EA045906B1 - THERAPEUTIC COMPOUNDS - Google Patents

Description

Introduction

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

BACKGROUND OF THE INVENTION

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper domain (bZIP) transcription factor and is a member of the Cap 'n' Collar (CNC) family of transcription factors. It is a major key in the inducible cellular defense system, mediating the expression of more than 100 genes associated with oxidative stress, which include phase I and II detoxification enzymes and antioxidant proteins. All of these genes contain an antioxidant response element (ARE) in the regulatory regions of their promoters, which is a target for Nrf2 binding. Under basal conditions, Nrf2 levels are tightly controlled by the adapter protein Keap1, a cytosolic actin-linked repressor protein that binds to Nrf2 and leads to proteasomal degradation via the Cul3-based E3 ubiquitin ligase complex. Under conditions of oxidative stress, Keapl is inactivated, which leads to an increase in the level of de novo synthesized Nrf2, which undergoes translocation into the nucleus, binds to ARE, and an increase in the expression of cytoprotective genes occurs.

It was shown that Nrf2 mRNA expression in subjects with COPD was significantly lower than that in control subjects, and Nrf2 mRNA levels were negatively correlated with the number of conditional years of smoking. Nrf2 protein levels in subjects with COPD were significantly lower than those in control subjects. Apoptosis of A549 cells induced by CSE increased in a time-dependent and concentration-dependent manner and was significantly increased by Nrf2 knockdown (Yamada, BMC Pulmonary Medicine, doi: 10.1186/s12890-016-0189-1). Therefore, increasing Nrf2 levels in the lungs of patients with COPD should reduce the intensity of inflammatory processes that lead to detrimental modifications of lung structure and slow disease progression. Nrf2 can also be expected to show beneficial results in other respiratory diseases in which oxidative stress components are present (Cho, Toxicol Appl Pharmacol, doi: 10.1016/j.taap.2009.07.024), such as acute, chronic and severe asthma (Sussan , Am J Physiol Lung Cell Mol Physiol, doi: 10.1152/ajplung.00398.2014), acute lung injury/acute respiratory distress syndrome with or without associated 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 idiopathic pulmonary fibrosis (Kikuchi, Respir Res, doi: 10.1186/1465-9921-11-31) and cystic fibrosis (Chen, PLoS One, doi:10.1371/journal.pone.0003367).

Nrf2 has been demonstrated to provide cardiac protection in models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, and heart failure (Chen, Physiol Genomics, doi: 10.1152/physiolgenomics.00041.2017). A phase II study of the Nrf2 activator, bardoxolone methyl, in patients with pulmonary arterial hypertension (PAH) was recently completed, and a phase III study is ongoing based on significant improvements in 6-minute walking distance. Bardoxolone reacts with Keap1 to form a covalent bond, but compounds that activate Nrf2 through mechanisms alternative to Keap1 binding would also be expected to be therapeutically useful in RAS, especially in patients who also have a concomitant connective tissue disorder (CTD). ), such as scleroderma or lupus erythematosus. Oxidative stress is increased in the diseased myocardium, leading to increased levels of reactive oxygen species, which have a negative effect on cardiac function (Bolli, Circ, doi: 10.1161/circ.76.2.3111744). Activation of Nrf2 has been shown to suppress oxidative stress, cardiac cell apoptosis, hypertrophy, fibrosis, and myocardial dysfunction in mouse models of pressure overload (Wang, J Card Failure, doi: 10.1016/j.cardfail.2012.06.003) and protect against ischemic/ of cardiac reperfusion injury in rodent models (Zhang, J Mol Cell Cardiol, doi: 10.1016/j.yjmcc.2010.05.01). In addition, excessive production of oxidants, detrimental to antioxidant defense mechanisms in the cardiovascular system, has also been described in metabolic diseases such as obesity, metabolic syndrome and diabetes mellitus, where activation of Nrf2 has also been proposed as a promising therapeutic strategy (da Costa et al. al, Front Pharmacol. 2019 Apr 12;10:382). In addition, the Nrf2 activator, sulforaphane, reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes (Axelsson et al, Sci Transl Med. 2017 Jun 14;9(394). Thus, it is expected that drugs activating Nrf2 should be applicable to a variety of cardiovascular and metabolic diseases, including but not limited to atherosclerosis, hypertension, heart failure, myocardial infarction and recovery, cardiac remodeling, types of cardiac arrhythmias, heart failure with reduced ejection fraction, diabetic cardiomyopathy, diabetic nephropathy, metabolic syndrome, obesity, diabetes mellitus (type 1 or type 2) and insulin resistance

- 1 045906 stenting.

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and high mortality rates due to lack of effective therapy. Early brain injury (EBI) and cerebral vasospasm (CVS) are two of the most important pathophysiological mechanisms of brain injury and are hallmarks of poor outcomes for patients with SAH (clinicaltrials.gov/ct2/show/NCT0261474, SFX01 After Subarachnoid Haemorrhage ( SAS)). Evidence from experimental studies of SAH suggests a protective role for the Nrf2/ARE pathway in EBI and CVS after SAH. Administration of sulforaphane (SFN) to rats after SAH increases the activity of the Nrf2-ARE pathway, attenuates vasospasm in the basilar arteries, and suppresses the release of proinflammatory cytokines (Zhao, Brain Res., doi: 10.1016/j.brainres.2016.09.035). Intracerebral hemorrhage (ICH) represents the primary event in 10-15% of the 15 million cases of stroke that occur annually worldwide. In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes and reduced 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 models of ICH, Nrf2 activators consistently demonstrated a protective effect by improving barrier function and attenuating swelling, inflammation, neuronal death, and neurological deficits (Chen-Roetling, Curr Pharm Des, doi: 10.2174/1381612822666161027150616). Ischemic stroke induces reactive oxygen species, causing oxidative and inflammatory responses in ischemic brain injury. Currently, recombinant tissue plasminogen activator is the only available therapy for the treatment of ischemic stroke. However, treatment does not prevent oxidative stress and inflammation in ischemic brain damage. D3T, a sulfur-containing dithiolethione compound, is found in cruciferous vegetables and has been reported to induce antioxidant genes through activation of Nrf2. D3T (Yen, J Immunol 2017, 198 (1 supplement) 206.20) has been shown to attenuate cerebral infarction and reduce the severity of neurological deficits in animals with stroke. In addition, D3T reduced the infiltration of inflammatory immune cells, including neutrophils and monocytes, into the CNS during ischemic brain injury. Moreover, D3T-induced suppression of inflammatory cytokine production was observed in wild-type microglia but not in Nrf2-deficient microglia. Moreover, the protective effect of D3T in attenuating the infarction of ischemic brain injury is abolished in Nrf2-deficient stroke animals and in stroke animals treated with a HO-1 inhibitor. These results suggest that D3T-mediated suppression of inflammation in ischemic brain injury is mediated through the Nrf2/HO-1 pathway, and therefore, targeting the Nrf2/HO-1 pathway may represent a promising therapeutic strategy for reducing neuroinflammatory inflammation. tissue in ischemic stroke.

Nrf2 is believed to play a key role in some types of hemoglobinopathy, such as beta-thalassemia and sickle cell disease (SCD). SCD is a recessive inherited disorder caused by a single missense mutation that results in hemoglobin S with a mutant beta-globin protein (HbS). At low oxygen concentrations, HbS polymerizes, resulting in deformed red blood cells that are susceptible to rupture, releasing free heme into the blood plasma. The resulting oxidative stress and inflammation lead to damage in many organs of the body. Disruption of Keap1 and the resulting constitutive activation of Nrf2 have been shown to lead to improved outcomes in an SCD mouse model (Zhu, Blood, doi:10.1182/blood-2017-10-810531; Keleku-Lukwete PNAS, doi:10.1073/pnas. l509158112). Activation of Nrf2 has been shown to slow the progression of hemolytic anemia and organ dysfunction (Ghosh, JCI Insight, doi: 10.1172/jci.insight.81090), and loss of Nrf2 function worsens the pathophysiology of SCD in SCD transgenic mice (Zhu, Blood, doi. org/10.1182/blood-2017-10-810531). Global activation of Nrf2 by the known compound D3T reduces lethality in a heme-induced acute chest syndrome SCD transgenic mouse model (Ghosh, Brit. J. Heamtology doi: 10. 1111/bjh. 15401). In addition, Nrf2 activators have also been shown to modulate fetal hemoglobin (HbF) expression by directly binding to the gamma globin promoter and modifying chromatin structure at the beta globin locus. In sickle erythroid cells, Nrf2 provides unique benefits by inducing HbF, which serves to inhibit hemoglobin S polymerization and protect against oxidative stress caused by chronic hemolysis (Zhu et al, Exp Biol Med (Maywood). 2019 Feb;244(2): 171-182). Thus, the development of small molecule Nrf2 activators has the potential to reduce the clinical severity of sickle cell disease and other diseases, such as beta thalassemia, in which increasing HbF levels have a beneficial effect.

Nrf2 function is altered in many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Friedreich's hereditary ataxia (Dinkova-Kostova, FEBS,

- 2 045906 doi: 10.1111/febs. 14379). Activation of Nrf2 mitigates many of the pathogenic processes involved in such neurodegenerative disorders by activating antioxidant defense mechanisms, inhibiting inflammation, improving mitochondrial function, and maintaining protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases (Joshi, Neurobiol Aging, doi:10.1016/j.neurobiolaging.2014.09.004; Alarcon-Aguilar, Neurobiol Aging, doi:10.1016/j.neurobiolaging.2014.01.143 ) and in human cell cultures expressing mutant proteins. Tecfidera (dimethyl fumarate) activates Nrf2 (in addition to other mechanisms) and is approved in the US for the treatment of relapsing-remitting multiple sclerosis. The Nrf2 activator omaveloxolone (RTA-408), currently in phase II trials for the treatment of the inherited neurodegenerative disorder Friedreich's ataxia, met its primary endpoint of change in the modified Friedreich's Ataxia Rating Scale (mFARS) relative to placebo after 48 weeks of treatment. Therefore, targeting Nrf2 signaling may provide a possible treatment option to delay the onset, slow the progression, and reduce the intensity of symptoms of neurodegenerative disorders.

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic joint inflammation and is characterized by periods of flare-ups and remissions. Sometimes multiple joints can be affected, resulting in permanent joint destruction and deformity. Nrf2 was found to be activated in the joints of arthritic mice and RA patients. Nrf2 knockout mice have more severe cartilage lesions and greater oxidative damage, and expression of Nrf2 target genes is increased in wild-type Nrf2 rather than knockout mice during the development of antibody-induced arthritis (Wruck, BMJ Annals of Rheumatic Diseases, doi:10.1136/ard.2010.132720). In addition, in an animal model of rheumatoid arthritis, when using serum transfer from K/BxN transgenic mice to Nrf2(-/-) mice, Nrf2 deficiency increased the incidence of arthritis, and the animals showed widespread disease affecting both the anterior and and hind legs (Maicas, Antioxidants & Redox Signaling, doi: 10.1089/ars.2010.3835).

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

Fumaderm, a mixture of dimethyl fumarate (DMF) and three monoethyl fumarate salts, received approval in Germany in 1994 for the treatment of psoriasis. A closely related bioactive form of DMF, monomethyl fumarate (MMF), has been shown to increase total and nuclear levels of Nrf2 in primary mouse keratinocytes and lead to increased mRNA expression of several effectors downstream in the Nrf2 pathway, such as heme oxygenase-1 and peroxiredoxin-1. 6 (Helwa, J Pharmacol. Exp. Ther., doi:10.1124/jpet. 116.239715). Benefits of treatment with Nrf2 activators may be observed in other skin diseases such as radiation-induced dermatitis/skin damage, atopic dermatitis, and wound healing (Wu et al, Mol Med Rep. 2019 Aug;20(2): 1761-1771).

Activation of Nrf2 has been shown to have beneficial effects in both liver and kidney diseases. NAFLD (non-alcoholic fatty liver disease) is considered 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 NAFLD subtypes increase the risk of cardiovascular events and mortality, NASH (non-alcoholic steatohepatitis) is the main diagnostic subtype of NAFLD, which indicates the predisposition of patients to develop cirrhosis and liver-related complications. There are currently approved drugs for the treatment of NAFLD and NASH. However, knockout of Nrf2 in mice significantly increases susceptibility to the development of NASH stimulated by either a methionine-choline-deficient diet (MCD) (Chowdry, Free Radic Biol Med, doi:10.1016/j.freeradbiomed.2009.11.007) or a high-fat diet (HF) (Okada, J Gastroenterol, doi:10.1007/s00535-012-0659-z), and pharmacological activation of Nrf2 has been shown to reverse the development of NASH in mouse models (Sharma, Cell Mol Gastroenterol Hepatol, doi:10.1016/jjcmgh. 2017.11.016). Positive results from treatment with Nrf2 activators may

- 3 045906 observed in other liver diseases such as toxin-induced liver disease, viral hepatitis and cirrhosis. Oxidative stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models of acute kidney injury (AKI), causing Nrf2 to be transiently and slightly activated. Genetic or pharmacological enhancement of Nrf2 activity in renal tubules significantly reduces the intensity of AKI-associated damage and prevents the progression of AKI to chronic kidney disease (CKD) by reducing oxidative stress. However, a phase III clinical trial conducted with the KEAP1 inhibitor CDDO-Me or bardoxolone-methyl in patients with stage 4 CKD and type 2 diabetes mellitus (T2DM) was stopped due to the occurrence of cardiovascular events. As recent pivotal studies have accumulated beneficial effects of KEAP1 inhibitors in mid-stage CKD, phase II trials have been re-initiated. Data from ongoing projects demonstrate that £2 activator/KEAP1 inhibitor increases 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 unsatisfactory treatment regimens. SCN-10, which leads to activation of the Nrf2 pathway, is currently in clinical trials for focal segmental glomerulosclerosis (FIRSTx - Oral SCN-10 in Primary Focal Segmental Glomerulosclerosis Study (FSGS); clinicaltrials.gov/ct2/show/NCT03422510) . In a phase II trial, bardoxolone-methyl was shown to lead to significant improvements in renal function in patients with one of 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-methylin-patients-with-focal-segmental-glomemlosclerosis-and- in-patients-from-all-four-cohorts-of-phoenix/). Alport syndrome is the second most common congenital cause of kidney failure, caused by a genetic defect in type IV collagen, a component in the construction of the glomerular basement membrane. Because bardoxolone methyl is believed to target underlying disease processes associated with mitochondrial dysfunction, inflammation, and oxidative stress, it is currently being investigated in these patients with the belief that Nrf2 activators would have potential utility in this disease.

Oxidative stress plays a critical role in the initiation and progression of cancer (Gorrini, Nat Rev Drug Discov., doi:10.1038/nrd4002). Due to the importance of Nrf2 in maintaining cellular redox homeostasis, it is thought to be a cytoprotective transcription factor and tumor suppressor. At lower homeostatic levels, Nrf2 can eliminate ROS, carcinogens, and other DNA damaging agents, leading to inhibition of tumor initiation and metastasis (Milkovic et al. Redox Biol. doi:10.1016/j.redox.2017.04.013). Evgen is currently conducting the SFX-01 (sulforaphane-cyclodextrin complex) study in metastatic breast cancer and its evaluation (STEM) (clinicaltrials.gov/ct2/show/NCT02970682). which provides for ER+/HER-metastatic breast cancer. Bardoxolone derivatives have been shown to prevent the development of lung cancer induced by vinyl carbamate in A/J mice (Liby, Cancer Res. doi:10.1158/0008-5472). Thus, Nrf2 activators may play a role in cancer prevention.

Age-related macular degeneration (AMD) is a leading cause of blindness in Western countries, and oxidative stress plays a major role in the pathogenesis and progression of AMD. Nrf2 activators have been shown to be able to protect cultured cells that mimic the outer layer of the retina from oxidative stress, suggesting the possibility of vision preservation in patients with early stage AMD (Bellezza, Front Pharmacol. 2018;9:1280). In addition, Nrf2 activators may also be used in other eye diseases such as Fuchs' corneal endothelial dystrophy and uveitis.

Therefore, there is a continuing need for agents capable of activating Nrf2, given the role of Nrf2 in multiple indications.

Brief description of the invention

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

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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

In another aspect, the present invention relates to a compound of the present invention as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof as defined herein, for use in the treatment of diseases or disorders,

- 4 045906 mediated by Nrf2 activation.

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

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

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

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

Another aspect of the present 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 mellitus, chronic kidney disease, Friedreich's hereditary ataxia, sickle cell disease, or non-alcoholic steatohepatitis.

In another aspect of the present invention, there is provided a method of treating chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes mellitus, chronic kidney disease, Friedreich's hereditary ataxia, sickle cell anemia, or non-alcoholic steatohepatitis, the method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof as defined herein.

The present invention further provides a method for synthesizing a compound or a pharmaceutically acceptable salt thereof as defined herein.

In another aspect of the present invention, a compound or a pharmaceutically acceptable salt thereof is provided that can be obtained, either obtained or directly obtained using the synthesis method defined herein.

In another aspect of the present invention, there are provided new intermediates defined herein that are suitable for use in any of the synthetic methods set forth herein.

Preferred, suitable and optional features of any particular aspect of the present invention are also preferred, suitable and optional features of any other aspect.

Detailed Description of the Invention

Definitions

Unless otherwise specified, the following terms as used in the specification and claims have the following meanings set forth below.

It should be understood that references to administering treatment or treatment include prevention as well as alleviation of observable symptoms of a condition. Therefore, providing treatment or treatment for a medical condition, disorder or condition includes: (1) preventing or delaying the onset of clinical symptoms of a medical condition, disorder or condition developing in a person who may suffer from or be predisposed to a medical condition, disorder or condition, but is not yet experiencing or exhibiting clinical or subclinical symptoms of the medical condition, disorder or condition, (2) suppression of the development of the medical condition, disorder or condition, i.e. stopping, reducing the rate or delaying the progression of the disease or its relapse (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) mitigation or attenuation of the manifestation of the disease, i.e. initiating regression of a medical condition, disorder or condition or at least one of its clinical or subclinical symptoms.

A therapeutically effective amount means an amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effect such treatment of the disease. The therapeutically effective amount will vary depending on the compound, the disease and its severity, as well as the age, weight of the mammal being treated, and the like.

As used herein, the term alkyl includes both straight and branched alkyl groups.

- 5 045906 no. chain. References to individual alkyl groups, such as propyl, are limited to the straight chain version only, and references to individual branched chain alkyl groups, such as isopropyl, are limited to the branched chain version only. For example, (C _1-6 )alkyl includes (C _1-4 )alkyl, (C _1-3 )alkyl, propyl, isopropyl and tert-butyl. Similar rules apply to other radicals, for example, phenyl( _C1-6 )alkyl includes phenyl( _C1-4 )alkyl, benzyl, 1-phenylethyl and 2phenylethyl.

As used herein, the term alkylene includes both straight and branched chain divalent alkyl groups. For example, C _1-4 alkylene includes methylene (-CH ₂ -), ethylene (-CH2CH2-), propylene and butylene.

As used herein, the term alkoxy includes both straight and branched chain alkyl groups linked by a single bond to an oxygen atom. For example, C _1-4 alkoxy includes methoxy, ethoxy, isopropoxy and t-butoxy.

The term (Cm-n) or group (C _mn ), used alone or as a prefix, refers to any group containing from m to n carbon atoms.

Cycloalkyl means a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 .

The term halogen refers to fluorine, chlorine, bromine and iodine.

The term haloalkyl is used herein to refer to an alkyl group, respectively, in which one or more hydrogen atoms have been replaced by halogen atoms (eg, fluorine). Examples of haloalkyl groups include fluoroalkyl groups such as -CHF2, -CH2CF3, or perfluoroalkyl/alkoxy groups such as -CF3 or -CF2CF3.

The term heterocyclyl, heterocyclic or heterocycle means a non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring system. s). Monocyclic heterocyclic rings contain approximately 3-12 (preferably 3 to 7) ring atoms, with 1-5 (preferably 1, 2 or 3) heteroatoms per ring selected from nitrogen, oxygen or sulfur atoms. Bicyclic heterocycles contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic rings can be fused, spiro- or bridged ring systems. Examples of heterocyclic groups include 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 hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, dihydroisoxazolyl (such as 4,5-dihydroisoxazolyl), dihydropyridinyl (such as 1,2-dihydropyridinyl or 1,6dihydropyridinyl), tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetra hydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl , octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. The concept of sulfur-containing heterocycles also includes heterocycles with an oxidized sulfur atom containing SO or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiene-1,1-dioxide and thiomorpholinyl-1,1-dioxide. Suitable representatives of heterocyclyl groups bearing 1 or 2 oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5- dioxopyrrolidinyl, 2,5dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclyl groups are saturated monocyclic 3-7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl-1,1 - dioxide, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by one skilled in the art, any heterocycle can be linked to another group through any suitable atom, such as a carbon or nitrogen atom. Preferably, the term heterocyclyl, heterocyclic or heterocycle will refer to 4-, 5-, 6- or 7-membered monocyclic rings as defined above.

The term heteroaryl or heteroaromatic means an aromatic mono-, bi- or polycyclic ring containing one or more (eg 1-4, in particular 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur atoms. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more often from five to ten ring members. The heteroaryl group may be, for example, a 5- or 6-membered

- 6 045906 monocyclic ring or 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five- and six-membered rings or two fused six-membered rings. Each ring may contain up to approximately four heteroatoms, typically selected from nitrogen, sulfur and oxygen atoms. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more often up to 2, for example, one heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms on heteroaryl rings can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of the nitrogen in indole or pyrrole. In general, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be less than five. Preferably, the term heteroaryl or heteroaromatic will refer to 5- or 6-membered monocyclic heteroaryl rings as defined above.

Non-limiting examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyrdiopyrazinyl, thieno-D-EDfuranyl , 2H-furo[3, 2-b]-pyranyl, 5H-pyrigo[2,3-d]-o-oxazinyl, Ш-pyrazolo[4,3D]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3d] ]pyrigazinyl, imidazoRD-^thiazolyl, imidazo[1,2-b][1,2,4]mriazinyl. Heteroaryl also includes partially aromatic bi- or polycyclic ring systems in which at least one ring is an aromatic ring and one or more other rings are non-aromatic, saturated or partially saturated rings, provided that at least one ring contains one or several heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,3]dioxolyl , 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4 -tetrahydropyrido[2,3Cpyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7-tetrahydrobenzoIisoxazolyl, 4,5,6,7tetrahydro-[1 ,2,3]triazolo[1,5-a]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-с][1,4]oxazinyl, 5,6dihydro-4I -pyrrolo[1,2-с][1,2,3]triazolyl, 6,7-dihydro-5H-pyrrolo[2,1-с][1,2,4]τtriazolyl, 5,6,7,8tetrahydro -[1,2,4]triazolo[4,3-a]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl and 1, 4,5,6tetrahydrocyclopenta^][1,2,3]triazol-5-yl.

Non-limiting examples of five-membered heteroaryl groups include, without limitation, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

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

Specific non-limiting examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, iso indolinyl, purinyl (for example, adeninyl , guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine and pyrazolopyridinyl groups.

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

Specific non-limiting examples of bicyclic heteroaryl groups containing a five-membered ring fused to a five-membered ring include, but are not limited to, 6,7-dihydro5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4H- pyrrolo[1,2-c][1,2,3]triazolyl and 1,4,5,6tetrahydrocyclopenta^][1,2,3]triazol-5-yl.

The term aryl means a cyclic or polycyclic aromatic ring containing from 5 to 12 carbon atoms. The term aryl includes both monovalent forms and divalent forms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In this particular embodiment, aryl is phenyl or naphthyl, in particular phenyl.

The term carboxylic acid group mimetic refers to surrogate structures or isosteres of a carboxylic acid group that typically retain the characteristics of the carboxylic acid group required for biological activity but modify the physicochemical properties of the resulting compound, such as acidity or lipophilicity. Such mimetic groups on

- 7 045906 based on a carboxylic acid are known to specialists in the field of medicinal chemistry. Examples of carboxylic acid mimetic groups include, but are not limited to, tetrazole, 3-trifluoromethyl-1,2,4triazole, hydroxamic acids, hydroxamic acid esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfonylureas, acylureas, thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one, thiadiazol-5(4H)-one, oxathiadiazol-2-oxide, oxαdiazol-5(4H)-thione, isoxazole, tetramic acid, cyclopentan-1,3-diones and cyclopentane- 1,2-diones.

The term optionally substituted refers to either groups, structures or molecules that are substituted or groups, structures or molecules that are not substituted.

In the event that optional substituents are selected from one or more groups, it should be understood that this definition implies that all substituents are selected from one of the specified groups or the substituents are selected from two or more specified groups.

The phrase compound of the present invention means those compounds that are disclosed herein, both generally and in a specific manner.

Compounds of the present invention

In a first aspect of the present invention there is provided a compound of formula I:

R ³ (I), where

R ¹ is selected from C1-4alkylene-K. ⁿ , heterocyclyl and 8-10 membered bicyclic heteroaryl, where said heterocyclyl is optionally substituted with one or more substituents independently selected from C1-4alkyl, -C(O) ^-R12 , SO2- ^R13 , C1-3αalkylene- ^OR14 and heteroaryl, which is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _3-7 cycloalkyl, halogen, OH, C _1-3 alkoxy and cyano; and wherein said 8-10 membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C ₃₇ cycloalkyl, halogen, OH and C _1-3 alkoxy;

R ² is selected from hydrogen, fluorine, chlorine and C _1-3 alkyl;

R ³ is selected from hydrogen, fluorine, chlorine, bromine, C _1-3 alkoxy, C _1-3 alkyl, C _1-3 haloalkyl and cyano;

R ⁴ represents hydrogen or C _1-4 alkyl;

R ⁵ represents -C(O)-C _1-4 alkyl, -C(O)-heteroaryl or -C(O)-aryl, wherein said heteroaryl and aryl are optionally substituted with one or more substituents selected from C _1-4 alkyl, halogen, hydroxy, C _1-3 alkoxy, CO2R ¹⁵ and cyano; or

^R4 and ^R5 , taken together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring, where:

said heterocyclyl ring contains one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring or optionally attached via a spiro bond to a C _3-7 cycloalkyl group; and said heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C _1-3 alkoxy, C 1 ₃ haloalkyl, cyano, NR ¹⁶ R ¹⁷ , C(O)R ¹⁸ , S(O)R ¹⁹ and SO2R ²⁰ ;

L ¹ and L ² are independently selected from the relationship and -CR ²¹ R ²² -;

R ⁶ and R ⁷ are independently selected from hydrogen, C _1-4 alkyl and C _3-7 cycloalkyl; or

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

R ⁸ selected from CO2R ²³ , C(O)NHSO ₂ C _1-3 alkyl, tetrazolyl, 3-trifluoromethyl-1,2,4-triazol-5-yl and a carboxylic acid mimetic group selected from hydroxamic acids, complex esters of hydroxamic acids, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfonylureas, acylureas, thiazolidinedione, oxazolidinedione, oxad5o.1-5(411)-one giadiazo.1-5(411')-one, oxathiadiazol- 2-oxide, oxadiazole-5(41 P-hyone, isoxazole, tetramic acid, cyclopentane-1,3-diones and cyclopentane-1,2-diones;

R ⁹ is selected from hydrogen, C _1-4 alkyl, hydroxy, C _1-3 alkoxy and halogen;

R ¹⁰ is selected from hydrogen and C _1-4 alkyl; or

- 8 045906

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

L ² represents a bond, and R ⁷ and R ¹⁰ taken together with the atoms to which they are attached form a 4-, 5-, 6- or 7-membered cycloalkyl or heterocyclyl ring, where:

said heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

said cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally bridged by an ^alkylene group connecting two carbon atoms of the ring, or R ⁹ is optionally a C _1-3 alkylene group connecting C* to a carbon atom rings; and said cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C _1-3 alkoxy, C _{1 3} haloalkyl and deuterium;

R ¹¹ is selected from -C(O)-R ²⁴ , -SO2-R ²⁵ , -NR ²⁶ C(O)-R ²⁷ , -NR ²⁸ SO2-R ²⁹ , heterocyclyl, aryl and heteroaryl, where the indicated aryl and heteroaryl groups optionally substituted with one or more substituents independently selected from C1-4alkyl, _{C1-3haloalkyl} , _{C3-7cycloalkyl} , _{C1-4alkyleneR30} ^, halogen, OH, C1-3alkoxy, heterocyclyl and cyano; and said heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-4alkyl, C13haloalkyl, ^{C3-7cycloalkyl} , C1-4alkylene, halogen, OH, C1-3alkoxy, oxo and cyano;

R ¹² is selected from C1-4alkyl, C3-7cycloalkyl, OR ³¹ , NR ³² R ³³ , aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C1-4alkyl, halogen, OH, C _{1- 3} alkoxy and cyano;

R ¹³ is selected from C1-4alkyl, C3-7cycloalkyl, heteroaryl, heterocyclyl and NR ³⁴ R ³⁵ , wherein said heteroaryl and heterocyclyl are optionally substituted with one or more substituents independently selected from C1-4alkyl, halogen, OH, _C1-3 alkoxy and cyano;

R ¹⁷ is selected from hydrogen, C _1-4 alkyl, C(O)C _1-3 alkyl and C(O)NR ³⁶ R ³⁷ ;

R ¹⁸ , R ¹⁹ and R ²⁰ are independently selected from C _1-4 alkyl, OH, C _1-3 alkoxy and NR ³⁸ R ³⁹ ;

R ²⁴ is selected from C _1-4 alkyl, NR ⁴⁰ R ⁴¹ and OR ⁴² ;

R ²⁵ is selected from C _1-4 alkyl and NR ⁴³ R ⁴⁴ ;

R ²⁷ is selected from C1-4alkyl, C3-7cycloalkyl, C1-3haloalkyl, heterocyclyl, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1 -4alkylene-I ⁴⁵ , halogen, OH, C1-3alkoxy and cyano;

