ring;

[0146] Optionally attached to C 3-7 Cycloalkyl or 3 to 5 membered heterocyclyl ring; and

[0147] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0148] (29)R 4 and R 5 Together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0149] optionally including one or more additional heteroatoms selected from oxygen and nitrogen;

[0150] optionally fused to an aryl ring;

[0151] Optionally attached to C 3-7 Cycloalkyl; and

[0152] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R20 ;

[0153] (30)R 4 and R 5 Together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0154] comprising one or more -C(O)- moieties attached to the nitrogen atom;

[0155] optionally including one or more additional heteroatoms selected from oxygen and nitrogen;

[0156] optionally fused to an aryl ring;

[0157] Optionally attached to C 3-7 Cycloalkyl; and

[0158] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo and OH;

[0159] (31)R 4 and R 5 together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl ring, wherein the heterocyclyl ring comprises a -C(O)- moiety attached to the nitrogen atom and is optionally fused to a benzene ring, or is optionally spiro-attached to a cyclopropyl group; and the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro and OH;

[0160] (32)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following:

[0161]

[0162] wherein the saturated ring of the heterocyclic moiety is optionally spiro-attached to C 3-7 cycloalkyl, and wherein the heterocyclic moiety is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo and OH;

[0163] (33)R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following:

[0164]

[0165] wherein the saturated ring of the heterocyclic moiety is optionally spiro-attached to a cyclopropyl group, and wherein the heterocyclic moiety is optionally substituted with one or more substituents independently selected from the group consisting of methyl, fluoro, and OH;

[0166] (34)R 4 and R 5 Together with the nitrogen atom to which they are attached they form the following heterocyclic moiety:

[0167]

[0168] wherein the heterocyclic moiety is optionally spiro-attached to a cyclopropyl group and is optionally substituted with one or more substituents independently selected from: methyl and fluoro;

[0169] (35)R 4 and R 5 Together with the nitrogen atom to which they are attached they form the following heterocyclic moiety:

[0170]

[0171] wherein the heterocyclic moiety is optionally spiro-attached to the cyclopropyl group and is optionally C 1-3 Alkyl substituted, wherein the cyclopropyl and / or C 1-3 The alkyl group is attached to the heterocyclic ring at the alpha or beta position to the carbonyl group;

[0172] (36)X 1 For the group -CR 6 And X 2 is the group -C*R 9 ;

[0173] (37)X 1 For the group -CR 6 And X 2 for nitrogen;

[0174] (38)X 1 is nitrogen and X 2 is the group -C*R 9 ;

[0175] (39)L 1 and L 2 are independently selected from a bond and -CH 2 -;

[0176] (40)L 1 is a key and L 2 -CH 2 -;

[0177] (41)L 1 CH 2 - and L 2 is the key;

[0178] (42)L 1 and L 2 All are keys;

[0179] (43)R 6 and R 7 are independently selected from hydrogen and C 1-4 alkyl;

[0180] (44)R 6 and R 7 are independently selected from hydrogen and methyl;

[0181] (45)R 6 is hydrogen;

[0182] (46)R 7 is hydrogen;

[0183] (47)R 6 and R 7 All are hydrogen;

[0184] (48)R 6 and R 7 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0185] (49)X 1 For the group -CR 6 , X 2 is nitrogen or a group -C*R 9 And R 8 -C(=O)NR 8a R 8b ;

[0186] (50)X 1 For the group -CR 6 , X 2 is the group -C*R 9 And R 8 -C(=O)NR 8a R 8b ;

[0187] (51)X 1 is nitrogen, X 2 is the group -C*R 9 And R 8 -C(=O)NR 8a R 8b ;

[0188] (52)X 1 For the group -CR 6 , X 2 is nitrogen and R 8 -C(=O)NR 8a R 8b ;

[0189] (53)X 1For the group -CR 6 , X 2 is nitrogen and R 8 -C(=O)R 8c ;

[0190] (54)R 8 C(=O)NR 8a R 8b ;

[0191] (55)R 8 -C(=O)R 8c ;

[0192] (56)R 8a is hydrogen or methyl;

[0193] (57)R 8a is hydrogen;

[0194] (58)R 8b For hydrogen, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0195] (59)R 8b For hydrogen, C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0196] (60)R 8b C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0197] (61)R 8bis hydrogen, methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl or cyclopropylmethyl, wherein the methyl, ethyl or n-propyl is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, OH, methoxy and cyano;

[0198] (62)R 8b is methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl or cyclopropylmethyl;

[0199] (63)R 8b is methyl;

[0200] (64)R 8a is hydrogen and R 8b For hydrogen, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0201] (65)R 8a is hydrogen and R 8b C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0202] (66)R 8a is hydrogen and R 8b is methyl, ethyl, n-propyl, cyclopropyl, cyclobutyl or cyclopropylmethyl;

[0203] (67)R 8a is hydrogen and R 8b is methyl;

[0204] (68)R 8a and R 8bTogether with the nitrogen atom to which they are attached, they form a 3-, 4-, or 5-membered heterocyclyl ring, wherein the heterocyclyl ring optionally includes one or more additional heteroatoms selected from oxygen, nitrogen and sulfur and is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0205] (69)R 8a and R 8b Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0206] (70)R 8a and R 8 Together with the nitrogen atom to which they are attached, they form an azetidinyl ring, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, fluoro, OH, methoxy and C 1-3 Fluoroalkyl;

[0207] (71)R 8c C 1-3 Alkyl or C 1-3 Fluoroalkyl;

[0208] (72)R 8c C 1-3 Fluoroalkyl;

[0209] (73)R 8c is fluoromethyl, difluoromethyl or trifluoromethyl;

[0210] (74)R 9 Selected from hydrogen, C 1-4 Alkyl, C 1-3 Alkoxy and halo;

[0211] (75)R 9 is selected from the group consisting of hydrogen, methyl, methoxy and fluorine;

[0212] (76)R 9 Selected from C 1-4 Alkyl, C 1-3 Alkoxy and halo;

[0213] (77)R 9 is selected from methyl, methoxy and fluoro;

[0214] (78)R 9 is hydrogen or C 1-4 alkyl;

[0215] (79)R 9 is hydrogen or methyl;

[0216] (80)R 9 is methyl;

[0217] (81)R 10 is selected from hydrogen and methyl;

[0218] (82)R 9 and R 10 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0219] (83)L 2 is a key and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5- or 6-membered cycloalkyl or heterocyclyl ring wherein:

[0220] The heterocyclyl ring includes 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0221] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally connected by a C 1-3 Alkylene bridge, or R 9 is a C that optionally connects C* to a carbon atom of the ring 1-3 Alkylene;

[0222] The cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and deuterium; and

[0223] The cycloalkyl and heterocyclyl rings are optionally spiro-attached to C 3-7 Cycloalkyl;

[0224] (84)L 1 and L 2 are all bonds and R7 and R 10 Together with the atoms to which they are attached, they form a 5- or 6-membered cycloalkyl or heterocyclyl ring wherein:

[0225] The heterocyclyl ring includes 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0226] The cycloalkyl ring optionally contains a carbon-carbon double bond and is optionally connected by a C 1-3 Alkylene bridge, or R 9 is a C that optionally connects C* to a carbon atom of the ring 1-3 Alkylene;

[0227] The cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and deuterium; and

[0228] The cycloalkyl and heterocyclyl rings are optionally spiro-attached to C 3-7 Cycloalkyl;

[0229] (85)L 2 is the key, X 1 For the group -CR 6 , X 2 is the group -C*R 9 And R 7 and R 10 Together with the atoms to which they are attached, they form a 5- or 6-membered cycloalkyl ring, wherein the cycloalkyl ring is optionally connected by a C 1-3 Alkylene bridge, or R 9 is a C that optionally connects C* to a carbon atom of the ring 1-3 wherein the cycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and deuterium;

[0230] (86)L 2 is the key, X 1 For the group -CR 6 , X 2 For the group -CR 9 And R 7 and R 10 Together with the atoms to which they are attached, they form a cyclohexyl ring, wherein the cyclohexyl ring optionally contains a carbon-carbon double bond and optionally is connected by a C 1-3 The cyclohexyl ring is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4Alkyl, halo, OH and deuterium;

[0231] (87)L 1 and L 2 All keys, X 1 For the group -CR 6 , X 2 is nitrogen and R 7 and R 10 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl ring, wherein said heterocyclyl ring is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 alkoxy and deuterium; and the heterocyclyl ring is optionally spiro-attached to C 3-7 Cycloalkyl;

[0232] (88)L 1 and L 2 All keys, X 1 For the group -CR 6 , X 2 is nitrogen and R 7 and R 10 together with the atoms to which they are attached form a pyrrolidinyl or piperidinyl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of methyl, halo, OH, methoxy, and deuterium; and said ring is optionally spiro-attached to a cyclopropyl group;

[0233] (89)L 1 and L 2 All keys, X 1 is nitrogen, X 2 For the group -CR 9 And R 7 and R 10 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclyl ring, wherein said heterocyclyl ring is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 alkoxy and deuterium; and the heterocyclyl ring is optionally spiro-attached to C 3-7 Cycloalkyl;

[0234] (90)L 1 and L 2 All keys, X 1 is nitrogen, X 2 For the group -CR 9 And R 7 and R 10together with the atoms to which they are attached form a pyrrolidinyl or piperidinyl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of methyl, halo, OH, methoxy, and deuterium; and said ring is optionally spiro-attached to a cyclopropyl group;

[0235] (91)R 11 Selected from -C(O)-R 24 、-SO 2 -R 25 、-NR 26 C(O)-R 27 、-NR 28 SO 2 -R 29 , and heteroaryl, wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclic and cyano groups;

[0236] (92)R 11 -C(O)-R 24 And R 24 Selected from NR 40 R 41 OR 42 ;

[0237] (93)R 11 For-NR 26 C(O)-R 27 And R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl and C 3-7 Cycloalkyl;

[0238] (94)R 11 For-NR 28 SO 2 -R 29 And R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl and heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl and C 3-7 Cycloalkyl;

[0239] (95)R 11 is heteroaryl, 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-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclic and cyano groups;

[0240] (96)R 11 is heteroaryl, 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-R 30 , C 1-3 Alkoxy and cyano groups;

[0241] (97)R 11 is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, CH 2 -R 30 and CH 2 CH 2 -R 30 ;

[0242] (98)R 11 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, indazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted with one or more substituents independently selected from the following: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclic and cyano groups;

[0243] (99)R 11 is a heteroaryl group selected from:

[0244]

[0245] Each heteroaryl group is optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, C 1-3 Haloalkyl, C3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocycloalkyl and cyano;

[0246] (100)R 11 is oxazolyl, isoxazolyl or 1,2,3-triazolyl, each of 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-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocycloalkyl and cyano;

[0247] (101)R 11 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-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocycloalkyl and cyano;

[0248] (102)R 11 is a heterocyclic group, 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-R 30 , halogenated, OH, C 1-3 alkoxy, oxo, and cyano;

[0249] (103)R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl and heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl and C 1-3 Haloalkyl;

[0250] (104)R 29 is methyl, ethyl or cyclopropyl;

[0251] (105)R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0252] (106)R 30 is selected from hydroxy, methoxy, cyclopropyl and cyano;

[0253] (107)R 40 is selected from hydrogen and methyl;

[0254] (108)R 41 is selected from hydrogen, methyl, cyclopropyl, methoxy and phenyl;

[0255] (109)R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 5-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0256] (110)R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 5-membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo and OH;

[0257] (111)R 40 and R 41 Together with the nitrogen atom to which they are attached they form a 5-membered heterocyclyl ring, wherein said heterocyclyl ring is optionally substituted with one or more substituents independently selected from methyl, fluoro and OH.

[0258] Suitably, R 1 is as defined in any of paragraphs (1) to (17) above. In one embodiment, R 1 is as defined in paragraph (2) or (3) above. In another embodiment, R 1 is as defined in paragraph (10) above. In yet another embodiment, R 1 is as defined in paragraphs (16) to (17) above.

[0259] Suitably, R 2 is as defined in any of paragraphs (18) to (19) above. In an embodiment, R 2 is as defined in paragraph (19) above.

[0260] Suitably, R 3 is as defined in any of paragraphs (20) to (23) above. In another embodiment, R 3is as defined in paragraphs (22) to (23) above.

[0261] Suitably, R 4 is as defined in paragraph (24) above.

[0262] Suitably, R 5 is as defined in paragraph (25) above.

[0263] Suitably, R 4 and R 5 is as defined in any of paragraphs (26) to (35) above. In another embodiment, R 4 and R 5 is as defined in paragraph (27) above. In an embodiment, R 4 and R 5 is as defined in paragraphs (32) to (35) above. In yet another embodiment, R 4 and R 5 is as defined in paragraph (35) above.

[0264] Suitably, X 1 and X 2 is as defined in any of paragraphs (36) to (38) above. Preferably, X 1 and X 2 is as defined in paragraph (36) above. In another embodiment, X 1 and X 2 is as defined in any of paragraphs (49) to (53) above. More preferably, X 1 and X 2 is as defined in paragraph (50) above.

