Tetrahydroisoquinoline compounds as Nrf2 activators

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to tetrahydroisoquinoline compounds. More specifically, the present invention relates to tetrahydroisoquinoline compounds that are Nrf2 activators. The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or disorders associated with inhibition of Nrf2 activation and / or Keap1-Nrf2 protein-protein interaction. [Background technology]

[0002] Erythroid transcription factor 2-related transcription 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 component of the inducible cellular defense system and mediates the expression of over 100 oxidative stress-related genes, including phase I and II detoxification enzymes and antioxidant proteins. All of these genes contain antioxidant response elements (AREs) in their promoter regulatory regions, which are binding targets of Nrf2. Under basal conditions, Nrf2 levels are tightly controlled by the adaptor protein Keap1, a cytosolic actin-binding repressor protein that binds to Nrf2 and triggers its proteasomal degradation via a Cul3-based E3 ubiquitin ligase complex. Under conditions of oxidative stress, Keap1 is inactivated, translocates to the nucleus, and binds to AREs, resulting in increased levels of newly synthesized Nrf2, which leads to the upregulation of cytoprotective gene expression.

[0003] It has been shown that Nrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects, and Nrf2 mRNA was negatively correlated with pack-years. Nrf2 protein levels in COPD subjects were significantly lower than that in control subjects. CSE-induced A549 cell apoptosis was increased in a time- and concentration-dependent manner and was significantly increased by Nrf2 knockdown (Yamada, BMC Pulmonary Medicine, doi:10.1186 / s12890-016-0189-1). Therefore, increased Nrf2 levels in the lungs of COPD patients should result in a reduction of inflammatory processes that lead to harmful structural changes in the lungs and slow disease progression. Nrf2 is a key regulator of pulmonary fibrosis, including 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 Rep, doi:10.1007 / s40495-016-0053-2), pulmonary fibrosis, including pulmonary fibrosis of unknown etiology (Kikuchi, Respir Res, doi:10.1186 / 1465-9921-11-31), and cystic fibrosis (Chen, PLoS It may also be expected to show positive benefits in other respiratory diseases that present an oxidative stress component, such as Nrf2 activators (Cuadrado et al., Trends Pharmacol Sci, doi:10.1016 / j.tips.2020.07.003). Indeed, the combination of cytoprotection by Nrf2 activators by restoring redox and proteostasis, promoting resolution of inflammation, and promoting repair in the lungs has highlighted their potential for the treatment of COVID-19 (Cuadrado et al., Trends Pharmacol Sci, doi:10.1016 / j.tips.2020.07.003).

[0004] The cardioprotective properties of Nrf2 have been demonstrated in models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, and heart failure (Chen, Physiol Genomics, doi:10.1152 / physiolgenomics.00041.2017). The Nrf2 activator bardoxolone methyl recently completed a phase II trial in patients with pulmonary arterial hypertension (PAH), and phase III trials are underway based on significant improvements in 6-minute walk distance. While bardoxolone reacts covalently with Keap1, compounds that activate Nrf2 via mechanisms other than Keap1 binding should also be expected to be therapeutically useful in patients with PAH, especially those who also have underlying connective tissue disorders (CTDs) such as scleroderma or lupus erythematosus. Oxidative stress is elevated in diseased myocardium, resulting in increased levels of reactive oxygen species that negatively impact cardiac function (Bolli, Circ, doi:10.1161 / circ.76.2.3111744). Nrf2 activation has been shown to suppress myocardial oxidative stress, cardiac 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 cardiac 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 in the cardiovascular system in the context of impaired antioxidant defenses has also been described in metabolic diseases such as obesity, metabolic syndrome, and diabetes, and activation of Nrf2 has also been proposed as a promising therapeutic strategy (da Costa, Front Pharmacol., doi:10.3389 / fphar.2019.00382).Additionally, 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 improve glycemic control and induce weight loss in obese patients, generally proportional to baseline BMI (Chertow et al., J Diabetes Complications, doi:10.1016 / j.jdiacomp.2018.09.005). Age-related mitochondrial dysfunction and oxidative damage are major causes of multiple health problems, including sarcopenia and cardiovascular disease. Treatment of aging mice with the Nrf2 activator sulforaphane restored Nrf2 activity, mitochondrial function, cardiac function, exercise capacity, glucose tolerance, and skeletal muscle satellite cell activation / differentiation (Bose et al., Aging Cell, doi:10.1111 / acel.13261). Therefore, drugs that activate Nrf2 are expected to be useful for several cardiovascular and metabolic diseases, including, but not limited to, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, heart failure with reduced ejection fraction, diabetic cardiomyopathy, diabetic nephropathy, metabolic syndrome, obesity, diabetes (type 1 or type 2), and insulin resistance.

[0005] 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 related to brain damage and poor prognosis in patients with SAH (clinicaltrials.gov / ct2 / show / NCT0261474,SFX01 After Subarachnoid Heemorrhage (SAS)). Evidence from experimental SAH studies indicates a protective role of the Nrf2 / ARE pathway in EBI and CVS after SAH. Administration of sulforaphane (SFN) to rats after SAH enhanced the activity of the Nrf2-ARE pathway, attenuated vasospasm in the basilar artery, and suppressed the release of inflammatory cytokines (Zhao, Brain Res., doi:10.1016 / j.brainres.2016.09.035). Intracerebral hemorrhage (ICH) is the primary event in 10–15% of the 15 million strokes that occur worldwide each year. In vitro studies have demonstrated that Nrf2 activators rapidly increase HO-1 expression in astrocytes, reducing their vulnerability to hemoglobin or hemin. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss, and neurological damage (Chen-Roetling, Curr Pharm Des, doi:10.2174 / 1381612822666161027150616). Ischemic stroke induces reactive oxygen species, triggering oxidative and inflammatory responses in the ischemic brain. To date, recombinant tissue plasminogen activator is the only available treatment for ischemic stroke. However, this treatment does not prevent oxidative stress and inflammation in the ischemic brain. D3T, a sulfur-containing dithiothrethione compound found in cruciferous plants, has been reported to induce antioxidant genes through activation of Nrf2.D3T has been shown to attenuate cerebral infarction and ameliorate neurological deficits in stroke animals (Yen, J Immunol 2017, 198(1 supplement) 206.20). Additionally, D3T reduced CNS-infiltrating inflammatory immune cells, including neutrophils and monocytes, in the ischemic brain. Furthermore, D3T-induced suppression of inflammatory cytokine production was observed in wild-type, but not Nrf2-deficient, microglia. Furthermore, the protective effect of D3T on attenuating ischemic cerebral infarction was abolished in Nrf2-deficient stroke animals and stroke animals administered an HO-1 inhibitor. These results suggest that D3T-mediated suppression of inflammation in the ischemic brain is mediated via the Nrf2 / HO-1 pathway, and therefore, targeting the Nrf2 / HO-1 pathway may be a promising therapeutic strategy for ameliorating neuroinflammation in ischemic stroke.

[0006] Nrf2 is thought to play an important role in several hemoglobinopathies, such as beta-thalassemia and sickle cell disease (SCD). SCD is a recessive genetic disorder caused by a single missense mutation resulting in a mutated beta-globin protein, hemoglobin S (HbS). Under low oxygen concentrations, HbS polymerizes, causing deformation of red blood cells, which are prone to rupture and release free heme into the plasma. The resulting oxidative stress and inflammation cause damage in multiple organs. Loss of Keap1 and the resulting constitutive activation of Nrf2 have been shown to improve prognosis in SCD model mice (Zhu, Blood, doi:10.1182 / blood-2017-10-810531; Keleku-Lukwete PNAS, doi:10.1073 / pnas.1509158112). Nrf2 activation has been shown to slow the progression of hemolytic anemia and organ failure (Ghosh, JCI Insight, doi:10.1172 / jci.insight.81090), and loss of Nrf2 function exacerbates SCD pathophysiology in transgenic SCD mice (Zhu, Blood, doi:10.1182 / blood-2017-10-810531). Global activation of Nrf2 by the known compound D3T reduces mortality in a heme-induced acute chest syndrome model in transgenic SCD mice (Ghosh, Brit. J. Hematology doi:10.1111 / bjh.15401). Additionally, Nrf2 activators have been shown to regulate fetal hemoglobin (HbF) expression by direct binding to the gamma-globin promoter and by modifying chromatin structure at the beta-globin locus. In sickle cell cells, Nrf2 confers a unique benefit through the induction of HbF to inhibit hemoglobin S polymerization and protect against oxidative stress resulting from chronic hemolysis (Zhu et al., Exp Biol Med doi:10.1177 / 1535370219825859). Thus, the development of small molecule activators of Nrf2 has the potential to ameliorate the clinical severity of other diseases in which increased HbF is beneficial, such as sickle cell disease and beta-thalassemia.

[0007] The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Friedreich's ataxia (Dinkova-Kostova, FEBS, doi:10.1111 / febs.14379). Nrf2 activation attenuates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of proteostasis. Small-molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative disease (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 cultures of human cells expressing mutant proteins. Tecfidera (dimethyl fumarate) activates Nrf2 (in addition to other mechanisms) and is approved in the United States to treat relapsing-remitting multiple sclerosis. The Nrf2 activator omaveloxolone (RTA-408), currently in Phase II trials for the treatment of Friedrich's ataxia, a genetic neurodegenerative disorder, met its primary endpoint of change in the modified Friedrich's Ataxia Rating Scale (mFARS) compared with placebo after 48 weeks of treatment. Therefore, targeting Nrf2 signaling may offer a therapeutic option to delay the onset, slow progression, and alleviate symptoms of neurodegenerative disorders. Due to the role of oxidative stress and mitochondrial dysfunction in CNS disorders, Nrf2 activators have also been suggested for the treatment of chronic pain and schizophrenia.

[0008] Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints and is characterized by periods of disease flares and remission. Multiple joints can be 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 additional oxidative damage, and the expression of Nrf2 target genes is enhanced in Nrf2 wild-type but not knockout mice during antibody-induced arthritis (Wruck, BMJ Annals of Rheumatic Diseases, doi:10.1136 / ard.2010.132720). Furthermore, in an animal model of rheumatoid arthritis using serum transfer from K / BxN transgenic mice to Nrf2(- / -) mice, Nrf2 deficiency accelerated the incidence of arthritis, and animals showed widespread disease affecting both the front and back paws (Maicas, Antioxidants & Redox Signaling, doi:10.1089 / ars.2010.3835).

[0009] Ulcerative colitis (UC) and Crohn's disease (CD) are chronic relapsing-remitting forms of ulcerative colitis (IBD) caused by dysfunction of the intestinal epithelium. Damage to intestinal epithelial cells can disrupt the intestinal epithelial barrier function and promote abnormal immune responses and inflammatory states. Therefore, an intact intestinal epithelium is crucial for a healthy intestine, and cytoprotective agents that can target intestinal epithelial cells would be beneficial for the treatment of UC and CD. Antioxidant levels and oxidative stress biomarkers typically correlate with disease severity in IBD, and several genome-wide association studies have linked IBD-associated single nucleotide polymorphisms (SNPs) to multiple genes involved in the response to oxidative stress, many of which are regulated by Nrf2 (Khor et al., Nature, doi:10.1038 / nature10209). CPUY192018, a small molecule inhibitor of the Keap1-Nrf2 protein-protein interaction (and therefore an Nrf2 activator), demonstrated cytoprotective effects in experimental models of UC induced by dextran sulfate sodium in both NCM460 cells and mouse colon (Lu, Scientific Reports, doi:10.1038 / srep26585). Also, Nrf2 knockout mice have been shown to exhibit increased susceptibility to colitis-associated colorectal cancer (Khor, Cancer Prev Res (Phila), doi:10.1158 / 1940-6207).

[0010] Fumaderm, a mixture of three salts of dimethyl fumarate (DMF) and monoethyl fumarate, was approved in Germany in 1994 for the treatment of psoriasis. A potential form of DMF, monomethyl fumarate (MMF), has been shown to increase global and nuclear Nrf2 levels in primary mouse keratinocytes and result in enhanced mRNA expression of several Nrf2-downstream effectors, such as heme oxygenase-1 and peroxiredoxin-6 (Helwa, J Pharmacol. Exp. Ther., doi:10.1124 / jpet.116.239715). Other skin disorders, such as radiation-induced dermatitis / skin damage, atopic dermatitis, and wound healing, may benefit from treatment with Nrf2 activators (Wu et al., Mol Med Rep. 2019 Aug;20(2):1761-1771).

[0011] 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 can 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 major diagnostic subtype of NAFLD that predisposes patients to cirrhosis and liver-related complications. There are currently approved drug treatments for NAFLD and NASH. However, knockout of Nrf2 in mice significantly predisposes to NASH stimulated by either a methionine- and choline-deficient (MCD) diet (Chowdry, Free Radic Biol Med, doi:10.1016 / j.freeradbiomed.2009.11.007) or a high-fat (HF) diet (Okada, J Gastroenterol, doi:10.1007 / s00535-012-0659-z), and pharmacological activation of Nrf2 has been shown to reverse NASH in mouse models (Sharma, Cell Mol Gastroenterol Hepatol, doi:10.1016 / j.jcmgh.2017.11.016). Other liver diseases, such as toxicity-induced liver disease, viral hepatitis, and cirrhosis, may benefit from treatment with Nrf2 activators. Oxidative stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models of acute kidney injury (AKI) in which Nrf2 is transiently and slightly activated. Genetic or pharmacological enhancement of Nrf2 activity in renal tubules significantly ameliorates AKI-associated damage and prevents the progression of AKI to chronic kidney disease (CKD) by reducing oxidative stress. However, a phase III clinical trial of KEAP1 inhibitors, CDDO-Me or bardoxolone-methyl, for patients with stage 4 CKD and type 2 diabetes mellitus (T2DM) was discontinued due to the occurrence of cardiovascular events. Recent clinical studies have shown accumulating positive effects of KEAP1 inhibitors in moderate stages of CKD, leading to the resumption of phase II trials.Data from an ongoing project demonstrate that an Nrf2 activator / KEAP1 inhibitor improves glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns (Nezu, Am J Nephrol, doi:10.1159 / 000475890). Inflammatory responses 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 inadequate treatment regimens. CXA-10, which upregulates the Nrf2 pathway, is currently in clinical trials for focal segmental glomerulosclerosis (FIRSTx—Trial of Oral CXA-10 in Primary Focal Segmental Glomerulosclerosis (FSGS); clinicaltrials.gov / ct2 / show / NCT03422510). A Phase II study showed that bardoxolone methyl significantly improved renal function in patients with autosomal dominant polycystic kidney disease (ADPKD), CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), or FSGS after 12 weeks of treatment. (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. Bardoxolone methyl is currently being studied in these patients because it is thought to affect the underlying pathological processes related to mitochondrial dysfunction, inflammation, and oxidative stress, suggesting that Nrf2 activators may be useful in this disease.