R ²⁹ is selected from C1-4alkyl, C3-7cycloalkyl, C1-3haloalkyl, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1-4alkylene ^ ⁴⁶ , halogen, OH, C1-3 alkoxy and cyano;

R ³⁰ is selected from hydroxy, C _1-3 alkoxy, C _3-7 cycloalkyl, cyano and NR ⁴⁷ R ⁴⁸ ;

R ⁴⁰ is selected from hydrogen and C _1-4 alkyl;

R ⁴¹ is selected from hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl, C _1-3 alkoxy, aryl and heteroaryl; or

R ⁴⁰ and R ⁴¹ , taken together with the nitrogen atom to which they are attached, form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring, wherein said heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C-alkoxy, C _3-7 cycloalkyl and cyano;

R ⁴⁵ and R ⁴⁶ are independently selected from hydroxy, C _1-3 alkoxy and C _3-7 cycloalkyl; And

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ²¹ , R 22 , R ²³ , R ²⁶ , R ²⁸ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , ^{R 38 ,} R ³⁹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁷ and R ⁴⁸ are independently selected from hydrogen, C _1-4 alkyl and C _3-7 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

Specific compounds of the present invention include, for example, compounds of formula I or pharmaceutically acceptable salts thereof, wherein, unless otherwise indicated, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L ¹ , L ² , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²⁴ , R ²⁵ , R ²⁷ , R ²⁹ , R ³⁰ , R ⁴⁰ and R ⁴¹ has any of the meanings previously defined herein or in any of paragraphs (1) to (86) hereinafter:

(1) R ¹ represents C _1-4 alkylene^ ⁿ ;

(2) R ¹ is CH2-R ¹¹ ;

(3) R ¹ is CH2CH2-R ¹¹ ;

(4) R ¹ represents CH(Me)-R ¹¹ ;

(5) R ¹ is heterocyclyl, optionally substituted with one or more substituents independently selected from C1-4alkyl, -C(O) ^-R12 , SO2- ^R13 , heteroaryl and _C1-3alculene - ^OR14 , wherein said heteroaryl optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _3-7 cycloalkyl, halogen, OH, C _1-3 alkoxy and cyano;

(6) R ¹ is heterocyclyl, optionally substituted with one or more substituents independently selected from C1-4alkyl, -C(O) ^-R12 , SO2- ^R13 , heteroaryl and _C1-3alculene - ^OR14 ,

- 9 045906 wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl and C _3-7 cycloalkyl;

(7) R ¹ is piperidinyl or pyrrolidinyl, each of which is optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , heteroaryl and C1- ₃ alkylene-OR ¹⁴ , wherein indicated heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _3-7 cycloalkyl, halogen, OH, C _1-3 alkoxy and cyano;

(8) R ¹ is pyrrolidinyl, optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , heteroaryl and C1-3alkylene-OR ¹⁴ , wherein said heteroaryl is optionally substituted with C1-4alkyl or With _3-7 cycloalkyl;

(9) R ¹ is selected from one of the following groups:

Where represents the point of attachment of the group to the oxygen atom of the rest of the compound, and where each group is optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , heteroaryl and C1-3alkylene-OR ¹⁴ , where said heteroaryl is optionally substituted with C1-4alkyl or _{C3-7cycloalkyl} ;

(10) R ¹ is an 8-10 membered bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _3-7 cycloalkyl, halogen, OH and C _1-3 alkoxy;

(11) R ¹ is an 8-membered bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from C _1-4 alkyl, OH and C _1-3 alkoxy;

(12) R ¹ is 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4Hpyrrolo[1,2-c][1,2 ,3]triazolyl or 1,4,5,6-tetrahydrocyclopenta[1,2,3]triazol-5-yl, each of which is optionally substituted with one or more substituents independently selected from C14alkyl, C3-7cycloalkyl, halogen, OH and C1-3 alkoxy;

(13) R ¹ selected from one of the following groups:

- 10 045906 where represents the point of attachment of the group to the oxygen atom of the rest of the compound, and where each group is optionally substituted by one or more substituents independently selected from C _1-4 alkyl, C _1-3 haloalkyl, C _3-7 cycloalkyl, C _{1- 4} alkylene^ ³⁰ , halogen, OH, C _1-3 alkoxy, heterocycloalkyl and cyano;

(14) R ¹ is selected from one of the following groups:

where represents the point of attachment of the group to the oxygen atom of the rest of the compound, and where each group is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _1-3 haloalkyl, C _3-7 cycloalkyl, C _1-4 alkylene^ ³⁰ , C _1-3 alkoxy and cyano;

(15) R ¹ is selected from one of the following groups:

where represents the point of attachment of the group to the oxygen atom of the rest of the compound, and where each group is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _1-3 haloalkyl, C _3-7 cycloalkyl, C _1-4 alkylene^ ³⁰ , halogen, OH, C _1-3 alkoxy, heterocycloalkyl and cyano;

(16) R ¹ selected from one of the following groups:

- 11 045906

where represents the point of attachment of the group to the oxygen atom of the rest of the compound, and where each group is optionally substituted by one or more substituents independently selected from C _1-4 alkyl and C _1-3 haloalkyl; (17) R ¹ is:

where represents the point of attachment of the group to the oxygen atom of the rest of the compound, and where the group is optionally substituted with one or more substituents independently selected from C _1-4 alkyl and C _1-3 haloalkyl; (18) R ¹ is:

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

(20) R ² represents hydrogen or fluorine;

(21) R ³ is selected from hydrogen, chlorine, bromine, C _1-3 alkoxy, C _1-3 alkyl, C _1-3 haloalkyl and cyano;

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

(23) R ³ is selected from hydrogen and chlorine;

(24) R ³ is chlorine;

(25) R ⁴ represents hydrogen;

(26) R ⁵ is -C(O) _-C1-4 alkyl or -C(O)-aryl, wherein said aryl group is optionally substituted with one or more substituents selected from _C1-4 alkyl, halogen, hydroxy, With _1-3 alkoxy, CO2R ¹⁵ and cyano;

(27) R ⁴ is hydrogen and R ⁵ is -C(O)-C _1-4 alkyl or -C(O)-aryl, wherein said aryl group is optionally substituted with one or more substituents selected from C _{1- 4} alkyl, halogen, hydroxy, C _1-3 alkoxy, CO2R ¹⁵ and cyano;

(28) R ⁴ is hydrogen and R ⁵ is -C(O)-C _1-4 alkyl or -C(O)-aryl, wherein said aryl group is optionally substituted with one or more substituents selected from halogen, hydroxy and CO2R ¹⁵ ;

(29) R ⁴ is hydrogen and R ⁵ is -C(O)-aryl, wherein said aryl group is phenyl, optionally substituted with one or more substituents selected from fluorine, hydroxy and CO2R ¹⁵ ;

(30) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring, where:

said heterocyclyl ring contains one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring or optionally attached via a spiro bond to a C _3-7 cycloalkyl group; and said heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C _1-3 alkoxy, C 1 ₃ haloalkyl, cyano, NR ¹⁶ R ¹⁷ , C(O)R ¹⁸ , S(O)R ¹⁹ and SO ₂ R ²⁰ ;

(31) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl or heterocyclyl ring, where:

said heterocyclyl ring contains a -C(O)- moiety attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring or optionally attached via a spiro bond to a C _3-7 cycloalkyl group; and said heteroaryl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C _1-3 alkoxy and cyano;

(32) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C _{1- 3} alkoxy and cyano;

- 12 045906 (33) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from C _1-4 alkyl, halogen and OH;

(34) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a pyrazolyl ring, optionally substituted by one or more substituents independently selected from C _1-4 alkyl, halogen and OH;

(35) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl ring, wherein said heterocyclyl ring contains a -C(O)- moiety attached to the nitrogen atom and is optionally fused with an aryl or heteroaryl ring or optionally attached via a spiro linkage to a C _3-7 cycloalkyl group; and said heterocyclyl ring is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen and OH;

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

(37) ^R4 and ^R5 , taken together with the nitrogen atom to which they are attached, form a heterocyclic moiety selected from one of the following:

wherein the saturated ring of the heterocyclic moiety is optionally attached via a spiro bond to a C _3-7 cycloalkyl group, and wherein said heterocyclic moiety is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen and OH;

(38) ^R4 and ^R5 , taken together with the nitrogen atom to which they are attached, form a heterocyclic moiety selected from one of the following:

wherein the saturated ring of the heterocyclic moiety is optionally attached via a spiro bond to the cyclopropyl group, and wherein said heterocyclic moiety is optionally substituted with one or more substituents independently selected from methyl, fluorine and OH;

(39) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form the following heterocyclic fragment:

wherein the heterocyclic moiety is optionally attached via a spiro linkage to the cyclopropyl group and is optionally substituted with one or more substituents independently selected from methyl and fluorine;

(40) R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form the following heterocyclic fragment:

ABOUT.

wherein the heterocyclic moiety is optionally attached via a spiro linkage to a cyclopropyl group and optionally substituted with a C _1-3 alkyl group, wherein said cyclopropyl and/or C _{1 3} alkyl group is attached to the heterocyclic ring in an alpha or beta position relative to the carbonyl group;

- 13 045906 (41) L ¹ and L ² are independently selected from the connection and -CH ₂ -;

(42) L ¹ represents a bond and L ² represents -CH ₂ -;

(43) L ¹ represents CH ₂ -, and L ² represents a bond;

(44) both of L ¹ and L ² are bonds;

(45) R ⁶ and R ⁷ are independently selected from hydrogen and C _1-4 alkyl;

(46) R ⁶ and R ⁷ are independently selected from hydrogen and methyl;

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

(48) R ⁸ is selected from CO2R ²³ , C(O)NHSO ₂ C ₁ - ₃ alkyl, tetrazolyl and 3-trifluoromethyl-1,2,4-triazol-5yl;

(49) R ⁸ is selected from CO2R ²³ , C(O)NHSO ₂ C _1-3 alkyl and tetrazolyl;

(50) R ⁸ is selected from CO ₂ H, C(O)NHSO ₂ Me and tetrazolyl;

(51) R ⁸ represents CO2H;

(52) R ⁹ is selected from hydrogen, C _1-4 alkyl, C _1-3 alkoxy and halogen;

(53) R ⁹ is selected from hydrogen, methyl, methoxy and fluorine;

(54) R ⁹ is selected from C _1-4 alkyl, C _1-3 alkoxy and halogen;

(55) R ⁹ is selected from methyl, methoxy and fluorine;

(56) R ⁹ represents hydrogen or C _1-4 alkyl;

(57) R ⁹ is hydrogen or methyl;

(58) R ⁹ is methyl;

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

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

(61) L ² represents a bond, and R ⁷ and R ¹⁰ , taken together with the atoms to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl or heterocyclyl ring, where:

said heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

said cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally bridged by a C-alkylene group connecting two carbon atoms of the ring, or R ⁹ is optionally a C _1-3 alkylene group connecting C* to a carbon atom rings; and said cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen, OH, C 1 _-3 alkoxy and deuterium;

(62) L ¹ and L ² are both bonds, and R ⁷ and R ¹⁰ , taken together with the atoms to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl or heterocyclyl ring, where:

said heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

said cycloalkyl ring optionally contains a carbon-carbon double bond and is optionally bridged by a C _1-3 alkylene group connecting two carbon atoms of the ring, or R ⁹ is optionally a C _1-3 alkylene group connecting C* to a carbon atom of the ring ; and said cycloalkyl and heterocyclyl rings are optionally substituted with one or more substituents independently selected from C1 _-4 alkyl, halogen, OH, C1 _-3 alkoxy and deuterium;

(63) L ² represents a bond, and R ⁷ and R ¹⁰ , taken together with the atoms to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl ring, wherein said cycloalkyl ring is optionally bridged in the form ^ ^alkylene group connecting two ring carbon atoms, or ^R9 is optionally a C _1-3 alkylene group connecting C* to a ring carbon atom, and said cycloalkyl ring is optionally substituted with one or more substituents independently selected from C _1-4 alkyl , halogen, OH, C _1-3 alkoxy and deuterium;

(64) L ² represents a bond, and R ⁷ and R ¹⁰ taken together with the atoms to which they are attached form a cyclohexyl ring, wherein said cyclohexyl ring optionally contains a carbon-carbon double bond and is optionally bridged by a C13 alkylene group connecting two carbon atoms of the ring, or R ⁹ optionally represents a C1-3alkylene group connecting C* to a carbon atom of the ring, and said cyclohexyl ring is optionally substituted with one or more substituents independently selected from C14alkyl, halogen, OH and deuterium;

(65) R ¹¹ is selected from -C(O)-R ²⁴ , -NR ²⁶ C(O)-R ²⁷ and heteroaryl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C1 ₃ haloalkyl, C _3-7 cycloalkyl, C _1-4 alkylene^ ³⁰ , halogen, OH, C^alkoxy, heterocyclyl and cyano;

(66) R ¹¹ is -C(O)-R ²⁴ , and R ²⁴ is selected from NR ⁴⁰ R ⁴¹ and OR ⁴² ;

(67) R ¹¹ is -NR ²⁶ C(O)-R ²⁷ , and R ²⁷ is selected from C _1-4 alkyl, C _3-7 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or Not

- 14 045906 how many substituents, independently selected from C _1-4 alkyl and C _3-7 cycloalkyl;

(68) R ¹¹ is heteroaryl, optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, ^C1-4alkylene , halogen, OH, C1-3alkoxy, heterocyclyl and cyano;

(69) R ¹¹ is heteroaryl, optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, ^C1-4alkylene , C1-3alkoxy and cyano;

(70) R ¹¹ is heteroaryl, optionally substituted with one or more substituents independently selected from methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chlorine, fluorine, cyclopropyl, methoxy, cyano, oxetanyl, CH2-R ³⁰ and CH2CH2-R ³⁰ ;

(71) R ¹¹ is pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted with one or more substituents , independently selected from C _1-4 alkyl, C _1-3 haloalkyl, C _3-7 cycloalkyl, C _1-4 alkyleneR ³⁰ , halogen, OH, ^^alkoxy, heterocyclyl and cyano;

(72) R ¹¹ is heteroaryl selected from:

wherein each heteroaryl is optionally substituted with one or more substituents independently _selected from C _1-4 alkyl, C _1-3 haloalkyl, C _3-7 cycloalkyl, C _1-4 alkylene^ ³⁰ , halogen, OH, C _1-3 alkoxy, heterocycloalkyl and cyano;

(73) R ¹¹ is oxazolyl, isoxazolyl or 1,2,3-triazolyl, each of which is optionally substituted with one or more substituents independently selected from C1-4alkyl, C13haloalkyl, C3-7cycloalkyl, C1-4alkylene- ^I30 , halogen , OH, C1-3alkoxy, heterocycloalkyl and cyano;

(74) R ¹¹ is 1,2,3-triazolyl, optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, ^{C1-4alkyleneR30} , halogen, OH, C1-3alkoxy, heterocycloalkyl and cyano;

(75) R ¹¹ is heterocyclyl, optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, ^{C1-4alkyleneR30} , halogen, OH, C1-3alkoxy, oxo and cyano;

(76) R ¹¹ is heterocyclyl, optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _1-3 haloalkyl, halogen, OH and oxo;

(77) R ¹¹ is dihydroisoxazolyl or dihydropyridinyl, optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _1-3 haloalkyl, halogen, OH and oxo;

(78) R ²⁹ is selected from C _1-4 alkyl, C _3-7 cycloalkyl, C _1-3 haloalkyl and heteroaryl, wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl and C _{1- 3} haloalkyl;

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

(80) R ³⁰ is selected from hydroxy, C _1-3 alkoxy, C _3-7 cycloalkyl and cyano;

- 15 045906 (81) R ³⁰ selected from hydroxy, methoxy, cyclopropyl and cyano;

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

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

(84) R ⁴⁰ and R ⁴¹ , taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl or heterocyclyl ring, said heteroaryl and heterocyclyl rings being optionally substituted by one or more substituents independently selected from C1 ₄ alkyl, halogen, OH, C-alkoxy, C _3-7 cycloalkyl and cyano;

(85) R ⁴⁰ and R ⁴¹ , taken together with the nitrogen atom to which they are attached, form a 5-membered heterocyclyl ring, said heterocyclyl ring being optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen and HE;

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

Preferably, R ¹ is as defined in any of items (1) to (18) above. In one embodiment, R ¹ is as defined in paragraph (2) above. In another embodiment, R ¹ is as defined in paragraphs (7)-(9) above. In another embodiment, R ¹ is as defined in any of paragraphs (13) to (18) above. In a further embodiment, R ¹ is as defined in paragraphs (16)-(18) above.

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

Preferably, R ³ is as defined in any of paragraphs (21) to (24) above. In another embodiment, R ³ is as defined in paragraphs (23)-(24) above.

Preferably, R ⁴ is as defined in paragraph (25) above.

Preferably, R ⁵ is as defined in paragraph (26) above.

Preferably, R ⁴ and R ⁵ are as defined in any of paragraphs (27) to (29) above. In another embodiment, R ⁴ and R ⁵ are as defined in paragraph (29) above. In one embodiment, R ⁴ and R ⁵ are as defined in paragraphs (30)-(40) above. In another embodiment, R ⁴ and R ⁵ are as defined in paragraphs (37)-(40) above. In another embodiment, R ⁴ and R ⁵ are as defined in paragraph (34) above. In a further embodiment, R ⁴ and R ⁵ are as defined in paragraph (40) above.

Preferably, L ¹ and L ² are as defined in any of paragraphs (41) to (44) above. In another embodiment, L ¹ and L ² are as defined in paragraph (44) above.

Preferably, R ⁶ and R ⁷ are as defined in any of paragraphs (45) to (47) above. In another embodiment, R ⁶ and R ⁷ are as defined in paragraph (46) above.

Preferably, R ⁸ is as defined in any of paragraphs (48) to (51) above. In another embodiment, R ⁸ is as defined in paragraphs (50)-(51) above. In one embodiment, R ⁸ is as defined in paragraph (51) above.

Preferably, R ⁹ is as defined in any of paragraphs (52) to (58) above. In another embodiment, R ⁹ is as defined in paragraphs (57)-(58) above. In one embodiment, R ⁹ is as defined in paragraph (58) above.

Preferably, R ¹⁰ is as defined in paragraph (59) above.

Preferably R ⁹ and R ¹⁰ are as defined in paragraph (60) above.

Preferably, L ² , R ⁷ and R ¹⁰ are as defined in any of paragraphs (61) to (64) above. In another embodiment, L ² , R ⁷ and R ¹⁰ are as defined in paragraph (64) above.

Preferably, R ¹¹ is as defined in any of paragraphs (65) to (77) above. In another embodiment, R ¹¹ is as defined in paragraphs (72)-(74) above. In another embodiment, R ¹¹ is as defined in paragraphs (73)-(74) above. In a further embodiment, R ¹ is as defined in paragraph (2) above, and R ¹¹ is as defined in paragraphs (72)-(74) above.

Preferably, R ²⁹ is as defined in paragraphs (78) to (79) above. In one embodiment, R ²⁹ is as defined in paragraph (79) above.

Preferably, R ³⁰ is as defined in paragraphs (80) to (81) above. In one embodiment, R ³⁰ is as defined in paragraph (81) above.

Preferably R ⁴⁰ is as defined in paragraph (82) above.

Preferably R ⁴¹ is as defined in paragraph (83) above.

Preferably, R ⁴⁰ and R ⁴¹ are as defined in any of paragraphs (84) to (86) above. In another embodiment, R ⁴⁰ and R ⁴¹ are as defined in paragraph (86) above.

- 16 045906

In an additional group of compounds, the compounds are characterized by the structural formula IA shown below:

R ³ (IA), where L ¹ and L ² as well as R ¹ - R ¹⁰ are as previously defined herein.

In an additional group of compounds, the compounds are characterized by the structural formula IA shown above, where R ¹ is as defined in any of paragraphs (7)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23)(24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; L ¹ and L ² are as defined in any of paragraphs (41) to (44) above; R ⁶ and R ⁷ are as defined in any of paragraphs (45) to (47) above; R ⁸ is as defined in any of paragraphs (48) to (51) above; R ⁹ is as defined in any of paragraphs (52) to (58) above; and R ¹⁰ is as defined in paragraph (59) above.

In an additional group of compounds, the compounds are characterized by the structural formula IB shown below:

R ⁵

R3 (IB), wherein R1- ^R6 , ^R8 and ^R9 are as previously defined herein.

In the additional group of compounds, the compounds are characterized by the structural formula IB shown above, where R ¹ is as defined in any of paragraphs (7)-(18) above; R ² is as defined in paragraph (20) above;

R ³ is as defined in any of paragraphs (23) to (24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; R ⁶ represents hydrogen or methyl; R ⁸ is as defined in any of paragraphs (48) to (51) above; and R ⁹ is as defined in any of paragraphs (52) to (58) above.

In an additional group of compounds, the compounds are characterized by the structural formula IB shown above, where R ¹ is as defined in any of paragraphs (13)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23)(24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; R ⁶ represents hydrogen or methyl; R ⁸ is as defined in any of paragraphs (50) to (51) above; and R ⁹ is as defined in any of paragraphs (57) to (58) above.

- 17 045906

In an additional group of compounds, compounds are characterized by the IC structural formula shown below:

R ⁵

R ³

6 9 ^(1C) 'where R1-R ⁶ and R ⁹ are as previously defined herein.

In an additional group of compounds, the compounds are characterized by the structural formula IC shown above, wherein R ¹ is as defined in any of paragraphs (7) to (18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23)(24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; R ⁶ represents hydrogen or methyl; and R ⁹ is as defined in any of paragraphs (57) to (58) above.

In an additional group of compounds, compounds are characterized by the structural formula ID shown below:

where R1- ^R3 , ^R6 and ^R9 are as previously defined herein.

In an additional group of compounds, the compounds are characterized by the structural formula ID shown above, where R ¹ is as defined in any of paragraphs (7)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23)(24) above; R ⁶ represents hydrogen or methyl; and R ⁹ is as defined in any of paragraphs (57) to (58) above.

In an additional group of compounds, the compounds are characterized by the structural formula ID shown above, where R ¹ is as defined in any of paragraphs (9) and (13)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23) to (24) above; R ⁶ represents hydrogen; and R ⁹ is as defined in paragraph (58) above.

In the additional group of compounds, the compounds are characterized by the structural formula IE shown below:

where R1-R ⁶ , R ⁸ and R ⁹ are as previously defined herein.

In the additional group of compounds, the compounds are characterized by the structural formula IE shown above, where R ¹ is as defined in any of paragraphs (7)-(18) above; ^R2 is

- 18 045906 as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (21)(24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; R ⁶ represents hydrogen or methyl; R ⁸ is as defined in any of paragraphs (48) to (51) above; and R ⁹ is as defined in any of paragraphs (52) to (58) above.

In an additional group of compounds, the compounds are characterized by the structural formula ID shown above, where R ¹ is as defined in any of paragraphs (13)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23)(24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; R ⁶ represents hydrogen or methyl; R ⁸ is as defined in any of paragraphs (50) to (51) above; and R ⁹ is as defined in any of paragraphs (57) to (58) above.

In an additional group of compounds, compounds are characterized by the structural formula IF shown below:

R5

R ³ (IF), where R1-R ⁶ and R ⁹ are as previously defined herein.

In an additional group of compounds, the compounds are characterized by the structural formula IF shown above, where R ¹ is as defined in any of paragraphs (7)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23)(24) above; R ⁴ and R ⁵ are as defined in any of paragraphs (37) to (40) above; R ⁶ represents hydrogen or methyl; and R ⁹ is as defined in any of paragraphs (57) to (58) above.

In an additional group of compounds, compounds are characterized by the structural formula IG as shown below:

where R1- ^R3 , ^R6 and ^R9 are as previously defined herein.

In an additional group of compounds, the compounds are characterized by the structural formula IG shown above, where R ¹ is as defined in any of paragraphs (7)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (21)(24) above; R ⁶ represents hydrogen or methyl; and R ⁹ is as defined in any of paragraphs (57) to (58) above.

In an additional group of compounds, the compounds are characterized by the structural formula IG shown above, where R ¹ is as defined in any of paragraphs (9) and (13)-(18) above; R ² is as defined in paragraph (20) above; R ³ is as defined in any of paragraphs (23) to (24) above; R ⁶ represents hydrogen; and R ⁹ is as defined in paragraph (58) above.

Specific compounds of the present invention include any of the following:

- 19 045906 (1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazol-3 carboxamide o)ethoxy) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1carboxylic acid;

(lS,2R)-2-((S)-8-(2-(benzo[d]ocazol-2-capboκcamido)ethoxy)-l-((l,3dioxoisoindolin-2-yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-8-(((S)-1 -acetylpyrrolidin-3 -yl)oxy)-1 -((1,3 -dioxoisoin olin-2yl)methyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(((8)-1 -(5-methylisoxazole3-carbonyl)pyrrolidine -3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-bromo-l-((l,3-dioκcoisoindolin-2-yl)methyl)-8-(((S)-l-(thiazol-5carbonyl)pyrrolide in-3 -yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(((8)-1 -(thiazol-5carbonyl)pyrrolid in-3 -yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(((8)-1 -(2-methylthiazol-5carbonyl)pyrrolid in -3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

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

(1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-1,2,3-triazol4-yl )methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic

- 20 045906 acid;

(1 S,2R)-2-((S)-1 -((1,3 -dioxoisoindolin-2-yl)methyl)-8-(( 1 -methyl-1Hbenzo[b]imidazol-5-yl)methoxy )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

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

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

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

(1 S,2R)-2-((S)-5->cnop-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(((8)-1 -(thiazol-5carbonyl )pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(1 S,2R)-2-((S)-1 -((1-oxoisoindolin-2-yl)methyl)-8-(((8)-1 -(thiazol-5carbonyl)pyrrolidin-3-yl) hydroxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

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

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

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

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

(18.2K)-2-((8)-5-bromo-8-(((8)-1-(2-methylthiazol-5-carbonyl)pyrrolidin-3-yl)oxy)1 -((1 - oxoisoind olin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-(((S)-1 -(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-(( 1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-(((S)-1 -(5-methylpyridazin-3-yl)pyrrolidin-3-yl)oxy)-1 ((1 -oxoisoind olin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

- 21 045906 (1 S,2R)-2-((S)-5-6poM-8-((4-MeTiin-4H-1,2,4-triazol-3-yl)methoxy)-1-(( 1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18,2I)-2-((8)-5-bromo-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((1oxoisoindolin-2-yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -methyl- 1H-imidazol-4-yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((5-methylisoxazol-3-yl)methoxy)-l-((l-oκcoisoindolin-2yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((2-ethyl-2H-l,2,3-τpiazol-4-yl)methoxy)-l-((loxoisoindoline-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((lS)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-l-((l-oκco-l,3,Зa,4,5, 6hexahydro-2H-isoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -methyl-1H-1,2,4-triazol-5-yl)methoxy)-1-((1oxoisoindolin-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((S)-5-bromo-l-((l-oκcoisoindolin-2-yl)methyl)-8-(πpyridazin-3ylmethoxy)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1 ((1 - oxoisoind olin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-(imidazo[l,2-a]πpyridin-7-ylmethoxy)-l-((loxoisoindolin-2-yl)methyl)-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((l-methyl-lH-benzo[d]imidazol-5-yl)methoxy)-l-((loxoisoindolin-2-yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindoline-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18,2I)-2-((8)-5-bromo-8-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-((1oxoisoindolin-2-yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 - 22 045906 carboxylic acid;

(18.2K)-2-((8)-5-bromo-8-((7-methoxy-1-methyl-1H-benzo[<1][1,2,3]triazol-5yl)methoxy)- 1 -((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -methyl-1H-benzo[(1] [1,2,3]triazol-5-yl)methoxy)-1 -((1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-((1oxoisoindolin-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((l-isoπpoπyl-lH-imidazol-2-yl)methoxy)-l-((loxoisoindolin-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4yl)methoxy)-1 -(( 1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((4-ethyl-4H-l,2,4-τpiazol-3-yl)methoxy)-l-((loxoisoindoline-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((5-cyano-l-ethyl-lH-imidazol-4-yl)methoxy)-l-((loxoisoindolin-2-yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

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

(1 S,2R)-2-(( 18)-5-bromo-8-( 1-(1 -methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1oxoisoindoline -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

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

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

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

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

(lS,2R)-2-((S)-5-chloro-l-((l-oκcoisoindolin-2-yl)methyl)-8-((l-(2,2,2-τpiφτopethyl)- 23 045906

1H-imidazol-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-(2,2-difluoroethyl)-1H-imidazol-2-yl)methoxy)-1-((1oxoisoindolin-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2R)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (1-oxoisoind olin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2R)-2-((8)-5-chloro-8-((1-ethyl-1H-pyrazol-3-yl)methoxy)-1 -((1-oxoisoind olin2-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2R)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1((1-oxoisoin olin- 2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-(( 1 -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18,2R)-2-((8)-5-fluoro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

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

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

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

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

(1 S,2R)-2-((S)-5-6poM-1 -((2-oxopyrrolidin-1 -yl)methyl)-8-(((8)-1 -(thiazol-5carbonyl)pyrrolidine -3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(18^)-2-((8)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((2oxopyrrolidin-1 -yl )methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 - 24 045906 carboxylic acid;

(18.2K)-2-((8)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-bromo-8-((5-isopropyl-1,2,4-oxadiazol-3 -yl)methoxy)-1 -((2oxopyrrolidin-1 -yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-8-(benzo[<1]isoxazol-3 -ylmethoxy)-5-bromo-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-8-(benzo[<1]isothiazol-3 -ylmethoxy)-5-chloro-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-1 -((2-oxopyrrolidin-1 -yl)methyl)-8-(pyridin-2-ylmethoxy)1,2,3,4-tetrahydroisoquinoline -2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-methylisothiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-8-(isothiazol-3-ylmethoxy)-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2,3,4-tetrahydroisoquinoline -2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-8-(benzo[<1]isoxazol-3 -ylmethoxy)-5-chloro-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