[0265] Appropriately, L 1 and L 2 is as defined in any of paragraphs (39) to (42) above. In another embodiment, L 1 and L 2 is as defined in paragraph (42) above.

[0266] Suitably, R 6 and R 7 is as defined in any of paragraphs (43) to (48) above. In another embodiment, R 6 and R 7是 As defined in paragraph (47) above.

[0267] Suitably, R 8 is as defined in any of paragraphs (54) to (55) above. In an embodiment, R 8is as defined in paragraph (54) above.

[0268] Suitably, R 8a is as defined in any of paragraphs (56) to (57) above. In an embodiment, R 8a is as defined in paragraph (57) above.

[0269] Suitably, R 8b is as defined in any of paragraphs (58) to (63) above. In an embodiment, R 8b is as defined in paragraph (62) or (63) above.

[0270] Suitably, R 8a and R 8b is as defined in any of paragraphs (64) to (70) above. In an embodiment, R 8a and R 8b is as defined in paragraph (67) or (70) above.

[0271] In certain embodiments, in any of the above paragraphs, provided that R 8a and R 8b It cannot be hydrogen at the same time.

[0272] Suitably, R 8c is as defined in any of paragraphs (71) to (73) above. In an embodiment, R 8c is as defined in paragraph (73) above.

[0273] Suitably, R 9 is as defined in any of paragraphs (74) to (80) above. In one embodiment, R 9 is as defined in paragraph (79) or (80) above. In an embodiment, R 9 is as defined in paragraph (80) above.

[0274] Suitably, R 10 is as defined in paragraph (81) above.

[0275] Suitably, R 9 and R 10 is as defined in paragraph (82) above.

[0276] Appropriately, L 1 , L 2 , R 7 and R 10 is as defined in any of paragraphs (83) to (90) above. In another embodiment, L 1 , L 2 , R 7and R 10 is as defined in paragraphs (84) to (86) above. In an embodiment, L 2 , R 7 and R 10 is as defined in paragraph (86) above.

[0277] Suitably, R 11 is as defined in any of paragraphs (91) to (102) above. In another embodiment, R 11 is as defined in paragraphs (92) to (93) above. In another embodiment, R 11 is as defined in paragraphs (99) to (101) above. In yet another embodiment, R 1 is as defined in paragraph (2) above and R 11 is as defined in paragraphs (99) to (101) above.

[0278] Suitably, R 29 is as defined in paragraphs (103) to (104) above. In an embodiment, R 29 is as defined in paragraph (104) above.

[0279] Suitably, R 30 is as defined in paragraphs (105) to (106) above. In an embodiment, R 30 is as defined in paragraph (106) above.

[0280] Suitably, R 40 is as defined in paragraph (107) above.

[0281] Suitably, R 41 is as defined in paragraph (108) above.

[0282] Suitably, R 40 and R 41 is as defined in any of paragraphs (109) to (111) above. In another embodiment, R 40 and R 41 is as defined in paragraph (111) above.

[0283] In an embodiment, the compound having formula (I) does not include (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide, or (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide.

[0284] Desirably, the compound of formula (I) has substructures (IA) to (IQ) as described below.

[0285] In another group of compounds, the compound has structural formula IA as shown below:

[0286]

[0287] Where L 1 , L 2 , X 1 , X 2 and R 1 To R 10 is defined as follows.

[0288] In another group of compounds, the compound has the structural formula IA shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; 1 and X 2 is as defined in any of paragraphs (36) to (38) above; 1 and L 2 is as defined in any of paragraphs (39) to (42) above; R 6 and R 7 is as defined in any of paragraphs (43) to (48) above; R 8 is as defined in any of paragraphs (54) to (55) above; R 9 is as defined in any of paragraphs (74) to (80) above; and R 10is as defined in paragraph (81) above.

[0289] In another group of compounds, the compound has the structural formula IB shown below:

[0290]

[0291] Where L 1 , L 2 , X 1 and R 1 To R 10 is as defined above.

[0292] In another group of compounds, these compounds have the structural formula IB as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; 1 is as defined in any of paragraphs (36) to (38) above; 1 and L 2 is as defined in any of paragraphs (39) to (42) above; R 6 and R 7 is as defined in any of paragraphs (43) to (48) above; R 8 is as defined in any of paragraphs (54) to (55) above; R 9 is as defined in any of paragraphs (74) to (80) above; and R 10 is as defined in paragraph (81) above.

[0293] In another group of compounds, the compounds have the structural formula IC shown below:

[0294]

[0295] Where R 1 To R 6 , R 8 and R 9 is as defined above.

[0296] In another group of compounds, these compounds have the structural formula IC as shown above, wherein R 1is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8 is as defined in any of paragraphs (54) to (55) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0297] In another group of compounds, the compounds have the following structural formula IDs:

[0298]

[0299] Where R 1 To R 6 , R 8a , R 8b and R 9 is as defined above.

[0300] In another group of compounds, these compounds have the structural formula ID shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (18) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (44) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combination R 8a and R 8b is as defined in any of paragraphs (68) to (70) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0301] In another group of compounds, the compound has the structural formula IE shown below:

[0302]

[0303]

[0304] Where R 1 To R 3 , R 6 , R 8a , R 8b and R 9 is as defined above.

[0305] In another group of compounds, these compounds have the structural formula IE as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 6 is as defined in paragraph (44) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combination R 8a and R 8b is as defined in any of paragraphs (68) to (70) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0306] In another group of compounds, these compounds have the structural formula IE as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 6 is as defined in paragraph (45) above; 8a is as defined in paragraph (57) above; 8b is as defined in paragraph (63) above; or the combined R 8a and R 8b is as defined in paragraph (70) above; and R 9 is as defined in paragraph (79) above.

[0307] In another group of compounds, the compound has the structural formula IF shown below:

[0308]

[0309] Where R 1 To R 6 , R 8 and R 9 is as defined above.

[0310] In another group of compounds, these compounds have the structural formula IF as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8 is as defined in any of paragraphs (54) to (55) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0311] In another group of compounds, these compounds have the structural formula IF as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8 is as defined in paragraph (54) above; and R 9 is as defined in paragraph (79) above.

[0312] In another group of compounds, the compound has the structural formula IG shown below:

[0313]

[0314] Where R 1 To R 6 , R 8a , R 8b and R 9 is as defined above.

[0315] In another group of compounds, these compounds have the structural formula IG as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combined R 8a and R 8b is as defined in any of paragraphs (67) to (70) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0316] In another group of compounds, the compound has Formula IC or Formula IF, or a pharmaceutically acceptable salt thereof:

[0317]

[0318] Where R 1 To R 6 and R 8 is as defined above and R 9 is methyl; provided that the compound is not (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide.

[0319] In another group of compounds, these compounds have the structural formula IC or IF as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6is as defined in paragraph (45) above; 8 is as defined in any of paragraphs (54) to (55) above; and R 9 It is methyl.

[0320] In another group of compounds, these compounds have the structural formula IC or IF as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8 is as defined in paragraph (54) above; and R 9 It is methyl.

[0321] In another group of compounds, the compound has the structural formula IH shown below:

[0322]

[0323] Where R 1 To R 3 , R 6 , R 8a , R 8b and R 9 is as defined above.

[0324] In another group of compounds, these compounds have the structural formula IH as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 6 is as defined in paragraph (45) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combined R 8a and R 8b is as defined in any of paragraphs (67) to (70) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0325] In another group of compounds, the compound has the structural formula IJ shown below:

[0326]

[0327] Where R 1 To R 6 , R 8a and R 8b is as defined above.

[0328] In another group of compounds, these compounds have the structural formula IJ as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combined R 8a and R 8b is as defined in any of paragraphs (67) to (70) above.

[0329] In another group of compounds, the compound has the structural formula IK shown below:

[0330]

[0331] Where R 1 To R 5 , R 8a , R 8b and R 9 is as defined above.

[0332] In another group of compounds, these compounds have the structural formula IK as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5is as defined in any of paragraphs (27) and (32) to (35) above; R 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combined R 8a and R 8b is as defined in any of paragraphs (67) to (70) above; and R 9 is as defined in any of paragraphs (74) to (80) above.

[0333] In another group of compounds, the compound has the structural formula IL shown below:

[0334]

[0335] Where R 1 To R 6 , R 8a and R 8b is as defined above.

[0336] In another group of compounds, these compounds have the structural formula IL as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combined R 8a and R 8b is as defined in any of paragraphs (67) to (70) above.

[0337] In another group of compounds, the compound has the structural formula IM shown below:

[0338]

[0339] Where R 1 To R 6 , R 8a and R 8b is as defined above.

[0340] In another group of compounds, these compounds have the structural formula IM as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; 8a is as defined in any of paragraphs (56) to (57) above; R 8b is as defined in any of paragraphs (58) to (63) above; or the combined R 8a and R 8b is as defined in any of paragraphs (67) to (70) above.

[0341] In another group of compounds, the compound has the structural formula IN shown below:

[0342]

[0343] Where R 1 To R 6 and R 8c is as defined above.

[0344] In another group of compounds, these compounds have the structural formula IN as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 4 and R 5 is as defined in any of paragraphs (27) and (32) to (35) above; R 6 is as defined in paragraph (45) above; and R 8c is as defined in any of paragraphs (71) to (73) above.

[0345] In another group of compounds, the compound has the formula IP or IQ, or a pharmaceutically acceptable salt thereof:

[0346]

[0347] Where R1 To R 3 , R 6 and R 8 is as defined above, R 9 is methyl and R 49 and R 50 are independently selected from hydrogen, C 1-4 Alkyl and halo; or R 49 and R 50 Together with the carbon atom to which they are attached they form a cyclopropyl or cyclobutyl ring.

[0348] In another group of compounds, these compounds have the structural formula IP or IQ as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is as defined in any of paragraphs (22) to (23) above; R 6 is as defined in paragraph (45) above; 8 is as defined in any of paragraphs (54) to (55) above; R 9 is methyl; and R 49 and R 50 are independently selected from hydrogen and C 1-3 Alkyl; or R 49 and R 50 Together with the carbon atom to which they are attached they form a cyclopropyl or cyclobutyl ring.

[0349] In another group of compounds, these compounds have the structural formula IP or IQ as shown above, wherein R 1 is as defined in any of paragraphs (2) to (3), (10) or (16) to (17) above; R 2 is as defined in paragraph (19) above; 3 is chlorine; R 6 is as defined in paragraph (45) above; 8 is as defined in paragraph (54) above; 9 is methyl; and R 49 and R 50 are independently selected from hydrogen and methyl; or R 49 and R 50 Together with the carbon atom to which they are attached they form a cyclopropyl ring.

[0350] Specific compounds of the present invention include any of the following:

[0351] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-(methylamino)-4-oxobutoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0352] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(ethylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0353] (1S,2R)-2-((S)-1-(cyclopropanecarboxamidomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0354] (1S,2R)-2-((S)-8-((1H-pyrazol-5-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0355] (1S,2R)-2-((S)-1-(acetylaminomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0356] (1S,2R)-N-methyl-2-((S)-1-((2-oxooxazolidin-3-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0357] 4-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)butanoic acid;

[0358] (R)-1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-2-carboxamide;

[0359] (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpyrrolidine-1-carboxamide;

[0360] 1-(((S)-5-chloro-2-((S)-1-(2,2-difluoroacetyl)piperidine-2-carbonyl)-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one;

[0361] (S)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methyl-5-azaspiro[2.4]heptane-5-carboxamide;

[0362] (1R,2S)-2-((R)-5-chloro-8-((5-(difluoromethyl)-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0363] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-oxo-4-(pyrrolidin-1-yl)butoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0364] 5-cyclopropyl-N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)isoxazole-3-carboxamide;

[0365] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-4,5-dimethylisoxazole-3-carboxamide;

[0366] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0367] N-(2-(((S)-2-((1R,2S)-2-(cyclopropylcarbamoyl)cyclohexane-1-carbonyl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0368] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(3-hydroxyazetidine-1-carbonyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0369] N-(2-(((S)-2-((1R,2S)-2-(cyclobutylcarbamoyl)cyclohexane-1-carbonyl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0370] 5-cyclopropyl-N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)isoxazole-3-carboxamide;

[0371] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)benzo[d]oxazole-2-carboxamide;

[0372] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)benzo[d]isoxazole-3-carboxamide;

[0373] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-((5-methylisoxazole)-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0374] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(pyrimidine-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0375] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-nicotinoylpyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0376] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-((5-methylisoxazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0377] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0378] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)thiazole-2-carboxamide;

[0379] (1S,2R)-2-((S)-8-(((S)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0380] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0381] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(oxazol-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0382] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0383] (1S,2R)-2-((S)-8-(((S)-1-(2,4-dimethylthiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0384] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazole-4-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0385] (R)-4-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-N,3-dimethyl-4-oxobutanamide;

[0386] (1S,2R)-N-methyl-2-((S)-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0387] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(pyrazin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0388] (S)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0389] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-propylcyclohexane-1-carboxamide;