[0012] Oxidative stress plays a crucial role in the initiation 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 homeostatic levels, Nrf2 can scavenge ROS, carcinogens, and other DNA-damaging agents, resulting in the inhibition of tumor initiation and metastasis (Milkovic et al. Redox Biol. doi:10.1016 / j.redox.2017.04.013). Evgen is currently evaluating SFX-01 (sulforaphane-cyclodextrin conjugate) 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 have a role in cancer prevention.

[0013] Age-related macular degeneration (AMD) is a leading cause of blindness in Western countries, and oxidative stress plays a major role in AMD pathogenesis and progression. Nrf2 activators have been shown to protect cultured cells mimicking the outer layers of the retina from oxidative stress, suggesting their potential to preserve vision in patients with early-stage AMD (Bellezza, Front Pharmacol. 2018;9:1280). In addition, Nrf2 activators may also be useful in other ocular conditions, such as Fuchs endothelial corneal dystrophy and uveitis.

[0014] Recently, Nrf-2 activators have also been suggested to have benefit in the treatment of preeclampsia through the suppression of oxidative stress and endothelial cell apoptosis (Jiang et al, Oxid Med Cell Longev doi:10.1155 / 2021 / 8839394). Summary of the Invention [Problem to be solved by the invention]

[0015] Therefore, given the role of Nrf2 in multiple indications, there is a continuing need for agents capable of activating Nrf2. [Means for solving the problem]

[0016] In one aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0017] 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.

[0018] In another aspect, the present 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.

[0019] In another aspect, the present 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.

[0020] 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.

[0021] In another aspect, the present invention relates to a method for treating a disease or disorder mediated by Nrf2 activation, 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.

[0022] Examples of diseases or disorders mediated by Nrf2 activation include chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease, and non-alcoholic steatohepatitis.

[0023] 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, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0024] 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 arterial 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 present invention provides a method of treating chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, 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.

[0026] The present invention further provides methods of synthesizing the compounds defined herein or pharmaceutically acceptable salts thereof.

[0027] In another aspect, the present invention provides compounds or pharmaceutically acceptable salts thereof that are obtainable by, or are obtained by, or are obtained directly by, a synthetic method as defined herein.

[0028] In another aspect, the present invention provides novel intermediates as defined herein that are suitable for use in any of the synthetic methods described herein.

[0029] The preferred, preferred and optional features of any particular aspect of the present invention are also preferred, preferred and optional features of any other aspect. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0031] Reference to "treating" or "treatment" should be understood to include alleviating symptoms of a condition as well as preventing them. Thus, "treating" a condition, disorder, or pathological condition includes (1) preventing or delaying the onset of the condition, disorder, or pathological condition in a person who may have or be predisposed to the condition, disorder, or pathological condition but who has not yet experienced or manifested clinical or subclinical symptoms thereof; (2) inhibiting the condition, disorder, or pathological condition, i.e., arresting, alleviating, or delaying the onset or recurrence of the disease (in the case of maintenance therapy) or at least one of its clinical or subclinical symptoms; or (3) eliminating or attenuating the disease, i.e., reversing the condition, disorder, or pathological condition or at least one of its clinical or subclinical symptoms.

[0032] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal to be treated for a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0033] As used herein, the term "alkyl" encompasses both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are limited to the straight-chain form only, and references to individual branched-chain alkyl groups, such as "isopropyl," are limited to the branched-chain form only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. Similar paraphrases apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0034] As used herein, the term "alkylene" includes both straight and branched chain divalent alkyl groups. For example, "C 1~4 "Alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-), propylene, and butylene.

[0035] As used herein, the term "alkoxy" includes both straight and branched chain alkyl groups single-bonded to oxygen. For example, "C 1~4 "Alkoxy" includes methoxy, ethoxy, isopropoxy and t-butoxy.

[0036] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0037] "Cycloalkyl" means a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bicyclic rings can be fused or spiro-linked; examples of bicyclic cycloalkyl groups 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.

[0038] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0039] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include fluoroalkyl groups (such as -CHF2, -CH2CF3, etc.) or perfluoroalkyl / perfluoroalkoxy groups (such as -CF3 or -CF2CF3).

[0040] The term "heterocyclic" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocycles contain about 3 to 12 (preferably 3 to 7) ring atoms in the ring, together with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Bicyclic heterocycles contain 7 to 17 ring atoms in the ring, preferably 7 to 12 ring atoms. Bicyclic heterocycles can be fused, spiro, or bridged ring systems. Heterocyclic groups include, for example, cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydro-oxathionyl, dihydroisoxazolyl (e.g., 4,5-dihydroisoxazolyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 1,6-dihydropyridinyl), tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include oxidized sulfur-containing heterocycles containing SO or SO groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl (tetrahydrothienyl 1,1-dioxide, thiomorpholinyl 1,1-dioxide, etc.) Suitable groups for heterocyclic groups having one or two oxo (=O) or thioxo (=S) substituents include, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocycles 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. Those skilled in the art will appreciate that any heterocycle can be bonded to another group through any suitable atom, such as a carbon atom or a nitrogen atom. Preferably, the term "heterocyclic" refers to a 4-, 5-, 6-, or 7-membered monocycle as defined above.

[0041] This specification also utilizes compound terms to describe groups containing multiple functionalities. Such terms will be understood by those skilled in the art. For example, C 1~4 Alkylene-C 3~7 Cycloalkyl is C 3~7 C substituted with cycloalkyl groups 1~4 It means alkylene.

[0042] The term "optionally substituted" refers to both groups, structures, or molecules that are substituted and those that are not substituted.

[0043] Where an optional substituent is selected from "one or more" groups, this definition is understood to include selecting all of the substituents from one of the specified groups or selecting the substituents from two or more of the specified group.

[0044] The phrase "compounds of the invention" refers to both the compounds disclosed generically and specifically herein.

[0045] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I [ka] (In the formula, R 1 is C1~4 Alkylene-R 4 and; R 2 is selected from COH and tetrazolyl; R 3 is selected from hydrogen and methyl; X is CR 5 R 6 or O; R 4 is 1,2,3-triazolyl, 1,2,4-triazolyl or pyrimidinyl, and the triazolyl or pyrimidinyl group is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; and optionally fused to a cycloalkyl or heterocyclyl ring; R 5 is hydrogen, C 1~4 Alkyl, C 3~7 Cycloalkyl and C 1~3 haloalkyl; and R 6 is hydrogen and C 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached form a 3- or 4-membered cycloalkyl ring; m is 0 or 1; and n is 1 or 2) or a pharmaceutically acceptable salt thereof, provided that the compound of formula I is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof, provided that the compound is not one of:

[0046] Particular compounds of the present invention include, for example, compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein, unless otherwise specified, R 1 , R2, R 3 , R 4 , R 5 , R 6 , X, n, and m each have any of the meanings defined above or in any of the following paragraphs (1) to (54). For the avoidance of doubt, the scope of the present invention includes compounds of formula I or a pharmaceutically acceptable salt thereof, wherein any of the substituent definitions defined herein may be combined with any of the other substituent definitions defined herein: (1)R 1 is C 1~4 Alkylene-R 4 and; (2)R 1 is CH2-R 4 and; (3)R 1 is CH2CH2-R 4 and; (4)R 2 is CO2H; (5)R 2 is tetrazolyl; (6)R 3 is hydrogen; (7)R 3 is methyl; (8)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 1,2,3-triazolyl optionally substituted with one or more substituents independently selected from alkoxy and cyano; (9)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl and C 1~4 Alkylene-C 3~71,2,3-triazolyl optionally substituted with one or more substituents independently selected from cycloalkyl; (10)R 4 is C 1~4 Alkyl and C 1~3 1,2,3-triazolyl optionally substituted with one or more substituents independently selected from fluoroalkyl; (11)R 4 is 1,2,3-triazolyl optionally substituted with one or more substituents independently selected from methyl, difluoromethyl and trifluoromethyl; (12)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 1,2,3-triazolyl-4-yl optionally substituted with one or more substituents independently selected from alkoxy and cyano; (13)R 4 is 1H-1,2,3-triazolyl-4-yl optionally substituted with one or more substituents independently selected from methyl, difluoromethyl, and trifluoromethyl; (14)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 1-methyl-1H-1,2,3-triazolyl-4-yl optionally substituted with alkoxy or cyano; (15)R 4 is 1-methyl-1H-1,2,3-triazolyl-4-yl optionally substituted with methyl, difluoromethyl or trifluoromethyl; (16)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 1,2,4-triazolyl optionally substituted with one or more substituents independently selected from alkoxy and cyano; (17)R 4 is C 1~4 Alkyl and C 1~3 1,2,4-triazolyl optionally substituted with one or more substituents independently selected from fluoroalkyl; (18)R 4 is 1,2,4-triazolyl optionally substituted with one or more substituents independently selected from methyl, difluoromethyl and trifluoromethyl; (19)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 4H-1,2,4-triazol-3-yl optionally substituted with one or more substituents independently selected from alkoxy and cyano; (20)R 4 is 4H-1,2,4-triazol-3-yl optionally substituted with one or more substituents independently selected from methyl, difluoromethyl and trifluoromethyl; (21)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 4-methyl-4H-1,2,4-triazol-3-yl optionally substituted with alkoxy or cyano; (22)R 4is 4-methyl-4H-1,2,4-triazol-3-yl optionally substituted with methyl, difluoromethyl or trifluoromethyl; (23)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 pyrimidinyl optionally substituted with one or more substituents independently selected from alkoxy and cyano; (24)R 4 is C 1~4 Alkyl and C 1~3 pyrimidinyl optionally substituted with one or more substituents independently selected from haloalkyl; (25)R 4 is pyrimidinyl optionally substituted with one or more substituents independently selected from methyl, difluoromethyl and trifluoromethyl; (26)R 4 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 pyrimidin-5-yl optionally substituted with one or more substituents independently selected from alkoxy or cyano; (27)R 4 is pyrimidin-5-yl optionally substituted with methyl, difluoromethyl or trifluoromethyl; (28)R 4 is 1,2,3-triazolyl fused to a cycloalkyl or heterocyclyl ring; (29)R 4 is 1,2,3-triazol-4-yl fused to a cycloalkyl or heterocyclyl ring; (30)R 4 is the following group: [ka] and the group is selected from one of 1~4 Alkyl and C 1~3 optionally substituted with fluoroalkyl; (31)R 4 is the following group: [ka] wherein said group is optionally substituted with methyl or difluoromethyl; (32)R 4 is the following group: [ka] and the group is selected from one of 1~4 Alkyl and C 1~3 optionally further substituted with fluoroalkyl; (33)R 4 is the following group: [ka] wherein said group is optionally further substituted with methyl, difluoromethyl, or trifluoromethyl; (34)R 4 is the following group: [ka] Selected from one of; (35)R 1 is CH2-R 4 and R 4 is the following group: [ka] said group being selected from one of: 1~4 Alkyl and C 1~3 optionally substituted with fluoroalkyl; (36)R 1 is CH2-R 4 and R 4is the following group: [ka] and the group is selected from one of 1~4 Alkyl and C 1~3 optionally further substituted with fluoroalkyl; (37)R 1 is CH2-R 4 and R 4 is the following group: [ka] wherein the group is optionally further substituted with methyl, difluoromethyl, or trifluoromethyl; (38)R 1 is CH2-R 4 and R 4 is the following group: [ka] Selected from one of; (39)R 1 is CH2-R 4 and R 4 is the following group: [ka] Selected from one of; (40) X is O; (41) X is CR 5 R 6 and; (42)R 5 is hydrogen, methyl, cyclopropyl and C 1~3 fluoroalkyl; (43)R 5 is selected from hydrogen and methyl; (44)R 5 is methyl; (45)R 6 is selected from hydrogen and methyl; (46)R 6 is hydrogen; (47)R 5 is methyl and R 6 is hydrogen; (48)R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropyl ring; (49) n is 1 and X is CR 5 R 6 and; (50) n is 1 and X is CR 5 R 6 and R 5 is methyl and R 6 is hydrogen; (51) n is 1 and X is CR 5 R 6 and R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropyl ring; (52) n is 2 and X is O; (53) m is 0; (54)m is 1.

[0047] Preferably, R 1 is defined in any one of paragraphs (1) to (3) or (35) to (39) above. In one embodiment, R 1 is defined in paragraph (2) above. In one embodiment, R 1 is defined in paragraph (39) above.

[0048] Preferably, R 2 is defined in any one of paragraphs (4)-(5) above. In one embodiment, R 1 is defined in paragraph (4) above.

[0049] Preferably, R 3 is defined in any one of paragraphs (6)-(7) above. In one embodiment, R 3 is defined in paragraph (7) above.

[0050] Preferably, R4 is defined in any one of paragraphs (8) to (34) above. In one embodiment, R 4 is defined above in paragraphs (32) to (34). In one embodiment, R 4 is defined in paragraph (34) above.

[0051] Suitably, X is as defined in any one of paragraphs (40) to (41) above. In one embodiment, X is as defined in paragraph (41) above.

[0052] Preferably, R 5 is defined in any one of paragraphs (42) to (44) above. In one embodiment, R 5 is defined in paragraph (44) above.

[0053] Preferably, R 6 is defined in any one of paragraphs (45)-(46) above. In one embodiment, R 6 is defined in paragraph (46) above.

[0054] Preferably, R 5 and R 6 is defined in any one of paragraphs (47)-(48) above. In one embodiment, R 5 and R 6 is defined in paragraph (48) above.

[0055] Preferably, n is as defined in any one of paragraphs (49) to (52). In one embodiment, n is as defined in paragraph (49) above.

[0056] Preferably, m is defined in any one of paragraphs (53) to (54) above. In one embodiment, m is defined in paragraph (54) above.