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

(1 S,2R)-2-((S)-5-6poM-8-((l -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -(((R) -4methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((6-oxo5 -azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -(((S) -4methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-chlorop-l-((2-oxopyrrolidin-1-yl)methyl)-8-(pyride in-3-ylmethoxy)1,2,3,4 -tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-ethyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

^)-4-((8)-8-(benzo[<1]isoxazol-3 -ylmethoxy)-5-chloro-1 -((2-oxopyrrolidin-1 yl)methyl)-3,4-dihydroisoquinoline-2 (1H)-yl)-3-methyl-4-oxobutanoic acid;

1-(((8)-2-((1^28)-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-8(benzo[c1]isoxazol-3 -ylmethoxy)-5 - chloro-1,2,3,4-tetrahydroisoquinolin-1 yl)methyl)pyrrolidin-2-one;

- 25 045906 (18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2oxopyrrolidin-1 -yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (4-methyl-1H-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-1 -((2-oxopyrrolidin-1 -yl)methyl)-8-(pyrimidin-5ylmethoxy)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclopentane-1-carboxylic acid;

(1K,28)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclopentane-1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-1 -((2-oxopyrrolidin-1 -yl)methyl)-8-(pyridazin-3 ylmethoxy)-1,2,3,4-tetrahydroisoquinoline -2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18,2R)-2-((8)-5-chloro-8-(( 1 -methyl-1H-benzo[(1] [1,2,3]triazol-5-yl)methoxy)-1 - ((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-(imidazo[1,2-a]pyrimidin-2-ylmethoxy)-1-((2oxopyrrolidin-1-yl)methyl)-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-(isoxazolo[5,4-b]pyridin-3-ylmethoxy)-1-((2oxopyrrolidin-1-yl)methyl)-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2oxopyrrolidine-1 - yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2- 26 045906 oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

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

-((S)-5 -chloro-8-((5 -(difluoromethyl)-1 -methyl-1 Η-1,2,3 -triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran2-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-indazol-3-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methoxy)-1-((2oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-8-(benzo[<1]isoxazol-3 -ylmethoxy)-5-chloro-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

2-((8)-5 -chloro-8-((5 -(difluoromethyl)-1 -methyl-1 Η-1,2,3 -triazol-4-yl)methoxy)-1-((2oxopyrrolidine-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4difluorocyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - ((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1 - yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1K,28)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - ((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 fluorocyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1 - yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-27 045906 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - (((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - (((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - (((R)-3 -methyl-2-oxopyrrolid in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( ((R)-3-methyl-2-oxopyrrolide in-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( ((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( ((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1-( ((8)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( (2-oxopyrrolide in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 ethylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( (2-oxopyrrolide in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 ethylcyclopentane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-ethyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( (2-oxopyrrolide in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclopentane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-ethyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( (2-oxopyrrolid in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diφτopmethyl)-l-isopropyl-lH-l,2,3-τpiazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

- 28 045906 (18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4yl)methoxy)-1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4,5-dimethylisoxazol-3-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-chloro-5-methylisoxazol-3-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-methylisoxazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(2-methoxyethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 - ((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -((2 -oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2R)-2-((8)-5-chloro-1 -(((S)-3 -methyl-2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 -methyl-5( trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2R)-2-((8)-5-chloro-1 -(((R)-3 -methyl-2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 -methyl-5 (trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

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

(18.28)-2-((8)-5-chloro-1-((A)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5(trifluoromethyl )-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((l-cyclopropyl-5-(diτopmethyl)-lH-l,2,3-τpiazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((4-(diφτopmethyl)pyrimidin-5-yl)methoκci)-l-((6-oκco-5- 29 045906 azaspiro[2.4 ]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)methoxy)-1-((6oxo-5-azaspiro[ 2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7tetrahydrobenzo[(1]isoxazole-3 -yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-8-((2,5-bis(difluoromethyl)-2H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

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

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

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic-4,4-d2 acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1- ((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1- carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4yl)methoxy)- 1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)methoxy) -7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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;

(18.2R)-2-((8)-5-chloro-8-(( 1 -methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1 -((6oxo-5 -azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-30 045906 methylcyclohexane-1-carboxylic acid;

(18.28)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( ((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

1-(((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2((1K,28) -2-methyl-2-(2H-tetrazol-5-yl)cyclohexan-1-carbonyl)-1,2,3,4tetrahydroisoquinolin-1 -yl)methyl)pyrrolidin-2-one;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-( (4,4-dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-methyl-4-(trifluoromethyl)isoxazol-3-yl)methoxy)-1-((6oxo-5-azaspiro[2.4 ]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(1S,2R)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol4-yl )methoxy)-1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6- oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-(difluoromethyl)-5-methylisoxazol-3-yl)methoxy)-1-((6oxo-5-azaspiro[2.4] heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo- 5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((K)- 4-methyl2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

- 31 045906 (18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -(((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -((( K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((18)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[<1]isoxazol-3-yl)methoxy)-1((2-oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((6,7-difluorobenzo[<1]isoxazol-3-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-8-((3 -methyl-1,2,4-oxadiazol-5-yl)methoxy)-1 -((2oxopyrrolidin-1 -yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-8-((5-methyl-1,2,4-oxadiazol-3 -yl)methoxy)-1 -((2oxopyrrolidin-1 -yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.28)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4(trifluoromethyl)pyrimidin- 5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-1-methyl-2-((8)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)- 1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo- 5- 32 045906 azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-с][1,4]oxazine -3yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid ;

(18.2K)-2-((8)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-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;

(18.2K)-2-((8)-5-fluoro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6- oxo-5 azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2 carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)methoxy) -1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(15.27?)-2-((5)-5-chloro-8-((6,7-dihydro-5R-pyrrolo[2,1-c][1,2,4]triazol-3yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-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;

(18.2R)-2-((8)-5-chloro-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan- 5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((5,6,7, 8tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-(((8)-1-(methylsulfonyl)pyrrolidin-3-yl)oxy)-1-((6oxo-5-azaspiro[2.4 ]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-8-(((S)-1 -acetylpyrrolidin-3 -yl)oxy)-5-chloro-1 -((6-oxo-5azaspiro[2.4]heptane -5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1- 33 045906 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine -3yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid ;

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

(18^)-2-((8)-5-bromo-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -((2 -oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diφτopmethyl)-l-(ocetan-3-yl)-lH-l,2,3-τpiazol-4yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

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

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( ((E)-2-methyl-5-oxopyrrole id in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( ((8)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18^)-2-((8)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro[1,2,3]triazolo[1 ,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy)1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18^)-2-((8)-5-bromo-8-((5-(difluoromethyl)-1 -methyl-1H-1,2,3-triazol-4yl)methoxy)-1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((l-methyl-5-(oxetan-3-yl)-lH-l,2,3-τpiazol-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;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( (3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(lS,6R)-6-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy)1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohex-3-eu-1-carboxylic acid;

- 34 045906

5-(((8)-2-((1K,28)-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-5-chloro-8-((5(difluoromethyl)-1 - methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1 yl)methyl)-5-azaspiro[2.4]heptan-6-one;

(18.2K)-2-((8)-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-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)thiazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptane-5 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-methylthiazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((2-methyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo- 5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(1K,38,4K,68)-4-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid ;

(18,38,4K,6K)-4-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid ;

(18.2K)-2-((18)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-с][1,2,4]triazol-7-yl) oxy)1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K,48.5K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic-4,5-d2 acid ;

(18.2R)-2-((8)-5-chloro-8-(( 1 -methyl-2-oxo-1,2-dihydropyridin-3 -yl)methoxy)-1 -((6oxo-5 -azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((18)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2R)-2-((8)-5-chloro-8-(( 1 -methyl-6-oxo-1,6-dihydropyridin-2-yl)methoxy)-1 -((6oxo-5 -azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((18)-5-chloro-8-((1-methyl-1,4,5,6-tetrahydrocyclopenta[c1][1,2,3]triazol5-yl)oxy) -1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 35 045906

1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)4,4-difluoro-1-methylcyclohexane-1-carboxylic acid;

(18.2K,48)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid;

(18,2K,4K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic-4-d acid;

(18.2K,48)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid;

(18.2K,58)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid;

(18.2K,5K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid;

(18,2K,4K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid;

(28,3K)-3-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)tetrahydro-2H-pyran-2-carboxylic acid;

(1K,2K,68)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid;

(1K,2K,6K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid;

(18,28,3K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid and (15, 25,35)-2-((5)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1R-1,2,3-triazol-4yl)methoxy)-1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid;

or pharmaceutically acceptable salts thereof.

[0092] In one embodiment, the compound of formula I is selected from the following compounds:

(18.2K)-2-((8)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((8)-1-(thiazol-5carbonyl)pyrrolide in-3 -yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane - 36 045906

1-carboxylic acid;

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

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

(lS,2R)-2-((S)-5-chloro-l-((l,3-dioκcoisoindolin-2-yl)methyl)-8-(((S)-l-(thiazol-5carbonyl)pyrrolide in-3 -yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

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

(1 S,2R)-2-((S)-5-6poM-8-(((S)-1 -(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-(( 1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1 ((1 - olin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid oxoisoind;

(1 S,2R)-2-((S)-5-6poM-8-((l -methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindoline-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18^)-2-((8)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -((1 -oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

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

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

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

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy)1-( (1-oxoisoind olin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

- 37 045906 (18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1((1-oxoisoin olin- 2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid;

(18,2R)-2-((8)-5-chloro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18,2R)-2-((8)-5-cyano-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-8-(benzo[c1]isoxazol-3 -ylmethoxy)-5-bromo-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-8-(benzo[c1]isoxazol-3 -ylmethoxy)-5-chloro-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -(((R) -4methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((6-oxo5 -azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(1 S,2R)-2-((S)-5-6poM-8-((l -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -(((S) -4methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-ethyl-lH-l,2,3-τpiazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclopentane-1-carboxylic acid;

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

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

- 38 045906 (18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) · 1 -((2-oxopyrrolide in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2oxopyrrolidine-1 - yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2oxopyrrolidin-1-yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylic acid;

(18.2K)-2-((8)-8-(benzo[<1]isoxazol-3 -ylmethoxy)-5-chloro-1 -((2-oxopyrrolidin-1 yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - ((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1 - yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - (((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1 - (((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- (((8)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)

- 39 045906

1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4,5-dimethylisoxazol-3-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1 -methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(2-methoxyethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 - ((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -((2 -oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2R)-2-((8)-5-chloro-1 -(((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 -methyl-5 (trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptane-5 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7tetrahydrobenzo[(1]isoxazole-3 -yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic-4,4-d2 acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1- ((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 - carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4yl)methoxy)- 1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-40 045906 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)methoxy) -7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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 methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) 1- ((4,4-dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(1S,2R)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol4-yl )methoxy)-1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6- oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-(difluoromethyl)-5-methylisoxazol-3-yl)methoxy)-1-((6oxo-5-azaspiro[2.4] heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo- 5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -(( (K)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -((( K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

- 41 045906 (18.2K)-2-((18)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[c1]isoxazol-3-yl)methoxy)-1((2- oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-1-methyl-2-((8)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)- 1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-с][1,4]oxazine -3yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid ;

(18.2K)-2-((8)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-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;

(18.2K)-2-((8)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6- oxo-5 azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2·carbonyl)-1-methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)methoxy) -1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(15.27?)-2-((5)-5-chloro-8-((6,7-dihydro-5R-pyrrolo[2,1-c][1,2,4]triazol-3yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-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;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((5,6,7, 8tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2·carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-8-(((8)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((6-oxo-5- 42 045906 azaspiro[ 2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine -3yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid ;

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

(lS,2R)-2-((S)-5-bromo-8-((l-methyl-5-(τpiφτopmethyl)-lH-l,2,3-τpiazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diφτopmethyl)-l-(ocetan-3-yl)-lH-l,2,3-τpiazol-4yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

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

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( ((8)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

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

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-bromo-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((l-methyl-5-(oxetan-3-yl)-lH-l,2,3-τpiazol-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;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1 -( (3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(lS,6R)-6-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohex-3-eu-1-carboxylic acid;

(lS,2R)-2-((S)-5-chloro-8-((5-(diτopmethyl)-l-methyl-lH-l,2,3-τpiazol-4-yl)methoxy) 7-fluoro -1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-43 045906 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(1K,38,4K,68)-4-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid ;

(18.2K,48.5K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic-4,5-d2 acid ;

(18.2K)-2-((18)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K,48)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid and (18, 2K,4K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic-4-d acid;

or pharmaceutically acceptable salts thereof.

[0093] In one embodiment, the compound of formula I is selected from the following compounds:

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (2-oxopyrrolide in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclopentane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin- 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -((2 -oxopyrrolide in-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptane-5 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7tetrahydrobenzo[th]isoxazole-3- yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

- 44 045906 (18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) · 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic-4,4- d2 acids;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1- ((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 - carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)methoxy) -7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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 methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6- oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-cyclopropyl-1 -methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -((( K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)methoxy) -1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine -3- 45 045906 yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane- 1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro[1,2,3]triazole o [1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-(( 6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1-methyl-5-(oxetan-3-yl)-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;

(18.6K)-6-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1-( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohex-3-ene-1-carboxylic acid;

(18.2K)-2-((8)-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-2carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(1K,38,4K,68)-4-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-methylbicyclo[4.1.0]heptan-3-carboxylic acid ;

(18.2K,48.5K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic-4,5-d2 acid ;

(18.2K,48)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-4-fluoro-1-methylcyclohexane-1-carboxylic acid and (18, 2K,4K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-((6 -oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylic-4-d acid;

or pharmaceutically acceptable salts thereof.

In one embodiment, the compound of formula I is selected from the following compounds: (18,2K)-2-((8)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3 -triazol-4yl)methoxy)-1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1 -methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( ((K)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-46 045906 carbonyl)-1-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (b-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-

-methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1 -( (b-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-

-methylcyclohexane-1-carboxylic-4,4-d2 acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1- ((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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;

(18.2K)-2-((8)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3yl)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 acids;

(18.2K)-2-((8)-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 methylcyclohexan-1-carboxylic acid;

(18.2K)-2-((8)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((b- oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid;

(18.2K)-2-((8)-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-2carbonyl)-1-methylcyclohexane-1-carboxylic acid and (18.2K ,4K)-2-((8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-((6- oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-

2-carbonyl)-1-methylcyclohexane-1-carboxylic-4-d acid;

or pharmaceutically acceptable salts thereof.

The various functional groups and substituents included in the compounds of the present invention are generally selected so that the molecular weight of the compound does not exceed 1000. More often, the molecular weight of the compound will be less than 750, such as less than 700 or less than 650.

Suitable or preferred features of any of the compounds of the present invention may also be suitable features of any other aspect.

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

Compounds that have the same molecular formula but differ in the nature or sequence of bonds between their atoms or the arrangement of their atoms in space are called isomers. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not mirror images of each other are called diastereomers, and stereoisomers that are non-superimposed mirror images of each other are called enantiomers. If a compound has an asymmetric center, for example associated with four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described according to the rules of the R- and S-sequence of Cahn and Prelog, or by a method in which, based on the rotation of the molecules in the plane of polarized light, isomers are designated as dextrorotatory or levorotatory (i.e. (+)- or (-)-isomers, respectively). Chiral compound mo

- 47 045906 may exist either as a single enantiomer or as a mixture of enantiomers. A mixture containing equal parts of enantiomers is called a racemic mixture.

Typically, the compounds of the present invention have one or more asymmetric centers; therefore, such compounds can be obtained as individual (R)- or ^)-stereoisomers or as mixtures thereof. Unless otherwise indicated, description or reference to a particular compound in the present specification and claims is intended to include both individual enantiomers, diastereoisomers, and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials materials or by separation of the racemic form. Some of the compounds of the present invention may have centers of geometric isomerism (E- and Z-isomers). It should be understood that the present invention covers all optical isomers, diastereoisomers and geometric isomers, as well as mixtures thereof, having Nrf2 activation activity.

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

It should also be understood that certain compounds of the present invention may exist in solvated as well as non-solvated forms, such as, for example, hydrated forms. It should be understood that the present invention covers all such solvated forms that have Nrf2 activation activity.

It should also be understood that certain compounds of the present invention may exhibit polymorphism, and that the present invention covers all such forms that have Nrf2 activation activity.

The compounds of the present invention may exist in a number of different tautomeric forms, and references to the compounds of the present invention include all such forms. For the avoidance of doubt, if a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all other forms are still covered by the compounds of the present invention. Examples of tautomeric forms include keto, enol, and enolate forms, as in the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/iminoalcohol, amidine/amidine, nitroso/oxime, thioketone/ethiol, and nitro/acinitro.

_Z O \ OH H ⁺ \ o -c-< C=C Q=c'

IX /X n ⁺ / x keto enol enolate

The compounds of the present invention containing an amino functional group can also form N-oxides. Reference herein to a compound of formula I that contains an amino function also includes an N-oxide. If a compound contains several amino functional groups, then one or more nitrogen atoms can be oxidized to form Noxide. Specific examples of N-oxides are N-oxides of a tertiary amine or a nitrogen atom from a nitrogen-containing heterocycle. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (eg, peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by a procedure from L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amino compound is reacted with mchloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

The compounds of the present invention can be administered in the form of a prodrug, which is cleaved in the human or animal body to release the compound of the present invention. A prodrug can be used to modify the physical properties and/or pharmacokinetic properties of a compound of the present invention. A prodrug can be formed if the compound of the present invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives, which can be formed at the carboxy group or hydroxy group of the compound of the present invention, and in-vivo cleavable amide derivatives, which can be formed at the carboxy group or amino group of the compound of the present invention.

Accordingly, the present invention includes such compounds of formula I as previously defined herein if they can be obtained by organic synthesis and if they are made available in the human or animal body by cleavage of a prodrug based thereon. Accordingly, the present invention includes those compounds of formula I that are prepared with

- 48 045906 using methods of organic synthesis, as well as such compounds that are formed in the human or animal body due to metabolic transformations of the precursor of the compound, i.e. a compound of formula I may be a synthetically produced compound or a metabolically produced compound.

A suitable pharmaceutically acceptable prodrug of a compound of formula I is one which, based on reasonable medical judgment, is considered suitable for administration to a human or animal body without exhibiting undesirable pharmacological activity and without undue toxicity.

Various forms of the prodrug have been described, for example, in the following documents:

a) Methods in Enzymology, volume 42, pp. 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 N. Bundgaard, pp. 113-191 (1991);

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

e) H. Bundgaard, etal., Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al., Chern, Pharm, Bull., 32, 692 (1984);

g) T. Higuchi and V. Stella, Pro-Drugs as Novel Delivery Systems, A.C.S. Symposium

Series, volume 14; And

h) E. Roche (author), Bioreversible Carriers in Drug Design, Pergamon Press, 1987.

A suitable pharmaceutically acceptable prodrug of a compound of formula I which contains a carboxy group is, for example, an in vivo cleavable ester thereof. The in vivo cleavable ester of a compound of formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to form the parent acid. Suitable pharmaceutically acceptable esters of carboxy group containing compounds include C1 esters. ₆ alkyl esters such as methyl, ethyl and tert-butyl, _C1-6 alkoxymethyl esters such as methoxymethyl esters, _C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C38 cycloalkylcarbonyloxy -C _1-6 acyl esters, such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters, such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters esters, and C1 ₆ alkoxycarbonyloxy-C _1-6 alkyl esters, such as methoxycarbonyloxymethyl and 1methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable prodrug of a compound of formula I which contains a hydroxy group is, for example, its in vivo cleavable ester or ether. An in vivo cleavable ester or ether of a compound of formula I that contains a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to form the parent hydroxy compound. Suitable groups forming pharmaceutically acceptable hydroxy esters include inorganic ester forming groups such as phosphoric acid esters (including phosphoramidite cyclic esters). Additional suitable groups forming pharmaceutically acceptable hydroxy esters include C _1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C _1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N, N(C _1-6 ) _2- carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, Nalkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1 ₄ alkyl)piperazin-1-ylmethyl. Suitable groups that form pharmaceutically acceptable hydroxy ethers include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable prodrug of a compound of formula I which contains a carboxy group is, for example, its in vivo cleavable amide, for example an amide formed by an amine such as ammonia, a C _1-4 alkylamine such as methylamine, (C1 ₄ alkyl) _2- amine such as dimethylamine, Na-ethyl-N-methylamine or diethylamine, _C1-4 alkoxy-C24alkylamine such as 2-methoxyethylamine, phenyl- _C1-4 alkylamine such as benzylamine, and amino acids such as glycine or its ester.

- 49 045906

A suitable pharmaceutically acceptable prodrug of a compound of formula I which contains an amino group is, for example, its in vivo cleavable amide derivative. Suitable pharmaceutically acceptable amides formed by an amino group include, for example, those formed by C _1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,Ndialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C _1-4 alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of Formula I may be due in part to one or more metabolites that are formed in the human or animal body following administration of a compound of Formula I. As previously defined herein, the in vivo effects of a compound of Formula I may also be due to metabolic changes of a precursor compounds (prodrugs).

It should also be understood that the compounds of formula I can also be covalently linked (in any suitable position) to other groups, such as, for example, solubilizing moieties (eg, PEG polymers), moieties allowing their attachment to a solid support (such as , such as biotin-containing fragments), and targeting ligands (such as antibodies or antibody fragments).

Synthesis

It should be understood that all suggested reaction conditions in the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare the starting materials, including the choice of solvent, reaction medium, reaction temperature, experimental duration and work-up procedure, may be selected by a person skilled in the art.

One skilled in the art of organic synthesis will appreciate that the functional groups present in various regions of the molecule must be compatible with the reagents and reaction conditions employed.

The necessary starting materials can be obtained using standard organic chemistry procedures. The preparation of such starting materials is described within the framework of the following illustrative embodiments of the method and within the scope of the accompanying examples. Alternatively, the necessary starting materials can be obtained through procedures similar to those illustrated, which are within the skill of the average person skilled in the art of organic chemistry.

It should be understood that during the synthesis of the compounds of the present invention using the methods described below, or during the synthesis of certain starting materials, it may be necessary to protect certain substituent groups to prevent unwanted reactions involving them. One skilled in the art of chemistry will appreciate when such protection is necessary and how such protecting groups can be introduced and later removed.

For examples of protecting groups, see one of the many general textbooks on the topic, such as Protecting groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), T. Greene & P. Wuts. Protecting groups can be removed by any suitable method described in the literature or known to one skilled in the art of chemistry as suitable for removing said protecting group, such methods being selected such that removal of the protecting group has minimal impact on groups located elsewhere in the molecule.

Thus, if the reagents contain, for example, groups such as amino, carboxy or hydroxy groups, it may be necessary to protect the group in some of the reactions mentioned herein.

By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group, such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the protecting groups mentioned above will of course vary depending on the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group, such as a tert-butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric, or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example BF ₃ .OEt2. A suitable alternative protecting group for the primary amino group is, for example, a phthayl group, which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

One skilled in the art will appreciate that the compounds of the present invention can be prepared in a variety of ways known in the art. Compounds of formula I can be prepared from

- 50 045906 using the methods below, using the methods given in the experiments section, or using similar methods. The described routes illustrate only some of the methods that can be used for the synthesis of compounds of formula I, and one skilled in the art will understand that the order of reaction steps is not limited to the described steps. It should also be understood that the definitions of nucleophile and electrophile are not limited to those described herein, and in some cases the definitions may need to be reversed. Different approaches to chemical synthesis strategies are described in Organic Synthesis: The Disconnection Approach, 2nd edition, S. Warren and R. Wyatt (2008).

General method A.

In a typical synthesis procedure, the phthalimide, if used as a protecting group, is removed using typical reagents (eg, hydrazine) and the amine is reacted with appropriate reagents to introduce the desired NR4R ⁵ substitution. The third step involves introducing the desired ester through conventional methods such as alkylation with an alkyl halide or activated alcohol (eg mesylate, triflate) or the Mitsunobu reaction using reagents such as DBAD or DEAD and a suitable phosphine. The Boc protecting group is then removed, typically by treatment with HCl. The group L ¹ C(R ⁶ )(R ⁷ )L ² C(R ⁸ )(R ⁹ )R ¹⁰ can be introduced from an appropriately substituted and protected bis acid derivative; ideally where one acid group is activated to react with the amino group of the tetrahydroisoquinoline (THIQ) backbone and the other acid group is suitably protected, for example as a benzyl or dimethoxybenzyl ester, either by ring opening of a suitable cyclic anhydride, or by reaction with acid chloride. Typical amide coupling reagents such as HATU are used to activate the acid. In the final step, the protecting group is removed from the carboxylic acid by a suitable technique such as hydrolysis, hydrogenolysis, strong acids such as HCl or TFA, or a Lewis acid such as BBr3.

General method B.

In a further exemplary procedure, the order of the steps may be reversed from General Method A. The first two steps are carried out as described in General Method A. In the third step, the Boc protecting group (CO ₂ tBu) is then removed, typically by treatment with HCl. The L ¹ C(R ⁶ )(R ⁷ )L ² C(R ⁸ )(R ⁹ )R ¹⁰ group can then be introduced in the fourth step described in General Method A, followed by the introduction of the desired ester by conventional methods such as alkylation using an alkyl halide or activated alcohol (eg mesylate, triflate) or the Mitsunobu reaction using reagents such as DBAD or DEAD and a suitable phosphine. In the final step, the protecting group is removed from the carboxylic acid by a suitable technique such as hydrolysis, hydrogenolysis, strong acids such as HCl or TFA, or a Lewis acid such as BBr ₃ .

- 51 045906

General method C.

In a further exemplary procedure, the order of the steps may be reversed from the general Methods A and B. The desired ester is introduced in the first step, again using the conventional methods described in General Methods A and B above. The phthalimide protecting group is removed in the second step, and the amine is reacted with appropriate reagents to introduce the required NR4R ⁵ substitution. The Boc protecting group is then removed and the L ¹ C(R ⁶ )(R ⁷ )L ² C(R ⁸ )(R ⁹ )R ¹⁰ group can then be introduced in the fifth step. The final step involves removing the carboxylic acid protecting group as described in the general methods above.

The THIQ backbone, in which R ³ is bromine, can be constructed according to the route indicated in Scheme 1.

Scheme 1: a) SOCl ₂ , EtOAc; b) 2-(3-methoxyphenyl)ethan-1-amine, Et ₃ N, DCM; c) NBS, DMF; d) P ₂ O ₅ , MeCN; e) benzeneruthenium(II) chloride dimer, (1S,2S)-(+)-Nn-tosyl-1,2-diphenylethylene-diamine, Et ₃ N, HCO ₂ H, MeCN; f) HCl, THF; g) BBr ₃ , DCM; h) Boc ₂ O, DCM. By generally known methods, compounds in which R ⁸ is -COOH can be converted to compounds containing other groups defined for R ⁸ in Formula 1, such as tetrazole, by reacting the corresponding nitrile with an azide, as shown in Scheme 2.

Scheme 2: a) HATU, DIPEA, NH ₄ Cl, DMF; b) POCl ₃ , imidazole, pyridine; c) ⁿ Bu ₃ SnN ₃ , xylene.

Variants at the R ³ position can be advantageously prepared from the compounds of the present invention or intermediates thereof, in which R ³ is bromine, through chemical reactions well known in the art, as illustrated in Schemes 3 and 4. Compounds of the present of the invention, in which R ³ represents H or Cl, can be prepared from intermediate compounds in which R ³ represents Br, in accordance with the method indicated in Scheme 3.

Scheme 3: a) H ₂ , 10% Pd/C, THF, EtOH; b) BBr ₃ , DCM; c) Boc ₂ O, DCM; d) NCS, DMF.

As shown in Scheme 4, conversion of the bromine substituent R ³ to a suitable boronate or boronic acid allows the production of fluorine and trifluorine derivatives. Bromine can be converted to an alkyl group by reaction with a suitable alkyl boronate using a suitable palladium catalyst; for example, when alkyl is methyl, a suitable boronate is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, and suitable

- 52 045906 The current palladium catalyst is Pd(dppf)Cl2. Compounds in which R ³ is cyano can be prepared from bromo derivatives by treatment with a cyanating agent such as Zn(CN)2 using a palladium catalyst such as Pd(PPh ₃ ) ₄ .

Scheme 4: a) dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, X-phos Pd,

CN hypoboric acid; b) CF ₃ SO ₃ Ag, SelectFluor®; c) bis(pinacolato)diboron, Pd(dppf)Cl ₂ ; d) potassium trimethoxy(trifluoromethyl)boranide, Cu(OAc) ₂ ; e) Pd(dppf)Cl ₂ , alkylborane; f) Zn(CN) ₂ , Pd(PPh ₃ ) ₄ .

The compounds of the present invention in which -NR4R ⁵ is an indolinone can be prepared by reducing the corresponding phthalimide sequentially with sodium borohydride and then triethylsilane according to Scheme 5.

Scheme 5: a) NaBH ₄ , MeOH; b) TFA, Et ₃ SiH.

R ³ R ³ R ³

The compounds of the present invention in which the -NR ⁴ R ⁵ group is a pyrrolidinone can be prepared from intermediates in which -NR4R ⁵ is a phthalimide group by removing the phthalimide group with hydrazine, followed by converting the resulting primary amine to pyrrolidinone by reaction with the corresponding lactone or ω-haloester or to indolinone according to the pathways indicated in Scheme 6.

Scheme 6: a) N ₂ H ₄ , EtOH; b) methyl 4-bromobutanoate, Et ₃ N, PhMe.