[0390] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2-methoxyethyl)cyclohexane-1-carboxamide;

[0391] (1S,2R)-N-(2,2-difluoroethyl)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0392] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2,2,2-trifluoroethyl)cyclohexane-1-carboxamide;

[0393] (1S,2R)-N-(cyanomethyl)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0394] (1S,2R)-N-(2,2-difluoro-3-hydroxypropyl)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0395] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2-hydroxyethyl)cyclohexane-1-carboxamide;

[0396] 1-((S)-1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-1-oxopropan-2-yl)-3-methylurea;

[0397] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0398] 5-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-5-oxopentylamide;

[0399] 4-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-4-oxobutanamide;

[0400] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-ethylcyclohexane-1-carboxamide;

[0401] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(3-hydroxypropyl)cyclohexane-1-carboxamide;

[0402] (1S,2R)-N-methyl-2-((S)-1-(propionamidomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0403] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-pyrazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0404] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0405] (S)-methyl 2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carboxylate;

[0406] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0407] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-ethylcyclohexane-1-carboxamide;

[0408] (1S,2R)-2-((S)-5-bromo-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0409] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0410] (1S,2R)-2-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

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

[0412] (2R,3R)-4-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N,2,3-trimethyl-4-oxobutanamide;

[0413] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0414] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0415] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrazin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0416] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0417] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrimidin-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0418] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclopentane-1-carboxamide;

[0419] (1S,2R)-2-((S)-5-chloro-8-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0420] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0421] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0422] (1S,2R)-2-((S)-5-chloro-8-(isoxazolo[5,4-b]pyridin-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0423] (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0424] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0425] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

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

[0427] (1S,2R)-2-((S)-5-chloro-8-(imidazo[1,2-a]pyrimidin-2-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0428] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0429] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0430] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2,2-difluoro-3-hydroxypropyl)cyclohexane-1-carboxamide;

[0431] (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0432] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0433] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-indazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0434] 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methyltetrahydrofuran-2-carboxamide;

[0435] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0436] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0437] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0438] (S)-3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylmorpholine-4-carboxamide;

[0439] (S)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpyrrolidine-1-carboxamide;

[0440] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0441] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0442] (S)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0443] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0444] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0445] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0446] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0447] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0448] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0449] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide;

[0450] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0451] (1S,2R)-2-((S)-5-chloro-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0452] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0453] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0454] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0455] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0456] (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;

[0457] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0458] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0459] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0460] (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-carboxamide;

[0461] (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-carboxamide;

[0462] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; or

[0463] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0464] or a pharmaceutically acceptable salt thereof.

[0465] In an embodiment, the compound of formula (I) is selected from one of the following compounds:

[0466] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0467] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0468] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclopentane-1-carboxamide;

[0469] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0470] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0471] (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0472] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0473] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0474] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0475] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0476] (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0477] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0478] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0479] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0480] (S)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpyrrolidine-1-carboxamide;

[0481] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0482] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0483] (S)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0484] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0485] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0486] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

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

[0488] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0489] (1S,2R)-2-((S)-5-chloro-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0490] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0491] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0492] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0493] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0494] (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;

[0495] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0496] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0497] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0498] (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-carboxamide;

[0499] (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-carboxamide;

[0500] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0501] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide; or

[0502] (1R,2S)-2-((R)-5-chloro-8-((5-(difluoromethyl)-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0503] or a pharmaceutically acceptable salt thereof.

[0504] In an embodiment, the compound is a compound of Formula (IC) or Formula (IF) and is selected from one of the following compounds:

[0505] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0506] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0507] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0508] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0509] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0510] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0511] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0512] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0513] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0514] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0515] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0516] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide;

[0517] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0518] (1S,2R)-2-((S)-5-chloro-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0519] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0520] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0521] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0522] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0523] (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;

[0524] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0525] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0526] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0527] (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-carboxamide;

[0528] (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]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide; or

[0529] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0530] or a pharmaceutically acceptable salt thereof.

[0531] 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.

[0532] Suitable or preferred features of any compound of the invention may also be suitable features of any other aspect.

[0533] 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).

[0534] 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". The term "stereoisomer" is an isomer whose atoms are arranged differently in space. 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".

[0535] 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, 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.

[0536] 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.

[0537] 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.

[0538] 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.

[0539] 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.

[0540]

[0541] The compounds of the present invention comprising amine functional groups can also form N-oxides. The compounds with formula I comprising amine functional groups mentioned herein also include N-oxides. When the compound comprises several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. The specific examples of N-oxides are tertiary amines of nitrogen-containing heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry [Higher Organic Chemistry], edited by Jerry March, 4th edition, Wiley International Science Company (Wiley Interscience), 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).

[0542] The compounds of the invention can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the invention. Prodrugs can be used to alter the physical properties and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain suitable groups or substituents to which property-modifying groups can be attached.

[0543] 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.

[0544] 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.

[0545] Various forms of prodrugs have been described, for example, in the following documents:

[0546] a) Methods in Enzymology [ Enzymatic methods ], No. 42 Volume, pp. 309-396, edited by K. Widder et al., (Academic Press, 1985);

[0547] b) Design of Pro-drugs, edited by H.Bundgaard (Elsevier, 1985);

[0548] 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);

[0549] d) H.Bundgaard, Advanced Drug Delivery Reviews , 8 , 1-38(1992);

[0550] e) H.Bundgaard et al., Journal of Pharmaceutical Sciences , 77 ,285(1988);

[0551] f) N. Kakeya et al., Chem.Pharm.Bull. , 32 ,692(1984);

[0552] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; and

[0553] h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0554] 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).

[0555] 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).

[0556] synthesis

[0557] 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.

[0558] 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.

[0559] 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.

[0560] 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.

[0561] 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.

[0562] 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.

[0563] 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 groups must vary with the selection of protecting groups. 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 can be, for example, by hydrogenation over a catalyst such as palladium carbon, or by using a Lewis acid such as BF 3 .OET 2 Arylmethoxycarbonyl groups such as benzyloxycarbonyl can be removed by treatment with .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.

[0564] 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 that can be used to synthesize 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).

[0565] Tetrahydroisoquinoline (THIQ) skeleton (where R 3 is bromine) can be constructed according to the pathway outlined in Scheme 1.

[0566]

[0567] Scheme 1: a) SOCl 2 , EtOAc; b) 2-(3-methoxyphenyl)ethane-1-amine, Et 3 N, DCM; c) NBS, DMF; d) P 2 O 5 , MeCN; e) phenylruthenium (II) chloride dimer, (1S, 2S)-(+)-N-p-toluenesulfonyl-1,2-diphenylethylene-diamine, Et 3 N, HCO 2 H, MeCN; f) HCl, THF; g) BBr 3 , DCM; h) Boc 2 O. DCM.

[0568] R 3 The variants of the present invention can be prepared from the compounds of the present invention or their intermediates (wherein R 3 is bromine), are conveniently prepared from chemical reactions well known in the art, as shown in Schemes 2 and 3. 3 The compounds of the present invention wherein R is H or Cl can be prepared by the method outlined in Scheme 2 3 It is prepared as an intermediate of Br.

[0569]

[0570] Option 2: a) H 2 , 10% Pd / C, THF, EtOH; b) BBr 3 , DCM; c) Boc2 O, DCM; d) NCS, DMF.

[0571] As shown in Scheme 3, bromine R 3 Conversion of the substituent to the appropriate borate or boronic acid allows the preparation of fluoro and trifluoro derivatives. Bromine can be converted to alkyl by reaction with an appropriate alkyl borate and an appropriate palladium catalyst; for example, when the alkyl is methyl, the appropriate borate is 2,4,6-trimethyl-1,3,5,2,4,6-trimethylcyclotriboroxane and the appropriate palladium catalyst is Pd(dppf)Cl 2 . Where R 3 Compounds with cyano groups can be cyanated by using a cyanating agent such as Zn(CN) 2 and palladium catalysts such as Pd(PPh 3 ) 4 Treatment was prepared from the bromo derivative.

[0572]

[0573] Scheme 3: a) dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine, X-phos Pd, diboric acid; b) CF 3 SO 3 Ag, c) Bis(pinacol)diboron, Pd(dppf)Cl 2 ; d) Potassium trimethoxy(trifluoromethyl)borate, Cu(OAc) 2 ; e) Pd(dppf)Cl 2 , alkylborane; f) Zn(CN) 2 、Pd(PPh 3 ) 4 .

[0574] According to Scheme 4, the compound of the present invention (wherein -NR 4 R 5 represents indolinone) can be prepared by sequential reduction of the corresponding phthalimide with sodium borohydride and then triethylsilane.

[0575]

[0576] Scheme 4: a) NaBH 4 , MeOH; b) TFA, Et 3 SiH.

[0577] The compounds of the present invention (wherein the group -NR 4 R 5 represents pyrrolidone) can be obtained from an intermediate (wherein -NR 4 R 5represents a phthalimide group) is prepared by removal of the phthalimide group with hydrazine and then conversion of the resulting primary amine to a pyrrolidone by reaction with an appropriate lactone or ω-haloester or to an indolinone according to the route outlined in Scheme 5.

[0578]

[0579] Option 5: a) N 2 H 4 , EtOH; b) 4-bromobutyric acid methyl ester, Et 3 N. PhMe.

[0580] The compounds of the present invention (wherein R 2 is a halogenated substituent) can be obtained from an intermediate or example of the present invention (wherein R 2 is hydrogen) by treatment with a suitable halogenating agent such as N-chlorosuccinimide as shown in Scheme 6.

[0581]

[0582] Scheme 6: a) NCS, DCM / DMF.

[0583] General Method A

[0584] In a typical synthetic procedure, the phthalimide, when used as a protecting group, is removed using typical reagents such as hydrazine, and the amine is reacted with a suitable reagent to install the desired substituent NR 4 R 5 The third step involves installation of the desired ether by conventional methods such as alkylation using an alkyl halide or activated alcohol (e.g., mesylate, triflate) or the 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. 1 X 1 (R 7 )L 2 X 2 (CO 2 R)R 10 The group can be introduced from a suitably substituted and protected bis acid derivative; ideally, one of the acid groups is activated to react with the amine of the tetrahydroisoquinoline (THIQ) backbone, while the other acid group is suitably protected, for example as a benzyl or dimethoxybenzyl ester, or by ring opening of an appropriate cyclic anhydride, or by reaction with an acyl chloride. A typical amide coupling agent (such as HATU) is used for acid activation.

[0585]

[0586] In the penultimate step, the reaction is carried out by a suitable method such as hydrolysis, hydrogenolysis, strong acid (such as HCl or TFA) or Lewis acid (such as BBr 3 ) to remove the protecting group to give the carboxylic acid. In the final step, the carboxylic acid is converted to a primary, secondary or tertiary amide using amide coupling reactions and reagents well known in the art, such as HATU and 1,1'-carbonyldiimidazole (CDI).

[0587] General Method B

[0588]

[0589] In another typical procedure, the order of the steps may be altered compared to General Method A. The desired ether is installed in the first step, again by conventional methods as described above in General Method A. The phthalimide protecting group is removed in the second step and the amine is reacted with a suitable reagent to install the desired substituent NR 4 R 5 The Boc protecting group is then removed and L can then be introduced in the fifth step 1 X 1 (R 7 )L 2 X 2 (CO 2 R)R 10 The final step involves removal of the carboxylic acid protecting group as described in the general procedure above.

[0590] The synthesis of example carboxylic acid compounds is described in co-pending application PCT / GB2019 / 053012 (WO 2020 / 084300).

[0591] General Method C

[0592]

[0593] In another typical procedure, L 1 X 1 (R 7 )L 2 N(R)R 10 The group may be introduced from a suitably substituted and protected monoacid derivative; ideally where the acid group is activated for reaction with the amine of the tetrahydroisoquinoline (THIQ) backbone and the amine group is suitably protected, for example as tert-butoxycarbonyl, or by reaction with an appropriate acid chloride.

[0594] Pharmaceutical composition

[0595] 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.

[0596] 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.

[0597] 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).

[0598] 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.

[0599] Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients can be selected for the particular functions they can provide in the composition. For example, certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the carrying or transport of one or more compounds of the invention from one organ or part of the body to another organ or another part of the body once administered to a patient. Certain pharmaceutically acceptable excipients can be selected for their ability to enhance patient compliance.

[0600] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, solubilizers, suspending agents, emulsifying agents, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. 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.

[0601] Those skilled in the art have the knowledge and skills enabling them to select suitable amounts of suitable pharmaceutically acceptable excipients for the present invention. In addition, skilled artisans can utilize a number of resources that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Macmillan Publishing Co.), Handbook of Pharmaceutical Additives (Gower Publishing Co.), and Handbook of Pharmaceutical Excipients (American Pharmaceutical Association and Pharmaceutical Press).

[0602] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Macmillan Publishing Co.).

[0603] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, 0.5 mg to 0.5 g (more suitably 0.5 mg to 100 mg, e.g. 1 mg to 30 mg) of active agent compounded with an appropriate and convenient amount of excipient (which may vary from about 5% to about 98% by weight of the total composition).