[0057] In a further group of compounds, the compounds have the structural formulas IA-IK shown below (which are subformulas of formula I): [ka] (In the formula, R 1 ~R 6 , X and m are as defined above). or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the compound has the structural formula IA shown above, where R 1 is as defined in any one of paragraphs (1) through (3) above; R 2 is as defined in any one of paragraphs (4)-(5) above; R 3 is as defined in any one of paragraphs (6)-(7) above; and X is as defined in any one of paragraphs (40)-(41) above; provided that the compound of formula IA is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0059] In a further group of compounds, the compounds have the structural formula IA shown above, wherein R 1 is as defined in paragraph (2) above; R 2 is as defined in paragraph (4) above; R 3 is as defined in paragraph (7) above; and X is as defined in paragraph (41) above.

[0060] In one embodiment, the compound has the structural formula IB shown above, where R 1 is as defined in any one of paragraphs (1) through (3) above; R 2 is as defined in any one of paragraphs (4)-(5) above; R 3 is as defined in any one of paragraphs (6)-(7) above; and X is as defined in any one of paragraphs (40)-(41) above.

[0061] In a further group of compounds, the compounds have the structural formula IB shown above, and R 1 is as defined in paragraph (2) above; R 2is as defined in paragraph (4) above; R 3 is as defined in paragraph (7) above; and X is as defined in paragraph (41) above.

[0062] In one embodiment, the compound has the structural formula IC shown above, and R 1 is as defined in any one of paragraphs (1) through (3) above; R 2 is as defined in any one of paragraphs (4)-(5) above; R 3 is as defined in any one of paragraphs (6)-(7) above; and m is as defined in any one of paragraphs (53)-(54) above.

[0063] In a further group of compounds, the compounds have the structural formula IC shown above, and R 1 is as defined in paragraph (2) above; R 2 is as defined in paragraph (4) above; R 3 is as defined in paragraph (7) above; and m is as defined in paragraph (54) above.

[0064] In one embodiment, the compound has the structural formula ID shown above, wherein R 1 is as defined in any one of paragraphs (1) through (3) above; R 2 is as defined in any one of paragraphs (4)-(5) above; R 3 is as defined in any one of paragraphs (6)-(7) above; R 5 is as defined in any one of paragraphs (42) to (44) above; R 6 is as defined in any one of paragraphs (45)-(46) above; or R 5 and R 6is as defined in any one of paragraphs (47)-(48) above; and m is as defined in any one of paragraphs (53)-(54) above; provided that the compound of formula ID is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0065] In a further group of compounds, the compounds have the structural formula ID shown above, and R 1 is as defined in paragraph (2) above; R 2 is as defined in paragraph (4) above; R 3 is as defined in paragraph (7) above; R 5 is as defined in paragraph (44) above; R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and m is as defined in paragraph (54) above.

[0066] In one embodiment, the compound has the structural formula IE shown above, where R 1 is as defined in any one of (1) to (3) above; R 3 is as defined in any one of paragraphs (6)-(7) above; R 5 is as defined in any one of paragraphs (42) to (44) above; R 6 is as defined in any one of paragraphs (45)-(46) above; or R 5 and R 6 is as defined in any one of paragraphs (47)-(48) above; provided that the compound of formula IE is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0067] In a further group of compounds, the compounds have the structural formula IE shown above, and R 1 is as defined in paragraph (2) above; R 3 is as defined in paragraph (7) above; R 5 is as defined in paragraph (44) above; R 6 is as defined in paragraph (46) above; or R 5 and R 6is as defined in paragraph (48) above.

[0068] In one embodiment, the compound has the structural formula IF shown above, wherein R 2 is as defined in any one of paragraphs (4)-(5) above; R 3 is as defined in any one of paragraphs (6)-(7) above; R 4 is as defined in any one of paragraphs (8) to (34) above; R 5 is as defined in any one of paragraphs (42) to (44) above; R 6 is as defined in any one of paragraphs (45)-(46) above; or R 5 and R 6 is as defined in any one of paragraphs (47)-(48) above; and m is as defined in any one of paragraphs (53)-(54) above; with the proviso that the compound of formula IF is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0069] In a further group of compounds, the compounds have the structural formula IF shown above, and R 2 is as defined in paragraph (4) above; R 3 is as defined in paragraph (7) above; R 4 is as defined in paragraph (34) above; R 5 is as defined in paragraph (44) above; R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and m is as defined in paragraph (54) above.

[0070] In one embodiment, the compound has the structural formula IG shown above, wherein R 3is as defined in any one of paragraphs (6)-(7) above; R 4 is as defined in any one of paragraphs (8) to (34) above; R 5 is as defined in any one of paragraphs (42) to (44) above; R 6 is as defined in any one of paragraphs (45)-(46) above; or R 5 and R 6 is as defined in any one of paragraphs (47)-(48) above; provided that the compound of formula IG is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0071] In a further group of compounds, the compounds have the structural formula IG shown above, and R 3 is as defined in paragraph (7) above; R 4 is as defined in paragraph (34) above; R 5 is as defined in paragraph (44) above; R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above.

[0072] In one embodiment, the compound has the structural formula IH shown above, wherein R 4 is as defined in any one of paragraphs (8) to (34) above; R 5 is as defined in any one of paragraphs (42) to (44) above; R 6 is as defined in any one of paragraphs (45)-(46) above; or R 5 and R 6 is as defined in any one of paragraphs (47)-(48) above; and m is as defined in any one of paragraphs (53)-(54) above; provided that the compound of formula IH is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0073] In a further group of compounds, the compounds have the structural formula IH shown above, and R 4is as defined in paragraph (34) above; R 5 is as defined in paragraph (44) above; R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and m is as defined in paragraph (54) above.

[0074] In one embodiment, the compound has the structural formula IJ shown above, and R 4 is as defined in any one of paragraphs (8) to (34) above; and m is as defined in any one of paragraphs (53) to (54) above.

[0075] In a further group of compounds, the compounds have the structural formula IJ shown above, and R 4 is as defined in any one of paragraphs (32) to (34), such as paragraph (34) above; and m is as defined in paragraph (54) above.

[0076] In one embodiment, the compound has the structural formula IK shown above, and R 2 is as defined in any one of paragraphs (4)-(5) above; R 4 is as defined in any one of paragraphs (8) to (34) above; and m is as defined in any one of paragraphs (53) to (54) above; provided that the compound of formula IK is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0077] In a further group of compounds, the compounds have the structural formula IK shown above, and R 2 is as defined in paragraph (4) above; R 4 is as defined in paragraph (34) above; and m is as defined in paragraph (54) above.

[0078] In a further group of compounds, the compounds have the structural formula IL (which is a subformula of formula I) shown below: [ka] (In the formula, R 5 and R 6 is as defined above, and R 7 and R 8 is hydrogen, C 1~4Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-C 3~7 Cycloalkyl, halo, OH, C 1~3 independently selected from alkoxy and cyano; or R 7 and R 8 together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl ring) or a pharmaceutically acceptable salt thereof; provided that the compound of formula IL is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid provided that the

[0079] In one embodiment, the compound has the structural formula IL shown above, where R 5 is as defined in any one of paragraphs (42) to (44) above, and R 6 is as defined in any one of paragraphs (45)-(46) above; or R 5 and R 6 is as defined in any one of paragraphs (47)-(48) above; and R 7 and R 8 is hydrogen, C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl and C 1~2 Alkylene-C 3~7 independently selected from cycloalkyl; R 7 and R 8 together with the atoms to which they are attached form a 6-membered heterocyclyl ring.

[0080] In a further group of compounds, the compounds have the structural formula IL shown below, where R 5 is as defined in paragraph (44) above, and R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; and R 7 and R 8 are independently selected from methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, and CH2-cyclopropyl; or R 7 and R 8together with the atoms to which they are attached form a 6-membered heterocyclyl ring.

[0081] In a further group of compounds, the compounds have the structural formula IL shown below, where R 5 is as defined in paragraph (44) above, and R 6 is as defined in paragraph (46) above; or R 5 and R 6 is as defined in paragraph (48) above; R 7 is methyl; and R 8 is hydrogen, methyl or difluoromethyl.

[0082] Particular compounds of the present invention are: 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the compound of formula I is the following compound: 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; and (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or It is selected from pharmaceutically acceptable salts thereof.

[0084] The various functional groups and substituents comprising the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, for example, less than 700 or less than 650.

[0085] Suitable or preferred features of any compound of the present invention may also be suitable features of any other embodiment.

[0086] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid). In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., calcium salts or magnesium salts), ammonium salts, or salts with organic bases that produce physiologically acceptable cations (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine).

[0087] Compounds with the same molecular formula but different properties, bonding order, or spatial arrangement of atoms are called "isomers." Isomers with different spatial arrangement of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, pairs of enantiomers can exist. Enantiomers can be described by the absolute configuration of their asymmetric center, as expressed by the Cahn-Prelog R- and S-sequencing rules, or by the direction in which the molecule rotates the plane of polarized light, as dextro- or levo-dominate (i.e., (+) or (-) dominance, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0088] The compounds of the present invention typically have one or more asymmetric centers; therefore, such compounds can be produced as individual (R) or (S) isomers or mixtures thereof. Unless otherwise specified, the description or naming of a specific compound in the specification and claims is intended to encompass both individual enantiomers, diastereoisomers, and mixtures thereof (racemic or otherwise). Methods for determining stereochemistry and separating stereoisomers (e.g., by synthesis from optically active starting materials or by separating racemates) are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the 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 isomers, diastereoisomers, and geometric isomers and mixtures thereof that have Nrf2 activation activity.

[0089] The present invention also encompasses compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D), 3 H(T) can be any isotope; C can be 12 C. 13 C. 14 C can be any isotope; O can be 16 O. 18 It can be any isotope such as O.

[0090] It should also be understood that certain compounds of the present invention can exist in unsolvated as well as solvated forms, such as hydrated forms, etc. It should be understood that the present invention encompasses all such solvated forms that possess Nrf2 activation activity.

[0091] It is to be understood that certain compounds of the present invention may have polymorphic forms, and that the present invention encompasses all such forms that possess Nrf2 activating activity.

[0092] The compounds of the present invention can exist in several different tautomeric forms, and reference to the compounds of the present invention encompasses all such forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, even if only one is specifically described or presented, all other forms are encompassed by the compounds of the present invention. Tautomeric forms include, for example, the following exemplary tautomeric pair forms: keto, enol, and enolate: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acintro. [ka]

[0093] Compounds of the present invention containing an amine functionality can form N-oxides. References herein to compounds of Formula I containing an amine functionality also encompass N-oxides. In some compounds containing an amine functionality, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides include N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 147-148. More specifically, N-oxides can be generated by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane, according to the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514).

[0094] The compounds of the present invention can be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. The compounds of the present invention can form prodrugs when they have a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at a carboxy or hydroxy group in the compounds of the present invention and in vivo cleavable amides that can be formed at a carboxy or amino group in the compounds of the present invention.

[0095] Therefore, when the compound represented by formula I defined above can be obtained by organic synthesis or by cleaving its prodrug in the human or animal body, these compounds are included in the present invention. Therefore, in addition to the compound represented by formula I produced by organic synthesis means, the present invention also includes this type of compound produced by metabolism of a precursor compound in the human or animal body. That is, the compound represented by formula I may be a compound produced by synthesis or a compound produced by metabolism.

[0096] Suitable pharmaceutically acceptable prodrugs of compounds of Formula I are those that, based on sound medical judgment, are suitable for administration to the human or animal body, do not exhibit undesirable pharmacological activity, and are not excessively toxic.

[0097] Various forms of prodrugs are described, for example, in the following documents: a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0098] The in vivo effects of the compounds of Formula I may be exerted in part by one or more metabolic products produced in the human or animal body following administration of the compounds of Formula I. As noted above, the in vivo effects of the compounds of Formula I may also be exerted through metabolism of a precursor compound (prodrug).

[0099] It should also be understood that other groups, such as solubilizing moieties (e.g., PEG polymers), moieties that enable them to be attached to solid supports (e.g., biotin-containing moieties, etc.), targeting ligands (e.g., antibodies or antibody fragments), etc., can be covalently attached to compounds of Formula I at any suitable position.

[0100] synthesis When referring to the synthetic methods described below and those used to prepare starting materials, it should be understood that all reaction conditions presented (including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures) can be selected by one skilled in the art.

[0101] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0102] Necessary starting materials can be obtained by standard organic chemistry procedures. The preparation of such starting materials is illustrated in the accompanying Examples, along with representative process variations that follow. Alternative starting materials necessary can be obtained by analogous procedures to those exemplified, within the ordinary skill of an organic chemist.

[0103] It will be understood that during the synthesis of the compounds of the invention, or of certain starting materials in the processes defined below, it may be desirable to protect certain substituents to prevent undesired reactions. Those skilled in the chemical arts will understand the circumstances under which such protection is necessary and how such protecting groups can be put in place and subsequently removed.

[0104] For examples of protecting groups, see any of the many general texts on the subject, such as "Protective groups in Organic Synthesis (3rd Ed), John Wiley & Sons, NY (1999)", T. Greene & P. ​​Wuts. Removal of the protecting group can be carried out by any convenient method described in the literature or known to those skilled in the chemical arts that is suitable for removing the protecting group in question. Such methods are selected so that removal of the protecting group has minimal adverse effects on other groups in the molecule.

[0105] Thus, in some of the reactants mentioned herein, if the reactant contains groups such as, for example, amino, carboxy, hydroxy, etc., it may be desirable to protect this group.

[0106] For example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, such as an alkanoyl group (such as an acetyl group), an alkoxycarbonyl group (such as a methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl group), an arylmethoxycarbonyl group (such as a benzyloxycarbonyl group), or an aroyl group (such as a benzoyl group). The deprotection conditions for the above-mentioned protecting groups will necessarily vary with the protecting group chosen. Thus, for example, an acyl group (such as an alkanoyl group, an alkoxycarbonyl group, an aroyl group, etc.) can be removed by hydrolysis with a suitable base, such as, for example, an alkali metal hydroxide (such as, for example, lithium hydroxide, sodium hydroxide). Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, etc., and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid (for example, BF3·OEt2).A suitable other 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 hydrazine.