R ³

Compounds of the present invention in which R ² is a halogen substituent can be prepared from intermediates or examples of the present invention in which R ² is hydrogen by treatment with a suitable halogenating agent such as N-chlorosuccinimide, as shown in diagram 7.

Scheme 7: a) NCS, DCM/DMF.

- 53 045906

Pharmaceutical compositions

The compounds of the present invention will generally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Therefore, according to a further aspect of the present invention, there is provided a pharmaceutical composition that contains a compound of the present invention as previously defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluent or carrier.

The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound of the present invention can be extracted and then administered to a patient, such as in the case of powders or syrups. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage form, each physically discrete unit containing a safe and effective amount of a compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention typically contain from 1 mg to 1000 mg.

The compositions of the present invention may be in a form suitable for oral administration (for example, tablets, capsules, caplets, pills, lozenges, powders, syrups, tinctures, suspensions, solutions, emulsions, sachets and starch capsules), for topical use (for example, in the form of creams, ointments, lotions, solutions, pastes, sprays, foams and gels), for transdermal administration, such as through transdermal patches, for administration by inhalation (for example, in the form of dry powders, aerosols, suspensions and solutions) , for administration by insufflation (eg, as a fine powder) or for parenteral administration (eg, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing, or as a suppository for rectal dosing).

As used herein, a pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition, or carrier useful in imparting the form or consistency of a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed, thereby preventing interactions that would significantly reduce the effectiveness of the compound of the present invention when administered to a patient, and interactions that would result in pharmaceutical compositions that are not pharmaceutically acceptable. In addition, each excipient must be of sufficiently high purity to be pharmaceutically acceptable.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the specific function they may perform in the composition. For example, certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the preparation of uniform dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the preparation of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to assist in the delivery or transport of the compound or compounds of the present invention after administration to a patient from one organ or part of the body to another organ or part of the body. Certain pharmaceutically acceptable excipients may be selected for their ability to increase patient compliance with a prescribed treatment regimen.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents agents, flavor and stock masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity enhancers, antioxidants, preservatives, stabilizers, surfactants and buffering agents. One skilled in the art will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may perform alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Those skilled in the art have the knowledge and skill to select suitable pharmaceutically acceptable excipients in suitable amounts for use in the present invention. In addition, there are a number of resources available to one skilled in the art that describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients.

- 54 045906 active substances. 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).

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

The amount of active ingredient that is combined with one or more excipients to form a unit dosage form will necessarily vary depending on the patient being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, 0.5 mg to 0.5 g of active agent (more preferably 0.5 to 100 mg, e.g. 1 to 30 mg) formulated with an appropriate and suitable amount of excipients, which may vary from about 5 to about 98 percent of the total weight of the composition.

The dosage size of a compound of formula I for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration in accordance with generally known medical principles.

When using a compound of the present invention for therapeutic or prophylactic purposes, it will generally be administered to achieve a daily dose ranging from, for example, 0.1 mg/kg to 75 mg/kg body weight, administered as appropriate. in divided doses. In general, lower doses will be administered when using the parenteral route. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range of, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Likewise, for administration by inhalation, a dose ranging from, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration, particularly in tablet form, may also be suitable. Typically, unit dosage forms will contain from about 0.5 mg to 0.5 g of a compound of the present invention.

Routes of administration

The compounds of the present invention, or a pharmaceutical composition containing an active compound, can be administered to a subject via any convenient route of administration, either systemically/peripherally or locally (ie, at the site of desired action).

Routes of administration include, but are not limited to, oral (eg, by mouth); buccal; sublingual; transdermal (including, for example, using a bandage, patch, etc.); transmucosal (including, for example, using a bandage, patch, etc.); intranasal (for example, using a nasal spray); ophthalmic (for example, using eye drops); pulmonary (eg, through inhalation or insufflation therapy, eg via aerosol, eg through the mouth or nose); rectal (for example, using a suppository or enema); vaginal (for example, using a vaginal suppository); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal; by implanting a depot or reservoir, for example, subcutaneously or intramuscularly.

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

Therapeutic Uses and Applications

The compounds of the present invention are Nrf2 activators. As a result, they represent therapeutic agents potentially useful for the treatment of diseases or conditions mediated by Nrf2 activation.

Thus, in one aspect, the present invention provides a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound of the present invention as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof as defined herein, for use in the treatment of diseases or disorders mediated by Nrf2 activation.

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

In another aspect, the present invention provides a method for treating a disease or disorder mediated by Nrf2 activation, the method comprising administering to a subject in need of

- 55 045906 in 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.

Examples of specific diseases or conditions for which the compounds of formula (I) and their pharmaceutically acceptable salts can be used include, without limitation, any of the following: chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury/acute respiratory distress syndrome with or without concomitant multiple organ failure syndrome, pulmonary fibrosis, including idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and recovery from it, cardiac remodeling, types of cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes mellitus, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell anemia, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D ), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's hereditary ataxia, lung cancer, breast cancer, cancer colon, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy, or uveitis.

In particular, the compounds of the present invention (including pharmaceutically acceptable salts) can be used in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes mellitus, chronic kidney disease, Friedreich's hereditary ataxia, sickle cell disease or non-alcoholic steatohepatitis.

In another aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury/acute respiratory distress syndrome with associated with or without multiple organ failure syndrome, pulmonary fibrosis, including idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and recovery, cardiac remodeling, types of cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction , diabetic cardiomyopathy, 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 syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D ), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's hereditary ataxia, lung cancer, breast cancer, colon cancer , age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy or uveitis.

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

Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury/acute respiratory distress syndrome with or without concomitant multiple organ dysfunction syndrome , pulmonary fibrosis, including idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and recovery from it, cardiac remodeling, types of cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes mellitus, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta thalassemia,

- 56 045906 sickle cell anemia, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral disease sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's hereditary ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy or uveitis.

Another aspect of the present invention provides the use of the 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 mellitus, chronic kidney disease, Friedreich's hereditary ataxia, sickle cell disease, or nonalcoholic steatohepatitis. .

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

In another aspect of the present invention, there is provided a method of treating chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes mellitus, chronic kidney disease, Friedreich's hereditary ataxia, sickle cell anemia, or non-alcoholic steatohepatitis, the method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof as defined herein.

In another aspect of the present invention, there is provided a method of activating Nrf2 in vitro, the method comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is provided a method of activating Nrf2 in vivo, the method comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof.

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

Combination therapies

The compounds of the present invention may be administered alone as monotherapy or may be administered in combination with one or more additional therapeutic agents. The choice of one or more additional therapeutic agents will, of course, vary depending on the disease or condition being treated or its severity.

The use of combination therapies to treat certain medical conditions is common practice.

In accordance with a specific aspect of the present invention, there is provided a combination suitable for use in the treatment of a disease or condition in which activation of Nrf2 is involved, which contains a compound of the present invention as previously defined herein, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

- 57 045906

In accordance with this aspect of the present invention, there is provided a combination suitable for use in the prevention or treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury/acute respiratory distress syndrome with or without associated multiple organ dysfunction syndrome, pulmonary fibrosis, including idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and recovery from it, cardiac remodeling, types of cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, 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 syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fat disease liver, nonalcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgAnephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis , Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's hereditary ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy or uveitis wherein the combination contains a compound of the present invention as previously defined herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

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

It should be understood that where the term combination is used herein, it refers to simultaneous, separate or sequential administration. In one aspect of the present invention, the combination refers to simultaneous administration. In another aspect of the present invention, the combination relates to separate administration. In a further aspect of the present invention, the combination relates to sequential administration. If the administration is sequential or separate, delaying the administration of the second component should not lead to loss of the beneficial effect of the combination.

According to a further aspect of the present invention, there is provided a pharmaceutical composition that contains a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents in combination with a pharmaceutically acceptable diluent or carrier.

One or more additional therapeutic agents may contain an additional compound of the present invention. Therefore, in one embodiment, a pharmaceutical composition is provided that contains two compounds of the present invention or pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable diluent or carrier.

According to a specific aspect of the present invention, there is provided a combination suitable for use in the prevention or treatment of an allergic disease, an inflammatory disease, or an autoimmune disease (eg, asthma or COPD); cardiovascular or metabolic disease (eg, diabetes); neurodegenerative disease; chronic kidney or liver disease; sickle cell anemia; pulmonary arterial hypertension; cancer or to promote transplantation.

According to a specific aspect of the present invention, there is provided a combination suitable for use in the prevention or treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes mellitus, chronic kidney disease, Friedreich's hereditary ataxia, sickle cell disease, or non-alcoholic steatohepatitis.

Examples of other therapeutic agents that may be used as part of a combination therapy with a compound of the present invention (e.g., as one of two or more active agents as part of a two-way or three-way combination) include, but are not limited to, the following:

(i) beta-2 adrenergic receptor agonists (which may be a racemate or a single enantiomer), including salmeterol, salbutamol, formoterol, salmefamol, fenoterol, carmoterol, ethanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline , vilanterol, olodaterol and their salts;

(ii) anticholinergics acting as muscarinic receptor antagonists, which include ipratopium (eg as bromide, CAS 22254-24-6, marketed as Atrovent), oxitropium and tiotropium (eg as bromide, CAS 136310- 93-5, being implemented

- 58 045906 under the name Spiriva), revatropath, LAS-34273, aclidinium, glycopyrronium, umeclidinium and their salts;

(iii) corticosteroid anti-inflammatory drugs; examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, fluticasone furoate, beclomethasone esters (eg, 17-propionate ester or 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (eg, mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide, butixocorta propionate, RPR-106541 and ST-126;

(iv) anti-inflammatory drugs, including non-steroidal anti-inflammatory drugs (NSAID); examples of NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (eg, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, JAK inhibitors, Pi3K inhibitors, leukotriene synthesis inhibitors (eg, montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (eg, adenosine2a agonists), cytokine antagonists (eg, chemokine antagonists such as CCR3 antagonist) or cytokine synthesis inhibitors or 5-lipoxygenase inhibitors;

(v) vasodilators and antiproliferative agents (eg, prostanoids and PDE5 inhibitors), including epoprostenol (Flolan), treprostinil (Remodulin), iloprost (Ventavis), treprostinil (Tivaso), bosentan (Traklir), ambrisentan (Letairis), sildenafil (Revacio ), tadalafil (Adcirca);

(vi) antidiabetic drugs including insulins, biguanides (eg, metformin), sulfonylureas (eg, glimepiride), meglitinides (eg, repaglinide), thiazolidinediones (eg, pioglitazone), dipeptidyl peptidase IV inhibitors (eg, sitagliptin), mimetics incretin/GLP-1 analogues (eg, liraglutide, exenatide, dilaglutide), sodium-glucose cotransporter-2 (SGLT2) inhibitors (eg, canagliflozin, dapagliflozin and empagliflozin) and α-glucosidase inhibitors (eg, acarbose);

(vii) hydroxyurea and other drugs used to treat sickle cell disease, such as L-glutamine, NCX1443, GBT440 (voxelotor), generic selectin antagonists (GMI-1070, rivipansel), humanized anti-P-selectin antibody (SelG1, crinalizumab ), Pselectin aptamers, sevuparin, regadenoson, ticagrelor, N-acetyl-cysteine (NAC), phosphodiesterase 9 inhibitors (for example, PF-04447943, IMR-687, BAY 73-6691, BAY 41-2271); and (viii) ASK1 inhibitors such as selonsertib, FXR agonists such as obeticholic acid, GS-9674, Px-102, ACC inhibitors such as GS-0976, and PPARa/5 agonists such as elafibranor.

The combinations mentioned above can be advantageously provided for use in the form of a pharmaceutical composition, and thus, pharmaceutical compositions containing the combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the present invention.

Such joint/combination treatment can be provided by simultaneous, sequential or separate dosing of the individual components of the treatment. In one embodiment, the individual compounds will be administered simultaneously in a combination pharmaceutical formulation.

Such combination therapies use the compounds of the present invention within the dosage range described herein and the other pharmaceutically active agent within its prescribed dosage ranges and/or dosage as described in the appropriate published literature.

Examples

General procedures

Methods for preparing the compounds of the present invention are illustrated in the following examples. Starting materials were prepared according to procedures known in the art, or as illustrated herein, or are commercially available. Commercially available reagents were used without further purification. If the reaction temperature is not specified, the reaction is carried out at ambient temperature, which is typically 18-27°C.

When the compounds described in the present invention were characterized by 1H NMR spectroscopy, the spectra were recorded on 500 MHz Broker, 400 MHz Broker, 250 MHz Broker, 300 MHz JEOL or 400 MHz JEOL instruments. If temperature was not specified, spectra were recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). If NMR spectra are complex due to the presence of interconverting isomers, then exemplary results of partial signal integration or characterization of the major isomer only are presented. The following abbreviations were used to denote the multiplicity of NMR signals: s=singlet, b=broad, t=triplet, q=quartet, m=multiplet, d=doublet.

Analytical LCMS

If the characteristics of the compounds described in the present invention were determined using LCMS data, then the retention time and molecular weight were determined using the methods listed in the table below. In cases where the compounds of the present invention are slowly interconverting stereoisomers, several retention times are presented.

- 59 045906 living.

Way Device Column Eluents Gradient 1 HP 1100 (quaternary pump with PDA detector) and mass spectrometer ZQ Phenomenex Luna S 18(2) (3 µm, 4.6x30 mm) 40°C A: 0.1% formic acid in water In: MeCN (containing 0.1% formic acid) 5-95% B from 0.3 to 4.3 min. la HP 1100 (quaternary pump with PDA detector) and mass spectrometer ZQ Gemini NXС18 (3 microns, 4.6x30 mm) 40°C A: 0.1% ammonia in water B: 0.1% ammonia in acetonitrile 5-95% B from 0.3 to 4.3 min. 2 Acquity H-Class (quaternary pump with detector Acquity UPLC CSH C18 (1.7 µm, 2.1x50 50°C A: 0.1% water, formic acid in water In: MeCN 3-99% B from 0.0 to 1.5 min.

- 60 045906

PDA) and mass spectrometer QDa mm) (containing 0.1% formic acid) 3 Acquity UPLC (pump FOR two-component mixtures with a PDA detector) and mass spectrometer ZQ Acquity UPLC VEN C18 (1.7 µm, 2.1x100 mm) 40°C A: 0.1% formic acid in water In: MeCN (containing 0.1% formic acid) 5-95% B from 0.4 to 6.0 min. Behind Acquity UPLC (binary pump with PDA detector) and mass spectrometer ZQ Acquity UPLC VEN C18 (1.7 µm, 2.1x100 mm) 40°C A: 0.03% water, ammonia In: MeCN (containing 0.03% ammonia) 5-95% from 0.4 min. up to 6.0 min. 4 Waters Acquity UPLC (diode array detector 210-350 nm) and SQD mass detector. HB ridge VEN S18 (2.5 µm, 2.1x50mm) 40°C A: 10 mM ammonium bicarbonate, pH 10 V: MeCN 2-98% B from 0.0 to 0.8 min. 4a Waters Acquity UPLC (diode array detector 210-350 nm) and SQD mass detector. HB ridge VEN S18 (2.5 µm, 2.1x50mm) 40°C A: 10 mM ammonium bicarbonate, pH 10 V: MeCN 2-98% B from 0.0 to 4.0 min. 5 Waters system Alliance 2795 HPLC (diode array detector 215-350 nm) and ZQ2000 mass detector XBridge IS C18 (2.5 µm, 2.1x20 mm) 40°C A: 10 mM ammonium bicarbonate, pH 10 V: MeCN 0-95% B from 0.18 to 2.0 min. 6 Waters Acquity UPLC1 (diode array detector 210-350 nm) and QDa mass detector Acquity UPLC CSH C18 (1.7 µm, 2.1x50 40°C A: 0.1% ant acid in water B: 0.1% 2-50% B from 0.0 to 1.0 min., 50% B up to 1.8 min.

- 61 045906

mm) formic acid in MeCN 6a Waters Acquity UPLC1 (diode array detector 210-350 nm) and QDa mass detector Acquity UPLC CSH C18 (1.7 µm, 2.1 >50 mm) 40°C A: 0.1% formic acid in water B: 0.1% formic acid in MeCN 2-95% B from 0.0 to 1.2 min., 95% B up to 1.4 min. 6b Waters Acquity UPLC1 (diode array detector 210-350 nm) and QDa mass detector Acquity UPLC CSH C18 (1.7 µm, 2.1 >50 mm) 40°C A: 0.1% formic acid in water B: 0.1% formic acid in MeCN 2-95% B from 0.0 to 4.0 min. 7 Waters Acquity UPLC2 (diode array detector 210-350 nm) and QDa mass detector XBridge C18 (2.5 µm, 2.1 >50 mm) 40°C A: 10 mM ammonium bicarbonate, pH 10 V: MeCN 2-98% B from 0.0 to 4.0 min., 98% B up to 4.60 min. 7a Waters Acquity UPLC2 (diode array detector 210-350 nm) and QDa mass detector XBridge C18 (2.5 µm, 2.1 >50 mm) 40°C A: 2% ammonia in water In: MeCN 2-95% B from 0.0 to 4.0 min., 95% B up to 4.60 min. 8 Waters Acquity UPLC3 (210-350 nm diode array detector) and SQD mass detector XBridge C18 (2.5 µm, 2.1 >50 mm) 40°C A; water From: MeCN D: 2% ammonia water 2-95% C in A (everywhere 5% D) from 0.0 to 4.50 min., 95% C up to 5.00 min. 9 Waters system Acquity UPLC Η-Class (pump for four-component mixtures with PDA 210- VEN S18 (1.7 µm, 2.1 >50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2-95% B with A (everywhere 5% C) from 0.0 to 1.2 min., 95% B, 5% C up to 1.40

- 62 045906

350 nm) and QDa mass detector min. 9a Waters system Acquity UPLC H-Class (pump for four-component x mixtures with PDA 210350 nm) and QDa mass detector VEN C18 (1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2-95% Bc (everywhere 5% C) from 0.0 to 4.0 min., 95% B 5% C to 4.60 min. 9b Waters system Acquity UPLC Η-Class (pump for quaternary mixtures with PDA 210350 nm) and QDa mass detector VEN S18 (1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2-50% B with A (everywhere 5% C) from 0.0 to 3.0 min., up to 95% B with 5% C at 4.0 min., 95% B, 5% C up to 4.60 min. 9c Waters system Acquity UPLC Η-Class (pump for quaternary mixtures with PDA 210350 nm) and QDa mass detector VEN S18 (1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2-50% B with A (everywhere 5% C) from 0.0 to 1.0 min., up to 95% B with 5% C at 1.8 min., 95% B, 5% C up to 2.0 min. 9d Waters system Acquity UPLC Η-Class (pump for quaternary mixtures with PDA 210350 nm) and QDa mass detector VEN S18 (1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2-20% B with A (everywhere 5% C) from 0.0 to 1.0 min., up to 95% B with 5% C at 1.8 min., 95% B, 5% C up to 2.0 min. 10 Waters system Acquity UPLC Η-Class CSHC18(1.7 µm, 2.1x50 40°C A: water In: MeCN 2-95% B with A (everywhere 5% D)

- 63 045906

(pump for quaternary x mixtures with PDA 210350 nm) and QDa mass detector mm) C: 2% ant acid in water from 0.0 to 4.0 min., 95% B, 5% D to 4.60 min. 10a Waters system Acquity UPLC Η-Class (pump for quaternary mixtures with PDA 210350 nm) and QDa mass detector CSHC18(1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ant acid in water 2-50% B with A (everywhere 5% D) from 0.0 to 3.0 min., up to 95% B with 5% D at 4.0 min., 95% B, 5% D up to 4.60 min. 10b Waters system Acquity UPLC Η-Class (pump for quaternary mixtures with PDA 210350 nm) and QDa mass detector CSHC18(1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ant acid in water 2-95% B with A (everywhere 5% D) from 0.0 to 1.2 min., 95% B, 5% D up to 1.40 min. 10c Waters system Acquity UPLC Η-Class (pump for quaternary mixtures with PDA 210350 nm) and QDa mass detector CSHC18(1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ant acid in water 2-50% B with A (everywhere 5% D) from 0.0 to 1.0 min., up to 95% B with 5% D at 1.8 min., 95% B, 5% D up to 2.0 min. eleven UPLC+Waters DAD+Waters SQD2, UPLC-MS with single quadrupole Acquity UPLC HSS Cis (1.8 µm, 2.1x100 mm) 40°C A: 0.1% formic acid in water In: MeCN (containing 0.1% formic 5-95% B from 0.4 to 6.0 min.

- 64 045906

acid) 12 UPLC+Waters DAD+Waters SQD2, UPLC-MS c single quadrupole Acquity UPLC VEN Shield RP18 (1.7 µm 2.1x100mm) 40°C A: 10 mM ammonium bicarbonate, pH 10 V: MeCN 5-95% B from 0.4 to 6.0 min. 13 Waters Acquity Sample Controller (quaternary pump with 210350 nm PDA and ELS and SQD mass detector) VEN S18 (1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ant acid in water 2% B with 5% C, and 93% A to 95% B, and 5% C from 0.0 to 4.50 min., 95% B, 5% C to 5.00 min. 13a Waters Acquity Sample Controller (quaternary pump with 210350 nm PDA and ELS and SQD mass detector) CSHC18(1.7 µm 2.1x50 mm) 40°C A: water In: MeCN C: 2% ant acid in water 2% B with 5% C, and 93% A to 95% B, and 5% C from 0.0 to 4.50 min., 95% B, 5% C to 5.00 min. 14 Waters Acquity Sample Controller (quaternary pump with 210350 nm PDA and ELS and SQD mass detector) VEN S18 (1.7 µm, 2.1x50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2% B with 5% C, and 93% A to 95% B, and 5% C from 0.0 to 4.50 min., 95% B, 5% C to 5.00 min. 14a Waters Acquity Sample Control Unit (quadruple pump) CSHC18(1.7 µm 2.1x50 mm) 40°C A: water In: MeCN C: 2% ammonia in water 2% B with 5% C, and 93% A to 95% B, and 5% C from 0.0 to 4.50 min.,

- 65 045906

x mixtures with PDA 210350 nm and ELS, as well as SQD mass detector) 95% B, 5% C up to 5.00 min. 15 Acquity H-Class (pump FOR quaternary mixtures with PDA detector) and mass spectrometer QDa HB ridge VEN S18 (2.5 µm, 2.1x50mm) 40°C A: 0.1% aq. ammonia In: MeCN (containing 0.1% ammonia) 3-95% B from 0.2 to 2.2 min., 95% B up to 2.7 min. 16 HP 1100 (quaternary pump with PDA detector) and mass spectrometer ZQ Gemini NXС18 (3 microns, 4.6x30 mm) 40°C A: 0.03% ammonia in water B: 0.03% ammonia in acetonitrile 5-95% B from 0.3 to 4.3 min., 95% B up to 5.3 min. 17 Waters Acquity Classic (996 PDA detector) and Waters ZMD mass spectrometer Acquity UPLC CSH C18 (1.7 µm, 2.1x50 mm) 40°C A: 0.1% formic acid in water B: MeCN (containing 0.1% formic acid) 3-99% B from 0.3 to 2.3 min., 99% B up to 2.4 min. 18 HP 1100 (quaternary pump with PDA detector) and mass spectrometer ZQ HB ridge VEN S18 (3.5 µm, 4.6x30 mm). 40°C A: 0.1% ammonia in water B: 0.1% ammonia in MeCN 5-95% B from 0.0 to 4.3 min., 95% B up to 5.3 min.

- 66 045906

Preparative HPLC

Preparative HPLC was performed using various variable wavelength UV preparative systems or Mass Directed AutoPrep (MDAP) systems listed in the table below. Collection was initiated by UV, MS, or a combination of both. UV detection was performed at a selected wavelength, typically 210 nm, 230 nm or 280 nm. Mass spectra were recorded on a mass spectrometer using alternating positive and negative electrospray ionization.

Way Device Column Eluents Gradient 1 Cleaning system Agilent 1260 infinity. Agilent 6100 Series LC/MS single quadrupole XSELECT CSH Prep Cl8 (5 µm OBD, 21x250 mm) K.T. A: 0.1% formic acid in water In: MeCN (containing 0.1% formic acid) 10-95% B for 22 min. With center in specific focused gradient 2 Cleaning system Agilent 1260 infinity. Agilent 6100 Series LC/MS single quadrupole XBridge Prep C18 (5 µm OBD, 21x250 mm) K.T. A: 0.1% ammonia in water B: MeCN (containing 0.1% ammonia) 10-95% B for 22 min. With center in specific focused gradient 3 Waters Preparative HPLC System Fractionlynx (pump 2525, detector 2996/2998 UV/VIS, liquid manual control 2767) with Waters Acquity systems with detection using Waters SQD LCMS Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl (10 µm, 19x150 mm) K.T. A: MeOH B: MeCN (containing 0.1% formic acid) Gradient like indicated 4 System Waters Sunfire K.T. A: MeOH Gradient like

- 67 045906

preparative HPLC Waters Fractionlynx (pump 2525, detector 2996/2998 UV/VIS, liquid manual control 2767) with Waters Acquity systems with detection using Waters SQD LCMS OBD Phenomenex Luna Phenyl Hexyl (10 mkm, 19x150 mm) B:MeCN (containing 10 mM ammonium bicarbonate) indicated 5 Waters Mass Directional Automatic Cleaning System (MD AP) XBridge Cl8 (5 mkm, 19>100 mm) K.T. A:MeOH B:MeCN C: 0.1% formic acid in water D: 10 nM ammonium bicarbonate (pH 10) Gradient like indicated, run time 14.0 min. 6 Waters Automatic Cleaning System (HPLC) XBridge Cl8 (5 mkm, 19x100 mm) K.T. A: MeOH In: MeCN C: 0.1% formic acid in water D: 10 nM bicarbonate Gradient like indicated

- 68 045906

ammonium (pH 10) 7 Gilson HPLC system (321 pump, 151/152/155/156 detector UV/VIS) Phenomenex Kinetex® 5 µm XB-C18 100 A, AXIA (50x21.2 mm and 250x21.2 mm) K.T. A:MeOH B: 0.1% formic acid in MeCN Gradient like indicated 7a Gilson HPLC system (321 pump, 151/152/155/156 detector UV/VIS) Phenomenex Kinetex® 5 µm EVOC18 100 A, AXIA (50x21.2 mm and 250x21.2 mm). K.T. A:MeOH B: 0.1% ammonia in MeCN Gradient like indicated 8 Waters Preparative HPLC System Fractionlynx (pump 2525, detector 2996/2998 UV/VIS, liquid manual control 2767) with Waters Acquity systems with detection using Waters SQD LCMS Phenomenex Luna Phenyl Hexyl (10 µm 21.2 x 150 mm) K.T. A: MeOH B: MeCN (containing 0.1% formic acid) Gradient like indicated 9 Waters Preparative HPLC System Phenomenex Luna Phenyl Hexyl (10 µm K.T. A:MeOH In: MeCN (containing Gradient like indicated

- 69 045906

Preparative chiral SFC was performed using one of the methods listed below. Method 1.

SFC Waters Thar Prep100 preparative system (P200 CO ₂ pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid manual control with Stacked Injection Module). Column: Diacel Chiralpak IA/IB/IC, YMC Amylose/Cellulose C (5 µm, 20-21.2x250 mm), maintained at 40°C. Conditions: supercritical fluid CO ₂ and eluents selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, with modifiers selected from Me ₂ NH, formic acid, as indicated. Gradient/isocratic as specified.

Method 2.

SFC Waters Thar Prep100 preparative system (P200 CO ₂ pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid manual control with Stacked Injection Module). Column: Phenomenex Lux Cellulose-4 (5 µm, 20-21.2x250 mm), maintained at 40°C. Conditions: CO2 supercritical fluid and eluents selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, with modifiers selected from Me2NH, formic acid, as indicated. Gradient/isocratic as specified.

Method 3.

SFC Waters Thar Prep100 preparative system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid manual control with Stacked Injection Module). Column: YMC Amylose-C/Amylose-SA/Cellulose-C/Cellulose-SB/Cellulose-SC (5 µm, 20x250 mm), maintained at 40°C. Conditions:

supercritical fluid CO ₂ and eluents selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, with formic acid. Gradient/isocratic as specified.

Method 3a.

SFC Waters Thar Prep100 preparative system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid manual control with Stacked Injection Module). Column: YMC Amylose-C/Amylose-SA/Cellulose-C/Cellulose-SB/Cellulose-SC (5 µm, 20x250 mm), maintained at 40°C. Conditions: supercritical fluid CO2 and eluents selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, c Me ₂ NH. Gradient/isocratic as specified.

Method 4.

SFC Waters Thar Prep100 preparative system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid manual control with Stacked Injection Module). Column: Phenomenex Lux Cellulose-3 (5 µm, 20-21.2x250 mm), maintained at 40°C. Conditions: supercritical fluid CO ₂ and eluents selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF, with modifiers selected from Me ₂ NH, formic acid, as indicated. Gradient/isocratic as specified.

- 70 045906

Abbreviations.

AcOH Acetic acid AIBN 2,2'-Azobis(2-methylpropionitrile) DAST (Diethylamino)sulfur trifluoride DBAD Di-/7?rs/77-butyl azodicarboxylate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA N, A-Diisopropylethylamine DMF N, A-Dimethylformamide DMSO Dimethyl sulphate oxide EDTA Ethylenediaminetetraacetic acid Et ₂ O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol h. Watch) HATU A-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b\pyridin-1-ylmethylene]-Amethylmethanaminium hexafluorophosphate-A-oxide NMRA Hexamethylphosphoramide PRESS High performance liquid chromatography IMS Industrial methylated alcohols IPA Isopropyl alcohol LCMS Liquid chromatography, mass spectrometry LDA Lithiumdiisopropylamine MDAP Mass-directed automatic cleaning MeCN Acetonitrile MeOH Methanol 2-MeTHF 2-Methyltetrahydrofuran min. Minute(s) N.B.S. A-Bromosuccinimide NCS A-Chlorosuccinimide NMR Nuclear magnetic resonance Pd/C Palladium on coal K.T. Room temperature sex Strong cation exchange SFC Supercritical fluid chromatography T ₃ P® Propylphosphonic anhydride solution T.F.A. Trifluoroacetic acid THF T ethrahydrofuran XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Synthesis of intermediate compounds.