[0604] According to well-known medical principles, for therapeutic or prophylactic purposes, the size of the dose of the compound having 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.

[0605] 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.

[0606] Route of administration

[0607] 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).

[0608] 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.

[0609] 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.

[0610] Therapeutic uses and applications

[0611] 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.

[0612] 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.

[0613] 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.

[0614] 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.

[0615] 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.

[0616] 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.

[0617] 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.

[0618] 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.

[0619] 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.

[0620] 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.

[0621] 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 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.

[0622] 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.

[0623] 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.

[0624] 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.

[0625] 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.

[0626] 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.

[0627] Combination therapy

[0628] 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 depend on the disease or condition to be treated and its severity.

[0629] Combination therapy is commonly used to treat certain medical conditions.

[0630] According to a particular aspect of the invention there is provided a combination useful for treating 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.

[0631] 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 Dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Allport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, chronic pain, schizophrenia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs corneal endothelial dystrophy, uveitis or preeclampsia, the combination comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0632] 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.

[0633] 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.

[0634] 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 a pharmaceutically acceptable diluent or carrier and in combination with one or more additional therapeutic agents.

[0635] 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.

[0636] 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.

[0637] 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.

[0638] 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:

[0639] (i) β2-adrenergic receptor agonists (which may be racemates or single enantiomers), including salmeterol, salbutamol, formoterol, salmethol, fenoterol, carmoterol, etanterol, namoterol, clenbuterol, pirbuterol, flebuterol, reproterol, bambuterol, indacaterol, terbutaline, vilanterol, olodaterol and their salts;

[0640] (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 their salts;

[0641] (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;

[0642] (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;

[0643] (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);

[0644] (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);

[0645] (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

[0646] (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.

[0647] 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.

[0648] 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.

[0649] 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).

[0650] The following numbered statements 1-30 are not claims, but rather describe certain aspects and embodiments of the present disclosure.

[0651] 1. A compound according to formula I, or a pharmaceutically acceptable salt thereof:

[0652]

[0653] in:

[0654] X 1 is nitrogen or a group -CR 6 ;

[0655] X 2 is nitrogen or a group -C*R 9 ;

[0656] R 1 Selected from C1-4 Alkylene-R 11 , heterocyclyl and 8-10 membered bicyclic heteroaryl, wherein the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO 2 -R 13 , C 1-3 Alkylene-OR 14 and heteroaryl, which is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 alkoxy and cyano; and wherein the 8-10 membered bicyclic heteroaryl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH and C 1-3 Alkoxy;

[0657] R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl;

[0658] R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl halides and cyano groups;

[0659] R 4 is hydrogen or C 1-4 alkyl;

[0660] R 5 -C(O)-C 1-4 Alkyl, -C(O)-C 3-7 cycloalkyl, -C(O)-heteroaryl or -C(O)-aryl, wherein the heteroaryl and aryl are optionally substituted with one or more substituents selected from the group consisting of: C 1-4 Alkyl, halo, hydroxy, C 1-3 Alkoxy, CO 2 R 15 and cyano; or

[0661] R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 4-, 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0662] comprising one or more -C(O)- moieties attached to the nitrogen atom;

[0663] optionally including one or more additional heteroatoms selected from oxygen, nitrogen and sulfur;

[0664] optionally fused to an aryl or heteroaryl ring;

[0665] Optionally attached to C 3-7 Cycloalkyl or 3 to 6 membered heterocyclyl ring; and

[0666] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0667] L 1 and L 2 independently selected from a bond and -CR 21 R 22 -, the premise is that if L 2 is a key, then X 1 and X 2 It can’t all be nitrogen;

[0668] R 6 and R 7 are independently selected from hydrogen, C 1-4 Alkyl, and C 3-7 Cycloalkyl; or

[0669] R 6 and R 7 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0670] R 8 C(=O)NR 8a R 8b or -C(=O)R 8c ;

[0671] R 8a is hydrogen or C 1-6 alkyl;

[0672] R 8b For hydrogen, C 1-6 Alkyl or C 3-7 Cycloalkyl, wherein the C 1-6 Alkyl or C 3-7 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: 1-4 Alkyl, C 3-7Cycloalkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;or

[0673] R 8a and R 8b Together with the nitrogen atom to which they are attached, they form a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0674] optionally including one or more additional heteroatoms selected from oxygen, nitrogen and sulfur; and

[0675] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 ;

[0676] R 8c C 1-3 Alkyl or C 1-3 Haloalkyl;

[0677] R 9 Selected from hydrogen, C 1-4 Alkyl, hydroxyl, C 1-3 Alkoxy and halo;

[0678] R 10 Selected from hydrogen and C 1-4 Alkyl; or

[0679] R 9 and R 10 Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; or

[0680] L 2 is a key and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5-, 6- or 7-membered cycloalkyl or heterocyclyl ring wherein:

[0681] The heterocyclyl ring includes 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0682] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally connected by a C 1-3 Alkylene bridge, or R 9 is a C that optionally connects C* to a carbon atom of the ring 1-3 Alkylene;

[0683] The cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 halogenated alkyl and deuterium; and

[0684] The cycloalkyl and heterocyclyl rings are optionally spiro-attached to C 3-7 Cycloalkyl;

[0685] R 11 Selected from -C(O)-R 24 、-SO 2 -R 25 、-NR 26 C(O)-R 27 、-NR 28 SO 2 -R 29 , heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are 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-R 30 , halogenated, OH, C 1-3 alkoxy, heterocyclyl and cyano; and the heterocyclyl is optionally substituted by one or more substituents independently selected from the following: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 alkoxy, oxo, and cyano;

[0686] R 12 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3Alkoxy and cyano groups;

[0687] R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and cyano groups;

[0688] R 17 Selected from hydrogen, C 1-4 Alkyl, C(O)C 1-3 Alkyl and C(O)NR 36 R 37 ;

[0689] R 18 , R 19 and R 20 Independently selected from C 1-4 Alkyl, OH, C 1-3 Alkoxy and NR 38 R 39 ;

[0690] R 24 Selected from C 1-4 Alkyl, NR 40 R 41 OR 42 ;

[0691] R 25 Selected from C 1-4 Alkyl and NR 43 R 44 ;

[0692] R 27 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 haloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted 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-R 45 , halogenated, OH, C 1-3 Alkoxy and cyano groups;

[0693] R 29 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3haloalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl are 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-R 46 , halogenated, OH, C 1-3 Alkoxy and cyano groups;

[0694] R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ;

[0695] R 40 Selected from hydrogen and C 1-4 alkyl;

[0696] R 41 Selected from hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-3 Alkoxy, aryl and heteroaryl; or

[0697] R 40 and R 41 Together with the nitrogen atom to which they are attached, they form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring, wherein the heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups;

[0698] R 45 and R 46 Independently selected from hydroxyl, C 1-3 Alkoxy and C 3-7 Cycloalkyl; and

[0699] R 14 , R 15 , R 16 , R 21 , R 22 , R 23 , R 26 , R 28 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39, R 42 , R 43 , R 44 , R 47 and R 48 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl.

[0700] 2. A compound according to statement 1, wherein the compound has the structural formula IA or IB shown below

[0701]

[0702] Where L 1 , L 2 , X 1 , X 2 and R 1 To R 10 is as defined in statement 1.

[0703] 3. A compound according to Statement 1 or Statement 2, wherein L 2 is a key and R 7 and R 10 Together with the atoms to which they are attached, they form a 4-, 5- or 6-membered cycloalkyl or heterocyclyl ring wherein:

[0704] The heterocyclyl ring includes 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0705] The cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally connected by a C 1-3 Alkylene bridge, or R 9 is a C that optionally connects C* to a carbon atom of the ring 1-3 Alkylene;

[0706] The cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and deuterium; and

[0707] The cycloalkyl and heterocyclyl rings are optionally spiro-attached to C 3-7 Cycloalkyl.

[0708] 4. A compound according to statement 1, wherein the compound has one of the structural formulas IC, ID, IF, IG, IJ, IK, IL, IM or IN shown below:

[0709]

[0710] Where R 1 To R 6, R 8 , R 8a , R 8b , R 8c and R 9 is as defined in Statement 1 and is a cyclohexyl, cyclopentyl, piperidinyl, pyrrolidinyl or morpholinyl ring:

[0711] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and deuterium; and

[0712] Optionally attached to C 3-7 Cycloalkyl.

[0713] 5. A compound according to any one of statements 1 to 4, wherein R 1 C 1-4 Alkylene-R 11 , such as CH 2 -R 11 .

[0714] 6. A compound according to any one of Statements 1 to 5, wherein R 11 Selected from -C(O)-R 24 、-SO 2 -R 25 、-NR 26 C(O)-R 27 、-NR 28 SO 2 -R 29 and heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclyl and cyano.

[0715] 7. A compound according to any one of Statements 1 to 6, wherein R 11 is heteroaryl, 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-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclyl and cyano.

[0716] 8. A compound according to any one of Statements 1 to 7, wherein R11 is a heteroaryl group, which is optionally substituted by one or more substituents independently selected from the group consisting of methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, CH 2 -R 30 and CH 2 CH 2 -R 30 .

[0717] 9. A compound according to any one of Statements 1 to 7, wherein R 11 is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, indazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted with one or more substituents independently selected from the following: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclyl and cyano.

[0718] 10. A compound according to any one of Statements 1 to 7, wherein R 11 is a heteroaryl group selected from:

[0719]

[0720] Each heteroaryl group is 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-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclyl and cyano.

[0721] 11. A compound according to any one of statements 1 to 4, wherein R 1 Select from one of the following groups:

[0722]

[0723] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, heterocyclyl and cyano.

[0724] 12. A compound according to any one of statements 1 to 4, wherein R 1 is a heterocyclic group, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano.

[0725] 13. A compound according to any one of statements 1 to 4, wherein R 1 is piperidinyl or pyrrolidinyl, each of which is optionally substituted by one or more substituents independently selected from the following: -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano.

[0726] 14. A compound according to statement 13, wherein R 1 is pyrrolidinyl, which is optionally substituted by one or more substituents independently selected from the following: -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

[0727] 15. A compound according to any one of statements 1 to 4, wherein R 1 Select from one of the following groups:

[0728]

[0729] in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: -C(O)-R 12 、SO 2 -R 13 , heteroaryl and C 1-3 Alkylene-OR 14 wherein the heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

[0730] 16. A compound according to any one of Statements 1 to 15, wherein R 2 is hydrogen or fluorine.

[0731] 17. A compound according to any one of Statements 1 to 16, wherein R 3 is hydrogen or chlorine.

[0732] 18. A compound according to any one of Statements 1 to 17, wherein R 4 is hydrogen and R 5 -C(O)-C 1-4 Alkyl, -C(O)-C 3-7 cycloalkyl, or -C(O)-aryl, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of: C 1-4 Alkyl, halo, hydroxy, C 1-3 Alkoxy, CO 2 R 15 and cyano.

[0733] 19. A compound according to any one of Statements 1 to 17, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocyclyl ring, wherein the heterocyclyl ring:

[0734] comprising one or more -C(O)- moieties attached to the nitrogen atom;

[0735] optionally including one or more additional heteroatoms selected from oxygen, nitrogen and sulfur;

[0736] optionally fused to an aryl ring;

[0737] Optionally attached to C 3-7 Cycloalkyl or 3 to 5 membered heterocyclyl ring; and

[0738] Optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3Haloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO 2 R 20 .

[0739] 20. A compound according to any one of Statements 1 to 17, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following:

[0740]

[0741] wherein the saturated ring of the heterocyclic moiety is optionally spiro-attached to C 3-7 cycloalkyl, and wherein the heterocyclic moiety is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo and OH.

[0742] 21. A compound according to any one of Statements 1 to 20, wherein R 8 C(=O)NR 8a R 8b .

[0743] 22. A compound according to statement 21, wherein R 8a For hydrogen.

[0744] 23. A compound according to Statement 21 or 22, wherein R 8b For hydrogen, C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano.

[0745] 24. A compound according to statement 21, wherein R 8a and R 8b Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, cyano, NR 16 R 17 、C(O)R 18 、S(O)R 19 and SO2 R 20 .

[0746] 25. A compound according to any one of Statements 1 to 20, wherein R 8c C 1-3 Fluoroalkyl.

[0747] 26. A compound according to any one of Statements 1 to 25, wherein R 9 It is hydrogen or methyl.