[0107] Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways by known methods. Compounds of Formula I can be prepared by the methods described below, or by the methods shown in the experimental section, or by similar methods. The routes described herein are merely illustrative of some methods that can be used to synthesize compounds of Formula I, and those skilled in the art will understand that the order of reaction steps is not limited to the order described. It will also be understood that the assignment of nucleophiles and electrophiles is not limited to that described herein, and that in some cases it may be appropriate to reverse the assignment. Various approaches to chemical synthesis strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

[0108] General method A [ka] In a typical synthetic procedure, phthalimide, when used as a protecting group, is removed using a common reagent (e.g., hydrazine), and the amine is reacted with an appropriate reagent to incorporate the desired lactam. The third step involves the incorporation of the required ether via conventional methods such as alkylation with an alkyl halide or activated alcohol (e.g., mesylate, triflate), or a Mitsunobu reaction using a reagent such as DBAD or DEAD with an appropriate phosphine. The Boc protecting group is then removed, typically by treatment with HCl. In the fifth step, the cycloalkyl acid group can be activated for reaction with the amine of the tetrahydroisoquinoline (THIQ) scaffold. Activation of the acid occurs using a common amide coupling reagent such as HATU or CDI.

[0109] General method B [ka] In further general procedures, the order of steps can be changed compared to General Method A. The required ether is incorporated in the first step, again via the conventional method described in General Method A above. The phthalimide protecting group is removed in the second step, and the amine is reacted with an appropriate reagent to incorporate the desired lactam. The Boc protecting group is then removed, and then the cycloalkylamide moiety can be introduced in the fifth step.

[0110] The THIQ scaffold can be constructed according to the route shown in Scheme 1: [ka] Scheme 1: a) SOCl2, EtOAc; b) ammonium acetate, CH3NO2, AcOH; c) LiAlH4, THF; d) DIPEA, DCM; e) NCS, DMF; f) P2O5, sulfolane; g) NaBH(OAc)3, AcOH, DCM; h) BBr3, DCM; i) Chiral SFC chromatography.

[0111] Compound (R 2 is —COOH) can be converted to tetrazolyl via reaction of an appropriate nitrile with an azide as shown in Scheme 2. [ka] Scheme 2: a) HATU, DIPEA, NH4Cl, DMF; b) POCl3, imidazole, pyridine; c) n Bu3SnN3, xylene.

[0112] Following the route described in Scheme 3, removal of the phthalimide group with hydrazine, followed by conversion of the resulting primary amine to a pyrrolidinone by reaction with an appropriate lactone or ω-haloester, provides the compounds of the invention (—NR 4 R 5 The intermediate (-NR 4 R 5 The group represents phthalimide. [ka] Scheme 3: a) N2H4, EtOH; b) methyl 4-bromobutanoate, Et3N, PhMe.

[0113] Pharmaceutical Composition The compounds of the invention will usually, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Thus, according to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0114] The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form, or a safe and effective amount of the compound of the present invention can be extracted and then administered to a patient with a powder, syrup, or the like. Alternatively, the pharmaceutical compositions of the present invention can be prepared and packaged in unit dosage form, with each physically discrete unit containing a safe and effective amount of the compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0115] The compositions of the 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 wafers), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams and gels), transdermal administration such as via a transdermal patch, administration by inhalation (e.g., as dry powders, aerosols, suspensions and solutions), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0116] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or solvent that is involved in providing form or consistency to a pharmaceutical composition. Each excipient should be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the effectiveness of the compound of the present invention when administered to a patient and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. In addition, each excipient should be of sufficiently high purity to render it pharmaceutically acceptable.

[0117] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected.In addition, suitable pharmaceutically acceptable excipients can be selected for the specific function they can perform in the composition.For example, some pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of a uniform dosage form.Some pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of a suitable dosage form.Some pharmaceutically acceptable excipients can be selected for their ability to facilitate the transport or delivery of the compound of the present invention when administered from one organ or part of the body of a patient to another organ or part of the body.Some pharmaceutically acceptable excipients can be selected for their ability to improve patient compliance.

[0118] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavors, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. One skilled in the art will understand that certain pharmaceutically acceptable excipients may serve more than one function and may serve different functions depending on the amount of excipient present in the formulation and the other ingredients present in the formulation.

[0119] Those skilled in the art possess the knowledge and skill to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. In addition, there are several sources of information available to those skilled in the art that describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0120] 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 (Mack Publishing Company).

[0121] When combined with one or more excipients to produce a single dosage form, the amount of active ingredient will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg) of active agent, compounded with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98 percent by weight of the total composition.

[0122] The dose of a compound of formula I to be used for therapeutic or prophylactic purposes will, of course, vary according to principles of medicine, depending on the nature and severity of the animal's or patient's condition, its age and sex, and the route of administration.

[0123] Generally, when the compounds of the present invention are used for therapeutic or prophylactic purposes, a daily dose ranging from, for example, 0.1 mg / kg body weight to 75 mg / kg body weight, if divided doses are necessary, will be administered. Generally, lower dosages will be administered when parenteral routes are employed. Thus, for example, when administered intravenously or intraperitoneally, the dose will generally be in the range of, for example, 0.1 mg / kg body weight to 30 mg / kg body weight. Similarly, when administered by inhalation, the dose will be in the range of, for example, 0.05 mg / kg body weight to 25 mg / kg body weight. Oral administration, particularly in tablet form, may also be preferred. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of a compound of the present invention.

[0124] Route of administration The compounds of the invention or pharmaceutical compositions containing the active compounds can be administered to a subject by any conventional route of administration, either systemically / peripherally or locally (ie, to the desired site of action).

[0125] Routes of administration include, but are not limited to, oral administration (e.g., by ingestion); buccal administration; sublingual administration; transdermal administration (e.g., by patch, plaster, etc.); transmucosal administration (e.g., by patch, plaster, etc.); nasal administration (e.g., by nasal spray); ocular administration (e.g., by eye drops); pulmonary administration (e.g., by aerosol, e.g., orally or nasally, e.g., by inhalation or insufflation therapy). administration by intravenous, intra-arterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid, and intrasternal administration; by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0126] In a preferred embodiment, the compounds of the invention as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, are administered orally or via inhalation.

[0127] Therapeutic Uses and Applications The compounds of the present invention are activators of Nrf2. As a result, they are potentially useful therapeutic agents for the treatment of diseases or conditions mediated by Nrf2 activation.

[0128] Thus, in one aspect, the present 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.

[0129] In another aspect, the present 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.

[0130] 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.

[0131] In another aspect, the present invention relates to a method for treating a disease or disorder mediated by Nrf2 activation, 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.

[0132] Examples of specific diseases or conditions for which the compounds of formula (I) and their pharmaceutically acceptable salts may be used to treat include any one 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 pulmonary fibrosis of unknown cause, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, hypersensitivity reactions. These include, but are not limited to, bowel disorders, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxicity-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), Alport 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' endothelial corneal dystrophy, uveitis, or pre-eclampsia.

[0133] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) may be used in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0134] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic Provided is a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of fatty liver disease, non-alcoholic steatohepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport 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' endothelial corneal dystrophy, uveitis, or pre-eclampsia.

[0135] 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, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0136] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-steroidal anti-inflammatory drugs (NSAIDs), and the like. Provided is the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport 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' endothelial corneal dystrophy, uveitis, or pre-eclampsia.

[0137] In another aspect, the invention provides the use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0138] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, SUMMARY OF THE INVENTION

[0003] Provided are methods for treating hepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport 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' endothelial corneal dystrophy, uveitis, or pre-eclampsia, 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.

[0139] In another aspect, the present invention provides a method of treating chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, 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.

[0140] 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.

[0141] 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.

[0142] In another aspect, the present invention provides a method for activating Nrf2 in vitro and / or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[0143] Combination Therapy The compounds of the invention can be administered alone as monotherapy or in combination with one or more additional therapeutic agents, the choice of which will, of course, depend on the disease or condition to be treated and its severity.

[0144] The use of combination therapies to treat specific medical conditions is common.

[0145] According to a particular aspect of the present invention, there is provided a combination suitable for use in the treatment of a disease or condition associated with Nrf2 activation, comprising a compound of the present invention as defined herein before or a pharmaceutically acceptable salt thereof and another therapeutic agent.

[0146] According to aspects of the present invention, the present invention is directed to treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, In certain embodiments, the present invention provides a combination comprising a compound of the invention or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, which is suitable for use in the prophylaxis or treatment of chronic hepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport 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' endothelial corneal dystrophy, uveitis or pre-eclampsia.

[0147] In a further aspect of the invention, there is provided a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more further therapeutic agents.

[0148] When the term "combination" is used herein, it should be understood to mean simultaneous administration, staggered administration, or sequential administration. In one embodiment of the present invention, "combination" refers to simultaneous administration. In another embodiment of the present invention, "combination" refers to staggered administration. In a further embodiment of the present invention, "combination" refers to sequential administration. When sequential or staggered administration is performed, the delay in administration of the second component should be such that the beneficial effect of the combination is not lost.

[0149] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a combination of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents, together with a pharmaceutically acceptable diluent or carrier.

[0150] The one or more additional therapeutic agents may further comprise a compound of the invention. Thus, in certain embodiments, a pharmaceutical composition is provided comprising two compounds of the invention, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0151] According to certain aspects of the invention, combinations are provided which are suitable for use in the treatment of 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 arterial hypertension; cancer prevention or treatment; or for use in aiding transplantation.

[0152] In certain aspects of the invention, there are provided combinations which are suitable for use in the prevention or treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0153] Examples of other therapeutic agents that may 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: (i) beta2-adrenergic receptor agonists (which may be racemic or single enantiomers) including salmeterol, salbutamol, formoterol, salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline, vilanterol, olodaterol and salts thereof; (ii) anticholinergics that act as antagonists at muscarinic receptors, including ipratropium (e.g., as the bromide sold under the name Atrovent, CAS 22254-24-6), oxitropium and tiotropium (e.g., as the bromide sold under the name Spiriva, CAS 136310-93-5), revatropate, LAS-34273, aclidinium, glycopyrronium, umeclidinium and salts thereof; (iii) corticosteroid anti-inflammatory agents, examples of which include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, fluticasone furoate, beclomethasone esters (e.g., 17-propionate or 17,21-dipropionate esters), budesonide, flunisolide, mometasone esters (e.g., mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541, and ST-126; (iv) anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, JAK inhibitors, Pi3K inhibitors, inhibitors of leukotriene synthesis (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, CCR3 antagonists, etc.), or inhibitors of cytokine synthesis or 5-lipoxygenase inhibitors; (v) vasodilators and antiproliferative agents (e.g., prostanoids and PDE5 inhibitors), including epoprostenol (Floran), treprostinil (Remodulin), iloprost (Ventavis), treprostinil (Tyvaso), bosentan (Tracleer), ambrisentan (Retailis), sildenafil (Revatio), and tadalafil (Adcirca); (vi) antidiabetic drugs, including insulin, biguanides (e.g., metformin), sulfonylureas (e.g., glimepiride), meglitinides (e.g., repaglinide), thiazolidinediones (e.g., pioglitazone), dipeptidyl peptidase IV inhibitors (e.g., sitagliptin), incretin mimetics / GLP-1 analogs (e.g., liraglutide, exenatide, dulaglutide), sodium glucose cotransporter-2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, and empagliflozin), and α-glucosidase inhibitors (e.g., acarbose); (vii) hydroxyurea and other drugs used to treat sickle cell disease, such as L-glutamine, NCX1443, GBT440 (voxelotor), pan-selectin antagonists (GMI-1070, rivipancel), humanized anti-P-selectin antibodies (SelG1, clinalizumab), P-selectin aptamers, sebparin, regadenoson, ticagrelor, N-acetyl-cysteine ​​(NAC), phosphodiesterase 9 inhibitors (e.g., PF-04447943, IMR-687, BAY 73-6691, BAY 41-2271); and (viii) ASK1 inhibitors such as selonsertib, FXR agonists such as obeticholic acid, ACC inhibitors such as GS-9674, Px-102, GS-0976, and PPARα / δ agonists such as elafibranor.

[0154] The above-referenced combinations may conveniently be presented for use in the form of pharmaceutical formulations and therefore pharmaceutical formulations comprising a combination as defined above in association with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

[0155] Such combination / conjunction treatment may be achieved by way of the simultaneous, sequential or differential administration of the individual components of the treatment, hi one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0156] Such combination therapy utilizes the compounds of the present invention in dosage ranges described herein and other pharmaceutically active agents, such as in approved dosage ranges and / or dosages described in the relevant published references. [Example]

[0157] General steps: The following examples illustrate procedures for preparing compounds of the present invention. Starting materials are prepared according to procedures known in the art or illustrated herein, or are commercially available. Commercially available reagents were used without further purification. If no reaction temperature is specified, reactions were carried out at room temperature (usually 18-27°C).

[0158] The compounds described in this invention are 1 When characterized by H NMR spectroscopy, spectra were recorded on a 500 MHz Bruker, 400 MHz Bruker, 250 MHz Bruker, 300 MHz JEOL, or 400 MHz JEOL instrument. If temperature was not included, the spectrum was recorded at ambient temperature. Chemical shift values ​​are expressed in parts per million (ppm). When NMR spectra are complex due to the presence of interconverting isomers, approximate partial integrations of the signals are reported, or only characterization of the major isomer is reported. The following abbreviations are used for NMR signal multiplicity: s = singlet, b = broad, t = triplet, q = quartet, m = multiplet, d = doublet.

[0159] Analytical LCMS When the compounds described in this invention are characterized by LCMS data, retention times and molecular weights are determined using the methods listed in the table below. When the compounds of this invention appear as slowly interconverting stereoisomers, multiple retention times are reported.

[0160] [Table 1]

[0161] Preparative Chiral SFC Preparative chiral SFC was performed using a variation of the method described below.

[0162] Method 1: Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with Stacked Injection Module). Column: Diacel Chiralpak IA / IB / IC, YMC amylose / cellulose C (5 μm, 20-21.2 × 250 mm) maintained at 40°C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, with modifier selected from MeNH, formic acid as specified. Gradient / isocratic as specified.

[0163] [Table 2]

[0164] Synthesis of intermediates Intermediate 1: (E)-1-Fluoro-2-methoxy-4-(2-nitrovinyl)benzene [ka] A solution of 4-fluoro-3-methoxybenzaldehyde (57 g, 370 mmol; CAS: 128495-46-5), ammonium acetate (14.25 g, 185 mmol), and nitromethane (100.14 mL, 1850 mmol) in acetic acid (150 mL) was heated at 100 °C for 5 h. The reaction mixture was cooled to room temperature overnight. The resulting solid was collected by filtration, washed with diethyl ether, and the solid was dried in vacuo. The solid was suspended in DCM (1 L) and washed with water. The organic layer was filtered to remove the precipitate, dried (NaSO), filtered, and concentrated in vacuo to give the title compound (42 g, 200 mmol, 54%). The precipitate was dissolved in 2-MeTHF, and the organic layer was washed with water, brine, dried (NaSO), and evaporated to give the final product as a yellow solid (11 g, 55.2 mmol, 15% yield). The acetic acid mother liquor was evaporated and diluted with IMS. The resulting solid was collected by filtration and washed with IMS to give another batch of product (1.5 g). These batches were combined to give the title compound (54.5 g, 74%), which was used without further purification. 1 H NMR(300MHz,CDCl3)δ 7.95(d,1H),7.52(d,1H),7.16-7.08(m,3H),3.95(s,3H).