Intermediate 1 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride.

- 71 045906

To a stirred suspension of 2-(1,3-dioxoisoindolin-2-yl)acetic acid (555 g, 2.71 mol; CAS: 4702-13-0) in EtOAc (958 ml) at RT. thionyl chloride (1039 ml, 14.24 mol) was added. The mixture was heated at reflux for 1.5 hours, then cooled to room temperature. The reaction mixture was concentrated in vacuo to give the title compound (605 g, 99%) which was used without further purification. ^1H NMR (300 MHz, CDCl ₃ ) δ 7.96-7.87 (m, 2H), 7.85-7.74 (m, 2H), 4.81 (d, 2H).

Intermediate 2: 2-(1,3-Dioxoisoindolin-2-yl)-N-(3-methoxyphenethyl)acetamide.

To a stirred solution of 2-(3-methoxyphenyl)ethan-1-amine (160 g, 1.06 mol, CAS: 2039-67-0) and triethylamine (248 ml, 2.04 mol) in DCM (2.4 L ) a solution of intermediate 1 (232 g, 1.04 mol) in DCM (1.2 L) was added at 5°C. The reaction mixture was stirred at room temperature. for 18 hours, then hydrochloric acid (2 M; 2.4 L) was added and the mixture was stirred for 1 hour. The mixture was filtered and the precipitate was washed with water, then dried in vacuo. The residue was dissolved in DCM (10.0 L), and washed with saturated aqueous NaHCO ₃ , and the organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give a white solid (267 g). The organic layer from the first separation was washed with water, saturated aqueous NaHCO3 and the organic layers were dried over _MgSO4 , filtered and concentrated in vacuo to give an additional portion of a white solid (61.4 g). The isolated solids were combined to give the title compound as a white solid (328 g, 82%), used without further purification. LCMS (method 7): 1.68 min, 339.1 [M+H] ⁺ .

Intermediate 3. No. (2-Bromo-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide.

To a stirred solution of intermediate 2 (328 g, 970 mmol) in DMF (3.2 L) was added NBS (173 g, 970 mmol) portionwise over 0.5 h. The reaction mixture was heated to 40°C, then cooled to k.t. and left to stand at room temperature. for 18 hours. The reaction mixture was poured into water (5.0 L), and the resulting precipitate was collected by filtration and washed with water. The residue was diluted with DCM, the aqueous phase was isolated and the combined organic phases were concentrated in vacuo to give the title compound (314 g, 76%) used without further purification. ^1H NMR (300 MHz, CDCl ₃ ) δ 7.90-7.73 (m, 4H), 7.37 (dd, 1H), 6.78 (d, 1H), 6.64 (td, 1H) , 5.80 (s, 1H), 4.31 (d, 2H), 3.79-3.75 (m, 3H), 3.59-3.54 (m, 2H), 2.94 (dd , 2H).

Intermediate 4: 2-((5-bromo-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline1,3-dione.

Phosphoric anhydride (630 g, 4.44 mol) was added to a suspension of intermediate 3 (312 g, 748 mmol) in MeCN (5.0 L). The reaction mixture was heated at 60°C for 4 hours, cooled to room temperature. and left to stand at room temperature. for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to a volume of 500 ml. The filtered solids were dissolved in water (4.0 L) and combined with the organic layer. The combined mixture was heated at 40°C for 1 hour, cooled to room temperature. and saturated aqueous NaHCO ₃ was added to the stirred mixture to adjust the pH to 8. The precipitated solid was collected by filtration and washed with water (1.0 L). The residue was dried in vacuo at 40°C to give the title compound (293 g, 92%) which was used without further purification. LCMS (method 7): 2.34 min, 401.1 [M+H]+.

- 72 045906

Intermediate 5. ^)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-methoxy-3,4dihydroisoquinoline-2( 1 ^-carbaldehyde.

A solution of benzeneruthenium(II) chloride dimer (3.78 g, 7.6 mmol, CAS: 37366-09-9) and (1S,2S)-(+)-N-ntosyl-1,2-diphenylethylenediamine (6.78 g, 18.5 mmol, CAS: 167316-27-0) in MeCN (300 ml) under argon and stirred at room temperature. for 1 hour. To this mixture were added MeCN (2.1 L) and DCM (300 ml), followed by the addition of intermediate 4 (205 g, 457 mmol) and MeCN (1.4 L). A solution of formic acid and triethylamine (1:1; 760 ml) was added to the reaction mixture and the reaction mixture was stirred at room temperature. in an argon atmosphere for 72 hours. The reaction mixture was diluted with water (2.0 l) and NaHCO ₃ was added to it to adjust the pH to 8.0. The mixture was diluted with DCM (3.0 L) and the organic layers were washed with water, dried over MgSO ₄ and filtered. The organic layers were passed through a silica plug, eluted with 66% EtOAc in DCM and the combined organic layers were concentrated in vacuo to give the title compound (215 g, 99%) used without further purification. LCMS (method 4): 0.91 min, 431.1 [M+H] ⁺ .

Intermediate 6. ^)-2-((5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindoline-1,3-dione.

To a suspension of intermediate 5 (215 g, 451 mmol) in THF (1.5 L) was added HCl (2 M aqueous solution; 2.14 L, 4.33 mol) and the mixture was refluxed for 18 hours. Reaction the mixture was cooled to room temperature. and saturated aqueous NaHCO ₃ was added slowly to adjust the pH to 8. The mixture was extracted with DCM (2x2.0 L) and the combined organic layers were dried over MgSO ₄ and filtered. The solution was concentrated in vacuo and the residue was recrystallized twice from MeCN (1.0 L + 250 ml). The resulting precipitate was filtered and dried in vacuo to give the title compound (113 g, 59%) which was used without further purification. LCMS (Method 7a): 2.30 min, 401.1 [M+H] ⁺ ; ^1H NMR (300 MHz, CDG3) δ 7.86 (dt, 2H), 7.76-7.69 (m, 2H), 7.43 (d, 1H), 6.64 (d, 1H), 4.53 (dd, 1H), 4.12-3.92 (m, 2H), 3.91-3.81 (m, 3H), 3.64 (s, OH), 3.43-3, 32 (m, 1H), 3.06 (qd, 1H), 2.56-2.82 (m, 2H).

Intermediate 7. ^)-2-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindoline-1,3-dione.

To a solution of intermediate 6 (141 g, 351 mmol) in DCM (2.5 L) at 0° C., boron tribromide (1M in DCM; 1.34 L, 1.44 mol) was added dropwise over 1 hour and the reaction mixture was stirred at room temperature. for 18 hours. The reaction mixture was cooled to 0°C, MeOH (150 ml) was added slowly and the mixture was stirred for 1.5 hours. The resulting precipitate was isolated by filtration, washed with DCM and dried in vacuo at 50°C with yielding the title compound (intermediate 7-HBr) (129 g, 71%). Hydrochloric acid (2 M aqueous solution; 3.0 L) was added to the combined organic layers and the mixture was stirred for 1 hour. The resulting precipitate was isolated by filtration and dried in vacuo at 50°C to give the title compound (intermediate 7 -HCl) (44.1 g, 27%). The acidic aqueous phase was isolated and adjusted to pH 8 by adding Na ₂ CO ₃ and extracted with DCM. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (3.67 g, 2%) which was used without further purification. LCMS

- 73 045906 (method 9a): 1.87 min, 389.1 [M+H]+.

Intermediate 8. tert-butyl^)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate.

HE

To a stirred suspension of intermediate 7-HBr (129 g, 251 mmol) in DCM (1 L) was added triethylamine (89 mL, 636 mmol) and di-tert-butyl dicarbonate (41.5 g, 190 mmol). Additional di-tert-butyl dicarbonate (7.3 g, 33.5 mmol) was added and the mixture was stirred for 2 hours. The last portion of di-tert-butyl dicarbonate (3.37 g, 15.45 mmol) was added and the mixture was stirred at .T. for 18 hours. The reaction mixture was diluted with water and the mixture was extracted with DCM. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound (145 g, estimated amount), used without further purification. LCMS (method 9a): 2.54 min, 487.1 [M-H] ^- .

Intermediate 9. ^)-2-((8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline1,3-dione.

Pd/C (10%; 25 mg) was added to a solution of intermediate 6 (250 mg, 0.62 mmol) in THF (6 mL) and EtOH (6 mL). The mixture was stirred at room temperature. in a hydrogen atmosphere for 48 hours at atmospheric pressure. Additional Pd/C (10%; 10 mg) was added and the mixture was stirred under hydrogen for 72 hours. The mixture was then filtered through a pad of Celite®, washed with EtOH (10 ml) and MeOH (10 ml). The filtrate was concentrated in vacuo. Purification by flash column chromatography (19% EtOAc in DCM with 1% 7 M NH3 in MeOH, to 16% EtOAc in DCM with 4% 7 M NH3 in MeOH) afforded the title compound (153 mg, 76%) . LCMS (Method 4): 0.76 min, 323.23 [M+H] ⁺ .

Intermediate 10. ^)-2-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione.

To a solution of intermediate 9 (200 mg, 0.62 mmol) in DCM (2 ml) at -10°C under argon was added boron tribromide (1M in DCM; 3.1 ml, 3.1 mmol). The reaction mixture was heated to room temperature. and stirred for 1 hour. The reaction mixture was cooled to 0°C and MeOH (1 ml) was added. The mixture was warmed to RT, concentrated in vacuo and the residue was stirred in saturated aqueous NaHCO3 (10 ml) and EtOAc (10 ml) for 15 min. The layers were separated and the aqueous phase was extracted with EtOAc (15 ml). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (130 mg, 68%) used without further purification. LCMS (Method 4): 0.66 min, 309.19 [M+H] ⁺ .

Intermediate 11. tert-Butyl^)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy3,4-dihydroisoquinoline-2(III)-carboxylate.

- 74 045906

To a solution of intermediate 10 (3.4 g, 11.03 mmol) in DCM (400 ml) was added di-tert-butyl dicarbonate (2.9 g, 13.23 mmol). The reaction mixture was stirred at room temperature. for 2 hours. Saturated aqueous NaHCO ₃ (150 ml) was added and the mixture was stirred for 15 minutes. The layers were separated and the organic layer was washed with water (100 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was diluted with a 1:1 mixture of IPA and heptanes (50 ml) and the mixture was stirred for 1 hour. The solid was filtered and washed with pentane (50 ml) to give the title compound (3.8 g, 85%) used without additional cleaning. LCMS (Method 4): 0.82 min, 407.4 [M-N] ^- .

Intermediate 12. tert-Butyl^)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8hydroxy-3,4-dihydroisoquinoline-2(III)-carboxylate.

Method 1: To a solution of intermediate 11 (77.72 g, 188 mmol) in DMF (1.50 L) was added N-chlorosuccinimide (27.5 g, 206 mmol). The mixture was heated at 50°C for 72 hours, then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with water (x2), brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was combined with an additional batch of crude material (70.97 mmol), which was dissolved in DCM (750 ml), and allowed to crystallize. The resulting precipitate was collected by filtration, washed with DCM and dried in vacuo to give the title compound (80 g, 65%) used without further purification. LCMS (Method 9a): 2.57 min, 441.2 [M-H] ^- .

Method 2: To a suspension of intermediate 55-HBr (57.3 g, 135.2 mmol) in DCM (1000 ml) was added DIPEA (59.7 ml, 343 mmol) followed by di-tert-butyl dicarbonate (22.1 g, 101 mmol; CAS: 24424-99-5). The reaction mixture was stirred at room temperature. for 66 hours. Additional di-tert-butyl dicarbonate (3.56 g, 16.31 mmol) was added and the mixture was stirred for 2 hours, followed by the addition of additional di-tert-butyl dicarbonate (1.6 g, 7. 33 mmol), and the mixture was stirred for another 1 hour. The reaction mixture was washed with water and the organic layers were separated, dried (MgSO ₄ ) and filtered. The organic layers were concentrated in vacuo (to ~500 ml) and the mixture was left at room temperature. for 18 hours. The precipitate was isolated by filtration, washed with Et ₂ O and dried in vacuo (50°C) to obtain the title compound (43.3 g, 72%). LCMS (method 9a): 2.33 min, 441.1 [M-H] ^- . ^1H NMR (300 MHz, CDCl ₃ ) d 7.91-7.85 (m, 2H), 7.74 (dq, 2H), 7.23-7.18 (m, 1H), 6.80- 6.76 (m, 1H), 5.49-5.78 (1H), 4.08 (dd, 1H), 3.83-4.00 (1H), 3.22-3.54 (1H) , 2.87-3.04 (1H), 2.612.84 (1H), 1.20 (s, 4H), 1.03 (d, 5H). The organic layers were concentrated in vacuo and combined with the crude material from the next experiment (method 3) for further purification.

Method 3: To a suspension of intermediate 55-HCl (49.3 g, 130 mmol) in DCM (1.0 L) was added DIPEA (57.36 ml, 329 mmol) followed by di-tert-butyl dicarbonate (22.49 g, 103.05 mmol; CAS: 24424-99-5). The reaction mixture was stirred at room temperature. for 66 hours. Additional di-tert-butyl dicarbonate (0.46 g, 2.12 mmol) was added and the mixture was stirred for 2 hours, followed by the addition of additional di-tert-butyl dicarbonate (0.5 g, 2.12 mmol). 29 mmol) and the mixture was stirred for another 1 hour. The reaction mixture was washed with water and the organic layers were separated, dried (MgSO4) and filtered. The organic layers were concentrated in vacuo (to ~500 ml) and the mixture was left at room temperature. for 18 hours. The precipitate was isolated by filtration, washed with Et2O and dried in vacuo (50°C) to give the title compound (26.95 g, 46%). LCMS (method 9a): 2.38 min., 441.1 [M-H] ^- . The organic layers were concentrated in vacuo and combined with the concentrated organic layers from Method 2 for further purification by flash column chromatography (silica; 40% EtOAc in heptane) to yield an additional batch of the title compound (32.4 g, 72.7 mmol). LCMS (method 9): 2.56

- 75 045906 min, 441.1 [M-N] ^- .

Intermediate 13. tert-Butyl-(^)-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

To a stirred suspension of intermediate 11 (400 mg, 0.98 mmol) in MeOH (8 mL) was added NaBH ₄ (148 mg, 3.9 mmol) under argon at RT. The reaction mixture was stirred at room temperature. for 72 h, then quenched with saturated aqueous NH ₄ Cl (~15 ml) and acidified by adding 10% aqueous citric acid. The product was collected by filtration, washed with water and dried in vacuo. The residue was azeotroped with MeCN to give the title compound (343 mg, 85%) which was used without further purification. LCMS (Method 5): 1.86, 1.99 min, 409.1 [M-H] ⁺ .

Intermediate 14. ^)-2-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindolin-1-one.

To a solution of intermediate 13 (50 mg, 0.122 mmol) in TFA (1 ml) was added triethylsilane (0.03 ml, 0.18 mmol). The reaction mixture was stirred at room temperature. for 3 hours and then concentrated in vacuo. The residue was partitioned between DCM (2 ml) and saturated aqueous NaHCO ₃ (5 ml). The layers were separated and the aqueous layer was washed with DCM (10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (30 mg, 84%) used without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ 7.88 (m, 1H), 7.61-7.41 (m, 3H), 7.06 (t, 1H), 6.77 (d, 1H), 6.62 (d, 1H), 4.83 (d, 1H), 4.52 (d, 1H), 4.41 (d, 1H), 3.90 (d, 1H), 3.58 (dd , 1H), 3.22-3.03 (m, 2H), 2.83-2.61 (m, 2H).

Intermediate 15. tert-Butyl-(^)-5-bromo-8-hydroxy-1-((1-hydroxy-3oxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

NaBH ₄ (0.53 g, 14.1 mmol ) and MeOH (15 ml). The solution was heated to room temperature. and stirred for 30 minutes. The second portion of NaBH ₄ (0.53 g, 14.1 mmol) was added and stirring was continued for 45 minutes. Additional NaBH ₄ (0.36 g, 9.4 mmol) was added and the mixture was stirred at RT. for 15 hours. The reaction mixture was diluted with water, acidified to pH 3-4 with 10% citric acid and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (4.4 g, 97%) used without further purification. LCMS (Method 2): 1.46 min, 511.2/513.2 [M+Na] ⁺ .

Intermediate 16. ^)-2-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindolin-1-one.

- 76 045906

Triethylsilane (2.5 mL, 15.65 mmol) was added to a stirred solution of intermediate 15 (4.44 g, 9.07 mmol) in TFA (50 mL, 652 mmol). The mixture was stirred at room temperature. for 90 min, then diluted with DCM (200 ml). Saturated aqueous NaHCO ₃ was carefully added followed by ammonia (aqueous 30-33 wt.%; 100 ml). The aqueous layer was extracted with DCM and the combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. MeCN (40 ml) and DCM (10 ml) were added to the residue and the resulting suspension was sonicated for 5 min. The solid was collected by filtration, rinsed with MeCN/DCM (4:1; 10 mL) and concentrated in vacuo to give the title compound (1.92 g, 56%). LCMS (method 2): 0.86 min, 373.1/375.1 [M+H]+.

Intermediate 17. tert-Butyl-(^)-5-chloro-8-hydroxy-1-((1-hydroxy-3oxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate.

To a stirred solution of intermediate 12 (2.18 g, 4.92 mmol) in anhydrous THF (72 mL) under argon at 0°C was added NaBH ₄ (0.28 g, 7.38 mmol) followed by anhydrous MeOH (8 ml). The mixture was stirred at 0°C for 5 minutes, heated to room temperature and stirred for 75 minutes. Additional NaBH ₄ (0.28 g, 7.38 mmol) was added and the mixture was stirred at RT. for another 2 hours. Additional NaBH ₄ (0.19 g, 4.92 mmol) was added and the mixture was stirred at room temperature. for another 19 hours. The mixture was quenched with saturated aqueous NaHCO ₃ (120 ml), then acidified to pH 5 with 10% aqueous citric acid (220 ml). The mixture was extracted into EtOAc (3x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (2.18 g, estimated amount), used without further purification. LCMS (method 2): 1.44 min, 467.2/469.2 [M+Na]+.

Intermediate 18. ^)-2-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindolin-1-one.

To a stirred solution of intermediate 17 (1.98 g, 4.45 mmol) in TFA (33.6 mL, 436.2 mmol) under argon was added triethylsilane (1.07 mL, 6.68 mmol) and the resulting the solution was stirred at room temperature. for 2 hours. The mixture was diluted with DCM (300 ml) and saturated aqueous NaHCO ₃ solution (440 ml) was carefully added with stirring to adjust the pH to 8-9. The aqueous layer was extracted further with DCM (2x300 ml) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with diethyl ether (30 ml) and the solid was collected by filtration, washed with diethyl ether (x3) and dried in vacuo at 40°C. Purification by flash column chromatography (Puriflash 40 g, 0-5% MeOH in DCM) gave the title compound (420 mg, 35%). LCMS (method 1): 0.79 min, mass/charge 329.1 [M+H]+.

Intermediate 19. tert-butyl-^)-1-(aminomethyl)-5-bromo-8-hydroxy-3,4dihydroisoquinoline-2(1^-carboxylate.

- 77 045906

To a stirred suspension of intermediate 8 (3.41 g, 7 mmol) in EtOH (100 ml) was added hydrazine hydrate (1.7 ml, 34.95 mmol) and the resulting red mixture was heated at 65°C for 7 hours. with the formation of a colorless precipitate. The mixture was cooled to RT and the precipitated solid was removed by filtration and the solids were washed with EtOH (20 ml). The filtrates were concentrated in vacuo to give the title compound (3.24 g, estimated amount) used without further purification. LCMS (method 2): 1.01 min, 357.1 [M+H] ⁺ .

Intermediate 20. tert-Butyl-^)-5-bromo-8-hydroxy-1-((2-oxopyrrolidin-1yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate.

Stirred solution of methyl 4-bromobutanoate (1.52 mmol, 8.4 mmol; CAS: 4897-84-1), intermediate 19 (3.24 g, 7 mmol) and triethylamine (1.47 ml, 10.55 mmol) in toluene (70 ml) was refluxed for 18 hours. The second portion of methyl 4-bromobutanoate (250 mg, 1.38 mmol) was added and the mixture was refluxed for a further 5 hours. The mixture was cooled to .t., diluted with EtOAc and washed with 10% aqueous citric acid, water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (100 g silica gel, Biotage SNAP, 0-100% EtOAc in DCM, then 0-100% MeOH in DCM) afforded the title compound (1.41 g, 47%). LCMS (method 2): 1.48 min, 447.2 [M+Na] ⁺ .

Intermediate connection 2L. ^)-1-((5-Bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)pyrrolidin-2-one.

A stirred solution of intermediate 20 (826 mg, 1.94 mmol) in DCM (60 ml) was treated with TFA (3 ml, 39.2 mmol) and the resulting solution was stirred at RT. 2 hours. The mixture was diluted with DCM (50 ml) and water (50 ml) and made alkaline to pH 8 by adding saturated aqueous NaHCO ₃ . The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (593 mg, 94%) used without further purification. LCMS (Method 2): 0.74 min, 325.1 [M+H]+ with Br isotope.

Intermediate dihydroisoquinoline-2(1I)-carboxylate.

22. tert-Butyl-^)-1-(aminomethyl)-5-chloro-8-hydroxy-3,4-

Method 1: To a solution of intermediate 12 (2.35 g, 5.31 mmol) in EtOH (50 ml) was added hydrazine hydrate (1.29 ml, 26.5 mmol) and the mixture was refluxed for 24 hours. Reaction the mixture was cooled to room temperature. and filtered. The filtrate was concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g Puriflash HC/Biotage SNAP silica gel, 0-30% EtOAc in MeOH) gave the title compound (1.49 g,

- 78 045906

90%). LCMS (Method 2): 1.01 min, 313.0 [M+H] ⁺ .

Method 2: To a stirred suspension of intermediate 12 (40.0 g, 90.3 mmol) in EtOH (150 ml) was added hydrazine monohydrate (16.9 ml, 226 mmol, CAS: 7803-57-8) and the resulting the mixture was heated to 75°C and stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with additional IMS and filtered. The filter cake was washed with cold EtOH and the combined filtrates were concentrated in vacuo to ~400 mL. The solution was left to stand for 18 hours, then filtered to remove precipitate and the precipitate was washed with cold EtOH. The filtrates were concentrated in vacuo and EtOH (100 ml) and MeCN (100 ml) were added to the residue. The suspension was filtered and concentrated in vacuo to give the title compound (24.5 g, 82% yield).

Intermediate 23. tert-Butyl-^)-5-chloro-8-hydroxy-1-((2-oxopyrrolidin-1yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate.

To a solution of intermediate 22 (1.65 g, 5.28 mmol) in toluene (40 ml) was added methyl 4-bromobutanoate (1.24 g, 6.86 mmol; CAS: 4897-84-1) and triethylamine (1, 1 ml, 7.93 mmol). The reaction mixture was refluxed for 24 hours, after which additional parts of methyl 4-bromobutanoate (1.24 g, 6.86 mmol) in toluene (1 ml) and triethylamine (1.1 ml, 7.93) were added mmol) and the reaction mixture was refluxed for a further 6.5 hours. The mixture was concentrated in vacuo, the residue was dissolved in EtOAc and washed successively with brine (20 ml), water (20 ml), dried over MgSO ₄ and concentrated in vacuo. Purification by flash column chromatography on Teledyne ISCO CombiFlash® Rf+ (200 g Puriflash HC/Biotage SNAP silica gel, 0-100% EtOAc in cyclohexane) gave the title compound (1.29 g, 64%). LCMS (method 2): 1.43 min, 403 [M+Na] ⁺ .

Intermediate 24. ^)-1-((5-Chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)pyrrolidin-2-one.

To a stirred mixture of intermediate 23 (203 mg, 0.530 mmol) in anhydrous DCM (8 mL) under argon, TFA (0.82 mL, 10.66 mmol) was added dropwise and the resulting solution was stirred at room temperature. for 1.5 hours. The reaction mixture was diluted with water (5 ml) and adjusted to pH 8-9 by adding saturated aqueous NaHCO ₃ solution (~8 ml). The aqueous layer was extracted with DCM (3x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (173 mg, estimated amount) used without further purification. LCMS (method 2): 0.75 min, 281.1 [M+H]+.

Intermediate 25. (^^)-2-((Benzyloxy)carbonyl)cyclohexane-1-carboxylic acid.

To a suspension of cis-1,2-cyclohexanedicarboxyl anhydride (10 g, 65.0 mmol, CAS: 13149-00-3) and quinidine (23 g, 71.4 mmol) in toluene (200 ml) at -10°C was added benzyl alcohol (21 g, 195 mmol) dropwise over 30 min. in an argon atmosphere. The reaction mixture was then stored in a refrigerator at 0°C for 5 days. After heating to room temperature. the mixture was diluted with EtOAc (150 ml) and toluene (150 ml). The solution was washed with aqueous HCl (1 M; 2x200 ml), then with saline (200 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to 350 ml, and a solution of (R)alphamethylbenzylamine (7.86 g, 65 mmol) in toluene (75 ml) was added. The resulting mixture was stirred at room temperature. within 30 min. before introducing the seed in the form of small crystals of pure ammonium salt (obtained by using a small aliquot of the solution and concentrating to dryness

- 79 045906 state) and stirred for a further 18 hours. The solids were then collected by filtration and washed with toluene (50 ml), then dried in vacuo. The solids were then partitioned between EtOAc (250 ml) and 1M aqueous HCl (200 ml). The EtOAc layer was collected, washed with brine (100 mL), dried over MgSO ₄ and concentrated in vacuo to give the title compound (10 g, 58%, >99% ee). Chiral HPLC (Chiralpak IA 4.6x250 mm, 90:10 hep/IPA+0.1% TFA, flow rate 1 ml/min.); k.t. = 6.2 min. LCMS (Method 4): 0.51 min, 236.3 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.26 (m, 5H), 5.20-5.04 (m, 2H), 2.92-2.85 (m, 2H), 2 .09-1.99 (m, 2H), 1.851.75 (m, 2H), 1.61-1.35 (m, 4H).

Intermediate 26: Benzyl (1S,2R)-2-(chlorocarbonyl)cyclohexane-1-carboxylate.

To a solution of intermediate 25 (0.50 g, 1.90 mmol) in DCM (5 mL) was added oxalyl chloride (0.82 mL, 9.53 mmol). The reaction mixture was stirred at RT for 3 hours, then the reaction mixture was concentrated in vacuo and the residue azeotroped in vacuo with toluene (2x20 ml) to obtain the title compound (0.57 g, 100%) used without additional cleaning. 1H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.20 (m, 5H), 5.19-5.08 (m, 2H), 3.22-3.00 (m, 2H), 2 .17-2.01 (m, 2H), 1.92-1.77 (2H, 1H), 1.60-1.37 (m, 4H).

Intermediate 27. (^^)-2-[(2,4-Dimethoxyphenyl)methoxycarbonyl]cyclohexanecarboxylic acid; (^)-1-phenylethanamine.

A solution of (2,4-dimethoxyphenyl)methanol (32.7 g, 195 mmol, CAS: 7314-44-5) in toluene (50 ml) was added dropwise to a suspension of cis-1,2-cyclohexanedicarboxyl anhydride (10.0 g , 64.9 mmol, CAS: 13149-00-3) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (23, 2 g, 71.4 mmol, CAS: 56-54-2) in toluene (150 ml) at -5°C for 1 hour. The solution was then transferred to the refrigerator and left to settle for 12 days. The reaction mixture was washed with 1 M aqueous HCl (200 ml), brine (100 ml), and the organic layer was dried over MgSO ₄ and filtered. A portion (ca. 2 ml) of the filtrate was concentrated in vacuo and ether (2 ml) was added to the residue, followed by (^)-1-phenylethanamine (1 drop; CAS 3886-69-9). The resulting solid was collected by trituration. (Q)-1-phenylethanamine (8.4 mL, 64.9 mmol) was added to the remaining filtrate with stirring. The solid collected from the previous trituration was added to this solution and left with stirring at room temperature. for 18 hours. The precipitated solid was collected by filtration, washed with ether (200 ml) and dried to give the title compound (16.4 g, 57%) which was used without further purification. ^1H NMR (300 MHz, MeOD) δ 7.42-7.20 (m, 6H), 6.49-6.44 (m, 2H), 5.11-4.90 (m, 2H), 4 .32 (q, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.76-2.65 (m, 2H), 2.13-1.33 (m, 11H ). The above reaction was repeated with 10 g of cis-1,2cyclohexanedicarboxyl anhydride to obtain 20.6 g of the title compound (68%).

Intermediate 28. (^^)-2-(((2,4-Dimethoxybenzyl)oxy)carbonyl)cyclohexane-1carboxylic acid.

Intermediate 27 (16.4 g, 36.98 mmol) was partitioned between citric acid (10% aqueous solution; 80 mL) and EtOAc (400 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (11.5 g, 99%) which was used without further purification. ^1H NMR (300 MHz, MeOD) δ 7.17 (d, 1H), 6.51-6.44 (m, 2H), 5.02 (dd, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 2.81-2.79 (m, 2H), 2.01-1.99 (m, 2H), 1.751.71 (m, 2H), 1.47-1, 41 (m, 4H).

Intermediate 29. Methylcyclohexane-1-carboxylic acid.