[0748] 27. A compound according to statement 1, which is selected from any of the following:

[0749] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-(methylamino)-4-oxobutoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0750] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(ethylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0751] (1S,2R)-2-((S)-1-(cyclopropanecarboxamidomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0752] (1S,2R)-2-((S)-8-((1H-pyrazol-5-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0753] (1S,2R)-2-((S)-1-(acetylaminomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0754] (1S,2R)-N-methyl-2-((S)-1-((2-oxooxazolidin-3-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0755] 4-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)butanoic acid;

[0756] (R)-1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-2-carboxamide;

[0757] (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpyrrolidine-1-carboxamide;

[0758] 1-(((S)-5-chloro-2-((S)-1-(2,2-difluoroacetyl)piperidine-2-carbonyl)-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one;

[0759] (S)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methyl-5-azaspiro[2.4]heptane-5-carboxamide;

[0760] (1R,2S)-2-((R)-5-chloro-8-((5-(difluoromethyl)-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0761] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-oxo-4-(pyrrolidin-1-yl)butoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0762] 5-cyclopropyl-N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)isoxazole-3-carboxamide;

[0763] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-4,5-dimethylisoxazole-3-carboxamide;

[0764] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0765] N-(2-(((S)-2-((1R,2S)-2-(cyclopropylcarbamoyl)cyclohexane-1-carbonyl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0766] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(3-hydroxyazetidine-1-carbonyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0767] N-(2-(((S)-2-((1R,2S)-2-(cyclobutylcarbamoyl)cyclohexane-1-carbonyl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)-5-methylisoxazole-3-carboxamide;

[0768] 5-cyclopropyl-N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)isoxazole-3-carboxamide;

[0769] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)benzo[d]oxazole-2-carboxamide;

[0770] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)benzo[d]isoxazole-3-carboxamide;

[0771] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-((5-methylisoxazole)-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0772] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(pyrimidine-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0773] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-nicotinoylpyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0774] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-((5-methylisoxazol-4-yl)sulfonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0775] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0776] N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl)thiazole-2-carboxamide;

[0777] (1S,2R)-2-((S)-8-(((S)-1-(cyclopropanecarbonyl)pyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0778] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0779] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(oxazol-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0780] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0781] (1S,2R)-2-((S)-8-(((S)-1-(2,4-dimethylthiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0782] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazole-4-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0783] (R)-4-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-N,3-dimethyl-4-oxobutanamide;

[0784] (1S,2R)-N-methyl-2-((S)-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0785] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(pyrazin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0786] (S)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0787] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-propylcyclohexane-1-carboxamide;

[0788] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2-methoxyethyl)cyclohexane-1-carboxamide;

[0789] (1S,2R)-N-(2,2-difluoroethyl)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0790] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2,2,2-trifluoroethyl)cyclohexane-1-carboxamide;

[0791] (1S,2R)-N-(cyanomethyl)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0792] (1S,2R)-N-(2,2-difluoro-3-hydroxypropyl)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0793] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2-hydroxyethyl)cyclohexane-1-carboxamide;

[0794] 1-((S)-1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-1-oxopropan-2-yl)-3-methylurea;

[0795] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0796] 5-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-5-oxopentylamide;

[0797] 4-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-4-oxobutanamide;

[0798] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-ethylcyclohexane-1-carboxamide;

[0799] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(3-hydroxypropyl)cyclohexane-1-carboxamide;

[0800] (1S,2R)-N-methyl-2-((S)-1-(propionamidomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0801] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-pyrazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0802] (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0803] (S)-methyl 2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carboxylate;

[0804] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0805] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-ethylcyclohexane-1-carboxamide;

[0806] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide;

[0807] (1S,2R)-2-((S)-5-bromo-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0808] (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0809] (1S,2R)-2-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0810] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0811] (2R,3R)-4-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N,2,3-trimethyl-4-oxobutanamide;

[0812] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0813] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0814] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrazin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0815] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-2-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0816] (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrimidin-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0817] 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclopentane-1-carboxamide;

[0818] (1S,2R)-2-((S)-5-chloro-8-(2-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0819] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0820] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0821] (1S,2R)-2-((S)-5-chloro-8-(isoxazolo[5,4-b]pyridin-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0822] (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0823] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0824] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0825] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0826] (1S,2R)-2-((S)-5-chloro-8-(imidazo[1,2-a]pyrimidin-2-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0827] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0828] (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0829] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-(2,2-difluoro-3-hydroxypropyl)cyclohexane-1-carboxamide;

[0830] (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0831] (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0832] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-indazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0833] 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methyltetrahydrofuran-2-carboxamide;

[0834] (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0835] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0836] (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0837] (S)-3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylmorpholine-4-carboxamide;

[0838] (S)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpyrrolidine-1-carboxamide;

[0839] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0840] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0841] (S)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-1-carboxamide;

[0842] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0843] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0844] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide;

[0845] (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0846] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0847] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0848] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide;

[0849] (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0850] (1S,2R)-2-((S)-5-chloro-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)-N,1-dimethylcyclohexane-1-carboxamide;

[0851] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0852] (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0853] (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide;

[0854] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0855] (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;

[0856] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0857] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0858] (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)-N,1-dimethylcyclohexane-1-carboxamide;

[0859] (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-carboxamide;

[0860] (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-carboxamide;

[0861] (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; or

[0862] (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide;

[0863] or a pharmaceutically acceptable salt thereof.

[0864] 28. A pharmaceutical composition comprising a compound according to any one of Statements 1 to 27, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0865] 29. A compound according to any one of Statements 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Statement 28 for use in therapy.

[0866] 30. A compound according to any one of statements 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to statement 28, for use in the treatment of 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, arrhythmia, 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 carcinoma 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), Fuchsian endothelial corneal dystrophy, uveitis, or preeclampsia.

[0867] Examples

[0868] General procedure:

[0869] 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.

[0870] 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.

[0871] Analytical LCMS

[0872] Where compounds described in this invention were characterized by LCMS data, retention times and molecular weights were determined using the methods listed in the following tables. Where compounds of this invention exhibit slowly interconverting stereoisomers, multiple retention times are reported.

[0873]

[0874]

[0875]

[0876]

[0877]

[0878] Preparative HPLC

[0879] Preparative HPLC is carried out using various preparation systems with variable wavelength UV detection or mass spectrometry directional automatic preparation (Mass Directed AutoPrep, MDAP) system listed in the table below. Collection is triggered by UV, MS or a combination of the two. UV detection is carried out at a selected wavelength of typically 210nm, 230nm or 280nm. Mass spectrum is recorded on a mass spectrometer using alternating scanning positive and negative electrospray ionization.

[0880]

[0881] abbreviation:

[0882]

[0883] Intermediates

[0884] The following intermediates and their synthetic routes are described in co-pending application PCT / GB2019 / 053012:

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892] Synthesis of Example Compounds

[0893] For methods of synthesizing the desired carboxylic acids, see the experimental methods in PCT / GB2019 / 053012 (WO 2020 / 084300), and the following representative syntheses:

[0894] (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-(methylamino)-4-oxo (2-( ...

[0895]

[0896] Step a. To a stirred solution of intermediate 11 (1.0 g, 2.45 mmol) in anhydrous THF (15 mL) was added benzyl 4-hydroxybutyrate (570 mg, 2.94 mmol; CAS: 91970-62-6) and triphenylphosphine (963 mg, 3.67 mmol; CAS: 603-35-0) and to this was added dropwise a solution of DBAD (845 mg, 3.67 mmol) in anhydrous THF (5 mL) over 15 min. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. Flash column chromatography (silica, 20% EtOAc in heptane) afforded (S)-tert-butyl 8-(4-(benzyloxy)-4-oxobutoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.47 g, assumed quantitative). LCMS (method 1, using 2-98% B in 0.80 min, 98% B to 1.30 min): 1.05 min, 585.5 [M+H] + .

[0897] Step b. A suspension of the above intermediate (1.47 g, 2.51 mmol) and 10% Pd / C (535 mg, 0.251 mmol) in anhydrous THF (20 mL) was stirred at room temperature under hydrogen atmosphere (atmospheric pressure) for 18 h. The reaction mixture was stirred by Filter, wash with methanol, and concentrate the filtrate in vacuo. Flash column chromatography (silica, 30-50% EtOAc in heptane) afforded (S)-4-((2-(tert-butoxycarbonyl)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)butanoic acid (1.00 g, 80%). LCMS (Method 1): 1.62 min, 495.2 [M+H] + .

[0898] Step c. To a stirred solution of the above intermediate (200 mg, 0.40 mmol) in anhydrous THF (2 mL) was added CDI (262 mg, 1.62 mmol; CAS: 530-62-1) in one portion at room temperature. After 1 h, the reaction mixture was cooled to 0 °C and methylamine (2 M in THF; 0.40 mL, 1.62 mmol; CAS: 74-89-5) was added. The reaction mixture was stirred at room temperature for 18 h, diluted with water, extracted with EtOAc, and the combined organics were washed with brine, washed with MgSO 4 Dry, filter and concentrate in vacuo. Flash column chromatography (silica, EtOAc) afforded (S)-tert-butyl 1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-(methylamino)-4-oxobutoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (120 mg, 58%). LCMS (Method 2 using XBridge IS C18 2.5 μm 2.1 x 20 mm column, 0-95% B 0.18 to 2.00 min, 95% B to 2.60 min): 1.99 min, 508.2 [M+H] + .

[0899] Step d. To a stirred solution of the above intermediate (120 mg, 0.24 mmol) in 1,4-dioxane (1 mL) was added hydrogen chloride (3 M in dioxane, 2 mL) and the reaction mixture was stirred at room temperature for 3 h. The suspension was concentrated in vacuo and triturated from TBME to give (S)-4-((1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-N-methylbutanamide hydrochloride (105 mg, assumed quantitative) which was used without further purification. LCMS (Method 2 using XBridge IS C18 2.5 μm 2.1 x 20 mm column, 0-95% B 0.18 to 2.00 min, 95% B to 2.60 min): 1.68 min, 408.2 [M+H] + .

[0900] Step e. To a stirred solution of the above intermediate (120 mg, 0.27 mmol) and triethylamine (0.11 mL, 0.81 mmol) in anhydrous DCM (1.5 mL) was added a solution of intermediate 26 (83 mg, 0.297 mmol) in DCM (0.5 mL) dropwise at 0°C. The reaction mixture was stirred at 0°C for 0.5 h and then at room temperature for 1 h. Water was added, the mixture was extracted with EtOAc, and the combined organics were washed with brine, washed with MgSO 4 Dry, filter and concentrate in vacuo. Purification by flash column chromatography (silica, 20% EtOAc in heptane then 100% EtOAc) afforded benzyl (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-(methylamino)-4-oxobutoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (80 mg, 45%). LCMS (Method 1 using 2-98% B in 0.80 min, 98% B to 1.30 min): 0.93 min, 652.6 [M+H] + .

[0901] Step f. A suspension of the above intermediate (80 mg, 0.12 mmol) and 10% Pd / C (26 mg, 0.12 mmol) in anhydrous THF (2 mL) was stirred at room temperature for 24 h under a hydrogen atmosphere (atmospheric pressure). The reaction mixture was stirred by Filter, wash with methanol, and concentrate the filtrate in vacuo. Purify by flash column chromatography (0-10% MeOH in DCM) to give the title compound (6.1 mg, 9%). LCMS (Method 1): 1.56 min, 562.4 [M+H] + .

[0902] Amide coupling method

[0903]

[0904] Amide coupling method A: Example 2: (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl 8-(4-(methylamino)-4-oxobutoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-methyl Amide

[0905]

[0906] To a stirred solution of (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(4-(methylamino)-4-oxobutoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (50 mg, 0.09 mmol; synthesized above) in THF (5 mL) was added 1,1′-carbonyldiimidazole (58 mg, 0.36 mmol; CAS: 530-62-1) and the reaction mixture was heated to 50° C. for 2 h. The reaction mixture was cooled to 0° C. and methylamine (2 M in THF; 0.9 mL, 1.8 mmol; CAS: 74-89-5) was added thereto. After 45 min, the mixture was diluted with 0.5 M aqueous HCl (8 mL), the mixture was extracted with EtOAc (2×10 mL) and the combined organics were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography (15-80% MeCN in pH 10 ammonium bicarbonate buffered water, 12 g C18 cartridge) to give the title compound (16 mg, 31%). LCMS (Method 1): 2.01 min, 575.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.89-7.77(m,4H),7.71(m,1H),7.23-7.13(m,2H),6.86(d,1H),6.78(d,1H),6.01(dd,1H) ,4.18-4.03(m,2H),3.98(m,1H),3.85(m,1H),3.76(dd,1H),3.63(m,1H),3.26(m,1H),2.96(m ,1H),2.76(m,1H),2.59(d,3H),2.55-2.37(m,2H),2.35(d,3H),2.15(m,2H),2.04(m,1H),1.9 2(m,1H),1.53(m,1H),1.41(m,1H),1.35-1.19(m,2H),0.93(m,1H),0.66(m,1H),0.17(m,1H).