[0165] Intermediate 2: 2-(4-fluoro-3-methoxyphenyl)ethan-1-amine [ka] To a stirred solution of lithium aluminum hydride in THF (2 M; 12.7 g, 335 mmol) pre-cooled in an ice-salt bath, sulfuric acid (8.92 mL, 167 mmol) was added dropwise under nitrogen. The mixture was stirred for 15 minutes until all gas evolution had subsided. A solution of Intermediate 1 (22 g, 112 mmol) in 2-MeTHF (660 mL) was added dropwise, ensuring the temperature remained below 20°C. The cooling bath was removed, and the mixture was heated under reflux for 5 minutes, then cooled in an ice-salt bath. IPA (57 mL) was added dropwise, followed by sodium hydroxide (2 M, 39 mL). MgSO4 was added, and the mixture was stirred for 30 minutes, then filtered through Celite®. The filter cake was washed with 2-MeTHF / IPA about 98:2 (about 1.5 L), followed by 10% MeOH in DCM (about 1.5 L). The filtrate was concentrated in vacuo to give the title compound (18.8 g, 99%), which was used without further purification. 1 H NMR(400MHz,CDCl3)δ 7.02-6.97(m,1H),6.80(dd,1H),6.74-6.68(m,1H),3.89-3.88(s,3H),2.96(t,2H),2.71(t,2H),1.24-1.18(m,2H).

[0166] Intermediate 3: 2-(1,3-dioxoisoindolin-2-yl)-N-(4-fluoro-3-methoxyphenethyl)acetamide [ka] To a solution of intermediate 2 (49.3 g, 291 mmol) and DIPEA (101.5 mL, 583 mmol) in DCM (250 mL) cooled under nitrogen in an ice-salt bath was added dropwise a solution of intermediate 1 (65.2 g, 291 mmol) in DCM (1.25 L). The mixture was stirred over 2 hours, warming from 0° C. to room temperature. The resulting precipitate was isolated by filtration and washed thoroughly with DCM. The solid was dried in vacuo to give the title compound (83 g, 80%), which was used without further purification. 1H NMR(400MHz,CDCl3)δ 7.89-7.86(m,2H),7.77-7.74(m,2H),6.90(dd,1H),6.78(dd,1H),6.66(d dd,1H),5.75(s,1H),4.29(s,2H),3.88(s,3H),3.52(q,2H),2.79(t,2H).

[0167] Intermediate 4: N-(2-chloro-4-fluoro-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide [ka] A mixture of intermediate 3 (82.6 g, 232 mmol) and NCS (34.05 g, 255 mmol) in DMF (780 mL) was heated to 50 °C and stirred at 50 °C for 1 h, then cooled and concentrated in vacuo. Water (ca. 2 L) was added to the resulting residue and the resulting precipitate was stirred for 1 h. The solid was isolated by filtration, washed with water, EtO, air-dried, and dried in vacuo to give the title compound (85.8 g, 94%), which was used without further purification. LCMS (Method 2): 1.43 min, 391.3 [M+H] + .

[0168] Intermediate 5: 2-((5-chloro-7-fluoro-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] A suspension of sulfolane (794 mL, 8330 mmol) and Intermediate 4 (30.0 g, 76.8 mmol) was heated to 90 °C, resulting in dissolution of the solid. Phosphorus pentoxide (65.4 g, 461 mmol; CAS: 1314-56-3) was added in one portion, and the mixture was stirred at 90–100 °C for 1 h. The mixture was cooled to approximately 30 °C and poured into stirred water (3 L). The solution was neutralized to pH 7.5 with NaCO, and the mixture was filtered. The precipitate was diluted in DCM (500 mL), and the organic phase was washed with water, brine, dried over MgSO, and concentrated in vacuo to give the title compound (27.0 g, 68.8 mmol, 90% yield). LCMS (Method 2): 1.64 min, 373.2 [M+H] + .

[0169] Intermediate 6: 2-((5-chloro-7-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] A stirred suspension of intermediate 5 (50.3 g, 135 mmol) in DCM (600 mL) under argon was cooled in an ice bath. To this was added acetic acid (15.5 mL, 270 mmol) and sodium triacetoxyborohydride (57.2 g, 270 mmol) in portions over 30 minutes. The mixture was stirred for 18 hours while warming to room temperature. To the mixture was then added additional acetic acid (3.09 mL, 54.0 mmol) and sodium triacetoxyborohydride (11.4 g, 54.0 mmol), and stirring was continued for 2.5 hours. The mixture was diluted with DCM and neutralized with a saturated solution of sodium bicarbonate. This was extracted with additional DCM, and the combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound (48.8 g, 77%). LCMS (Method 1): 0.96 min, 375.0 [M+H] + .

[0170] Intermediate 7: 2-((5-chloro-7-fluoro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione hydrobromide [ka] To a stirred suspension of Intermediate 6 (37.0 g, 98.7 mmol) in DCM (500 mL) cooled in an ice bath under nitrogen, boron tribromide in DCM (1 M; 395 mL, 395 mmol; CAS: 10294-33-4) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 72 h. The liquid was quenched by dropwise addition to ice water, causing a solid to precipitate. Ice water was added to the remaining residue in the reaction flask, and the mixture was sonicated for 0.5 h, causing a solid to precipitate. Both suspensions were filtered, and the collected solids were combined, washed with water, azeotroped with methanol, and dried in vacuo to give the title compound (43.0 g, 99%). LCMS (Method 1): 0.92 min, 361.0 [M+H] + .

[0171] Intermediate 8: tert-butyl (S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] To a suspension of Intermediate 7 (43.0 g, 97.4 mmol) in DCM (900 mL) under nitrogen, DIPEA (67.5 mL, 389 mmol) was added, followed by portionwise addition of di-tert-butyl dicarbonate (19.1 g, 87.6 mmol; CAS: 24424-99-5), and the resulting mixture was stirred until no more gas was evolved. The reaction mixture was diluted with water and extracted with DCM, and the combined organic phases were washed with water (×4), brine, dried (MgSO), and concentrated in vacuo. The residue was refluxed in MeCN (900 mL) for 2 h, cooled, and the solid isolated by filtration to give a beige solid that was air-dried for 18 h to give 34 g of racemic material. The racemate was separated by SFC (Method 1: YMC Amylose-C 20 x 250 mm, 5 μm 20 / 80 EtOH (0.1% DEA) / CO₂, 100 mL / min, 120 bar, 40 °C, DAD 230 nm) to give the title compound (first-eluting enantiomer; 15.9 g, 35% yield). The absolute configuration was confirmed by small-molecule X-ray crystallography of the carboxylic acid final compound resulting from enantiomer 2. LCMS (Method 2): 1.50 min, 459.2 [M−H]. 1 H NMR(400MHz;DMSO-d6)δ 7.95-7.80(m,4H),7.42-7.37(m,1H),5.60-5.45(m,1H),4.19-3.75(m,3H), 3.45-3.35(m,1H),2.83-2.79(m,1H),2.63-2.53(m,1H),1.03-0.95(m,9H).

[0172] Intermediate 9: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclohexane-carboxylic acid; (1R)-1-phenylethanamine [ka] A solution of (2,4-dimethoxyphenyl)methanol (43.6 g, 259 mmol, CAS: 7314-44-5) in toluene (80 mL) was added dropwise to a suspension of cis-1,2-cyclohexanedicarboxylic anhydride (20.0 g, 130 mmol, CAS: 13149-00-3) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (46.3 g, 143 mmol, CAS: 56-54-2) in toluene (150 mL) at −5° C. The solution was then transferred to a refrigerator and allowed to stand for 4 days. The reaction mixture was allowed to warm to room temperature, washed with 1 M aqueous HCl (200 mL) until the pH reached 1, washed with water, brine (100 mL), filtered through a phase separator, and concentrated in vacuo. The residue was diluted with toluene (100 mL) and (1R)-1-phenylethanamine (16.5 mL, 130 mmol; CAS 3886-69-9) was added. The mixture was seeded with a few crystals of the solid material from the previous batch and stirred at room temperature for 24 hours. The resulting solid was collected, washed with toluene, triturated with EtO, and the solid was further sonicated in EtO, filtered in vacuo, and dried to give the title compound (45.9 g, 80%). LCMS (Method 1): 1.44 min, 345.0 [M+Na] + .

[0173] Intermediate 10: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclohexane-1-carboxylic acid [ka] Intermediate 9 (45.9 g, 103 mmol) was partitioned between citric acid (10% aqueous solution; 300 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with water, brine, dried over Na2SO4, filtered in vacuo, concentrated, and dried in vacuo to give the title compound (33.7 g, assumed quantitative), which was used without further purification. 1H NMR(400MHz,CDCl3)δ 7.22-7.20(m,1H),6.46-6.43(m,2H),5.15-5.04(q,2H),3.80(s,3H),3.79(s,3 H),2.89-2.81(m,2H),2.08-2.00(m,2H),1.81-1.73(m,2H),1.58-1.38(m,4H).

[0174] Intermediate 11: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclohexane-1-carboxylic acid [ka] To a stirred solution of Intermediate 10 (20.4 g, 63.1 mmol) in anhydrous THF (150 mL) cooled to −25° C. under argon was added LDA (2 M in THF / hexanes; 158 mL, 158 mmol) dropwise. The mixture was stirred at −25° C. for 30 minutes, then iodomethane (11.8 mL, 189 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature over 4 hours. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc, the combined organic phases washed with 10% aqueous citric acid, the aqueous layer further extracted with EtOAc, the combined organic phases washed with brine, dried over Na2SO4, filtered in vacuo, and concentrated to give the title compound (23.6 g, assumed quantitative). LCMS (Method 1): 1.60 min, 359.1 [M+Na] + .

[0175] Intermediate 12: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-(2,4-dimethoxybenzyl)(1S,2R)-1-methylcyclohexane-1,2-dicarboxylate [ka] To a stirred solution of Intermediate 11 (21.2 g, 63.1 mmol) in DMF (112 mL) under argon at room temperature, HATU (31.2 g, 82.1 mmol; CAS: 148893-10-1) was added, and the reaction mixture was stirred for 5 minutes. To the mixture was added DIPEA (12.1 mL, 69.5 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo. Purification on a Teledyne ISCO CombiFlash® Rf+ (330 g silica column Puriflash HC, 0-50% EtOAc in cyclohexane) afforded the title compound (25.0 g, 87%). LCMS (Method 1): 1.70 min, 477.2 [M+Na] + .

[0176] Intermediate 13: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclopentane-carboxylic acid; (1R)-1-phenylethanamine [ka] To a stirred suspension of (3aR,6aS)-4,5,6,6a-tetrahydro-3aH-cyclopenta[c]furan-1,3-dione (14.8 g, 106 mmol, CAS: 35878-28-5) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (37.7 g, 117 mmol, CAS: 56-54-2) in toluene (100 mL) was added (2,4-dimethoxyphenyl)methanol (35.5 g, 211 mmol) in toluene (70 mL) dropwise at −5° C. The solution was then transferred to a refrigerator and allowed to stand for 4 days. The solution was warmed to room temperature and washed with 1M aqueous HCl (400 mL) until pH 1. The organic layer was washed with water and brine, filtered through a phase separator, and concentrated in vacuo. The residue was diluted with toluene (90 mL), to which (1R)-1-phenylethanamine (13.4 mL, 106 mmol; CAS 3886-69-9) was added, and the reaction mixture was stirred at room temperature for 24 hours. The resulting solid was collected, washed with toluene, triturated with EtO, and the solid was further sonicated in EtO, filtered, and dried in vacuo to give the title compound (34.0 g, 75%). LCMS (Method 1): 1.34 min, 331.0 [M+Na] + .

[0177] Intermediate 14: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclopentane-1-carboxylic acid [ka] Intermediate 13 (34.0 g, 79.1 mmol) was partitioned between 10% aqueous citric acid (300 mL) and EtOAc (300 mL). The aqueous solution was further extracted with EtOAc, and the combined organic phases were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo to give the title compound (24.9 g, assumed quantitative), which was used without further purification. LCMS (Method 1): 1.33 min, 331.0 [M+Na] + .

[0178] Intermediate 15: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclopentane-1-carboxylic acid [ka] To a stirred solution of diisopropylamine (0.57 mL, 4.05 mmol; CAS: 108-18-9) in anhydrous HF (3.6 mL) at −78° C. under argon, n-butyllithium (2.5 M in THF; 1.6 mL, 4.05 mmol) was added, and the reaction mixture was stirred at −78° C. for 15 minutes. To this was added Intermediate 14 (500 mg, 1.62 mmol) in anhydrous THF (3.6 mL) dropwise, and the reaction mixture was stirred at −78° C. for 15 minutes. Iodomethane (0.3 mL, 4.86 mmol) was then added, and the reaction mixture was stirred at −78° C. for 15 minutes, then warmed to 0° C. over 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride (50 mL) and 10% aqueous citric acid, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (561 mg, assumed quantitative), which was used without further purification. LCMS (Method 1): 1.47 min, 345.0 [M+Na] + .

[0179] Intermediate 16: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-(2,4-dimethoxybenzyl)(1S,2R)-1-methylcyclopentane-1,2-dicarboxylate [ka] To a stirred solution of intermediate 15 (561 mg, 1.74 mmol) in DMF (1.5 mL) was added HATU (728 g, 1.91 mmol), and the resulting mixture was stirred at room temperature under argon for 5 minutes. DIPEA (0.33 mL, 1.91 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-50% EtOAc in isohexane) to give the title compound (307 mg, 40%). LCMS (Method 1): 1.62 min, 463.1 [M+Na] + .

[0180] Synthesis of Examples Example 1: 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one [ka] Process a To a stirred solution of intermediate 8 (3.65 g, 7.92 mmol) in DMF (14 mL) at room temperature under nitrogen, 4-(chloromethyl)-5-(difluoromethyl)-1-methyl-triazole (1.87 g, 10.3 mmol; CAS: 2138555-23-2) and cesium carbonate (7.74 g, 23.8 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. To this, water was added, and the mixture was extracted with EtOAc. The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g silica column Puriflash HC, 100% DCM followed by 0-30% EtOAc in DCM) to give tert-butyl (S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (4.07 g, 85%). LCMS (Method 1): 1.78 min, 628.1 [M+Na] + .