(III^)-2-(((2,4-Dimethoxybenzyl)oxy)carbonyl)-2- 80 045906

To a stirred solution of intermediate 28 (11.5 g, 35.68 mmol) in anhydrous THF (92 mL) was added LDA (2M in THF/heptane/ethylbenzene; 44.6 mL, 89.19 mmol) dropwise at -25 °C in an argon atmosphere for over 2 hours. The mixture was stirred at -25 °C for 30 minutes, then iodomethane (6.66 ml, 107.03 mmol) was added dropwise and the reaction mixture was stirred at -25 °C in for 1 hour. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was washed with 10% aqueous citric acid, a further aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (eluting with 2-5% MeOH in DCM) gave the title compound (2.1 g, 13%). ^1H NMR (400 MHz, MeOD) δ 7.20-7.16 (m, 1H), 6.51-6.44 (m, 2H), 5.07-4.94 (m, 2H), 3 .82-3.74 (m, 6H), 2.57-2.49 (m, 1H), 2.14-1.79 (m, 3H), 1.57-1.21 (m, 8H) .

Intermediate 30. (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclopentanecarboxylic acid; (^)-1-phenylethanamine.

(K .O, J I

O Ί ' ] rAV NH.

V L ° P ‘io VJ

To a stirred suspension of (3aR,6aS)-4,5,6,6a-tetrahydro-3aH-cyclopenta-[c]furan-1,3-dione (10 g, 71.36 mmol, CAS: 35878-28-5) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidin-2yl]methanol (25.46 g, 78.49 mmol, CAS: 56-54-2) in toluene (150 ml) was added dropwise (2,4dimethoxyphenyl)methanol (37.82 ml, 214.07 mmol) in toluene (50 ml) at -5°C over 1 hour. The solution was then transferred to the refrigerator and left stand for 5 days. The solution was washed with 1 M aqueous HCl (400 ml) and saline (100 ml). The organic layer was dried over MgSO ₄ and filtered. A portion (ca. 2 ml) of the filtrate was concentrated in vacuo and ether (2 ml) was added to the residue, followed by (^)-1-phenylethanamine (1 drop; CAS 3886-69-9). The resulting solid was collected by trituration. (Q)-1-phenylethanamine (9.2 mL, 71.36 mmol) was then added to the bulk of the filtrate with stirring. To this solution was added the solid collected from the previous trituration and left with stirring at room temperature. for 18 hours. The precipitated solid was collected by filtration, washed with ether (200 ml) and dried to give the title compound (18.6 g, 58%) which was used without further purification. 1H NMR (300 MHz, DMSO-d ₆ ) δ 7.37-7.10 (m, 6H), 6.53-6.45 (m, 2H), 5.02-4.77 (m, 2H) , 4.81-4.59 (m, 2H), 4.04-3.97 (m, 1H), 3.73 (d, 6H), 2.94-2.70 (m, 2H), 1 .85-1.19 (m, 9H).

Intermediate 31. (^^)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclopentane-1carboxylic acid.

Intermediate 30 (18.6 g, 43.4 mmol) was partitioned between 10% aqueous citric acid (72 mL) and EtOAc (300 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (13.2 g, 95%) which was used without further purification. 1H NMR (300 MHz, MeOD) δ 7.18 (d,

1H), 6.56-6.44 (m, 2H), 5.07-4.91 (m, 2H), 3.82-3.77 (m, 6H), 3.09-3.00 ( m, 2H), 2.01-1.55 (m, 6H).

Intermediate 32. (1R,2S)-2-(((2,4-Dimethoxybenzyl)oxy)carbonyl)-2methylcyclopentane-1-carboxylic acid.

To a stirred solution of intermediate 31 (13.2 g, 42.8 mmol) in anhydrous THF (120 mL) was added LDA (2 M in THF/heptane/ethylbenzene; 53.5 mL, 107 mmol) dropwise at -25° C in

- 81 045906 argon atmosphere for more than 45 minutes. The mixture was stirred at -25°C for 30 minutes, then iodomethane (2.67 ml, 42.81 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and then quenched with saturated aqueous NH4Cl. EtOAc was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with 10% citric acid, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (2-5% MeOH in DCM) gave the title compound (1.9 g, 14%). 1H NMR (300 MHz, MeOD) δ 7.21-7.16 (m, 1H), 6.51-6.44 (m, 2H), 4.98 (s, 2H), 3.78 (d, 6H), 2.69-2.59 (m, 1H), 2.21-1.29 (m, 9H).

Intermediate 33. 2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1-(2,4-dimethoxybenzyl)(1 S,2R)-1-methylcyclohexane -1,2-dicarboxylate.

To a stirred solution of crude intermediate 29 (13.5 g, 40.0 mmol) in DMF (72 ml) at RT. HATU (19.8 g, 52.0 mmol; CAS: 148893-10-1) was added under argon and the reaction mixture was stirred for 5 min. DIPEA (7.67 mL, 44.0 mmol) was added to the mixture and the mixture was stirred at RT. for 3.5 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification on a Teledyne ISCO CombiFlash® Rf+ (330 g Puriflash HC silica gel, 0-75% EtOAc in cyclohexane) gave the title compound (14.4 g, 79%). LCMS (Method 16): 1.59 min, 477.3 [M+Na]+. 1H NMR (400 MHz, CDCl ₃ ) δ: 8.70 (dd, 1H), 8.40 (dd, 1H), 7.41 (dd, 1H), 7.25-7.22 (m, 1H) , 6.43-6.40 (m, 2H), 5.16 (dd, 2H), 3.78 (d, 6H), 3.11 (dd, 1H), 2.32-2.13 (m , 3H), 1.73-1.52 (m, 5H), 1.47 (s, 3H).

Intermediate 34: 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1-(2,4-dimethoxybenzyl)(1S,2R)-1-methylcyclopentane -1,2-dicarboxylate.

To a stirred solution of intermediate 32 (1.5 g, 4.65 mmol) in DMF (8 mL) was added HATU (2.3 g, 6.05 mmol) and the resulting mixture was stirred at RT. in an argon atmosphere for 5 minutes. DIPEA (0.89 mL, 5.12 mmol) was added and the resulting mixture was stirred for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g Puriflash HC silica gel, 0-50% EtOAc in cyclohexane) to give the title compound (771 mg, 38%). LCMS (Method 16): 1.49 min, 463.3 [M+Naf. 1H NMR (400 MHz, CDCl ₃ ) δ: 8.71 (dd, 1H), 8.40 (dd, 1H), 7.42 (dd, 1H), 7.27-7.24 (m, 1H) , 6.42 (d, 2H), 5.24 (s, 2H), 3.78 (d, 6H), 3.15 (dd, 1H), 2.44-2.28 (m, 3H), 1.93-1.71 (m, 3H), 1.58 (d, 3H).

Intermediate 35. tert-Butyl-^)-5-chloro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan5-yl)methyl)-3,4-dihydroisoquinoline-2(III) -carboxylate.

To a stirred solution of intermediate 22 (2.70 g, 8.63 mmol) in toluene (30 ml) was added methyl 2-(1-(bromomethyl)cyclopropyl) acetate (2.14 g, 10.4 mmol; CAS: 855473-50-6) and triethylamine (1.8 ml, 13.0 mmol) in toluene (30 ml) and the reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature. and concentrated in vacuo. Saline was added thereto and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo.

The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g Puriflash HC silica gel column, 5-80% EtOAc in cyclohexane) to give the title compound (2.89 g, 82%). LCMS (Method 17): 1.66 min, 407.1 [M+H]+. Vysheuka

- 82 045906 The above reaction was repeated with 24.0 g of intermediate 22 and a yield of 24.8 g (79%).

Intermediate 36. ^)-5-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride.

on

A solution of intermediate 35 (2.35 g, 5.78 mmol) in HCl (4 M in dioxane; 29 mL, 116 mmol) was stirred at RT. for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with toluene (x2) to give the title compound (1.98 g, estimated amount), used without further purification. LCMS (method 17): 0.79 min, 307.1 [M+H]+.

Intermediate 37: 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-hydroxy-1-((6-oxo5-azaspiro[2.4]heptan-5-yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylate.

To a stirred solution of intermediate 36 (4.50 mg, 13.1 mmol) in DMF (39 mL) was added intermediate 33 (5.96 g, 13.1 mmol) and DIPEA (4.57 mL, 26.22 mmol ) and the reaction mixture was stirred under nitrogen atmosphere for 5 days. The reaction mixture was diluted with brine, extracted with EtOAc and concentrated in vacuo. The residue was redissolved in EtOAc (75 ml) and cooled to 0°C, and a precipitate formed. The solid was removed by filtration to give the title compound (5.05 g, 62%). LCMS (method 16): 1.52 min, 647.4 [M+Na] ⁺ .

Intermediate 38. Ethyl (C.)-4-iodo-3-methylbutanoate.

Trimethylsilyl iodide (38, 1 ml, 268 mmol). The solution was stirred at -20°C for 30 minutes. Triethyl orthoformate (22.3 mL, 134 mmol) was then added and the reaction mixture 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 the title compound (24.3 g, 71%). ^1H NMR (300 MHz, CDCl ₃ ) 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).

Intermediate 39. (^^)-6-(methoxycarbonyl)-6-methylcyclohex-3-ene-1-carboxylic acid.

BUT

To a stirred solution of (1K.^)-6-methoxycarbonylcyclohex-3-ene-1-carboxylic acid (10.5 g, 57.01 mmol; CAS: 88335-93-7) in anhydrous THF (150 ml), cooled to -25°C under argon, a solution of lithium diisopropylamide (1.0 M in THF/hexanes; 143 mL, 143 mmol) was added dropwise and the resulting solution was stirred at -25°C for 30 minutes. Iodomethane (10.65 ml, 171.0 mmol) was added dropwise and the solution was slowly heated to room temperature. for 4 hours. The mixture was quenched with saturated aqueous NH4Cl (200 ml), then partitioned between EtOAc (200 ml) and 10% aqueous citric acid (200 ml). The aqueous layer was extracted further with EtOAc (2x200 ml) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (11.4 g, relative amount). 1H NMR (400 MHz, CDCl ₃ ) δ 5.67-5.59 (m, 2H), 3.71 (s, 3H), 3.02-2.98 (m, 1H), 2.78-2 .72 (m, 1H),

- 83 045906

2.61-2.55 (m, 1H), 2.48-2.36 (m, 1H), 2.09-2.01 (m, 1H), 1.26 (s, 3H).

Intermediate 40. 2-(3H-[1,2,3]triαzolo[4,5-b]pyridin-3-yl)-1-methyl-(1S,2R)-1methylcyclohex-4-ene-1,2 -dicarboxylate.

To a stirred solution of intermediate 39 (2.15 g, 10.9 mmol) in DMF (50 ml) at RT. HATU (4.54 g, 11.9 mmol; CAS: 148893-10-1) was added under argon and the reaction mixture was stirred at RT. within 5 minutes. DIPEA (2.08 mL, 11.9 mmol) was added and the reaction mixture was stirred for an additional 4 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g Puriflash HC/Biotage SNAP silica gel column, 0-10% MeOH in DCM) to give the title compound (2.30 mg, 67%) . LCMS (method 16): 1.29 min, 339.0 [M+Na] ⁺ .

Intermediate 41. (E)-1-fluoro-2-methoxy-4-(2-nitrovinyl)benzene.

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 hours. The reaction mixture was cooled to room temperature. during the night. 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 precipitate, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound (42 g, 200 mmol, 54%). The residue was dissolved in 2-MeTHF and the organic layer was washed with water, brine, dried (Na ₂ SO ₄ ) and evaporated to give additional product (11 g, 55.2 mmol, 15% yield) as a yellow solid. The acetic acid stock solutions were evaporated and diluted using IMS. The resulting solid was collected by filtration and washed with IMS to obtain 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. ^1H NMR (300 MHz; CDCl3) δ: 7.95 (d, 1H), 7.52 (d, 1H), 7.16-7.08 (m, 3H), 3.95 (s, 3H) .

Intermediate 42: 2-(4-Fluoro-3-methoxyphenyl)ethane-1-amine.

Sulfuric acid (8.92 mL, 167.38 mmol) was added dropwise under nitrogen to a stirred solution of lithium aluminum hydride in THF (2 M; 12.7 g, 335 mmol) previously cooled in an ice-salt bath. The mixture was stirred for 15 minutes. until gas evolution completely stops. A solution of intermediate 41 (22 g, 111.6 mmol) in 2methyltetrahydrofuran (660 ml) was added dropwise, ensuring that the temperature remained <20°C. The cooling bath was removed and the mixture was refluxed for 5 minutes, then cooled in an ice-salt bath. IPA (57 ml) was added dropwise followed by sodium hydroxide (2 M, 39 ml). Magnesium sulfate was added and the mixture was stirred for 30 minutes, then filtered through Celite®. The filter cake was washed with 2-MeTHF/IPA, ~98:2 (~1.5 L), followed by a wash with 10% MeOH in DCM (-1.5 L). The filtrate was concentrated in vacuo to give the title compound (18.8 g, 99%) which was used without further purification. 1H NMR (400 MHz, CDCl3) 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), 1.241.18 (m, 2H).

Intermediate 43: 2-(1,3-Dioxoisoindolin-2-yl)-M-(4-fluoro-3-methoxyphenethyl)acetamide.

- 84 045906

O. /..............\ O

A

To a solution of intermediate 42 (49.3 g, 291 mmol) and DIPEA (101.5 mL, 583 mmol) in DCM (250 mL) under nitrogen, cooled in an ice-salt bath, a solution of intermediate 1 ( 65.2 g, 291 mmol) in DCM (1.25 L). The mixture was stirred while warming from 0° C. to room temperature over 2 hours. 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 (400 MHz, CDCl ₃ ) δ 7.89-7.86 (m, 2H), 7.77-7.74 (m, 2H), 6.90 (dd, 1H), 6.78 ( dd, 1H), 6.66 (ddd, 1H), 5.75 (s, 1H), 4.29 (s, 2H), 3.88 (s, 3H), 3.52 (q, 2H), 2.79 (t, 2H).

Intermediate 44. N(2-chloro-4-fluoro-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2 yl)acetamide.

A mixture of intermediate 43 (82.6 g, 232 mmol) and NCS (34.05 g, 254.97 mmol) in DMF (780 ml) was heated to 50°C and stirred for 1 hour at 50°C, then cooled and concentrated in vacuo. Water (~2 L) was added to the resulting precipitate and the resulting precipitate was stirred for 1 hour. The solid was isolated by filtration, washed with water, Et2O, air dried and dried in vacuo to give the title compound (85 .8 g, 94%), used without further purification. LCMS (Method 15): 1.43 min, 391.3 [M+H]+.

Intermediate 45. 2-((5-chloro-7-fluoro-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindolin-1, 3-dione.

A solution of intermediate 44 (5 g, 12.79 mmol) in nitromethane (200 ml) was stirred under nitrogen at 108°C and poured into a suspension of phosphoric anhydride (10.9 g, 76.77 mmol) in nitromethane, also at 108 °C, and the resulting mixture was stirred at 108 °C for 1 hour. The mixture was cooled to room temperature. and the solvent was decanted into the flask and concentrated in vacuo. The combined residues were diluted with ~500 mL water and the resulting mixture was heated at 40°C for 30 min. The mixture was cooled and neutralized with solid sodium carbonate in parts, then extracted with DCM (3x200 ml). The combined extracts were washed with saline, dried (MgSO ₄ ) and concentrated in vacuo. The residue was suspended in diethyl ether and EtOAc was added to the suspension. The resulting precipitate was isolated by filtration and dried in vacuo to give the title compound (4.1 g, 86% yield), which was used without further purification. LCMS (method 15): 1.64 min, 373.2 [M+H] ⁺ .

Intermediate 46: 2-((5-chloro-7-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindoline-1,3-dione.

A stirred suspension of intermediate 45 (37.1 g, 99.5 mmol) in DCM (450 ml) was cooled in an ice bath. To this was added acetic acid (6.27 ml, 109 mmol) and sodium triacetoxyborohydride (42.2 g, 199 mmol) was added in portions over 30 minutes. The mixture was stirred overnight, warming to room temperature. The mixture was diluted with water and neutralized with solid sodium carbonate. The mixture was extracted with DCM and the combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was triturated in EtOAc from the floor.

- 85 045906 with the title compound (16.8 g, 43% yield). The stock solutions were concentrated in vacuo and the residue was triturated in a mixture of Et ₂ O and EtOAc to give additional title compound (12.3 g, 30%) which was used without further purification. Total amount (29.1 g, 73%). LCMS (Method 15): 1.60 min, 374.2 [M+H]+.

Intermediate 47. 2-((5-Chloro-7-fluoro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindoline-1,3-dione hydrobromide.

To a stirred solution of intermediate 46 (12.3 g, 32.8 mmol) in DCM (246 mL), cooled in an ice bath under argon, was added dropwise boron tribromide in DCM (1 M; 131 mL, 131 mmol) in for 1.5 hours. The reaction mixture was heated to room temperature. and stirred for 20 hours. The reaction was quenched by adding ice water (130 ml) dropwise over 1 hour and the resulting mixture was stirred for 1 hour. The solid was collected by filtration, washed with water and dried in vacuo at 50°C for 18 hours to obtain the title compound (8.6 g, 60%), used without further purification. LCMS (method 2): 0.96 min, 361.0 [M+H]+.

Intermediate 48. tert-Butyl-^)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate .

To a suspension of intermediate 47 (16 g, 36.2 mmol) in DCM (280 ml) was added DIPEA (15.69 ml, 90.56 mmol) followed by di-tert-butyl dicarbonate (7.12 g, 32.6 mmol) and the resulting mixture was stirred at room temperature. in an argon atmosphere for 1 hour. The reaction mixture was diluted with water and the organic layer was isolated. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was triturated in 10% MeOH/DCM and the resulting solid was collected by filtration to give the title compound (8.50 g). The filtrate was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g Puriflash HC silica gel column, 0-10% EtOAc in DCM) to yield an additional batch of the title compound (2.5 g); combined yield (11 g, 66%; racemic mixture). Purification of a 2.0 g portion by chiral SFC (method 1; YMC Amylose-C 20/80 EtOH (0.1% diethylamine)/CO ₂ , 100 ml/min., 120 bar, 40°C) gave the following: title compound (first elution enantiomer; 0.99 g, 47%). Absolute stereochemistry was confirmed by low molecular weight X-ray crystallography of the final carboxylic acid compound formed from enantiomer 2. LCMS (Method 15): 1.41 min, 483.1 [M+Na]+. ^1H NMR (400 MHz; 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).

Intermediate 49. tert-Butyl-^)-1-(aminomethyl)-5-chloro-7-fluoro-8-hydroxy-3,4dihydroisoquinoline-2(III)-carboxylate.

To a stirred suspension of intermediate 48 (970 mg, 2.1 mmol) in EtOH (10.7 mL) was added hydrazine monohydrate (0.39 mL, 5.26 mmol; CAS: 7803-57-8) and the reaction mixture was heated at 75 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate was concentrated in vacuo. The residue was taken up in IMS (5 ml) and stirred at room temperature. for 18 hours. The solution was filtered, the solid was washed with cold IMS and the filtrate was concentrated in vacuo to give the title compound (700 mg,

- 86 045906 yield 96%), used without additional purification. LCMS (Method 15): 1.34 min, 331.2 [M+H]+.

Intermediate 50. tert-Butyl-^)-5-chloro-7-fluoro-8-hydroxy-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline- 2(III)-carboxylate.

Stirred solution of intermediate 49 (500 mg, 1.51 mmol), methyl 2-(1(bromomethyl)cyclopropyl) acetate (344 mg, 1.66 mmol; CAS: 855473-50-6) and triethylamine (0.32 ml, 2.27 mmol) in toluene (7 ml) was refluxed for 18 hours. Additional methyl 2-(1-(bromomethyl)cyclopropyl) acetate (156 mg, 0.75 mmol) and triethylamine ( 0.16 ml, 1.14 mmol) and the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature. and concentrated in vacuo. The residue was separated, diluted with brine, extracted with DCM and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in cyclohexane) to give the title compound (426 mg, 66%). LCMS (method 2): 1.64 min, 447.1 [M+Na]+.

Intermediate yl)acetamide.

compound 51. No. (2-Chloro-5-methoxyphenethyl)-2-(1,3-dioxoisoindoline-2-

To a stirred solution of intermediate 2 (870 g, 2.573 mol) in DMF (13.0 L), divided between 4 flasks, was added N-chlorosuccinimide (361 g, 2.701 mol; 128-09-6), divided equally between each reaction . The reaction mixtures were heated to 80°C for 2 hours, cooled to room temperature. and united into two parties. Each batch was concentrated in vacuo to approximately 1 L. The mixtures were allowed to stand for 18 hours and the resulting precipitates were collected by filtration. Each of the organic layers was diluted with DCM (2.5 L) and washed with water (2 L). The organic layers were concentrated in vacuo and the resulting slurry was combined with the previously isolated solid and filtered (both batches were processed separately). The solids were washed with Et2O and concentrated in vacuo to give the title compound in two batches (435.5 g and 419.2 g, 79%), used without further purification. LCMS (Method 9a): 2.02 min, 373.4 [M+H] ⁺ . ^1H NMR (300 MHz, CDCl ₃ ) δ 7.85-7.90 (m, 2H), 7.73-7.78 (m, 2H), 7.19 (d, 1H), 6.76- 6.80 (m, 1H), 6.70 (dd, 1H), 5.78 (s, 1H), 4.29 (d, 2H), 3.75-3.80 (m, 3H), 3.56 (q,2H), 2.94 (d,2H).

Intermediate 52: 2-((5-chloro-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline1,3-dione.

Phosphoric anhydride (813 g, 5.73 mol; CAS: 1314-56-3) was added to a suspension of intermediate 51 (419 g, 965 mmol) in MeCN (7.5 L) divided between 3 flasks. The mixture was heated to 60°C for 20 hours. The organic phase (approximately 1.5 L) was decanted from the sediment and concentrated in vacuo. Water (2.5 L) was added to the remaining solids. The acetonitrile concentrate was washed in this solution with water (500 ml) and the mixture was heated to 40°C for 1 hour. The resulting solution was allowed to cool to room temperature. and divided between two flasks. A saturated aqueous sodium carbonate solution was added thereto with stirring until the pH was approximately pH 9. The precipitated solid was collected by filtration and washed with water (500 ml). Unite

- 87 045906 the resulting residue was dried under vacuum at 40° C. to obtain the title compound (353 g, 93%), which was used without further purification. LCMS (method 9a): 2.42 min, 355.0 [M+H]+.

Intermediate 53. ^)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-methoxy-3,4dihydroisoquinoline-2(III)-carbaldehyde.

A solution of benzeneruthenium(II) chloride dimer (4.67 g, 9.35 mmol; CAS: 37366-09-9) and (18.28)-(+)-N-πtosyl-1,2-diphenylethylenediamine (8.38 g, 22.88 mmol; CAS: 167316-27-0) in MeCN (300 ml) under argon and stirred at room temperature. for 1 hour. The mixture was divided into two flasks and each was added to a flask containing MeCN (520 ml). MeCN (520 ml) and DCM (150 ml) were added to each mixture. Intermediate 52 (201 g, 565 mmol) was added to each flask followed by MeCN (520 mL). A 1:1 mixture of formic acid (470 ml, 12.6 mol; CAS: 64-18-6) and triethylamine (470 ml, 3.370 mol) was separated and added to two reaction flasks. The mixtures were stirred at room temperature. in an argon atmosphere for 3 days. To each, water (1 L) and solid sodium bicarbonate were added until the pH of the mixture was 8-9. DCM (1.5 L) was added to each reaction mixture and the aqueous layers were separated. The organics were washed with additional water and combined. The organic phase was filtered and passed through a silica plug, eluted with 2:1 EtOAc in DCM (approximately 4 L). The organic layers were concentrated in vacuo to give the title compound (192.3 g, ~76%; mixture with intermediate 54), used without further purification. LCMS (method 9a): 2.28 min, 385.4 [M+H] ⁺ .

Intermediate 54. ^)-2-((5-Chloro-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindoline-1,3-dione.

To a suspension of hydrochloric acid (2 M; 0.11 L, 221 mmol) in THF (1.4 L) was added intermediate 53 (192 g, 500 mmol) and the mixture was refluxed for 18 hours. The reaction mixture was cooled to k.t. and saturated sodium bicarbonate solution was gradually added until the mixture reached a pH of 8-9. The mixture was extracted with DCM (5 L) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. Recrystallization from acetonitrile gave a solid which was dried in vacuo (50° C.) to give the title compound (100.5 g, 55%) which was used without further purification. LCMS (method 9a): 2.36 min, 357.4 [M+H] ⁺ .

Intermediate 55. ^)-2-((5-Chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)isoindoline-1,3-dione.

To a solution of intermediate 54 (95.5 g, 268 mmol) in DCM (2 L) at 0°C was added boron tribromide (1 M in DCM; 1.02 L, 1.02 mol; CAS: 10294-33- 4) for 1 hour. The reaction mixture was heated to room temperature. and stirred for 48 hours. The reaction mixture was cooled to 0°C and quenched with MeOH (200 ml). The mixture was left for 2 hours and the precipitate was isolated by filtration.

The precipitate was washed with DCM and dried in vacuo (50°C) to obtain ^)-2-((5-chloro-8hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-isoindoline-1, 3-Dione hydrobromide (57.3 g, 51%).

- 88 045906

Aqueous hydrochloric acid (2 M; 2 L) was added to the stirred DCM filtrate solution and the mixture was stirred for 1 hour. The precipitate was isolated by filtration and dried in vacuo (50°C) to give ^)-2-((5-chloro -8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline1,3-dione (49.3 g, ~45%) as a mixture of hydrobromide and hydrochloride salts. The acidic aqueous phase was isolated and adjusted to pH 8-9 by adding solid sodium bicarbonate and extracted with DCM. The organic layers were dried (MgSO ₄ , filtered and concentrated in vacuo to give the title compound (2.53 g, 2%). 2-[[(^)-5-chloro-8-hydroxy-1,2,3, 4tetrahydroisoquinolin-1-yl]methyl]isoindoline-1,3-dione hydrobromide LCMS (Method 10): 0.99 min,

343.0

[M+N]+. 2-[[(^)-5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]isoindoline-1,3 dione hydrochloride, (method 9a), 1.84 min. , 343.3 [M+H]+. 2-[[(^)-5-chloro-8-hydroxy-1,2,3,4tetrahydroisoquinolin-1-yl]methyl]isoindoline-1,3-dione: LCMS (method 9a): 1.93 min, 343 ,3 [M+H]+.

Intermediate 56. tert-Butyl-^)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8methoxy-3,4-dihydroisoquinoline-2(III)-carboxylate.

To a suspension of intermediate 54 (5.0 g, 14.01 mmol) in DCM (100 ml) was added triethylamine (2.93 ml, 21.02 mmol) followed by di-tert-butyl dicarbonate (3.06 g, 14 .0 mmol; CAS: 24424-99-5). The reaction mixture was stirred at room temperature. for 72 hours, concentrated in vacuo and the residue was purified by flash column chromatography (silica; 0-60% EtOAc in heptane) to give the title compound (6.37 g, 99%). LCMS (Method 9a): 3.04 min, 357.4 [M+H-CO ₂ ^1B T ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88-7.82 (m, 2H), 7.70 (dq, 2H), 7.29 (d, 1H), 6.73 (dd, 1H), 5.43-5.90 (1H), 4.18-4.13 (m, 2H), 3, 95-3.86 (m, 4H), 3.30-3.62 (1H), 3.12-2.77 (m, 2H), 1.08 (d, 9H).

Intermediate 57. dihydroisoquinoline-2( 1 ^-carboxylate.

tert-butyl-^)-1-(aminomethyl)-5-chloro-8-methoxy-3,4-

To a stirred solution of intermediate 56 (6.3 g, 13.8 mmol) in EtOH (200 ml) was added hydrazine hydrate (3.35 ml, 68.9 mmol) and the reaction mixture was heated at 65°C for 32 hours. The mixture cooled to room temperature, filtered and the filter cake was washed with EtOH. The filtrate was concentrated in vacuo and the residue triturated with Et ₂ O. The mixture was filtered and the filter cake washed with Et ₂ O. The filtrate was concentrated in vacuo to give the title compound (4.5 g, 99%) used without further purification. LCMS (method 9): 0.95 min, 327.1 [M+H]+.

Method R ¹ A. 3-(Chloromethyl)-5-methylisothiazole.

To a stirred solution of (5-methylisothiazol-3-yl)methanol (203 mg, 1.57 mmol, CAS: 180359819-7) in chloroform (2 ml) under argon, thionyl chloride (0.23 ml, 3.14 mmol) and the resulting solution was stirred at room temperature. within 75 min. The reaction mixture was concentrated in vacuo to give 3-(chloromethyl)-5-methylisothiazole (224 mg, 97%), used without further purification. 1H NMR (400 MHz; DMSO- _d6 ) δ 7.21 (d, 1H), 4.76 (s, 2H), 2.56 (d, 3H).

Method R ¹ B. 4-(Chloromethyl)-5-(di(difluoromethyl)-1-methyl-1H-1,2,3-triazole.

Stage a. 5-(Difluoromethyl)-1-methyl-triazole-4-carboxylic acid (8.0 g, 45.2 mmol; CAS: 1423028-04-9) was suspended in EtOH (200 ml) and sulfuric acid (4.8 ml, 90.3 mmol). The resulting solution was heated at 80°C for 12 hours. The reaction mixture was concentrated in

- 89 045906 vacuo, and the residue was diluted with water, and adjusted to pH 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (2x100 ml) and the combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give ethyl 5(difluoromethyl)-1-methyl-triazole-4-carboxylate (7.3 g, 79%), used without additional purification. LCMS (method 16): 1.20 min, 206.1 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 7.51 (t, 1H), 4.47 (q, 2H), 4.294.28 (m, 3H), 1.45 (t, 3H).