[0907] Amide coupling method B: Example 6: N-(2-(((S)-1-((1,3-dioxoisoindolin-2-yl)-methyl)- 2-((1R,2S)-2-(ethylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)ethyl 2-Methylisoxazole-3-carboxamide

[0908]

[0909] To a stirred solution of (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazole-3-carboxamido)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (50 mg, 0.08 mmol) in THF (1 mL) was added ethylamine solution (2M in THF; 0.08 mL, 0.16 mmol), triethylamine (0.01 mL, 0.72 mmol) and HATU (37 mg, 0.096 mmol) and the reaction mixture was stirred at room temperature for 18 h. 10% aqueous citric acid (1 mL) was added, the mixture was extracted with EtOAc, the combined organics were dried (MgSO 4 ) and concentrated in vacuo. Purification by reverse phase column chromatography (30-80% MeCN in pH 10 ammonium bicarbonate buffered water, 12 g spherical beads C18 cartridge) gave the title compound (23 mg, 44%). LCMS (Method 1): 2.36 min, 642.5 [M+H] + . 1 H NMR(300MHz,DMSO)δ8.76(t,1H),7.91-7.76(m,4H),7.24-7.12(m,2H),6.89(d,1 H),6.80(d,1H),6.54(m,1H),6.03(dd,1H),4.25-4.04(m,3H),4.02-3.70(m,4H) ,3.62(m,1H),3.25(m,1H),3.03-2.67(m,4H),2.35(s,3H),2.10-1.82(m,2H),1. 58-1.38(m,2H),1.37-1.15(m,2H),0.94(m,1H),0.82-0.63(m,4H),0.23(m,1H).

[0910] Example 38: (1S,2R)-2-((S)-1-(cyclopropanecarboxamidomethyl)-8-(((S)-1-(thiazole-5-carbonyl) (pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide

[0911]

[0912] Step a. To a stirred solution of Example 17 (58 mg, 0.088 mmol) in IMS (1 mL) was added hydrazine hydrate (6 uL, 0.18 mmol; CAS: 10217-52-4) under argon and the reaction mixture was heated at 80°C for 2 h. The cooled reaction mixture was diluted with water, extracted with EtOAc, and the combined organics were concentrated in vacuo to give (1S,2R)-2-((S)-1-(aminomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide (46 mg, assumed quantitative). The crude product was used without further purification.

[0913] Step b. To a stirred solution of the above intermediate (46 mg, 0.088 mmol) and triethylamine (25 uL, 0.18 mmol) in DCM (1 mL) was added dropwise a solution of cyclopropanecarbonyl chloride (9 uL, 0.098 mmol; CAS: 4023-34-1) in DCM (0.5 mL) at 0°C under argon. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 h. The mixture was diluted with water, extracted with DCM, the combined organics were passed through a phase separator and concentrated in vacuo. Purification by MDAP (Method 1) provided the title compound (6 mg, 11%). 1 H NMR (400 MHz, DMSO-d 6 ; observed rotators, all reported) δ 9.30-9.14 (m, 1H), 8.59-8.03 (m, 2H), 7.48 (m, 0.4H), 7.29-7.11 (m, 1.6H), 7.10-6.85 (m, 1H), 6.84-6.71 (m, 1H), 5.80-5.65 (m, 0.6H), 5.39-5.21 (m, 0.5H), 5.20-5.08 (m, 0.5H), 5.06-4.93 (m, 0.4H), 4.54-2.97 (m, 9H), 2.97-2.04 (m, 9H), 2.00-0.77 (m, 8H), 0.76-0.47 (m, 4H).

[0914] Example 39: (1S,2R)-2-((S)-8-((1H-pyrazol-5-yl)methoxy)-1-((1,3-dioxoisoindole (indole-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide

[0915]

[0916] Step a. Pd / C (10%; 200 mg) was added to a solution of (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid benzyl ester (527 mg, 0.95 mmol; PCT / GB2019 / 053012 Example 2, step a) in THF (15 mL). The mixture was stirred at room temperature under hydrogen atmosphere at atmospheric pressure for 18 h. The mixture was then passed through The mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to give (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (392 mg, 89%).

[0917] Step b. (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide (541 mg, assumed quantitative) was prepared from the above intermediate (392 mg, 0.85 mmol) using a procedure similar to that described for Example 92, Step g. LCMS (Method 12): 1.27 min, 476.2 [M+H] + .

[0918] Step c. tert-butyl 5-((((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)methyl)-1H-pyrazole-1-carboxylate (110 mg, 54%) was prepared from the above intermediate (156 mg, 0.32 mmol) and tert-butyl 5-(bromomethyl)-1H-pyrazole-1-carboxylate (107 mg, 0.41 mmol; CAS: 186551-69-9) using a similar procedure as described for Example 67 step a. LCMS (Method 12): 1.61 min, 678.3 [M+H] + .

[0919] Step d. To a stirred solution of the above intermediate (110 mg, 0.17 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and azeotroped with toluene. Purification by MDAP (Method 1) provided the title compound (39 mg, 41%). LCMS (Method 3): 4.00 min, 556.2 [M+H] + . 1H NMR (400 MHz, DMSO-d 6 )δ12.78(bs,1H),7.89-7.66(m,5H),7.19(t,1H),7.14(m,1H),7.05(d,1H),6.80(d,1H ),6.65(bm,1H),6.05(dd,1H),5.25(d,1H),5.19(d,1H),4.17(dd,1H),3.81(m,1H),3. 73(dd,1H),3.63(m,1H),3.24(m,1H),2.97(m,1H),2.78(m,1H),2.35(d,3H),2.03(m,1 H),1.93(m,1H),1.52(m,1H),1.42-1.18(m,3H),0.92(m,1H),0.61(m,1H),0.18(m,1H).

[0920] Example 44: (1S,2R)-2-((S)-1-(acetylaminomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidine- 3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide

[0921]

[0922] To a stirred solution of (1S,2R)-2-((S)-1-(aminomethyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide (50 mg, 0.095 mmol; Example 38, step a) and triethylamine (15 uL, 0.10 mmol) in DCM (1 mL) was added acetyl chloride (8 uL, 0.10 mmol) at 0°C under argon and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. Water was added, the mixture was extracted with DCM and the combined organics were concentrated in vacuo. Purification by MDAP (Method 2) gave the title compound (12 mg, 22%). LCMS (Method 3): 3.05 min, 590.2 [M+Na] + . 1 H NMR (400 MHz, DMSO-d 6; observed rotators, all reported) δ9.26 (s, 0.3H), 9.25 (s, 0.3H), 9.23 (s, 0.2H), 9.18 (s, 0.2H), 8.45-8.37 (m, 0.8H), 8.27 (s, 0.2H), 8.05-7.97 (m, 0.5H), 7.95 (m, 0.3H), 7.87 (m, 0.2H), 7.41 (m, 0.5H), 7.27-7.10 (m, 1.5H),7.00-6.84(m,1H),6.81-6.69(m,1H),5.77-5.61(m,0.5H),5.30(m,0.2H),5.25(m,0.3H),5 .19-5.09(m,0.5H),5.08-4.94(m,0.5H),4.43-2.96(m,9H),2.95-1.96(m,9H),1.95-0.73(m,10H).

[0923] Example 45: (1S,2R)-N-methyl-2-((S)-1-((2-oxooxazolidin-3-yl)methyl)-8-(((S)-1- (thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide

[0924]

[0925] Step a. 2-Chloroethyl (((S)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)carbamate (68 mg, assumed quantitative) was prepared from (1S,2R)-2-((S)-1-(aminomethyl)-8-( ((S)-1-(Thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylcyclohexane-1-carboxamide (50 mg, 0.095 mmol; Example 38 step a) and 2-chloroethyl chloroformate (11 uL, 0.10 mmol; CAS: 627-11-2) were prepared using a procedure similar to that described for Example 44.

[0926] Step b. To a mixture of the above intermediate (68 mg, 0.1 mmol) and sodium hydride (60% dispersion in mineral oil; 5 mg, 0.1 mmol) was added anhydrous DMF (1 mL) at 0°C under argon and the reaction mixture was allowed to warm to room temperature and stirred for 48 h. Saturated ammonium chloride solution was added to the mixture, the mixture was extracted with DCM and the combined organics were passed through a phase separator and concentrated in vacuo. Purification by MDAP (Method 2) gave the title compound (14 mg, 24%). LCMS (Method 3): 3.15 min, 618.2 [M+Na] + . 1H NMR (400 MHz, DMSO-d 6 ; observed rotators, both reported in full) δ 9.26 (s, 0.5H), 9.24 (s, 0.5H), 8.47 (s, 0.5H), 8.40 (s, 0.5H), 7.31-7.14 (m, 2H), 6.99-6.88 (m, 1H), 6.84-6.72 (m, 1H), 5.88-5.73 (m, 1H), 5.35-5.02 (m, 1H), 4.46-3.40 (m, 10H), 3.39-3.24 (m, 2H), 3.15 (m, 1H), 2.92 (m, 1H), 2.73 (m, 1H), 2.59-2.08 (m, 7H), 1.85-1.59 (m, 3H), 1.55-1.06 (m, 4H).

[0927] Example 46: 4-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methyl (carbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)butanoic acid

[0928]

[0929] Step a. To a stirred solution of triphenylphosphine (6.09 g, 23.2 mmol) in THF (50 mL) was added DIAD (4.5 mL, 23.2 mmol) dropwise at 0°C and the reaction mixture was stirred for 0.5 h. A solution of benzyl 4-hydroxybutyrate (1.35 g, 6.96 mmol; CAS: 91970-62-6) in THF (10 mL) was added and stirred at 0°C for 30 min, followed by the addition of intermediate 11 (1.9 g, 4.64 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water, extracted with EtOAc, and the combined organics were filtered through Na 2 SO 4 Dry, filter and concentrate in vacuo. Purify by flash column chromatography (silica gel, 0-50% EtOAc in hexanes) to give (S)-tert-butyl 8-(4-(benzyloxy)-4-oxobutoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (520 mg, 23%).

[0930] Step b. (S)-benzyl 4-((1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)butanoate hydrochloride (1.07 g, assumed quantitative) was prepared from the above intermediate (1.14 g, 1.95 mmol) using a procedure similar to that described for Example 67, Step b. LCMS (Method 12): 1.11 min, 485 [M+H] +.

[0931] Step c. To a stirred solution of (1R,2S)-2-(methylcarbamoyl)-cyclohexanecarboxylic acid (43 mg, 0.23 mmol; CAS: 1821740-00-4) in DMF (0.5 mL) was added triethylamine (80 uL, 0.58 mmol) and HATU (88 mg, 0.23 mmol) at room temperature under argon and the reaction mixture was stirred for 10 min. A solution of the above intermediate (104 mg, 0.19 mmol) in DMF (1 mL) was added dropwise and the reaction mixture was stirred for 23 h. The mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organics were washed with saturated ammonium chloride, washed with Na 2 SO 4 Dried and concentrated in vacuo. Purification by flash column chromatography (12 g Puriflash silica cartridge, 0-5% MeOH in DCM) afforded benzyl 4-(((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-2-((1R,2S)-2-(methylcarbamoyl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)butanoate (120 mg, 80%). LCMS (Method 12): 1.63 min, 652 [M+H] + .

[0932] Step d. A solution of the above intermediate (118 mg, 0.18 mmol) in MeOH (0.1 M; 1.8 mL) was passed through a H- column with a 10% Pd / C cartridge at 1 mL / min at 50°C and 50 bar of hydrogen pressure. The solution was passed through a second time and then concentrated in vacuo. Purification by MDAP (Method 1) gave the title compound (23 mg, 23%). LCMS (Method 3): 4.05 min, 584.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.11(bs,1H),7.92-7.75(m,4H),7.26-7.06(m,2H),6.86(d,1H),6.79(d,1H),6.00(dd,1H),4.19-4.06(m,2H),4.01(m,1H),3.85(m,1H),3.76(m,1H),3.63(m,1H),3.26(m,1H),2.97(m,1H),2.82-2.46(m,3H),2.36(d,3H),2.23-2.10(m,2H),2.04(m,1H),1.93(m,1H),1.53(m,1H),1.41(m,1H),1.35-1.19(m,2H),0.93(m,1H),0.66(m,1H),0.17(m,1H)。

[0933] Example 48: (R)-1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazol-2-yl)methyl)- (oxadiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpiperidine-2-carboxamide

[0934]

[0935] Step a. To a stirred solution of intermediate 11 (5.0 g, 12.2 mmol) and (R)-(3-hydroxypyrrolidin-1-yl)(thiazol-5-yl)methanone (3.16 g, 15.9 mmol, CAS: 1690066-04-6) in anhydrous THF (100 mL) under argon was added tributylphosphine (3.98 mL, 15.9 mmol) followed by a solution of DBAD (3.66 g, 15.9 mmol; CAS: 870-50-8) in THF (50 mL) over 10 min. After stirring for 2 h, additional portions of tributylphosphine (3.98 mL, 15.9 mmol) and DBAD (3.66 g, 15.9 mmol) in THF (50 mL) were added and the reaction mixture was stirred at room temperature for 18 h. Then, additional (R)-(3-hydroxypyrrolidin-1-yl)(thiazol-5-yl)methanone (3.16 g, 15.9 mmol, CAS: 1690066-04-6), tributylphosphine (3.98 mL, 15.9 mmol) and DBAD (3.66 g, 15.9 mmol) in THF (50 mL) were added sequentially and the reaction mixture was stirred for 3 h. Water was added to the reaction mixture and the mixture was concentrated in vacuo. Purification by flash column chromatography on Interchim 4125 (330 g silica Puriflash HP, 0-10% MeOH in EtOAc) followed by flash column chromatography on Interchim 4100 (300 g silica Biotage SNAP, 0-10% MeOH in EtOAc) gave (S)-tert-butyl 1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.48 g, 90%). LCMS (Method 3): 1.47 min, 611 [M+Na] + .