[0181] Process b To a stirred solution of the above intermediate (4.07 g, 6.72 mmol) in EtOH (34 mL) was added hydrazine monohydrate (1.26 mL, 16.8 mmol; CAS: 7803-57-8), and the resulting mixture was heated at 75° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate was concentrated in vacuo and dried in vacuo to give tert-butyl (S)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.04 g, 95%). LCMS (Method 1): 1.12 min, 476.2 [M+H] + .

[0182] Process c To a stirred solution of the above intermediate (3.04 g, 6.39 mmol) in toluene (26 mL) was added methyl 2-[1-(bromomethyl)cyclopropyl]acetate (1.46 g, 7.03 mmol; CAS: 855473-50-6) and triethylamine (1.34 mL, 9.58 mmol) and heated under reflux for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue was partitioned between DCM and brine. The organic phase was separated, and the aqueous solution was further extracted with DCM (×2). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give tert-butyl (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)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.06 g, 84%). LCMS (Method 1): 1.66 min, 592.2 [M+Na] + .

[0183] Process d A solution of the above intermediate (3.06 g, 5.37 mmol) in HCl in dioxane (4 M; 26.8 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, azeotroped with chloroform, and concentrated in vacuo to give (S)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (2.93 g, quantitative). LCMS (Method 1): 0.98 min, 470.1 [M+H] + .

[0184] Process e To a stirred solution of the above intermediate (6.93 g, 13.7 mmol) and Intermediate 12 (9.33 g, 20.5 mmol) in DMF (16 mL) was added DIPEA (4.74 mL, 27.4 mmol), and the resulting mixture was stirred at room temperature under argon for 5 days. To a stirred solution of the above intermediate (2.72 g, 5.37 mmol) and Intermediate 12 (3.66 g, 8.05 mmol) in DMF (6.3 mL) was added DIPEA (1.86 mL, 10.74 mmol), and the resulting mixture was stirred at room temperature under argon for 4 days. The two reaction mixtures were combined, diluted with EtOAc and saturated sodium bicarbonate solution, and the mixture was extracted with EtOAc. The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (300 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (4.1 g, 27%). LCMS (Method 2): 3.39 min, 788.5 [M+H] + The impure product-containing fractions were combined, concentrated in vacuo, and further purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (200 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give another batch of product (7.06 g, 8.96 mmol). LCMS (Method 2): 3.40 min, 788.6 [M+H] +Both batches were combined to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro-[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (11.16 g, 14.158 mmol, 55%), which was used without further purification.

[0185] process f To a stirred solution of the above intermediate (11.16 g, 14.16 mmol) in DCM (68 mL) was added triethylsilane (2.26 mL, 14.16 mmol) followed by TFA (1.09 mL, 14.16 mmol), and the resulting mixture was stirred at room temperature for 2 h. Additional TFA (0.28 mL, 3.54 mmol) was added, and the mixture was stirred for 0.5 h. The reaction mixture was concentrated in vacuo, and the residue was dried in vacuo for 18 h. The residue was taken up in DCM, filtered and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (300 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane), followed by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g silica column Puriflash HC, 0-50% methyl acetate in cyclohexane), then on a Teledyne ISCO CombiFlash® Rf+ (300 g silica column Puriflash HC, 0-50% methyl acetate in cyclohexane). The filtrate was purified by flash column chromatography (HCl, 1-10% MeOH in DCM) to give (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid as a solid (4.4 g). Impure product-containing fractions were combined, concentrated in vacuo, and purified by flash column chromatography to give additional product (1.26 g). Both batches were combined to give (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid (5.66 g, 63%). LCMS (Method 4): 4.68 min, 638.1 [M+H] + .1 H NMR(400MHz,CDCl3)δ 7.20(d,1H),6.82(t,1H),5.48(dd,1H),5.40(d,1H),5.23(d,1H),4.16(s,3H),4.06 (dd,1H),4.00-3.89(m,1H),3.83(m,1H),3.24(d,1H),3.13(d,1H),3.08(dd,1H),2.9 9(m,1H),2.67(m,1H),2.57(dd,1H),2.47-2.36(m,2H),2.07(d,1H),1.85-1.72(m,2H ),1.70-1.43(m,3H),1.41-1.23(m,1H),1.12(s,3H),1.03(m,1H),0.69-0.50(m,4H).

[0186] Process g To a stirred solution of the above intermediate (315 mg, 0.49 mmol), HATU (206 mg, 0.54 mmol; CAS: 148893-10-1) and ammonium chloride (29 mg, 0.54 mmol) in DMF (1.6 mL) was added DIPEA (0.17 mL, 0.99 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-5% MeOH in DCM) to give (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxamide (270 mg, 86%). LCMS (Method 2): 2.53 min, 637.4 [M+H] + .

[0187] Process h To a stirred solution of the above intermediate (240 mg, 0.38 mmol) in DCM (2.5 mL) was added trifluoroacetic anhydride (0.16 mL, 1.13 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-5% MeOH in DCM) to give (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carbonitrile (197 mg, 84%). LCMS (Method 1): 1.56 min, 619.3 [M+H] + .

[0188] Process i To a stirred solution of the above intermediate (145 mg, 0.23 mmol) and azidotributyltin(IV) (0.41 mL, 1.5 mmol; CAS: 17846-68-3), α,α,α-trifluorotoluene (4.0 mL) was added, and the resulting mixture was heated under microwave irradiation at 180° C. for 19 hours. In a separate tube, to a stirred solution of the above intermediate (25 mg, 0.04 mmol) and azidotributyltin(IV) (0.09 mL, 0.32 mmol; CAS: 17846-68-3), α,α,α-trifluorotoluene (0.8 mL) was added, and the resulting mixture was heated under microwave irradiation at 180° C. for 19 hours. The reaction mixtures were combined, concentrated in vacuo, and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-5% MeOH in DCM) followed by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane). The product-containing fractions were combined and concentrated in vacuo. The residue was dissolved in MeCN / water (1:1) and lyophilized to give the title compound (51 mg, 33%). LCMS (Method 3): 4.54 min, 662.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 15.53(bs,1H),7.53(d,1H),7.18(t,1H),5.40-5.28(m,2H),5.20(m,1H),4.0 9-3.96(m,4H),3.90(dd,1H),3.56(m,1H),3.18(m,1H),2.92(d,1H),2.88-2.7 8(m,2H),2.75(m,1H),2.68(d,1H),2.30-2.10(m,2H),2.02(d,1H),1.93-1.76 (m,2H),1.75-1.61(m,2H),1.61-1.37(m,3H),1.30(s,3H),0.73-0.24(m,4H).

[0189] Example 2: (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid [ka] Process a To a suspension of sodium hydride (60% dispersion in mineral oil; 1.33 g, 33.3 mmol; CAS: 7646-69-7) in DMF (10 mL) cooled to 0 ° C., methyl 2-hydroxyacetate (2.14 mL, 27.8 mmol; CAS: 96-35-5) was added dropwise, and the resulting mixture was stirred at room temperature under argon for 0.5 hours. To this was added 2-(2-bromoethoxy)tetrahydropyran (4.61 mL, 30.5 mmol; CAS: 17739-45-6), and the resulting mixture was warmed to room temperature and stirred for 4 hours. Water was added, and the mixture was extracted with EtOAc. The combined organic phase was washed with water, brine, dried over Na SO , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g silica column Puriflash HC / Biotage SNAP, 0-50% EtOAc in cyclohexane) to give methyl 2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)acetate (2.14 g, 35%). 1 H NMR(400MHz;CDCl3)δ 4.64(dd,1H),4.20-4.19(m,2H),3.93-3.83(m,2H),3.78-3.75(m,5H),3.68-3.62(m,1H),3.54-3.48(m,1H),1.90-1.50(m,6H).

[0190] Process b To a stirred solution of the above intermediate (2.14 g, 9.81 mmol) in MeOH (20 mL) was added pyridinium p-toluenesulfonate (49 mg, 0.20 mmol; CAS: 24057-28-1), and the resulting mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give methyl 2-(2-hydroxyethoxy)acetate (1.12 g, 85%). 1 H NMR(400MHz; CDCl3)δ 4.16(s,2H),3.78-3.74(m,5H),3.71-3.68(m,2H),2.71(t,1H).

[0191] Process c To a stirred solution of the above intermediate (1.12 g, 8.4 mmol), imidazole (0.85 g, 12.5 mmol), and triphenylphosphine (2.85 g, 10.9 mmol) in EtO (4.2 mL) and MeCN (2.1 mL) cooled in an ice bath, iodine (2.97 g, 11.7 mmol) was added, and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with EtOAc, filtered, and the filtrate was washed with aqueous sodium sulfite and brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g silica column Puriflash HC, 0–50% EtOAc in cyclohexane) to give methyl 2-(2-iodoethoxy)acetate (1.39 g, 68%). 1 H NMR(400MHz;CDCl3)δ 4.16(s,2H),3.83(t,2H),3.77(s,3H),3.30(t,2H).

[0192] Process d To a stirred solution of tert-butyl (S)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (290 mg, 0.61 mmol; Example 1, step b) in toluene (2.5 mL) was added the above intermediate (193 mg, 0.79 mmol) and triethylamine (0.13 mL, 0.910 mmol), and the reaction mixture was stirred at 120° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give tert-butyl (S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (229 mg, 67%). LCMS (Method 1): 1.56 min, 582.2 [M+Na] + .

[0193] Process e A solution of hydrochloric acid (4 M in dioxane; 2.04 mL, 8.18 mmol) was added to the above intermediate (229 mg, 0.410 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and azeotroped with toluene to give (S)-4-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)morpholin-3-one hydrochloride (219 mg, quantitative). LCMS (Method 1): 0.85 min, 460.1 [M+H] + .

[0194] process f To a stirred solution of the above intermediate (203 mg, 0.41 mmol) and intermediate 12 (279 mg, 0.61 mmol) in DMF (1 mL) was added DIPEA (0.14 mL, 0.82 mmol), and the reaction mixture was stirred at room temperature under argon for 6 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (173 mg, 54%). LCMS (Method 1): 1.70 min, 778.3 [M+H] + .

[0195] Process g To a stirred solution of the above intermediate (173 mg, 0.22 mmol) in DCM (2 mL) was added triethylsilane (0.04 mL, 0.22 mmol) followed by TFA (0.02 mL, 0.22 mmol), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica column Puriflash HC, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo, and the residue was taken up in MeCN / water (1:1) and lyophilized to afford the title compound (94.3 mg, 67%). LCMS (Method 3): 4.45 min, 628.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.88(bs,1H),7.54(d,1H),7.34(t,1H),5.52(dd,1H),5.44(d,1H),5.25( d,1H),4.31(dd,1H),4.14(s,3H),3.98(d,1H),3.90(m,1H),3.84-3.70(m,2 H),3.69-3.50(m,2H),3.26(m,1H),2.98-2.86(m,2H),2.84-2.83(m,2H),2 .62(m,1H),2.19(m,1H),1.68-1.49(m,3H),1.47-1.19(m,4H),1.10(s,3H).

[0196] Example 3: (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid [ka] Process a To a stirred solution of (R)-4-methyldihydrofuran-2(3H)-one (13.4 g, 134 mmol, CAS: 65284-00-6) in EtOH (250 mL) at −20° C., trimethylsilyl iodide (38.1 mL, 268 mmol) was added dropwise. The solution was stirred at −20° C. for 30 minutes. Triethyl orthoformate (22.3 mL, 134 mmol) was then added, and the reaction was stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 5% EtOAc in heptane) to give ethyl (R)-4-iodo-3-methylbutanoate (24.3 g, 71%). 1 H NMR(300MHz,CDCl3)δ 4.15(q,2H),3.32-3.23(m,2H),2.46(dd,1H),2.24(dd,1H),2.07-1.99(m,1H),1.30-1.25(t,3H),1.06(d,3H).

[0197] Process b To a stirred solution of tert-butyl (S)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (145 mg, 0.30 mmol; Example 1, step b) in toluene (1.3 mL) was added the above intermediate (101 mg, 0.40 mmol) and triethylamine (0.06 mL, 0.46 mmol) and the reaction mixture was heated at 120° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine and extracted with DCM, and the combined organic phases were washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 15 um, 0-100% EtOAc in cyclohexane) to give tert-butyl (S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (89 mg, 52%). LCMS (Method 1): 1.63 min, 580.2 [M+Na] + .

[0198] Process c Hydrochloric acid (4 M in dioxane; 0.8 mL, 3.2 mmol) was added to the above intermediate (89 mg, 0.16 mmol), and the resulting reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (R)-1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-4-methylpyrrolidin-2-one hydrochloride (83 mg, quantitative). LCMS (Method 1): 0.93 min, 458.1 [M+H] + .

[0199] Process d To a stirred solution of the above intermediate (79 mg, 0.16 mmol) in DMF (0.5 mL) was added Intermediate 12 (109 mg, 0.24 mmol) and DIPEA (0.06 mL, 0.32 mmol), and the resulting mixture was stirred at room temperature under argon for 6 days. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc, and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (44 mg, 36%). LCMS (Method 1): 1.75 min, 776.3 [M+H] + .

[0200] Process e To a stirred solution of the above intermediate (44 mg, 0.060 mmol) in DCM (0.5 mL), triethylsilane (0.01 mL, 0.06 mmol) was added followed by TFA (0.004 mL, 0.06 mmol), and the reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. Purification was carried out by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica column Puriflash HC, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was taken up in acetonitrile / water (1:1) and lyophilized to give the title compound (26 mg, 71%). LCMS (Method 3): 4.61 min, 626.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.97(bs,1H),7.52(d,1H),7.35(t,1H),5.48-5.38(m,2H),5.21(d,1H),4.14(s,3H),3.98-3.80(m,2H),3.56(m,1H),3.02(m,1H),2 .95-2.71(m,4H),2.70-2.57(m,1H),2.37-2.22(m,2H),2.16(m,1H),1.73-1.50(m,4H),1.48-1.15(m,4H),1.08(s,3H),0.98(d,3H).