Stage b. Ethyl 5-(difluoromethyl)-1-methyl-triazole-4-carboxylate (7.2 g, 35.1 mmol) was dissolved in THF (50 ml) and the resulting solution was cooled to 0° C. under argon. Lithium aluminum hydride (1M in THF; 17.6 mL, 17.6 mmol) was added dropwise and the reaction mixture was stirred for 1 hour from 0°C to room temperature. Additional lithium aluminum hydride (1M in THF; 3 mL, 3 mmol) was added and the mixture was stirred for 30 minutes. The mixture was cooled in ice water, water (0.7 ml) was added dropwise followed by NaOH (3 M, 0.7 ml) and water (2 ml) and the resulting suspension was stirred for 30 minutes. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give (5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methanol (5.7 g, 100%). LCMS (method 15): 0.68 min, 164.1 [M+H] ⁺ . ^1H NMR (400 MHz; DMSO- _d6 ,) δ 7.45 (t, 1H), 5.42 (t, 1H), 4.62 (d, 2H), 4.13 (s, 3H).

Stage c. The above intermediate (6.16 g, 37.8 mmol) was dissolved in DCM (76 ml) and the mixture was sonicated. The solution was cooled in ice water and thionyl chloride (5.5 mL, 75.5 mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours from 0°C to room temperature. and concentrated in vacuo. The residue was diluted in chloroform and concentrated in vacuo to give the title compound (7.08 g, 39.0 mmol, estimated amount) used without further purification. LCMS (method 2) 0.90 min, 181.9 [M+H] ⁺ .

Method R ¹ C. 4-(Chloromethyl)-5-(methoxymethyl)-1-methyl-1H-1,2,3-triazole hydrochloride.

Stage R ¹ a. To a stirred solution of methyl 4-methoxyacetoacetate (0.78 ml, 6 mmol) and 4-acetamidobenzenesulfonyl azide (1.59 g, 6.6 mmol, CAS: 2158-14-7) in dry acetonitrile (80 ml) at 0°C in Dry triethylamine (2.51 mL, 18 mmol) was added dropwise over 5 minutes under argon. The mixture was stirred for 10 minutes, then stirred at room temperature. for 18 hours. The reaction mixture was filtered through Celite®, washed with DCM and the filtrate was concentrated in vacuo. The residue was taken up in DCM, filtered through Celite® and the filtrate was washed with water. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by silica gel flash chromatography (50 g silica gel, 25-60% EtOAc in heptane) gave methyl 2-diazo-4-methoxy-3-oxobutanoate (0.96 g, 91%). 1H NMR (300 MHz, CDCl ₃ ) δ: 4.53 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H).

Stage R ¹ b. Methylamine (2M in THF; 5.2 mL, 11.6 mmol) was added dropwise to acetic acid (5 mL) and a solution of the above intermediate (0.5 g, 2.9 mmol) in THF (2.5 mL) added under argon atmosphere. The mixture was heated at 95°C for 3 days. The reaction mixture was concentrated in vacuo, diluted with water and the crude product was extracted into EtOAc. The combined organic layers were washed with saturated sodium bicarbonate, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (20 g silica gel, 40-100% EtOAc in heptane) to give methyl 5-(methoxymethyl)-1-methyl-1H-1,2,3-triazole-4carboxylate (218 mg , 40%). 1H NMR (300 MHz, CDCl ₃ ) δ: 4.90 (s, 2H), 4.12 (s, 3H), 3.96 (s, 3H), 3.38 (s, 3H).

Stage R ¹ s. To a stirred solution of the above intermediate (218 mg, 1.18 mmol) in THF (1.5 ml) and EtOH (6 ml) under argon was added sodium borohydride (134 mg, 3.54 mmol), followed by lithium chloride (0 .5 M in THF; 5.9 ml, 2.94 mmol) and the mixture was heated at 40°C for 18 hours. The mixture was cooled and hydrolyzed with 10% citric acid, then volatiles were removed in vacuo. The residue was diluted with water and extracted with 2:1 IPA/chloroform. The combined organic layer was washed 1:1 with brine/saturated sodium bicarbonate, then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (5-(methoxymethia)-1-methyl-111-1,2,3 -phiazol-4-yl)methanol (89 mg, 51%). 1H NMR (300 MHz; CDCl3) δ: 4.73 (s, 2H), 4.56 (s, 2H), 4.02 (s, 3H), 3.35 (s, 3H).

Stage R ¹ d. To a stirred suspension of the above intermediate (360 mg, 0.38 mmol) in chloroform (18 ml) was added thionyl chloride (0.33 ml, 0.760 mmol) and the mixture was stirred at room temperature. for 3 hours. The reaction mixture was concentrated in vacuo to give 4-(chloromethyl)-5(methoxymethyl)-1-methyl-III-1,2,3-triazole hydrochloride (420 mg, 84%), used without further purification. 1H NMR (300 MHz, CDCl ₃ ) δ: 4.74 (s, 2H), 4.58 (s, 2H), 4.07 (s, 3H), 3.39 (s, 3H).

Method R ¹ D. 3-(Chloromethyl)-5-methyl-4-(trifluoromethyl)isoxazole.

- 90 045906

Stage R ¹ a. To a stirred solution of methyl 5-methylisoxazole-3-carboxylate (500 mg, 3.54 mmol, CAS: 19788-35-3) in TFA (8.0 ml, 105 mmol) was added N-iodosuccinimide (956 mg, 4. 25 mmol) and the reaction mixture was stirred at room temperature for 72 hours. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, saturated aqueous NaHCO3, water and Na2S2O3, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with IPA to give 4-iodo-3-(methoxymethyl)-5-methylisoxazole (542 mg, 57%). ^1H NMR (300 MHz, CDCl3) δ: 3.99 (s, 3H), 2.56 (s, 3H).

Stage R ¹ b. Copper iodide(!) (71 mg, 0.37 mmol) was added to a solution of the above intermediate (500 mg, 1.9 mmol) and HMPA (1.0 ml, 5.8 mmol) in DMF (8 ml). Methyl 2,2-difluoro-2(fluorosulfonyl)acetate (0.95 ml, 7.5 mmol, CAS: 680-15-9) was added dropwise and the reaction mixture was heated under microwave radiation for 1 hour at 85° WITH. The reaction mixture was partitioned between EtOAc and saturated aqueous ammonium chloride, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (80% DCM in heptane) to give methyl 5-methyl-4-(trifluoromethyl)isoxazole-3carboxylate (240 mg, 55%). 1H NMR (300 MHz, CDCl ₃ ) δ: 4.01 (s, 3H), 2.64 (s, 3H). ¹⁹ FW (283 MHz, CDCl3) δ: -56.72 (s, 3F).

Stages R ¹ c, d. The title compound was prepared from the above intermediate using Method R ¹ B and used without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ: 5.49 (dd, 2H), 2.61 (q, 3H).

Method R ¹ E. 3-(Chloromethyl)-4-(difluoromethyl)-5-methylisoxazole hydrochloride.

Stage R ¹ a. To a stirred solution of methyl 4-iodo-5-methylisoxazole-3-carboxylate (700 ml, 2.62 mmol, Example 154, step R ¹ a), potassium vinyl trifluoroborate (1.053 g, 7.86 mmol, CAS: 13682-77 -4) and triethylamine (1.1 ml, 7.86 mmol) in IPA (28 ml) and THF (28 ml), degassed with nitrogen, added [1,G-bis(diphenylphosphino)-ferrocene]dichloropalladium complex ( P) with DCM (214 mg, 0.26 mmol) and the reaction mixture was heated at 90°C for 16 hours, cooled to room temperature. and concentrated in vacuo. The residue was partitioned between water and DCM, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica, 33% EtOAc in heptane) to give methyl 5-methyl-4-vinylisoxazole-3-carboxylate (321 mg, 66%). ^1H NMR (300 MHz, CDCl3) δ 6.80 (dd, 1H), 5.52-5.44 (m, 2H), 3.98 (s, 3H), 2.55 (s, 3H).

Stage R ¹ b. To a solution of the above intermediate (321 mg, 1.92 mmol) in THF (27 ml) at RT. Osmium tetroxide (49 mg, 0.19 mmol, CAS: 20816-12-0) was added and the reaction mixture was stirred for 5 minutes. Sodium periodate (10% on silica, 12.5 g, 5.84 mmol) was added to it and the reaction mixture was stirred at room temperature. for 2 hours. The reaction mixture was filtered and the silica was washed with THF. The filtrate was concentrated in vacuo and purified by flash column chromatography (silica, 100% DCM) to give methyl 4-formyl-5methylisoxazole-3-carboxylate (286 mg, 79%). ^1H NMR (300 MHz, CDCl ₃ ) δ: 10.32 (s, 1H), 4.06 (s, 3H), 2.78 (s, 3H).

Stage R ¹ s. To a stirred solution of the above intermediate (286 mg, 1.69 mmol) and ethanol (0.1 mL, 1.69 mmol) in DCM (15 mL) was added a solution of bis(2methoxyethyl)aminosulfur trifluoride (50% in THF; 1. 44 ml, 3.38 mmol, CAS: 202289-38-1) and the reaction mixture was stirred at room temperature. for 16 hours. DCM was added thereto and the organic layers were washed with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 100% DCM) to give methyl 4-(difluoromethyl)-5-methylisoxazole-3-carboxylate (214 mg, 59%). 1H NMR (300 MHz, CDCl ₃ ) δ: 7.09 (t, 1H), 4.07-3.95 (m, 3H), 2.70-2.60 (m, 3H).

Stages R ¹ de. The title compound (283 mg) was prepared from the above intermediate using Method R ¹ B and used without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.89-6.53 (m, 1H), 4.81-4.61 (m, 2H), 2.54-2.52 (m, 3H).

- 91 045906

Intermediates in table. 1 was obtained in accordance with methods similar to methods R ¹ A-E, for use in the synthesis according to these examples.

Table 1

Example Way Structure Name Definition of characteristics 71 A 8^4 N=4 5—Cl 3 -(chloromethyl)isothiazole SH NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, 1H), 7.36 (d, 1H), 4.73 (s, 2H) 89 A C' L [1 p| 6-(chloromethyl)-3 - methyl-3 Nimidazo[4,5-th]pyridine LCMS (Method 2): 0.74 minutes, 181.9 [M+H] ⁺ 95 IN ъ 6-(chloromethyl)-3 methyl isox-azole o [5,4b} pyridine hydrochloride LCMS (Method 2): 1.05 minutes, 182.9 [M+H] ⁺ 124 IN XI 3 -(chloromethyl)-4.5 - dimethylisoxazole LCMS (Method 2): 1.05 minutes, 145.9 [M+H] ⁺ 125 IN Vq ClX^ ^N XI 4-chloro-3-(chloromethyl)-5- methylisoxazole SH NMR (400 MHz, CDC1 ₃ ) δ 4.56 (s, 2H), 2.43 (s, ZH) 128 With \ \ NN A--\ l iX ^υ VA n XI 4-(chloromethyl)-5-(2methoxyethyl)-1-methyl-1H1,2,3-triazole Ή NMR (300 MHz, CDC1 ₃ ) δ 4.73 (s, 2H), 4.01 (s, ZN), 3.60 (t, 2H), 3.30 (s, ZN), 2.99 ( t, 2H)

- 92 045906

129 C \N-N N XI 4-(chloromethyl)-5cyclopropyl-1-methyl-\H1,2,3-triazole Sh NMR (300 MHz, CDC1 ₃ ) δ 4.71 (s, 2H), 4.03 (s, 3H), 1.69 (m, 1H), 1.13 (m, 2H), 0.86 ( m, 2H) 139 A From example 193 stage d p NN F // ¹ y-b n ^f I τι 4-(chloromethyl)-2,5bis(difluoromethyl)-2R-1,2,3 triazole Ή NMR (400 MHz, CDC1 ₃ ) δ 7.32 (t, 1H), 6.90 (t, 1H), 5.26 (dd, 2H) 155 WITH About Kommersant' 4-(chloromethyl)-5(difluoromethyl)-1-(2,2,2trifluoroethyl)-III-1,2,3triazole Ή NMR (300 MHz, CDC1 ₃ ) δ 7.05 (t, 1H), 5.10 (q, 2H), 4.77 (s, 2H) 156 WITH \-Ν A ,N for HCl XI 4-(chloromethyl)-1,5-dimetholIT-1,2,3-triazole hydrochloride Ή NMR (300 MHz, CDC1 ₃ ) δ 7.88 (br, 1H), 4.84 (s, 2H), 4.14 (s, 3H), 2.49 (s, 3H) 181 A /Ν'Ν Ok/ ^~CI 3-(chloromethyl)-5,6-dihydro- 4R-pyrrolo[1,2-c]triazole LCMS (Method 16): 0.79 minutes, 158.0 [M+H] ⁺ 204 E с—, p / ft \A/ ^{N f} L Cl 4-(chloromethyl)-5- (difluoromethyl)thiazole Ή NMR (300 MHz, CDC1 ₃ ) δ 8.86 (s, 1H), 7.07 (t, 1H), 4.80 (s, 2H)

(4<)-1-(\5-M1ethi..l11iridazi11-3 -yl)pyrrolidin-3-ylmethanesulfonate.

Stage a. Mixture of 3-chloro-5-methylpyridazine (206 mg, 1.61 mmol, CAS: 89283-31-8) and (3R)pyrrolidin-3-ol (0.16 ml, 1.93 mmol, CAS: 2799-21 -5) in anhydrous 1,4-dioxane (3 ml) under argon was heated at 120°C for 21 hours. The mixture was diluted with aqueous NaHCO ₃ /brine (1:1; 50 ml) and extracted with ethyl acetate ( 5x50 ml), DCM (50 ml) and IPA/DCM (1:10; 8x50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (12 g Puriflash HC silica gel column, eluting with 0-10% MeOH in DCM) to give ^)-1-(5-methylpyridazin-3-yl)pyrrolidine -3-ylmethanesulfonate (123 mg, 43%). ^1H NMR (400 MHz, CDCl3) δ 8.37 (d, 1H), 6.43-6.41 (m, 1H), 4.69-4.64 (m, 1H), 3.72-3 .60 (m, 4H), 2.24 (d, 3H), 2.202.12 (m, 2H).

Stage b. To a stirred solution of the above intermediate (121 mg, 0.67 mmol) in DCM (5 ml) under argon at 0°C was added triethylamine (0.14 ml, 1.01 mmol), then methanesulfonyl chloride (0.06 ml, 0.810 mmol). The mixture was stirred at 0°C for 5 min, then at room temperature. for 1.75 hours. The mixture was diluted with water (10 ml) and extracted with DCM (5x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give ^)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-ylmethanesulfonate (154 mg, 88%), used without further purification. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 6.47 (s, 1H), 5.48-5.44 (m, 1H), 4.00 (d, 1H) , 3.84 (dd, 1H), 3.75-3.63 (m, 2H), 3.05 (s, 3H), 2.54-2.47 (m, 1H), 2.39-2 .30 (m, 1H), 2.28 (s, 3H).

- 93 045906

-(Chloromethyl)-3-methyl-3H-imidazo[4,5-b]pyridine.

Stage a. To a stirred solution of 3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg, 1.23 mmol, CAS: 1019108-05-4) in MeOH (5 ml) was added sulfuric acid (0.5 ml , 8.9 mmol) and the reaction mixture was refluxed for 16 hours. NaHCO ₃ solution was added slowly and the resulting precipitate was filtered and washed with water. The residue was dried in vacuo to give methyl 3H-imidazo[4,5-b]pyridine-5-carboxylate (234 ml, estimated amount), used without further purification. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.84 (s, 1H), 8.2 (bs, 1H), 7.97 (d, 1H), 3.95 (s, 3H).

Stage b. To a stirred solution of the above intermediate (287 mg, 1.6 mmol) in DMF (2 ml) was added potassium carbonate (448 mg, 3.2 mmol) and methyl iodide (0.20 ml, 3.2 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml) and extracted with 2-methyltetrahydrofuran (3x10 ml) and DCM (2x10 ml). The combined organic extracts were dried over MgSO ₄ and concentrated in vacuo to give methyl 3methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (305 mg, estimated amount; 2:1 mixture with regioisomer methyl-Emethyl-III -imidazo^^-Spyridine^-carboxylate). LCMS (method 2): 0.77 and 0.78 min, 192.1 [M+H]+.

Stage c. LiAlH4 (0.8 ml, 1.6 mmol, 2M in THF). The mixture was stirred at 0°C for 30 minutes, then diluted with EtOAc and quenched with a few drops of saturated aqueous NH4Cl. The mixture was stirred at room temperature. within 10 min. and the organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (40 g column, 0-100% 2 M methanol ammonia (2 M; 10%) in DCM in DCM) gave (3-methyl-3Himidazo^^-Cpyridine^-Umethanol ( 60 mg, 23%), used without further purification. LCMS (Method 2) 0.17 min, 164.1 [M+H]+

Stage d. To a stirred solution of the above intermediate (60 mg, 0.37 mmol) in chloroform (1 ml) under argon, thionyl chloride (0.054 ml, 0.74 mmol) was added dropwise and the reaction mixture was stirred at room temperature. for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (3x5 ml) to give the title compound (67 mg, estimated amount), used without further purification. LCMS (method 2) 0.93 min, 182.1 [M+H]+

5-(Chloromethyl)-4-(difluoromethyl)pyrimidine.

Stage a. To a stirred solution of ethyl 4-(difluoromethyl)pyrimidine-5-carboxylate (1.0 g, 4.95 mmol; CAS: 1600338-90-6) in THF (8 ml) and water (2 ml) was added lithium hydroxide monohydrate (0.23 g, 5.44 mmol) and the mixture was stirred at room temperature. for 18 hours. The mixture was concentrated in vacuo and the residue was diluted to pH 4 with aqueous HCl (6 M). The precipitate was collected by filtration and dried in vacuo to give a white solid (88 mg). The filtrate was further extracted with 2-methyltetrahydrofuran, dried (MgSO ₄ ), filtered and concentrated to give the product (105 mg). The filtrate was further extracted with n-butanol, dried (MgSO ₄ ), filtered and concentrated to give additional product (219 mg). Both batches yielded 4-(difluoromethyl)pyrimidine-5-carboxylic acid (0.50 g, 58%). LCMS (method 10c): 0.50 min, 174.9 [M+H] ⁺ .

Stage b. To a stirred solution of the above intermediate (219 mg, 1.26 mmol) in THF (11 ml) was added dropwise 4-methylmorpholine (0.19 ml, 1.76 mmol) and isobutyl chloroformate (0.22 ml, 1.70 mmol ) at -5°C in an argon atmosphere. The reaction mixture was stirred at -5°C for 1.5 hours, at room temperature. for 1.5 hours. The mixture was cooled to -5°C and a solution of sodium borohydride (71 mg, 1.89 mmol) in water (0.5 ml) was added dropwise and the reaction mixture was stirred for 45 minutes. The reaction mixture was diluted with water and extracted with DCM, and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (3% MeOH in DCM) to give (4-(difluoromethyl)pyrimidin-5-yl)methanol (11 mg, 4%). LCMS (method 10c): 0.40 min, 161.0 [M+H]+.

Stage c. To a solution of the above intermediate (11 mg, 0.070 mmol) in 1,4dioxane (0.15 ml) was added phosphorus oxychloride (0.07 ml, 0.70 mmol) and the reaction mixture was stirred at 100°C for 2 hours. the mixture was cooled to room temperature. and concentrated in vacuo. OS

- 94 045906 taka was diluted with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give 5-(chloromethyl)-4-(difluoromethyl)pyrimidine (31 mg, estimated amount), used without further purification. 1H NMR (300 MHz, CD ₃ OH) δ 9.21 (s, 1H), 9.05 (s, 1H), 6.90 (t, 1H), 4.89 (s, 2H).

-(Chloromethyl)-5,5-dimethyl-4,5-dihydroisoxazole.

Stage a. A solution of 2-methylprop-1-ene (15 wt.% in THF; 2.0 g, 35.6 mmol; CAS: 115-11-7), ethyl 2nitroacetate (7.9 ml, 71.3 mmol) and 1,4-Diazabicyclo[2.2.2]octane (0.4 g, 3.56 mmol; CAS: 280-57-9) in EtOH (145 ml) was heated in an autoclave at 80°C for 7 days. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica, 15% EtOAc in heptane) followed by reverse phase column chromatography on Isolera (Biotage C18 SNAP 30 g; 5-80% MeCN in water + 0.1 % ammonia) to give ethyl 5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylate (174 mg, 3%). ^1H NMR (300 MHz, CDCl ₃ ) δ 4.37-4.34 (m, 2H), 2.95 (s, 2H), 1.47 (s, 6H), 1.38 (t, 3H) .

Stage b. To a stirred suspension of sodium borohydride (100 mg, 2.64 mmol) in EtOH (1 ml) was added dropwise a solution of the above intermediate (174 mg, 1.02 mmol) in EtOH (2 ml) at 0°C. The reaction mixture was heated to room temperature. and stirred for 3 hours. The reaction mixture was concentrated in vacuo, diluted with water and acidified to pH 6 using acetic acid. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (5,5-dimethyl-4,5-dihydroisoxazol-3-yl)methanol (100 mg, 53%). 1H NMR (300 MHz, CDCl ₃ ) δ 4.41 (s, 2H), 2.76-2.79 (m, 3H), 1.45 (s, 6H).

Stage c. To a stirred solution of the above intermediate (92 mg, 0.71 mmol) in anhydrous DCM (1.5 ml) was added thionyl chloride (0.1 ml, 1.42 mmol) slowly at 0° C. The reaction mixture was heated to room temperature. and stirred at room temperature. for 18 hours. The reaction mixture was concentrated in vacuo and co-evaporated several times with toluene to obtain the title compound (72 mg, 48%), used in the next step without purification. 1H NMR (300 MHz, CDC13) δ 4.29 (s, 2H), 2.84 (s, 2H), 1.42 (s, 6H).

4-(Chloromethyl)-1,5-dimethyl-1H-1,2,3-triazole.

Stage a. Sulfuric acid (1.89 mL, 35.4 mmol) and the solution was heated at 70°C for 24 hours. Additional sulfuric acid (1.89 ml, 35.4 mmol) was added and the solution was heated at 70°C for 4 hours, then allowed to cool to .T. The reaction mixture was concentrated in vacuo and the residue was diluted with water (10 ml), adjusted to pH 8 with saturated sodium hydrogen carbonate solution and extracted with EtOAc. The organic layers were separated, dried (MgSO ₄ ) and concentrated in vacuo to give ethyl 1,5-dimethyl-1H-1,2,3triazole-4-carboxylate (4.66 g, 78%). 1H NMR (300 MHz, CDCl ₃ ) δ 4.46-4.39 (q, 2H), 4.00 (s, 3H), 2.58 (s, 3H), 1.44-1.39 (t , 3H).

Stage b. To a stirred solution of the above intermediate (4.66 g, 27.6 mmol) in THF (41 ml) at 0° C. under argon, a solution of lithium aluminum hydride (1M in THF; 27.56 ml, 27.56 mmol) was added dropwise ) and the reaction mixture was stirred for 1 hour at a temperature of 0°C to room temperature. The mixture was cooled in ice water, water (1.0 ml) was added dropwise followed by NaOH (3 M, 1.0 ml) and water (2 ml) and the resulting suspension was stirred for 30 minutes. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give (1,5-dimethyl-1H-1,2,3-triazol-4-yl)methanol (3.35 g, 96%). 1H NMR (300 MHz, CDC13) δ 7.33 (s, 1H), 4.64 (s, 2H), 3.90 (s, 3H), 2.30 (s, 3H).

Stage c. To a stirred solution of the above intermediate (3.35 g, 26.4 mmol) in DCM (40 ml) was cooled in ice water, thionyl chloride (3.84 ml, 52.7 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was stirred for 1 hour at a temperature from 0°C to room temperature. and concentrated in vacuo. The residue was diluted with chloroform and concentrated in vacuo to give the title compound (3.32 g, 87%). LCMS (Method 2) 1.14 minutes, 146.2 [M+H]+.

- 95 045906

3-(Chloromethyl)-7-(])torbenzo[c1]isoxazole.

Stage a. A solution of isopentyl nitrite (2.65 mL, 19.7 mmol) in diethyl ether (10 ml), and then sodium methoxide (0.78 g, 14.35 mmol) in methanol (11.7 ml) was added and the mixture was stirred at room temperature. for 18 hours. Water was added and the mixture was acidified using hydrochloric acid (aqueous solution, 1 M). The mixture was extracted with diethyl ether (x3), the combined organic layers were dried over sodium sulfate Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g Puriflash HC silica gel column, 0-50% EtOAc in cyclohexane) to give methyl-(E)-2-(2,3-difluorophenyl)-2 -(hydroxyimino)acetate (1.05 g, 54%). 1H NMR (400 MHz, CDCl ₃ ) δ: 9.08 (br. s, 1H), 7.31-7.04 (m, 2H), 3.90 (s, 3H).

Stage b. To a stirred solution of the above intermediate (950 mg, 4.42 mmol) in DMSO (9.5 ml) was added potassium carbonate (854 mg, 6.18 mmol) and the resulting mixture was heated at 75°C for 0.5 h. The reaction mixture was cooled to room temperature, diluted with water and the crude material was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give methyl 7fluorobenzo^]isoxazole-3-carboxylate (683 mg, 79%). LCMS (Method 2): 1.17 min, 194.0 [M-N] ^- . 1H NMR (400 MHz, CDCl ₃ ) δ: 7.92 (dd, 1H), 7.43-7.33 (m, 2H), 4.11 (s, 3H).

Stages cd. The title compound (502 mg) was prepared from the above intermediate using Method B R ¹ and used without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ: 7.64-7.62 (m, 1H), 7.34-7.30 (m, 2H), 4.92 (s, 2H).

3-(Chloromethyl)-6,7-difluorobenzo^]isoxazole.

The title compound (894 mg) was prepared from methyl 2-(2,3,4-trifluorophenyl)acetate (CAS: 1443340-20-2) using methods similar to 3-(chloromethyl)-7-fluorobenzo^]isoxazole (example 164). 1H NMR (400 MHz, CDCl ₃ ) δ: 7.57 (ddd, 1H), 7.28-7.21 (m, 1H), 4.89 (s, 2H).

-(Chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine.

Stage a. 4-Acetamidobenzenesulfonyl azide (7.95 g, 33.1 mmol, CAS: 215814-7) and the reaction mixture was cooled to 0°C under argon. DBU (3.97 mL, 33.1 mmol) was added dropwise over 10 min. The reaction mixture was heated to room temperature. and stirred for 3 hours. A saturated ammonium chloride solution was added thereto and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on Interchim 4125 (120 g Puriflash HP silica gel column, 0-15% EtOAc in DCM) provided methyl[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate(5 .48 g, 89%). 1H NMR (400 MHz, CDCl ₃ ) 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).

Stage 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 (x3 ). 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%). 1H NMR (400 MHz, CDC13) 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).

Stage 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 mixture was stirred at room temperature. under argon for 20 hours. The reaction mixture was cooled to 0°C and diluted with 10% citric acid (33 ml), then extracted with DCM. The combined organic layers were washed with water and concentrated in vacuo. Not

- 96 045906 the purified product was purified by flash column chromatography on Interchim Puriflash® 4100 (80 g Puriflash HP silica gel column, 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 (400 MHz, CDCl ₃ ) 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).

Stage d. Thionyl chloride (0.59 ml, 8.1 mmol) was added to intermediate 170-C (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 (x2) and concentrated in vacuo to give the title compound (702 mg, estimated amount), used without further purification. LCMS (Method 2): 0.90 min, 171.9 [M+H]+.

5-(Bromomethyl)-4-(trifluoromethyl)pyrimidine.

N^N N^N N^N

Stage a. To a stirred suspension of 4-(trifluoromethyl)pyrimidine-5-carboxylic acid (2.5 g, 13.0 mmol, CAS: 220880-12-6) in THF (124 ml) at -5°C under argon was added 4- methylmorpholine (1.65 ml, 15.0 mmol, CAS: 109-02-4) followed by dropwise addition of isobutyl chloroformate (1.86 ml, 14.32 mmol, CAS: 543-27-1). The reaction mixture was stirred at -5°C for 1.5 hours and then at room temperature. for 1.5 hours. The mixture was cooled to -5°C and 4methylmorpholine (0.43 ml, 3.90 mmol) and isobutyl chloroformate (0.42 ml, 3.25 mmol) were further added thereto. The reaction mixture was stirred at -5°C for 30 minutes, then stirred at room temperature. within 45 min. and cooled again to -5°C. A solution of sodium borohydride (738 mg, 19.5 mmol) in water (6 ml) was added dropwise over 25 minutes. and the reaction mixture was stirred for 20 minutes. Water was added, the mixture was extracted with DCM and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Interchim Puriflash® 4100 (120 g HP silica gel column, 0-50% EtOAc in cyclohexane) to give (4-(trifluoromethyl)pyrimidin-5-yl)methanol (334 mg, 17%) . LCMS (method 2): 0.74 min, 178.9 [M+H] ⁺ .

Stage b. To a stirred solution of the above intermediate (334 mg, 1.88 mmol) in DCM (9 ml) was added triphenylphosphine (492 mg, 1.88 mmol) and the reaction mixture was cooled to 0° under argon. A solution of tetrabromomethane (622 mg, 1.88 mmol) in DCM (2 ml) was added thereto and the reaction mixture was stirred at room temperature. for 18 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on an Interchim Puriflash® 4100 (Puriflash HP column with 40 g silica gel, 0-30% EtOAc in DCM) to give the title compound (273 mg, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.29 (m, s), 9.06 (m, s), 4.60 (2H, s).

3-(Bromomethyl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine.