[0936] Step b. 2-(((S)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione hydrochloride (498 mg, assumed quantitative) was prepared from the above intermediate (600 mg, 1.02 mmol) using a procedure similar to that described for Example 67, Step b.

[0937] Step c. To a stirred solution of the above intermediate (150 mg, 0.29 mmol) in DCM (1.5 mL) was added triethylamine (120 uL, 0.86 mmol) and triphosgene (34 mg, 0.11 mmol) in DCM (1 mL) under argon. The reaction mixture was stirred at room temperature for 20 min, to which was added a solution of (R)-piperidine-2-carboxylic acid tert-butyl ester hydrochloride (66 mg, 0.30 mmol; CAS: 140646-13-5) in DCM (1.5 mL) and triethylamine (200 uL, 1.43 mmol). The reaction mixture was stirred at room temperature for 2 h, then heated to 40 ° C for 5 days. The mixture was diluted with saturated sodium bicarbonate, extracted with DCM and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (12 g Puriflash silica cartridge, 0-10% MeOH in DCM) gave (R)-tert-butyl 1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-2-carboxylate (128 mg, 64%). LCMS (Method 12): 1.61 min, 700 [M+H] + .

[0938] Step d. To a stirred solution of the above intermediate (127 mg, 0.18 mmol) in DCM (3 mL) was added TFA (1.5 mL) and the reaction mixture was stirred at room temperature for 2 h 40 min. The mixture was concentrated in vacuo and azeotroped with toluene to give (R)-1-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-2-carboxylic acid (117 mg, assumed quantitative) which was used without further purification.

[0939] Step e. The title compound (50 mg, 42%) was prepared from the above intermediate (117 mg, 0.18 mmol) using a similar procedure as described for Example 92, Step g. LCMS (Method 3): 3.92 min, 657.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6; observed rotators, both reported in full) δ9.24 (s, 1H), 8.42 (s, 0.5H), 8.39 (s, 0.5H), 7.90-7.78 (m, 4H), 7.41 (m, 1H), 7.29-7.16 (m, 1H), 6.97 (d, 0.5H), 6.93 (d, 0.5H), 6.81 (d, 0.5H), 6.79 (d, 0.5H), 5.31-5.17 ( m,2H),4.37-4.23(m,1H),4.10(m,0.5H),4.02-3.72(m,4.5H),3.65-3.47(m,2H),3.45-3.23(m ,1H),2.98(m,1H),2.92-2.63(m,3H),2.58-2.22(m,5H),1.79-1.62(m,1H),1.41-0.79(m,5H).

[0940] Example 67: (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methyl Oxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methylpyrrolidine-1- Formamide

[0941]

[0942] Step a. To a stirred solution of intermediate 23 (2.6 g, 6.83 mmol) in DMF (59 mL) was added 4-(chloromethyl)-5-(difluoromethyl)-1-methyl-triazole (1.29 g, 7.09 mmol, CAS: 2138555-23-2) and cesium carbonate (8.01 g, 24.6 mmol) and the reaction mixture was stirred at room temperature under argon for 19 h. The reaction was filtered and the solids were washed with EtOAc (20 ml) and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water, the organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified by Teledyne ISCO Rf+ was purified by flash column chromatography on a 80 g silica gel column Puriflash HC, 0-10% MeOH in DCM to provide (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.63 g). The cesium carbonate residue was concentrated in DCM / H 2 O, and the aqueous layer was extracted with DCM. The combined organics were washed with MgSO4 and MgSO4. 2 SO 4Dry, filter and concentrate in vacuo to give another batch of product (2.35 g). The batches were combined to give (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.98 g, 83%). LCMS (Method 12): 1.42 min, 548.3 [M+Na] + .

[0943] Step b. To the above intermediate (1.11 g, 2.11 mmol) was added hydrochloric acid (4M in dioxane; 10.55 mL, 42.2 mmol) and the reaction mixture was stirred at room temperature for 20 min. MeOH was added to the reaction mixture and the mixture was concentrated in vacuo to give (S)-1-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one (0.99 g, assumed quantitative) which was used without further purification. LCMS (Method 12): 0.77 min, 426.0 [M+H] + .

[0944] Step c. To a stirred solution of N-(tert-butoxycarbonyl)-L-proline (78 mg, 0.36 mmol; CAS: 15761-39-4) in anhydrous DMF (1 mL) was added DIPEA (0.17 mL, 0.98 mmol) and HATU (137 mg, 0.36 mmol; CAS: 148893-10-1) under argon. The reaction mixture was stirred at room temperature for 10 min, and then the above intermediate (151 mg, 0.33 mmol) in anhydrous DMF (2 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 21 h and washed with saturated NaHCO 3 The aqueous solution was diluted, extracted with EtOAc, and the combined organics were washed with brine (30 mL), washed with MgSO 4 Dry, filter and concentrate in vacuo. The crude product was purified by Teledyne ISCO Purification by flash column chromatography on Rf200 (12 g silica gel column Puriflash HC, 0-10% MeOH in DCM) afforded (S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (159 mg, 78%). LCMS (Method 12): 1.30 min, 623.3 [M+H] + .

[0945] Step d. To a stirred solution of the above intermediate (158 mg, 0.25 mmol) in anhydrous 1,4-dioxane (4 mL) was added hydrogen chloride (4 M in dioxane; 4.0 mL, 16 mmol). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo to provide 1-(((S)-2-(L-prolyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one hydrochloride (154 mg, assumed quantitative). LCMS (Method 12): 0.84 min, 523.3 [M+H] + .

[0946] Step e. To a stirred mixture of the above intermediate (152 mg, 0.27 mmol) in anhydrous DCM (5 mL) was added N-methyl-1-imidazolecarboxamide (46 mg, 0.37 mmol; CAS: 72002-25-6), followed by triethylamine (0.1 mL, 0.73 mmol) and the resulting solution was stirred at room temperature under argon for 17 h. Additional N-methyl-1-imidazolecarboxamide (15 mg, 0.12 mmol) was added and the solution was stirred for another 7 h. The solution was washed with saturated NaHCO 3 The solution was diluted, extracted with DCM, and the combined organic extracts were washed with brine, dried (MgSO 4 ), filtered, and concentrated in vacuo. The residue was purified by MDAP (Method 3) to provide the title compound (115 mg, 73%). LCMS (Method 5): 3.03 min, 580.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ7.58(t,1H),7.41(d,1H),7.18(d,1H),5.99(m,1H),5.67(dd,1H),5.35-5.25(m,2H),4.70(m,1H),4.17(s,3H),4.02(dd,1H),3.87(dd,1 H),3.57(m,1H),3.40(m,1H),3.36-3.27(m,1H),3.20(m,1H),2.94(dd ,1H),2.87-2.69(m,3H),2.46(d,3H),2.17(m,1H),2.05-1.60(m,7H).

[0947] Example 84: 1-(((S)-5-chloro-2-((S)-1-(2,2-difluoroacetyl)piperidine-2-carbonyl)-8-((5-(difluoro methyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidine- 2-Keto

[0948]

[0949] Steps a & b. These steps were carried out using a procedure analogous to Example 67 steps c and d using (S)-(-)-1-(tert-butoxycarbonyl)-2-piperidinic acid (162 mg, 0.70 mmol; CAS: 26250-84-0).

[0950] Step c. To a stirred solution of 1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2-((S)-piperidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one (126 mg, 0.22 mmol) in DCM (1.5 mL) under nitrogen was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.07 mL, 0.26 mmol; CAS: 25952-53-8), 1-hydroxybenzotriazole hydrate (40 mg, 0.26 mmol; CAS: 123333-53-9) and DIPEA (0.15 mL, 0.88 mmol). The reaction mixture was stirred at room temperature for 10 min and 2,2-difluoroacetic acid (0.02 mL, 0.26 mmol; CAS: 381-73-7) was added thereto. The reaction mixture was stirred at room temperature for 3 days, diluted with DCM and directly purified by silica gel column chromatography (Puriflash 12 g, 0-50% EtOAc in isohexane) followed by silica gel column chromatography (Puriflash 12 g, 0-10% MeOH in DCM) and MDAP (Method 3) to give the title compound (7 mg, 5%). LCMS (Method 3) 4.24 min, 615.2 [M+H] + . 1H NMR (400 MHz, DMSO-d 6 )δ7.57(t,1H),7.40(d,1H),7.17(d,1H),6.72(t,1H),5.71(m,1H),5.33-5.25(m,2H),5.22(m,1H),4.17(s,3H),4.00(m,1H),3.87(dd,1H ),3.75(m,1H),3.70-3.20(m,2H),2.99(m,1H),2.85(m,2H),2.72(m,1H),2.19(m,1H),2.02(m,1H),1.93-1.53(m,7H),1.50-1.13(m,2H).

[0951] Example 88: (S)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methyl Oxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N-methyl-5-azaspiro [2.4] Heptane-5-carboxamide

[0952]

[0953] Steps a, b. These steps were carried out using a method analogous to Example 67 steps c and d using (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (86 mg, 0.36 mmol; CAS: 1129634-44-1).

[0954] Step c. To a solution of 1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2-((S)-5-azaspiro[2.4]heptane-6-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one hydrochloride (75 mg, 0.12 mmol) in DCM (1.9 mL) cooled to 2°C was added triethylamine (0.04 mL, 0.26 mmol) followed by N-methylcarbamoyl chloride (13.14 mg, 0.140 mmol; CAS: 6452-47-7). The reaction mixture was warmed to ambient temperature and stirred for 1 h and the mixture was combined with another batch (0.031 mmol). To the combined mixture was added water, the mixture was extracted with DCM and the combined organics were concentrated in vacuo. The crude product was purified by Biotage IsoleraOne TM (200-400 nm diode array detector, 12 g C18 column, 0.1 M NH 4 HCO 3 Purification by automated reverse phase column chromatography on 5-40% MeCN in buffer solution (50 mg, 54%) afforded the title compound (50 mg, 54%). LCMS (Method 6): 1.63 min, 606.3 [M+H]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ7.58(t,1H),7.41(d,1H),7.18(d,1H),5.95(m,1H),5.68(m,1H),5.38-5.21 (m,2H),4.79(dd,1H),4.17(s,3H),3.98(m,1H),3.86(dd,1H),3.53(m,1H),3.4 5-3.21(m,2H),3.18(d,1H),2.94(dd,1H),2.86-2.72(m,3H),2.45(d,3H),2.22 -2.09(m,2H),1.98(m,1H),1.89-1.66(m,2H),1.52(dd,1H),0.60-0.34(m,4H).

[0955] Example 98: (1R,2S)-2-((R)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazole-4- 1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- (2-(2-(2-(4-(2-nitrophenyl)cyclohexane)-1-carboxamide)

[0956]

[0957] Step a. To a stirred solution of intermediate 12 (16.5 g, 37.3 mmol) and cesium carbonate (43.7 g, 134 mmol) in DMF (300 mL) was added 4-(chloromethyl)-5-(difluoromethyl)-1-methyl-triazole hydrochloride (8.12 g, 37.3 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and the precipitate was isolated. The solid was azeotroped with MeOH and dissolved in Et 2 O and concentrated in vacuo to give (S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (18.5 g, 84%). LCMS (Method 16): 1.13 min, 488.2 [M-CO 2 t Bu+H] + .

[0958] Step b. Add hydrazine hydrate (7.65mL, 157mmol) to a solution of the above intermediate (18.5g, 31.4mmol) in EtOH (569mL). The reaction mixture is heated at 65°C for 18h and then cooled to room temperature. The suspension is filtered and the solid is rinsed with EtOH. The combined filtrate is concentrated in vacuo. The residue is washed with ether and filtered. The filtrate is concentrated in vacuo, azeotroped with IMS, and the precipitated solution is dissolved in DCM. The precipitate is removed by filtration, and the combined organic matter is purified by MgSO 4 Dry, filter and concentrate in vacuo to give (S)-tert-butyl 1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (13.5 g, 94%). LCMS (Method 16): 0.90 min, 458.2 [M+H] + .

[0959] Step c. A stirred mixture of the above intermediate (11.0 g, 22.0 mmol), triethylamine (4.60 mL, 33.0 mmol) and methyl 2-(1-(bromomethyl)-cyclopropyl)acetate (5.92 g, 28.6 mmol, CAS: 855473-50-6) in MeCN (210 mL) was heated at reflux for 72 h. The mixture was concentrated in vacuo. Purification by flash column chromatography (silica, 0-2% MeOH in DCM) gave (S)-tert-butyl 5-chloro-8-((5-(difluoromethyl)-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 (11.5 g, 95%). LCMS (Method 16): 1.02min, 452.2[M-CO 2 t Bu+H] + .