[0201] Example 4: (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid [ka] Process a To a stirred solution of methyl 2-(pyridin-2-yl)acetate (5.0 g, 33.1 mmol, CAS: 1658-42-0) in MeCN (83 mL) was added 4-acetamidobenzenesulfonyl azide (7.95 g, 33.1 mmol, CAS: 2158-14-7), and the reaction mixture was cooled to 0 °C under argon. To this was added DBU (3.97 mL, 33.1 mmol) dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. To this was added saturated ammonium chloride solution, and the mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on an Interchim 4125 (120 g silica column Puriflash HP, 0-15% EtOAc in DCM) gave methyl [1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (5.48 g, 89%). 1H NMR(400MHz,CDCl3)δ 8.86-8.83(m,1H),8.31-8.28(m,1H),7.56(ddd,1H),7.19-7.15(m,1H),4.06(s,3H).

[0202] Process b To a stirred solution of the above intermediate (2.0 g, 11.3 mmol) in EtOH (455 mL) was added Pd / C (10%; 1.20 g, 11.3 mmol), and the reaction mixture was degassed and filled with hydrogen (×3). The reaction mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. The mixture was filtered through Celite® and concentrated in vacuo to give methyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (1.98 g, 99%). 1 H NMR(400MHz, CDCl3)δ:4.41(t,2H),3.94(s,3H),3.11(t,2H),2.13-2.06(m,2H),1.98-1.91(m,2H).

[0203] Process c To a stirred suspension of the above intermediate (1.96 g, 11.1 mmol) in THF (88 mL) was added lithium borohydride (2 M in THF; 10.0 mL, 19.9 mmol) dropwise over 10 min. The reaction was stirred at room temperature under argon for 20 h. The reaction mixture was cooled to 0 °C, diluted with 10% citric acid (33 mL), and then extracted with DCM. The combined organic phases were washed with water and concentrated in vacuo. The crude product was purified by Interchim PuriFlash® 4100 (80 g silica column Puriflash HP, 0-30% EtOAc in DCM) to give (4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (620 mg, 35%). 1 H NMR(400MHz,CDCl3)δ 4.76(s,2H),4.38(t,2H),2.92-2.88(m,3H),2.17-2.10(m,2H),2.05-1.95(m,2H).

[0204] Process d Thionyl chloride (0.59 mL, 8.1 mmol) was added to the above intermediate (620 mg, 4.1 mmol). Chloroform (6.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, azeotroped with toluene (×2), and concentrated in vacuo to give 3-(chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine (702 mg, assumed quantitative), which was used without further purification. LCMS (Method 1): 0.90 min, 171.9 [M+H] + .

[0205] Process e To a stirred solution of intermediate 8 (434 mg, 0.94 mmol) in DMF (3 mL) was added the above intermediate (210 mg, 1.22 mmol) and cesium carbonate (920 mg, 2.82 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic phases were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in DCM) gave tert-butyl (S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (425 mg, 76%). LCMS (Method 1): 1.76 min, 596.2 [M+H] + .

[0206] process f To a stirred solution of the above intermediate (425 mg, 0.71 mmol) in EtOH (3.6 mL), hydrazine monohydrate (0.13 mL, 1.78 mmol; CAS: 7803-57-8) was added, and the reaction mixture was heated at 75° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate was concentrated in vacuo to give tert-butyl (S)-1-(aminomethyl)-5-chloro-7-fluoro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (298 mg, 85%). LCMS (Method 1): 1.07 min, 466.2 [M+H] + .

[0207] Process g To a stirred solution of the above intermediate (298 mg, 0.64 mmol) in toluene (3 mL) was added methyl 2-[1-(bromomethyl)cyclopropyl]acetate (146 mg, 0.70 mmol; CAS: 855473-50-6) and triethylamine (0.13 mL, 0.96 mmol), and the mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine and extracted with DCM, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-90% EtOAc in DCM) gave tert-butyl (S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (321 mg, 90%). LCMS (Method 1): 1.66 min, 582.3 [M+Na] + .

[0208] Process h Hydrochloric acid (4 M in dioxane; 2.9 mL, 11.5 mmol) was added to the above intermediate (321 mg, 0.57 mmol), and the resulting reaction mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (S)-5-((5-chloro-7-fluoro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (294 mg, 98%). LCMS (Method 1): 1.01 min, 460.2 [M+H] + .

[0209] Process i To a stirred solution of the above intermediate (135 mg, 0.27 mmol) and Intermediate 16 (204 mg, 0.47 mmol) in DMF (0.4 mL) was added DIPEA (0.1 mL, 0.60 mmol), and the reaction mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in DCM) gave 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylate (154 mg, 74%). LCMS (Method 1): 1.68 min, 764.4 [M+H] + .

[0210] Process j To a stirred solution of the above intermediate (154 mg, 0.20 mmol) in DCM (2.0 mL) at 0 °C, triethylsilane (0.14 mL, 0.89 mmol) was added followed by TFA (0.03 mL, 0.45 mmol), and the resulting mixture was stirred at room temperature for 1 h 15 min. Additional triethylsilane (0.04 mL, 0.22 mmol) and TFA (0.02 mL, 0.22 mmol) were added, and stirring was continued at room temperature for an additional 45 min. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene (×2). Purification by flash column chromatography on an Interchim PuriFlash® 4125 (40 g 15 μm silica column Puriflash HP, 0-5% MeOH in DCM) afforded the title compound (57 mg, 43%). LCMS (Method 3): 4.33 min, 614.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.11(d,1H),5.60(dd,1H),5.23(m,1H),5.15(m,1H),4.42(m,1H),4.3 1(m,1H),4.01(dd,1H),3.84(m,2H),3.35(d,1H),3.13-3.01(m,2H),2 .94(m,1H),2.87-2.65(m,5H),2.55(m,1H),2.34(d,1H),2.21-2.00(m ,4H),1.98-1.65(m,4H),1.44(m,1H),1.28(s,3H),0.66-0.50(m,4H).

[0211] Example 5: (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid [ka] Process a To a stirred solution of intermediate 8 (300 mg, 0.65 mmol) in DMF (1.2 mL) were added 3-(chloromethyl)-4,5-dimethyl-1,2,4-triazole (123 mg, 0.85 mmol; CAS: 881845-16-5) and cesium carbonate (636 mg, 1.95 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 4 hours. Additional 3-(chloromethyl)-4,5-dimethyl-1,2,4-triazole (19 mg, 0.13 mmol) and cesium carbonate (106 mg, 0.33 mmol) were added, and the resulting mixture was stirred for an additional hour. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column PuriflashHC, 0-5% MeOH in DCM) gave tert-butyl (S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (331 mg, 89%). LCMS (Method 1): 1.47 min, 570.2 [M+H] + .

[0212] Process b To a stirred solution of the above intermediate (331 mg, 0.58 mmol) in EtOH (3 mL) was added hydrazine monohydrate (0.11 mL, 1.45 mmol; CAS: 7803-57-8), and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate was concentrated in vacuo to give tert-butyl (S)-1-(aminomethyl)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (229 mg, 90%). LCMS (Method 1): 1.00 min, 440.1 [M+H] + .

[0213] Process c To a stirred solution of the above intermediate (229 mg, 0.52 mmol) in toluene (2.1 mL), methyl 2-[1-(bromomethyl)cyclopropyl]acetate (119 mg, 0.57 mmol; CAS: 855473-50-6) and triethylamine (0.11 mL, 0.780 mmol) were added, and the reaction mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, extracted with DCM, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-5% MeOH in DCM) gave tert-butyl (S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (95 mg, 34%). LCMS (Method 1): 1.36 min, 534.2 [M+H] + .

[0214] Process d Hydrochloric acid (4 M in dioxane; 0.89 mL, 3.56 mmol) was added to the above intermediate (95 mg, 0.18 mmol), and the resulting reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (S)-5-((5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (110 mg, assumed quantitative). LCMS (Method 2): 1.90 min, 434.3 [M+H] + .

[0215] Process e To a stirred solution of the above intermediate (84 mg, 0.18 mmol) and Intermediate 12 (121 mg, 0.27 mmol) in DMF (0.5 mL) was added DIPEA (0.06 mL, 0.36 mmol), and the resulting mixture was stirred at room temperature under argon for 3 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-5% MeOH in DCM) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (72 mg, 54%). LCMS (Method 1): 1.51 min, 752.3 [M+H] + .

[0216] process f To a stirred solution of the above intermediate (72 mg, 0.10 mmol) in DCM (0.9 mL) was added triethylsilane (0.02 mL, 0.10 mmol) followed by TFA (0.01 mL, 0.10 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was taken up in MeCN / water (1:1) and lyophilized to give the title compound (24 mg, 41%). LCMS (Method 3): 3.78 min, 602.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.84(bs,1H),7.55(d,1H),5.61(dd,1H),5.38-5.26(m,2H),4.03-3.88( m,2H),3.57(m,1H),3.51(s,3H),3.06(d,1H),3.00(m,1H),2.87(dd,1H), 2.80(dd,1H),2.72-2.59(m,2H),2.40-2.24(m,4H),2.21(d,1H),2.07(d, 1H),1.72-1.48(m,3H),1.47-1.17(m,4H),1.11(s,3H),0.63-0.43(m,4H).

[0217] Example 6: (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid [ka] Process a To a stirred solution of intermediate 8 (300 mg, 0.65 mmol) in DMF (1.2 mL) was added 4-(chloromethyl)-1-methyl-triazole (111 mg, 0.85 mmol; CAS: 269726-46-7) and cesium carbonate (636 mg, 1.95 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give tert-butyl (S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (332 mg, 92%). LCMS (Method 1): 1.68 min, 578.2 [M+Na] + .

[0218] Process b To a stirred solution of the above intermediate (332 mg, 0.60 mmol) in ethanol (3 mL) was added hydrazine monohydrate (0.11 mL, 1.49 mmol; CAS: 7803-57-8), and the resulting mixture was heated at 75 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate was concentrated in vacuo to give tert-butyl (S)-1-(aminomethyl)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (264 mg, assumed quantitative). LCMS (Method 1): 1.05 min, 426.1 [M+H] + .

[0219] Process c To a stirred solution of the above intermediate (254 mg, 0.60 mmol) in toluene (2.4 mL), methyl 2-[1-(bromomethyl)cyclopropyl]acetate (136 mg, 0.66 mmol; CAS: 855473-50-6) and triethylamine (0.12 mL, 0.89 mmol) were added, and the reaction mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, extracted with DCM, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give tert-butyl (S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (199 mg, 64%). LCMS (Method 1): 1.54 min, 542.2 [M+Na] + .

[0220] Process d Hydrochloric acid (4 M in dioxane; 1.9 mL, 7.65 mmol) was added to the above intermediate (199 mg, 0.38 mmol), and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give (S)-5-((5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (217 mg, assumed quantitative). LCMS (Method 1): 0.90 min, 420.1 [M+H] + .

[0221] Process e To a stirred solution of the above intermediate (175 mg, 0.38 mmol) and intermediate 12 (261 mg, 0.58 mmol) in DMF (0.5 mL) was added DIPEA (0.13 mL, 0.77 mmol), and the reaction mixture was stirred at room temperature under argon for 3 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc, and the combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (177 mg, 63%). LCMS (Method 1): 1.66 min, 738.3 [M+H] + .

[0222] process f To a stirred solution of the above intermediate (177 mg, 0.24 mmol) in DCM (2.2 mL), triethylsilane (0.04 mL, 0.24 mmol) was added followed by TFA (0.02 mL, 0.24 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica column Puriflash HC, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo to give the title compound (94 mg, 67%). 44 mg of the product was dissolved in MeCN / water (1:1) and lyophilized to give the title compound (37 mg, 25%). LCMS (Method 3): 4.26 min, 588.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.91(bs,1H),8.18(s,1H),7.50(d,1H),5.68(dd,1H),5.30(m,1H),5.2 2(m,1H),4.03(s,3H),4.00-3.88(m,2H),3.57(m,1H),3.28(d,1H),3.05- 2.95(m,2H),2.84-2.71(m,2H),2.64(m,1H),2.35-2.16(m,2H),2.10(d,1 H),1.73-1.48(m,3H),1.47-1.19(m,4H),1.10(s,3H),0.65-0.44(m,4H).

[0223] Example 7: (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid [ka] Process a A mixture of azidomethyl 2,2-dimethylpropanoate (2.36 g, 15 mmol; CAS: 872700-68-0) and 2-butyn-1-ol (1.05 g, 15 mmol; CAS: 764-01-2) was heated in a sealed vial under argon at 110 °C for 12 h. The mixture was cooled to room temperature and purified by flash column chromatography (silica, 0-80% EtOAc in cyclohexane) to give (4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)methyl pivalate (1.5 g, 44%). LCMS (Method 1): 1.05 min, 228.1 [M+H] + .

[0224] Process b To a stirred suspension of Intermediate 8 (5 g, 10.9 mmol) in EtOH (100 mL) was added hydrazine monohydrate (2.03 mL, 27.12 mmol; CAS: 7803-57-8), and the resulting mixture was heated at 85° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate was concentrated in vacuo to give tert-butyl (S)-1-(aminomethyl)-5-chloro-7-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.7 g, 95%). LCMS (Method 2): 2.17 min, 331.2 [M+H] +

[0225] Process c To a stirred solution of the above intermediate (3.4 g, 10.8 mmol) in toluene (75 mL) was added methyl 1-(bromomethyl)cyclopropaneacetate (2.6 g, 12.3 mmol; CAS: 855473-50-6) and triethylamine (2.6 mL, 18.5 mmol) in toluene (75 mL) and heated under reflux for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue was partitioned between EtOAc and water. The organic phase was separated, and the aqueous layer was further extracted with DCM. The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 0-50% EtOAc in DCM) to give tert-butyl (S)-5-chloro-7-fluoro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.6 g, 60%). LCMS (Method 1) 1.61 min, 447.1 [M+Na] +

[0226] Process d To a suspension of the above intermediate (1 g, 2.4 mmol) in 1,4-dioxane (2 mL), HCl in dioxane (4 M; 5.6 mL, 23.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the solid was azeotroped with MeOH and then MeOH / toluene to give (S)-5-((5-chloro-7-fluoro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (0.85 g, quantitative). LCMS (Method 1): 0.83 min, 324.9 [M+H] + .