[0960] Step d. (S)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (4.08 g, assumed quantitative) was prepared from the above intermediate (4.54 g, 8.22 mmol) using a procedure similar to that described for Example 67, Step b and used without further purification. LCMS (Method 12): 0.99 min, 452.2 [M+H] + .

[0961] Step e. A mixture of the above intermediate (12.4 g, 25.4 mmol), intermediate 33 (17.3 g, 38.1 mmol) and DIPEA (8.85 mL, 50.8 mmol) in DMF (30 mL) was stirred at room temperature under nitrogen for 6 days. The mixture was diluted with water (120 mL) and extracted with EtOAc. The combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified by Teledyne ISCO Rf+ was purified by flash column chromatography (330 g silica column Puriflash HC, 0-5% MeOH in DCM) and then by Teledyne ISCO Another purification was performed on Rf+ (330 g silica gel column Puriflash HC, 0-5% MeOH in DCM) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (14.7 g, 75%). LCMS (Method 3): 1.71 min, 770.5 [M+H] + .

[0962] Step f. A solution of the above intermediate (550 mg, 0.71 mmol) in hydrogen chloride / dioxane (4 M; 17.8 mL, 71.4 mmol) was stirred at room temperature for 10 min and concentrated in vacuo. The residue was triturated with methanol and then purified by reverse phase flash column chromatography on a Biotage Isolera (Biotage C18 SNAP 60 g, 20-60% MeCN in water, 0.1% formic acid) to provide (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]-heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid (250 mg, 56%). LCMS (method 10): 2.52 min, 620.3 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6)δ11.84(bs,1H),7.57(t,1H),7.38(d,1H),7.14(d,1H),5.77(m,1H),5.2 8(s,2H),4.16(s,3H),4.04-3.86(m,2H),3.59(m,1H),3.38-3.24(m,1H), 3.06-2.90(m,2H),2.84(m,1H),2.77-2.65(m,1H),2.61(d,1H),2.37-2.1 5(m,2H),2.10(d,1H),1.75-1.16(m,7H),1.10(s,3H),0.67-0.32(m,4H).

[0963] Step f Method 2. To a stirred solution of the above intermediate (14.7 g, 19.1 mmol) in DCM (92 mL) was added triethylsilane (3.05 mL, 19.1 mmol), followed by dropwise addition of TFA (1.76 mL, 22.9 mmol). The resulting solution was stirred for 1.5 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to about 5 mL. The residue was purified by chromatography on a Teledyne ISCO R + Flash column chromatography on a 220 g silica gel column Puriflash HC, 0-3% MeOH in DCM. The product was then dissolved in 10 mL of hot EtOH and allowed to cool to room temperature, and the resulting precipitate was collected by filtration and washed with cold EtOH. The material was then slurried in MeCN (30 mL) and collected by filtration to provide (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methyl-cyclohexane-1-carboxylic acid (9.45 g, 78%). LCMS (Method 3): 4.57 min, 620.4 [M+H] + .

[0964] Step g. To a stirred solution of the above intermediate (100 mg, 0.160 mmol) in DMF (0.5 mL) was added HATU (92 mg, 0.240 mmol; CAS: 148893-10-1), methylamine (2 M in THF; 0.81 mL, 1.61 mmol; CAS: 74-89-5) and DIPEA (0.17 mL, 0.97 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water, extracted with EtOAc, and the combined organics were washed with 10% citric acid, brine, purified by MgSO4 Dry and concentrate in vacuo. Purify using Isolera (Biotage C18 SNAP 30 g, 5-60% MeCN in water, 0.1% formic acid throughout) to give the title compound (18 mg, 17%). LCMS (Method 9): 2.33 min, 633.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )δ7.80(bm,1H),7.24(d,1H),6.93(t,1H),6.89(d,1H),5.97(m,1H),5.32-5. 18(m,2H),4.17(s,3H),4.07(dd,1H),3.96(m,1H),3.85(m,1H),3.52(d,1H), 3.07(m,1H),3.02-2.89(m,3H),2.83(m,1H),2.71(d,3H),2.55(m,1H),2.37( d,1H),2.20(d,1H),1.82-1.31(m,6H),1.22-1.07(m,4H),0.69-0.47(m,4H).

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] Biological assays

[0998] KEAP1 Kelch fluorescence polarization (FP) assay

[0999] Inhibition of the 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 MgCl 2 , 0.005% Tween-20, 0.005% BSA, 0.5% DMSO). Unlabeled peptide (LDEETGEFL-NH2) at 50 μM (negative control) and 0.5% DMSO (positive control) were used to determine the assay window.

[1000] 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).

[1001] Table 2

[1002]

[1003]

[1004] * = One-to-one test case > 10 μM.

[1005] Beas2B NQO1 mRNA cell-based assay

[1006] NRF2-mediated upregulation of the gene NAD(P)H:quinone receptor oxidoreductase 1 (NQO1) was measured using the following assay: 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% CO 2 ). On day 2, 25 μL of compound or control was added to the cells for 24 h. On day 3, the medium was aspirated from the plates and the cells were 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.

[1007] 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 specific primers 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 target gene mRNA increase compared to vehicle (0.1% DMSO) control and EC was 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 3.

[1008] Table 3

[1009]

[1010]

[1011] * = one-to-one or one-to-many test occasions > 0.5 μM, ** = one-to-one or one-to-many test occasions 10 μM.

[1012] ND = Not Determined

[1013] PK / PD Methods

[1014] 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.

[1015] At the indicated time points, 2 x 0.25 mL blood samples were collected via the tail vein into the K 2 The collected blood samples were then centrifuged to obtain plasma or poured into 1.5 mL PCR RNAlater tubes containing 650 μL RNAlater.

[1016] Place blood samples on wet ice immediately after collection. 2 0.25 mL blood samples in EDTA were centrifuged (+4°C, 1500 g, 10 min) and the resulting plasma was stored in appropriately labeled polypropylene tubes in a freezer 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.

[1017] As soon as possible after the last sample collection, each animal was sacrificed by an intraperitoneal overdose of Na pentobarbital anesthetic and death was confirmed by cervical dislocation.

[1018] 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).

[1019] 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).

[1020] 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.

[1021] 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.

[1022] 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 were used to measure representative aliquots of blood plasma and tissue homogenate for the test items targeted by LC-MS / MS. Standards were prepared by mixing aliquots of control plasma and tissue homogenate with test articles, and extracted as described for the experimental samples.

[1023] RNA extraction and real-time PCR analysis of NQO1 gene expression in in vivo PD studies were performed as described below.

[1024] 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 pharmaceutical composition comprising a compound according to Formula IC or Formula IF, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients: in: R 1 Selected from C 1-4 Alkylene-R 11 and a 4-7 membered monocyclic heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 , C 1-3 Alkylene-OR 14 and a 5- or 6-membered monocyclic heteroaryl group, the 5- or 6-membered monocyclic heteroaryl group being optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano groups; R 2 Selected from hydrogen, fluorine, chlorine and C 1-3 alkyl; R 3 Selected from hydrogen, fluorine, chlorine, bromine, C 1-3 Alkoxy, C 1-3 Alkyl, C 1-3 Alkyl halides and cyano groups; R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a heterocyclic moiety selected from one of the following: wherein the saturated ring of the heterocyclic moiety is optionally spiro-attached to C 3-7 cycloalkyl, and wherein the heterocyclic moiety is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo and OH; R 6 is hydrogen; R 8 C(=O)NR 8a R 8b ; R 8a is hydrogen; R 8b For hydrogen, C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of halo, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano groups; R 9 is methyl; R 11 is a heteroaryl group selected from: Each heteroaryl group is 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-R 30 , halogenated, OH, C 1-3 Alkoxy, 4-7 membered monocyclic heterocyclic group and cyano; R 12 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, OR 31 NR 32 R 33 , phenyl and 5 or 6-membered monocyclic heteroaryl, wherein the phenyl and 5 or 6-membered monocyclic heteroaryl are optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and cyano groups; R 13 Selected from C 1-4 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered monocyclic heteroaryl, 4-7-membered monocyclic heterocyclic group and NR 34 R 35 wherein the 5- or 6-membered monocyclic heteroaryl and the 4-7-membered monocyclic heterocyclyl are optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, halo, OH, C 1-3 Alkoxy and cyano groups; R 30 Selected from hydroxyl, C 1-3 Alkoxy, C 3-7 Cycloalkyl, cyano and NR 47 R 48 ; as well as R 14 , R 31 , R 32 , R 33 , R 34 , R 35 , R 47 and R 48 are independently selected from hydrogen, C 1-4 Alkyl and C 3-7 Cycloalkyl.

2. The pharmaceutical composition according to claim 1, wherein the compound has the structural formula ID or IG shown below: Where R 1 To R 6 , R 8a , R 8b and R 9 As defined in claim 1.

3. The pharmaceutical composition according to claim 1 or 2, wherein R 1 C 1-4 Alkylene-R 11 .

4. The pharmaceutical composition according to claim 1 or 2, wherein R 1 CH2-R 11 .

5. The pharmaceutical composition according to claim 1 or 2, wherein R 1 Select from one of the following groups: in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: C 1-4 Alkyl, C 1-3 Haloalkyl, C 3-7 Cycloalkyl, C 1-4 Alkylene-R 30 , halogenated, OH, C 1-3 Alkoxy, 4- to 7-membered monocyclic heterocyclic group and cyano.

6. The pharmaceutical composition according to claim 1 or 2, wherein R 1 is a 4- to 7-membered monocyclic heterocyclic group, which is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, -C(O)-R 12 、SO2-R 13 , 5 or 6-membered monocyclic heteroaryl and C 1-3 Alkylene-OR 14 wherein the 5- or 6-membered monocyclic heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano.

7. The pharmaceutical composition according to claim 1 or 2, wherein R 1 is piperidinyl or pyrrolidinyl, each of which is optionally substituted by one or more substituents independently selected from the following: -C(O)-R 12 、SO2-R 13 , 5 or 6-membered monocyclic heteroaryl and C 1-3 Alkylene-OR 14 wherein the 5- or 6-membered monocyclic heteroaryl is optionally substituted by one or more substituents independently selected from the following: 1-4 Alkyl, C 3-7 Cycloalkyl, halo, OH, C 1-3 Alkoxy and cyano.

8. The pharmaceutical composition according to claim 7, wherein R 1 is pyrrolidinyl, which is optionally substituted by one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , 5 or 6-membered monocyclic heteroaryl and C 1-3 Alkylene-OR 14 wherein the 5- or 6-membered monocyclic heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

9. The pharmaceutical composition according to claim 1 or 2, wherein R 1 Select from one of the following groups: in represents the point of attachment of the group to the oxygen atom of the rest of the compound and wherein each group is optionally substituted with one or more substituents independently selected from: -C(O)-R 12 、SO2-R 13 , 5 or 6-membered monocyclic heteroaryl and C 1-3 Alkylene-OR 14 wherein the 5- or 6-membered monocyclic heteroaryl is optionally replaced by C 1-4 Alkyl or C 3-7 Cycloalkyl substitution.

10. The pharmaceutical composition according to claim 1 or 2, wherein R 2 is hydrogen or fluorine.

11. The pharmaceutical composition according to claim 1 or 2, wherein R 3 is hydrogen or chlorine.

12. The pharmaceutical composition according to claim 1 or 2, wherein R 3 For chlorine.

13. The pharmaceutical composition according to claim 1 or 2, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached they form the following heterocyclic moiety: wherein the heterocyclic moiety is optionally spiro-attached to a cyclopropyl group and is optionally substituted with one or more substituents independently selected from the group consisting of methyl and fluoro.

14. The pharmaceutical composition according to claim 1 or 2, wherein R 8b C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, OH, C 1-3 Alkoxy, C 3-7 Cycloalkyl and cyano.

15. The pharmaceutical composition according to claim 14, wherein R 8b It is methyl.

16. The pharmaceutical composition according to claim 1, wherein the compound is selected from any one of the following compounds: (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-8-(Benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide; (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclopentane-1-carboxamide; (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-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)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; (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)-N,1-dimethylcyclohexane-1-carboxamide; (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; (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)-N,1-dimethylcyclohexane-1-carboxamide; (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)-N,1-dimethylcyclohexane-1-carboxamide; (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)-N,1-dimethylcyclohexane-1-carboxamide; (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-carboxamide; (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]heptane-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide; or (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-N,1-dimethylcyclohexane-1-carboxamide; or a pharmaceutically acceptable salt thereof.

17. Use of the pharmaceutical composition according to any one of claims 1 to 16 in the preparation of a medicament for treating a disease or disorder mediated by Nrf2 activation.

18. Use of a pharmaceutical composition according to any one of claims 1 to 16 in the preparation of a medicament for the treatment of 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, β-thalassemia, sickle cell leukocyte disease, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation dermatitis, atopic dermatitis, nonalcoholic fatty liver disease, toxin-induced liver disease, viral hepatitis and cirrhosis, 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.

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