[0227] Process e To a stirred solution of the above intermediate (0.85 g, 2.35 mmol) and intermediate 12 (1.6 g, 3.53 mmol) in DMF (6 mL) was added DIPEA (1 mL, 5.88 mmol), and the resulting mixture was stirred at room temperature for 24 hours. An additional portion of intermediate 12 (1 g, 2.2 mmol) and DIPEA (1 mL, 5.88 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc and saturated citric acid solution, and the mixture was extracted with EtOAc. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera Four™ (40 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (0.59 g, 39%). LCMS (Method 1): 1.68 min, 643.2 [M+H] +

[0228] process f To a solution of the above intermediate (0.58 g, 0.9 mmol), (4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)methyl pivalate (0.23 g, 0.99 mmol, Example 7, Step a) and triphenylphosphine (0.31 g, 1.17 mmol) in THF (5 mL) was added DEAD (0.21 mL, 1.35 mmol) dropwise. The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera Four™ (40 g silica column Puriflash HC 50 μM, 0-50% EtOAc in cyclohexane) followed by a Biotage Isolera Four™ (40 g silica column Puriflash HC 50 μM, 0-40% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (0.56 g, 73%). LCMS (Method 1) 1.93 min, 852.3 [M+H] + .

[0229] Process g To a solution of the above intermediate (0.55 g, 0.65 mmol) in DCM (3.6 mL) was added triethylsilane (0.52 mL, 3.23 mmol) followed by TFA (0.2 mL, 2.6 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and DCM, and the phases were separated. The organic phase was washed with water and filtered through a phase separator. The crude product was purified by flash column chromatography on a Biotage Isolera Four™ (40 g silica column Puriflash HC 50 μM, 0-5% MeOH in DCM) to give (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid (0.35 g, 77%). LCMS (Method 1): 1.70 min, 702.3 [M+H] + .

[0230] Process h To a solution of the above intermediate (0.35 g, 0.49 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (82.4 mg, 1.97 mmol) in water (0.5 mL), and the resulting solution was stirred at room temperature for 1 h. Ammonia (30-33 wt % aqueous solution; 0.5 mL) was added, and the mixture was stirred at room temperature for 18 h. The solution was diluted with EtOAc and water and then acidified to pH 5 by dropwise addition of HCl (1 M). The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera Four™ (40 g silica column Puriflash HC 15 μm, 5-80% EtOAc in cyclohexane) to give the title compound (60 mg, 21%). LCMS (Method 3) 4.27 min, 588.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 14.78(bs,1H),11.92(bs,1H),7.52(d,1H),5.79(dd,1H),5.28(dd,1H),5.18( dd,1H),4.03-3.90(m,2H),3.58(m,1H),3.18(d,1H),3.01(m,1H),2.90(dd,1H ),2.80(dd,1H),2.67(m,1H),2.55(d,1H),2.36-2.23(m,4H),2.19(d,1H),2.0 9(d,1H),1.72-1.47(m,3H),1.46-1.15(m,4H),1.11(s,3H),0.63-0.42(m,4H).

[0231] Biological assays KEAP1 Kelch Fluorescence Polarization (FP) Assay Inhibition of Kelch domain-NRF2 interaction was determined using a fluorescence polarization-based competition assay in black 384-well microplates. Compounds were tested at a starting concentration of 10 μM serially diluted 1:3 to generate 12-point dose-response curves on a Biomek FX robot. Each well contained 2 nM FITC-labeled NRF2 peptide (FITC-LDEETGEFL-NH2) and 25 nM human KEAP1 (N-terminus, residues 321-609) enzyme in a final volume of 20 μL of assay buffer (50 mM Tris-HCl pH 8.0, 100 mM NaCl, 5 mM MgCl2, 0.005% Tween-20, 0.005% BSA, 0.5% DMSO) in the presence of various concentrations of test compound. 50 μM unlabeled peptide (LDEETGEFL-NH2) (negative control) and 0.5% DMSO (positive control) were used to determine the assay window.

[0232] After 1 hour at room temperature, fluorescence polarization (excitation 470 nm / emission 530 nm) was measured using an Envision plate reader. 50Values ​​were determined by fitting the data to a four-parameter logistic fit using XLift or XE Runner in ActivityBase. The assay limit is when compounds below 10 nM cannot be distinguished. IC of example compounds 50 The values ​​are shown in Table 1 (NT = not tested).

[0233] [Table 3]

[0234] Beas2B NQO1 mRNA cell line assay The upregulation of the NRF2-mediated gene NAD(P)H:quinone receptor oxidoreductase 1 (NQO1) was measured using the following assay method: BEAS-2B cells (ATCC CRL-9609) were seeded in 96-well clear plates at 20,000 cells / well in 75 μL of cell culture medium and incubated overnight (37°C, 5% CO2). On day 2, 25 μL of compound or control was added to the cells for 24 hours. On day 3, the medium was aspirated from the plates, and expression analysis was performed directly from the cultured cells without RNA purification using the Cells-to-CT™ 1-Step TaqMan® Kit (Ambion A25603) according to the manufacturer's instructions.

[0235] 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 sample was diluted 1:5 using nuclease-free water, and 2.5 μL was transferred to a PCR plate. Real-time PCR was performed using a C-1000 thermal cycler (Bio-Rad) with human beta-actin as an internal standard. cDNA was amplified with primers specific for NQO1 using a 1-step RT-PCR master mix (Ambion Cells-to-CT™ 1-Step TaqMan® Kit A25603). The primer / probe set used for cDNA amplification was obtained from TaqMan Gene Expression Assays (Applied Biosystems). The comparative C (ΔΔC) relative quantification method was used to calculate the relative mRNA levels of the target gene NQO1 as described in the Applied Biosystems Chemistry Guide. Data are expressed as the increase in target gene mRNA compared to the vehicle (0.1% DMSO) control and are expressed as EC 50 Values ​​were determined by fitting the data to a four parameter logistic fit using XLift or XE Runner in ActivityBase. EC for example compounds 50 The values ​​are shown in Table 2 (NT = not tested).

[0236] [Table 4]

[0237] PK / PD method Male Wistar Han rats (Charles River labs) were dosed orally or intravenously with the test article at the specified dose levels. Intravenous doses were administered as a slow bolus via the tail vein. Oral formulations were administered into the stomach by gavage. The actual dose time was recorded.

[0238] At the designated time points, two 0.25 mL blood samples were collected via the tail vein into K2EDTA blood tubes, which were then centrifuged for plasma or decanted into 1.5 mL PCR RNAlater tubes containing 650 μL of RNAlater.

[0239] Immediately after collection, blood samples were placed on wet ice. As soon as practical, 0.25 mL blood samples in K2EDTA were centrifuged (+4°C, 1500g, 10 min), and the resulting plasma was placed in appropriately labeled polypropylene tubes and stored in a freezer set to maintain a temperature of -80°C until plasma pharmacokinetics were measured. An additional 0.25 mL blood sample in a 1.5 mL PCR RNAlater tube containing 650 μL of RNAlater was stored in a refrigerator at 4°C until blood pharmacokinetics were measured.

[0240] After the final sample collection, each animal was sacrificed as soon as practical by anesthetic overdose via IP injection of pentobarbitone Na, and death was confirmed by cervical dislocation.

[0241] The lungs were removed from each animal and divided into four equal pieces immediately after removal. The first two lung sections (labeled 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 the RNA (PD analysis). The remaining two sections (labeled left and right) were weighed and flash-frozen in polypropylene tubes by immersion in liquid nitrogen (PK analysis).

[0242] Liver was also collected from each animal. Six representative pieces (smaller than the lung pieces) (≤0.5 cm thick) from different regions were collected. Four pieces (≤0.5 cm thick) were placed in two separate 5 mL RNAlater tissue protection tubes (two pieces per tube) containing 5 mL of RNAlater stabilization reagent (tissue sections were completely immersed in the RNAlater solution) and stored at 4°C (PD analysis). The remaining two pieces were weighed and flash-frozen in separate polypropylene tubes by immersion in liquid nitrogen (maximum 0.5 g per tube, PK analysis).

[0243] 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 5 mL RNAlater tissue-protecting tubes containing 5 mL RNAlater stabilization reagent and stored at 4°C. The remaining two pieces were weighed, placed in individual polypropylene tubes, and flash-frozen by immersion in liquid nitrogen.

[0244] Test sample tubes containing RNAlater RNA stabilization reagent were stored at approximately +4°C to allow the RNA stabilization reagent to perfuse into the tissue. Snap-frozen sections were stored in a freezer set to maintain a temperature of -80°C.

[0245] PK study samples were quantified using a method based on protein precipitation and LC-MS / MS analysis. Prior to analysis, thawed tissue samples were weighed and homogenized at 4°C using an Omni-Prep Bead Ruptor (Omni Inc., Kennesaw, GA) after the addition of HPLC-grade water. Plasma and tissue homogenate samples were extracted using protein precipitation with acetonitrile acidified with 0.1% formic acid containing an internal standard. Samples were mixed and centrifuged at 4000 rpm for 30 minutes at 4°C to remove precipitated proteins, and the supernatant was appropriately diluted with HPLC-grade water in a 96-well plate. Representative aliquots of plasma and tissue homogenate were assayed for the test article by LC-MS / MS using a Waters Xevo TQ-S (Waters, Elstree, UK) against matrix-matched calibration curves and quality control standards. Standards were prepared by spiking test article into aliquots of control plasma and tissue homogenate and extracted as described for the experimental samples.

[0246] RNA extraction and real-time PCR analysis for NQO1 gene expression in the in vivo PD study were performed as detailed below.

[0247] Total RNA was isolated using the RNeasy plus mini RNA isolation kit (Qiagen) or the Mouse Ribopure™ Blood RNA isolation kit (ThermoFisher Scientific) according to the manufacturer's instructions and quantified using an Agilent 6000 Nano instrument. Real-time PCR was performed using a C-1000 thermal cycler (Bio-Rad) with rat beta-actin as an internal standard. cDNA was amplified with specific primers for NQO1 / Nqo1 using a universal master mix (Applied Biosystems). The primer / probe set used for cDNA amplification was obtained from TaqMan Gene Expression Assays (Applied Biosystems). The comparative C (ΔΔC) relative quantification method was used to calculate the relative mRNA levels of the target gene NQO1 as described in the Applied Biosystems Chemistry Guide. Data are expressed as the increase in target gene mRNA compared to the solvent-treated control for each tissue type.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ is C １～４ Alkylene-R ４ and R ２ CO ２ H and tetrazolyl; R ３ is selected from hydrogen and methyl; X is CR ５ R ６ or O; R ４ is 1,2,3-triazolyl, 1,2,4-triazolyl or pyrimidinyl, said triazolyl or pyrimidinyl group being C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-C ３～７ Cycloalkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy and cyano; and optionally fused to a cycloalkyl or heterocyclyl ring; R ５ is hydrogen, C １～４ Alkyl, C ３～７ Cycloalkyl and C １～３ haloalkyl; and R ６ is hydrogen and C １～４ alkyl; or R ５ and R ６ together with the carbon atom to which they are attached form a 3- or 4-membered cycloalkyl ring; m is 0 or 1; and n is 1 or 2. or a pharma- ceutical acceptable salt thereof, provided that the compound of formula I is the following compound: (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; or (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid or a pharma- ceutically acceptable salt thereof, provided that the compound is not one of:

2. The compound has the following structural formulas IA-IK: 【Chemistry 2】 (In the formula, R １ ~R ６ , X and m are as defined in claim 1. or a pharma- ceutically acceptable salt thereof.

3. R １ is CH ２ -R ４ 3. The compound of claim 1 or 2, wherein:

4. R ２ CO ２ The compound according to any one of claims 1 to 3, wherein R is H, or a pharma- ceutically acceptable salt thereof.

5. R ３ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

6. R ４ is C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl and C １～４ Alkylene-C ３～７ 6. The compound of any one of claims 1 to 5, which is 1,2,3-triazolyl optionally substituted with one or more substituents independently selected from cycloalkyl, or a pharma- ceutically acceptable salt thereof.

7. R ４ is C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl and C １～４ Alkylene-C ３～７ 6. The compound of any one of claims 1 to 5, which is 1,2,4-triazolyl optionally substituted with one or more substituents independently selected from cycloalkyl, or a pharma- ceutically acceptable salt thereof.

8. R ４ is C １～４ Alkyl and C １～３ 6. The compound of any one of claims 1 to 5, which is pyrimidinyl optionally substituted with one or more substituents independently selected from haloalkyl, or a pharma- ceutically acceptable salt thereof.

9. R ４ is the following group: 【Chemistry 3】 and the group is selected from one of １～４ Alkyl and C １～３ 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, optionally substituted with fluoroalkyl.

10. R ４ is the following group: 【Chemistry 4】 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, selected from one of:

11. X is CR ５ R ６ 11. The compound according to any one of claims 1 to 10, wherein:

12. R ５ is methyl, and R ６ The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

13. R ５ and R ６ or a pharma- ceutically acceptable salt thereof, wherein, together with the carbon atom to which they are attached, form a cyclopropyl ring.

14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein m is 1.

15. The compound of claim 1, wherein the compound has the structural formula IL: 【Chemistry 5】 (In the formula, R ５ and R ６ is as defined in claim 1, and R ７ and R ８ is hydrogen, C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-C ３～７ Cycloalkyl, halo, OH, C １～３ or R is independently selected from alkoxy and cyano; ７ and R ８ together with the atom to which they are attached form a 5- or 6-membered heterocyclyl ring.

2. The compound of claim 1 having the formula:

16. R ５ is methyl, and R ６ or a pharma- ceutically acceptable salt thereof.

16. The compound of claim 15, wherein:

17. R ５ and R ６ or a pharma- ceutically acceptable salt thereof, wherein: together with the carbon atom to which they are attached form a cyclopropyl ring.

18. R ７ is methyl, and R ８ The compound according to any one of claims 15 to 17, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen, methyl or difluoromethyl.

19. 5-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-2-((1R,2S)-2-methyl-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; and (1S,2R)-2-((S)-5-chloro-7-fluoro-8-((5-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; 2. The compound of claim 1, selected from:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharma- ceutically acceptable salt thereof.

21. 21. A pharmaceutical composition according to claim 20 for use in therapy.

22. 21. The pharmaceutical composition of claim 20 for use in the treatment of a disease or disorder mediated by Nrf2 activation.

23. 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 pulmonary fibrosis of unknown etiology, cystic fibrosis, COVID-19, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, sarcopenia, obesity, metabolic syndrome, diabetes mellitus, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis 21. The pharmaceutical composition of claim 20, for use in the treatment of chronic kidney disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport 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' endothelial corneal dystrophy, uveitis or pre-eclampsia.

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