Stage a. To a suspension of methyl 6,7-dihydro-4H-triazolo[5,1-c][1,4]oxazine-3-carboxylate (28 mg, 0.15 mmol, CAS: 2115637-63-1) in THF ( 1 ml) at 0°C under argon, lithium aluminum hydride (1M in THF; 0.15 ml, 0.15 mmol) was added dropwise and the resulting mixture was stirred for 1 hour. The reaction mixture was treated with water (7 µl), 3 M NaOH (7 μl) and water (14 μl) were added dropwise. The resulting mixture was stirred for 1 hour. The reaction mixture was diluted with THF and filtered through a pad of Celite®. Celite® was washed with THF and DCM and the filtrate was concentrated in vacuo to give (6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3yl)methanol ( 22 mg, 88%), used without further purification. LCMS (method 2): 0.18 min, 156.0 [M+H] ⁺

Stage b. To a solution of the above intermediate (120 mg, 0.73 mmol) in DCM (4.8 ml) at 0° C. under argon was added triphenylphosphine (206 mg, 0.79 mmol) followed by dropwise addition of a solution of tetrabromomethane (261 mg , 0.79 mmol) in DCM (3.2 ml). The reaction mixture was heated to room temperature. for 1 hour, then stirred at room temperature. over 16 hours. Additional triphenylphosphine (96 mg, 0.37 mmol) was added, followed by dropwise addition of a solution of tetrabromomethane (122 mg, 0.37 mmol) in DCM (3.2 ml). The reaction mixture was stirred for 3 hours at RT, then concentrated in vacuo. Purification by flash column chromatography on an Interchim Puriflash® 4100 (InterChim HP column with 40 g silica gel, 0-30% EtOAc in DCM) gave the title compound (89 mg, 55%). ^1H NMR (400 MHz, CDCl3) δ 4.93 (s, 2H), 4.55 (s, 2H), 4.44 (t, 2H), 4.11 (t, 2H).

(5-(Difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methylmethanesulfonate.

- 97 045906

Stage a. To a stirred solution of ethyl 4,4-difluoro-3-oxobutanoate (4.0 g, 24.1 mmol, CAS: 352-24-9) and AcOH (1.4 ml, 24.1 mmol) in anhydrous chloroform ( 50 ml) under argon at 0°C, oxetan-3-amine (1.8 mg, 24.1 mmol, CAS: 21635-88-1) was added dropwise, maintaining the temperature below 10°C. The resulting solution was heated at reflux for 48 hours, then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO ₃ solution, diluted with water and extracted into DCM. The combined organic layers were washed with saturated aqueous NaHCO ₃ and water and the layers were separated using a phase separation cartridge. The combined organic layers were concentrated in vacuo to give ethyl 4,4-difluoro-3-(oxetan-3-ylamino)but-2-enoate (5.3 g, 99%), which was used without further purification. LCMS (method 18): 1.24 min, 222.1 [M+H]+

Stage b. To a stirred solution of the above intermediate (2.0 g, 9.0 mmol) in MeCN (75 ml) at -20°C was added DBU (3.38 ml, 22.6 mmol), followed by dropwise addition of methanesulfonyl azide (2 .74 g, 22.6 mmol, CAS: 1516-70-7) in MeCN (25 ml), while maintaining the temperature below -19°C. The mixture was heated to room temperature and stirred for 72 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHSO4. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHSO4 (x2), dried over _MgSO4 , filtered and concentrated in vacuo. Purification by flash column chromatography on Interchim Puriflash® 4100 (80 g Puriflash HC silica gel column, 0-50% EtOAc in cyclohexane) gave ethyl 5-(difluoromethyl)-1-(oxetan-3-yl)-III -1,2,3triazole-4-carboxylate (1.52 g, 68%). LCMS (method 17): 1.10 min, 248.1 [M+H]+

Stage c. To a solution of the above intermediate (1.3 g, 5.3 mmol) in THF (18 ml) at -5°C was added dropwise lithium aluminum hydride (2M in THF; 2.6 ml, 5.3 mmol) and the reaction mixture stirred for 1 hour. The reaction mixture was quenched with water (10 ml) and extracted into DCM (2x100 ml). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the title compound (882 mg, 82%) used without further purification. LCMS (method 16): 0.60 min, 206.1 [M+H] ⁺

Stage d. To a solution of the above intermediate (400 mg, 1.95 mmol) in DCM (5 ml) was added triethylamine (0.54 ml, 3.9 mmol). The reaction mixture was cooled to 0°C and methanesulfonyl chloride (0.15 ml, 1.9 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 18 hours.

The reaction mixture was partitioned between distilled water (50 ml) and DCM (3x50 ml). The organic layer was isolated, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (462 mg, as a 1:1 mixture with 4-(chloromethyl)-5-(difluoromethyl)-1-(oxetan-3-yl )-1H1,2,3-triazole). 1H NMR (400 MHz, CDCh) δ 6.89-7.15 (t, 1H), 5.73-5.80 (m, 1H), 5.28-5.31 (m, 2H), 5.055, 09 (m, 2H), 4.77-4.78 (m, 2H), 3.15 (s, 1.5H).

4-(Chloromethyl)-1,5-bis(difluoromethyl)-1 H-1,2,3-triazole.

Stage a. To a solution of ethyl 4,4-difluoro-3-oxo-butanoate (1 ml, 7.64 mmol, CAS: 352-24-9) and azidomethyl pivalate (1.17 ml, 7.64 mmol, CAS: 872700-68 -0) in DMSO (13 ml) was added triethylamine (3.2 ml, 22.9 mmol) and the reaction mixture was heated at 70°C for 4 hours, then at room temperature. for 18 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (75 g silica gel column, 3040% EtOAc in heptane) to give ethyl 5-(difluoromethyl)-1-(2,2-dimethylpropanoyloxymethyl)triazole 4-carboxylate (1.15 g, 48%). ^1H NMR (300 MHz, CDCh) δ: 7.53 (t, 1H), 6.45 (s, 2H), 4.49 (q, 2H), 1.45 (t, 3H), 1.20 (s, 9H).

Stage b. To a stirred solution of the above intermediate (0.87 g, 2.85 mmol) in methyl alcohol (40 ml) was added triethylamine (0.4 ml, 2.87 mmol) and the solution was stirred at 70°C for 8 days. The reaction mixture was concentrated in vacuo, then under

- 98 045906 was subjected to azeotropic distillation using toluene. It was partitioned between hydrochloric acid (2 M) and EtOAc. The combined organic layers were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g silica gel column, 60-100% EtOAc in heptane) to give methyl 5(difluoromethyl)-1H-triazole-4-carboxylate (345 mg, 59%). The mixed fractions were repurified by flash column chromatography (10 g silica gel column, 20-100% EtOAc in heptane) to yield an additional batch (145 mg, 19%). LCMS (method 10b): 0.48 min, 175.9 [M-H] ^- .

Stage c. A mixture of methyl 5-(difluoromethyl)-III-triazole-4-carboxylate (360 mg, 1.83 mmol), sodium chlorodifluoroacetate (700 mg, 4.6 mmol) and cesium carbonate (894 mg, 2.74 mmol) in DMF (15 ml) was stirred at 70°C for 2 hours, then cooled to room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (Na2SO4), filtered and the filtrate was concentrated in vacuo to give methyl 1,5-bis(difluoromethyl)triazole-4carboxylate (417 mg, relative amount) as a 7:3 mixture with ethyl 1,4-bis(difluoromethyl)-III-1,2,3triazole-5-carboxylate. 1H NMR (300 MHz; CDCb, 298 K) δ: 7.68 (t, 0.3H), 7.55 (t, 0.3H), 7.40 (t, 0.7H), 7.17 ( t, 0.7H), 4.09 (m, 2H), 4.04 (s, 3H), 1.45 (m, 3H).

Stage d. To a stirred solution of sodium borohydride (106 mg, 2.8 mmol) in EtOH (13 mL) under nitrogen was added lithium chloride (0.5 M in THF; 4.59 mL, 2.3 mmol) and the above intermediate (417 mg, 1.84 mmol). The reaction mixture was heated at 60°C for 5 hours, then stirred at room temperature. for 18 hours. The reaction mixture was diluted with water and the crude product was extracted into IPA/chloroform (2:1). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g silica gel column, 40-60% EtOAc in heptane) to give [2,5-bis(difluoromethyl)triazol-4-yl]methanol (158 mg, 42%) and the desired compound [1,5bis(difluoromethyl)triazol-4-yl]methanol (47 mg, 11%). 1H NMR (300 MHz, CDCl ₃ ) δ: 7.63 (t, 1H), 7.19 (t, 1H), 4.98 (s, 2H), 1.96 (br s, OH).

Step f: To a stirred solution of [1,5-bis(difluoromethyl)triazol-4-yl]methanol (60 mg, 0.300 mmol) in chloroform (3 ml) was added thionyl chloride (0.07 ml, 0.900 mmol) and the mixture was stirred at k.t. for 21 hours. The reaction mixture was concentrated in vacuo to give the title compound (76 mg, 89%) which was used without further purification. 1H NMR (300 MHz, CDCl ₃ ) δ: 7.64 (t, 1H), 7.11 (t, lH), 4.81 (s, 2H).

4-(Chloromethyl)-1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazole.

Stage a. To a suspension of azidomethyl(trimethyl)silane (1.0 g, 7.7 mmol, CAS: 87576-94-1) and tert-butyldimethyl(2-propynyloxy)silane (1449.6 mg, 8.5 mmol, CAS: 76782-82 -6) in 2-methyl-2-propanol (20 ml) was added sodium (+)A-ascorbate (1.5 g, 7.7 mmol) in water (10 ml) followed by dropwise addition of copper sulfate (386, 4 mg, 1.55 mmol) in water (10 ml) for 20 minutes. and the reaction mixture was stirred vigorously at room temperature. during the night. The reaction mixture was diluted with EtOAc and water and extracted into EtOAc. The organic phase was washed with aqueous ammonia, brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on Interchim Puriflash® 4100 (80 g InterChim HP silica gel column, 0-50% EtOAc in isohexane) gave 4-(((tert-butyldimethylsilyl)oxy)methyl)-1((trimethylsilyl) methyl)-III-1,2,3-triazole (2.23 g, 95%). 1H NMR (400 MHz, CDCl ₃ ) δ 7.35 (s, 1H), 4.85 (s, 2H), 3.91 (s, 2H), 0.92 (s, 9H), 0.15 ( s.9H), 0.10 (s.6H).

Stage b. To a solution of the above intermediate (200 mg, 0.67 mmol) in THF (2.6 ml) at -78°C under argon was added n-butyllithium (2.5 M in hexanes; 0.32 ml, 0 .8 mmol). The mixture was stirred at -78°C for 1.25 hours, then heated to -60°C and stirred for 15 minutes, then cooled again to -78°C. Oxetan-3-one (241 mg, 3.34 mmol, CAS: 6704-31-0) was added dropwise and the mixture was stirred at -78°C for 1 hour before warming to room temperature. and stirred for another 1 hour. The reaction mixture was cooled to 0°C and quenched by dropwise addition of saturated NH ₄ Cl. The reaction mixture was diluted with EtOAc and extracted into EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on an Interchim Puriflash® 4100 (Puriflash InterChim HP column with 40 g silica gel, 0-50% EtOAc in cyclohexane) gave 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1 -((trimethylsilyl)methyl)-III-1,2,3-triazol-5-99 045906 yl)oxetan-3-ol (116 mg, 44%). 1H NMR (400 MHz, CDCl ₃ ) δ 5.06 (d, 2H), 4.94 (dd, 2H), 4.85 (s, 2H), 4.414.39 (m, 1H), 3.81 ( s, 2H), 0.89 (s, 9H), 0.23 (s, 9H), 0.11 (s, 6H).

Stage c. Sodium hydride (25 mg, 0.63 mmol) was added to a solution of the above intermediate (94 mg, 0.250 mmol) in THF (3.8 mL) at 0° C. under argon. The mixture was stirred at 0°C for 30 minutes, then carbon disulfide (0.13 ml, 0.63 mmol) was added and the reaction mixture was stirred at 0°C for 15 minutes, then warmed to room temperature. and stirred for 1 hour. Saturated aqueous NH ₄ Cl was added and the mixture was diluted with EtOAc and the layers were separated. The organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on Interchim Puriflash® 4100 (12 g InterChim HP silica gel column, 0-50% EtOAc in cyclohexane) gave O-(3-(4-(((tertbutyldimethylsilyl)oxy)methyl)-1 -methyl-1H-1,2,3-triazol-5-yl)oxetan-3-yl^-methylcarbonodithioate (92 mg, 89%) ^1H NMR (400 MHz, CDCL) δ 5.37 (d, 2H ), 5.22 (dd, 2H), 4.92-4.91 (m, 2H), 3.96 (s, 3H), 2.52 (s, 3H), 0.90 (m, 9H) , 0.11 (m, 6H).

Stage d. To a solution of the above intermediate (92 mg, 0.24 mmol) in toluene (1.3 ml) was added AIBN (7.8 mg, 0.05 mmol) followed by tributyltin hydride (0.08 ml, 0.28 mmol ), and the reaction mixture was heated in a closed vial to 120°C, and stirred for 4 hours. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography on Interchim Puriflash® 4100 (25 g Puriflash InterChim silica gel column, 0-30% EtOAc in cyclohexane) gave 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5 -(oxetan-3-yl)1N-1,2,3-triazole (55 mg, 76%). LCMS (method 15): 1.51 min, 284.2 [M+H]+

Step f: To a solution of the above intermediate (50 mg, 0.18 mmol) in THF (2 mL) under argon was added triethylamine trihydrofluoride (0.14 mL, 0.88 mmol) and the mixture was stirred at room temperature. for 16 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc and water and the crude product was extracted into EtOAc. The organic layer was washed with additional water, brine and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography using Interchim Puriflash® 4100 (12 g silica gel column, 0-10% MeOH in DCM) gave (1-methyl-5-(oxetan-3-yl)1N-1,2, 3-triazol-4-yl)methanol (16 mg, 51%). 1H NMR (400 MHz, CDCLj) δ 5.11 (dd, 2H), 4.95-4.87 (m, 4H), 4.49-4.40 (m, 1H), 4.03 (s, 3H), 2.20 (s, 1H).

Stage f. Triethylamine (26.4 μL, 0.19 mmol) was added to a solution of the above intermediate (16 mg, 0.09 mmol) in DCM (1 mL). The mixture was cooled to 0°C and methanesulfonyl chloride (7.3 μl, 0.09 mmol) was added dropwise. The reaction mixture was heated to room temperature. and stirred for 18 hours. The reaction mixture was partitioned between distilled water and DCM. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (11 mg, 59%). 1H NMR (300 MHz, CDCl ₃ ) δ 5.14 (dd, 2H), 4.92 (t, 2H), 4.85 (s, 2H), 4.49-4.41 (m, 1H), 4.06 (s, 3H).

(S)-6,7-Dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-ylmethanesulfonate.

Stage a. Trimethyloxonium tetrafluoroborate (0.69 g, 4.64 mmol; CAS: 420-37-1) was added to a solution of (3S)-3-[tert-butyl(dimethyl)silyl]oxypyrrolidin-2-one (1 g, 4. 64 mmol; CAS: 130403-91-7) in DCM (10 ml) and the reaction mixture was stirred at RT. for 16 hours. Formylhydrazine (0.28 g, 4.64 mmol; CAS: 624-84-0) was added to the reaction mixture and the reaction mixture was stirred for 3 hours at room temperature, then concentrated in vacuo. The residue was dissolved in MeOH (10 ml), transferred to a microwave vessel and heated under microwave radiation at 100°C for 4 hours. The reaction mixture was concentrated in vacuo and purified using flash column chromatography (silica, 10% MeOH in DCM) to give (S)-7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5Hpyrrolo[2,1-c][1,2,4]triazole (75 mg, 6%). 1H NMR (300 MHz, CDCL) δ 8.18 (s, 1H), 5.20 (q, 1H), 4.27-4.18 (m, 1H), 4.03-3.95 (m, 1H), 3.03-2.91 (m, 1H), 2.66-2.57 (m, 1H), 0.92-0.89 (s, 9H), 0.24 (s, 3H) , 0.16 (s, 3H).

Stage b. To a solution of the above intermediate (75 mg, 0.31 mmol) in THF (2 mL), cooled in an ice bath, was added a solution of tetrabutylammonium fluoride (1M in THF; 82 mg, 0.31 mmol; CAS: 429-41-4) . The reaction mixture was stirred at room temperature. for 3 hours and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, 10% MeOH in DCM) to give (S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol- 7-ola (35 mg, 71%). 1H NMR (300 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 5.87 (br, 1H), 5.54-5.29 (m, 1H), 4.31-4.22 (m , 1H), 4.03-3.95 (m, 1H), 3.10-2.98 (m, 1H), 2.81-2.71 (m, 1H).

Stage c. To a stirred solution of the above intermediate (35 mg, 0.28 mmol) and triethylamine (0.06 mL, 0.420 mmol) in DCM (2 mL), cooled in an ice bath, add

- 100 045906 methanesulfonyl chloride (0.03 ml, 0.340 mmol) was added. The reaction mixture was stirred at room temperature. for 4 hours and then diluted with water and extracted with DCM. The organic layers were dried over MgSO ₄ and concentrated in vacuo to give the title compound (19 mg, 23%) used without further purification. 1H NMR (300 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 6.02 (dd, 1H), 4.344.15 (m, 2H), 3.35-3.27 (m, 2H), 3.24 (s, 3H).

-Methyl-1,4,5,6-tetrahydrocyclopenta^][1,2,3]triazol-5-ylmethanesulfonate.

Stage a. 1-Azido-4-nitro-benzene ( 1.22 g, 7.5 mmol; CAS: 1516-60-5) and methylamine (2M in THF; 13.5 ml, 26.6 mmol). The reaction mixture was stirred at 80°C for 5 days. The reaction mixture was concentrated in vacuo and the crude material was purified by flash column chromatography (silica, 1:2 EtOAc:heptane) followed by (5% MeOH in DCM) to give 1-methyl-4,6-dihydro-III-spiro [cyclopenta^][1,2,3]triazole-5,2'-[1,3]dioxolane] (760 mg, 60%). LCMS (Method 9): 0.42 min, 182.1 [M+H]+.

Stage b. To a stirred solution of the above intermediate (468 mg, 2.58 mmol) in acetone (10 ml) was added Amberlyst® hydrogen form 15 (1000 mg, 2.58 mmol, CAS: 39389-20-3) and the reaction mixture was stirred at .T. for 18 hours. The reaction mixture was filtered through Celite® and the filter cake was washed with acetone followed by MeOH. The filtrate was concentrated in vacuo to give 1-methyl-4,6-dihydrocyclopenta[1,2,3]triazol5(III)-one (104 mg, 26%), used in the next step without purification. 1H NMR (300 MHz, CDCl _3- D) δ 4.17 (s, 3H), 3.05-3.18 (m, 4H), 3.74 (s, 1H).

Stage c. To a stirred solution of the above intermediate (169 mg, 1.98 mmol) in anhydrous THF (6.5 ml) was added a solution of lithium aluminum hydride (1M in THF; 1.85 ml, 1.85 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature. for 1 hour, cooled again to 0°C and Glauber's salt was added to it. The reaction mixture was heated to room temperature. and stirred for 30 minutes, filtered and the filtrate was concentrated in vacuo to give 1-methyl-1,4,5,6tetrahydrocyclopenta[1,2,3]triazol-5-ol (158 mg, 93%), used at the next stage without additional purification. LCMS (method 9-2-20% B with A and 5% C in 1.0 min., up to 95% B with 5% C at 1.8 min.): 0.38 min, 140.0 [M+ H] ⁺ .

Stage d. To a solution of the above intermediate (50 mg, 0.36 mmol) in DCM (1.5 mL) cooled in an ice bath, triethylamine (0.07 mL, 0.470 mmol) and methanesulfonyl chloride (0.03 mL, 0.400 mmol) were added. . The reaction mixture was stirred at room temperature. for 3 hours. The reaction mixture was diluted with DCM and washed with saturated aqueous sodium bicarbonate. The mixture was extracted with DCM and the combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the title compound (50 mg, 48%) used without further purification. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.40-5.24 (m, 1H), 4.07 (s, 3H), 3.82-2.12 (m, 7H).

Tetrahydro-2H-furo[3,4-b]pyran-5,7-dione.

Stage a. Sodium metal in kerosene (6.89 g, 300 mmol; CAS: 7440-23-5) was added to a solution of MeOH (4 drops) in Et ₂ O (75 ml). The mixture was stirred at room temperature. for 2 hours. A solution of tetrahydropyran-2-one (30.0 g, 300 mmol; CAS: 542-28-9) and dimethyl oxalate (35.4 g, 300 mmol; CAS: 553-90-2) in Et ₂ O (100 ml) was added dropwise and the mixture was stirred at room temperature. within 2 days. The reaction mixture was poured into ice water and extracted with Et2O. The aqueous phase was acidified with 10% sulfuric acid to pH 3 and extracted with Et ₂ O. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give methyl-2oxo-2-(2-oxotetrahydro-2H -pyran-3-yl)acetate (13.3 g, 24%) used without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ 4.42-4.39 (t, 2H), 3.90 (s, 3H), 2.86-2.83 (t, 2H), 1.96-1 .92 (m, 2H).

Stage b. A solution of the above intermediate (13.3 g, 71.4 mmol) in hydrochloric acid in MeOH (1.25 M; 103 ml, 129 mmol) was stirred at reflux for 20 hours, cooled to room temperature. and stirred at room temperature. during the night. The reaction mixture was neutralized with saturated sodium hydrogen carbonate solution, extracted with Et ₂ O and the combined organic layers were washed with brine, dried over MgSO 4 and concentrated

- 101 045906 in vacuo to obtain dimethyl 2-methoxytetrahydro-2H-pyran-2,3-dicarboxylate (11.5 g, 55%) as a mixture of diastereoisomers. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.00 (td, 1H), 3.88 (s, 3H), 3.70-3.63 (m, 6H), 3.14-3.08 ( m, 1H), 2.37 (t, 1H), 2.10-1.99 (m, 2H).

Stage c. Add 3 drops of sulfuric acid to the above intermediate (9.6 g, 41.34 mmol) in Kugelrohr and the mixture is subjected to slow flask-to-flask distillation, heating to 160°C at 2.2 mbar. The second fraction was collected (5.1 g), purified using Isolera (Biotage Silica ZIPSphere 45 g, 0-50% EtOAc in heptane) to give dimethyl 3,4-dihydro-2H-pyran-5,6dicarboxylate (289 mg, 3%). The third fraction was collected (1.07 g), purified using Isolera (Silicycle Siliaprep Silica 120 g, 0-50% EtOAc in heptane) to give dimethyl 3,4-dihydro-2H-pyran-5,6dicarboxylate (2.18 g, 9.801 mmol, 24%). ^1H NMR (400 MHz, CDCl ₃ ) δ 4.16 (t, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 2.37 (t, 2H), 1.96 -1.90 (m, 2H).

Stage d. A solution of the above intermediate (2.47 g, 12.34 mmol) and Pd/C (10%; 131 mg, 1.23 mmol) in EtOH (200 ml) was stirred under a hydrogen atmosphere at ambient pressure at RT. within 3 days. The reaction mixture was filtered through Celite® and concentrated to give dimethyl tetrahydro-2H-pyran-2,3-dicarboxylate (2.04 g, 70%) which was used without further purification. ^1H NMR (400 MHz, CDCl ₃ ) δ 4.23 (d, 1H), 4.08-4.04 (m, 1H), 3.81 (s, 3H), 3.71 (s, 3H) , 3.58 (td, 1H), 3.12 (q, 1H), 2.32 (m, 1H), 1.87-1.73 (m, 3H).

Step f: Potassium hydroxide (1.13 g, 20.2 mmol) was added to a solution of the above intermediate (2.04 g, 10.1 mmol) in water (15 ml) and the reaction mixture was stirred at room temperature. for 18 hours. The reaction mixture was acidified to pH ~2 with concentrated hydrochloric acid and extracted with chloroform:IPA (7:3). The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified using Biotage Isolera (Silicycle Siliaprep 25 g, 0-10% MeOH in DCM) to give tetrahydro-2H-pyran-2,3dicarboxylic acid (1.01 g, 46%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (br s, 2H), 4.17-4.08 (m, 2H), 3.653.57 (m, 1H), 3.24 (m, 1H ), 2.41-2.34 (m, 1H), 1.91-1.54 (m, 3H).

Stage f. DMF (1 drop) was added to a solution of the above intermediate (1.0 g, 5.74 mmol) and oxalyl chloride (0.58 ml, 6.89 mmol) in toluene (30 ml). The reaction mixture was stirred under reflux for 3 hours, cooled to room temperature. and left at room temperature. for 18 hours. The liquid was decanted from the residue in the flask and the solutions were concentrated in vacuo to give an oil (815 mg). From half of this purified material, tetrahydro^H-furo^D-Cyran^^-dione (249 mg, 23%) was obtained using Biotage Isolera (Biotage Silica ZIPSphere 10 g, 0-100% EtOAc in heptane), used in the next step without additional cleaning. ¹ H NMR (400 MHz, CDCl ₃ ) of the complex mixture included characteristic peaks for the title compound 5 4.73 (d, 1H), 3.11 (q, 1H).

2-(3H-[1,2,3]Triαzolo[4,5-b]nuridin-3-yl)-1-methyl-(1S,2R)-1-methylcyclohexane-1,2-dicarboxylate-4,4 -d2.

Stage a. To a solution of 2-benzyl-1-methyl-(1S,2R,4R)-4-hydroxy-1-methylcyclohexane-1,2dicarboxylate (325 mg, 1.06 mmol, step d, example 219) in DCM (10 ml) DessaMartin periodinan (585 mg, 1.38 mmol; CAS: 87413-09-0) was added and the resulting mixture was stirred at room temperature. under argon for 1 hour. The reaction mixture was quenched with sodium thiosulfate solution and the crude product was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-50% EtOAc in cyclohexane) to give 2-benzyl-1-methyl (1S,2R)-1-methyl -4-oxocyclohexane-1,2-dicarboxylate (284 mg, 88%). ^1H NMR (400 MHz; CDCl ₃ ) δ 7.377.32 (m, 5H), 5.12 (s, 2H), 3.60 (s, 3H), 2.98-2.84 (m, 2H) , 2.68-2.50 (m, 2H), 2.44-2.30 (m, 2H), 1.88-1.80 (m, 1H), 1.48 (s, 3H).

Stage b. To a solution of the above intermediate (50 mg, 0.160 mmol) in methanol^ ₄ (2 ml) was added p-toluenesulfonylhydrazide (31 mg, 0.16 mmol, CAS: 1576-35-8) and the resulting mixture was stirred at room temperature. T. under argon atmosphere for 1.5 hours. The reaction mixture was treated with sodium borondeuteride (21 mg, 0.49 mmol; CAS: 15681-89-7) and the resulting mixture was stirred for an additional 1.5 hours. The mixture was heated at 60 °C for 1.5 hours. Cool the mixture to room temperature, dilute with water and extract with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-20% EtOAc in cyclohexane) to give 2-benzyl-1-methyl-(1S,2R)-1methylcyclohexane- 1,2-dicarboxylate-4,4^ ₂ (32 mg, 66%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.29 (m, 5H), 5.11 (s, 2H), 3.57 (s, 3H), 2.66-2.61 ( m, 1H), 2.15-2.06 (m, 1H), 1.97 (dd, 1H), 1.84 (dd, 1H), 1.53-1.40 (m, 3H),

- 102 045906

1.30 (s, 3H).

Stage c. To a solution of the above intermediate (154 mg, 0.53 mmol) in EtOH (4 ml) was added Pd/C (10%; 50 mg, 0.47 mmol) and the resulting mixture was stirred under hydrogen atmosphere at atmospheric pressure for 7 hours. The reaction mixture was diluted using IMS and filtered through Celite®. The filtrate was concentrated in vacuo to give (1R,2S)-2(methoxycarbonyl)-2-methylcyclohexane-1-carboxylic-5,5D ₂ acid (101 mg, 95%). ^1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 2.58 (dd, 1H), 2.18-2.05 (m, 1H), 1.95-1.88 (m , 2H), 1.57-1.41 (m, 3H), 1.33 (s, 3H).

Stage d. To a stirred solution of the above intermediate (101 mg, 0.50 mmol) in DMF (1.1 ml) was added HATU (209 mg, 0.55 mmol; CAS: 148893-10-1) and the resulting mixture was stirred at .T. in an argon atmosphere for 5 minutes. DIPEA (0.1 ml, 0.55 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-50% EtOAc in cyclohexane) to give the title compound (130 mg, 81%). LCMS (method 2): 1.34 min, 321.0 [M+H] ⁺ . ^1H NMR (300 MHz, CDClj) δ 8.74-8.71 (m, 1H), 8.41 (dd, 1H), 7.43 (dd, 1H), 3.76 (s, 3H), 3.16-3.10 (m, 1H), 2.30-2.12 (m, 3H), 1.66-1.54 (m, 3H), 1.48 (s, 3H).

Synthesis of compounds from examples

Example 1. (1S,2R)-2-((S)-1-((1,3-Dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazol-3carboxamido)ethoxy)-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexanecarboxylic acid.

Stage a. To a stirred suspension of intermediate 11 (0.45 g, 1.1 mmol) and cesium carbonate (1.44 g, 4.4 mmol) in DMF (6 ml) at RT. K-(2-chloroethyl)-dibenzylamine hydrochloride (0.46 g, 1.5 mmol, CAS: 55-43-6) was added and the reaction mixture was heated to 100°C for 18 hours. The reaction mixture was concentrated in vacuo, diluted water (25 ml) and extracted with DCM (25 ml). The organic layer was washed with additional water (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give tert-butyl-^)-8-(2-(dibenzylamino)ethoxy)-1-((1,3-dioxoisoindoline2- yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate (1.10 g, conditionally quantitative). 1H NMR (400 MHz, DMSO- _d6 , rotamers observed, both reported) δ 7.98-7.75 (m, 4H), 7.447.03 (m, 11H), 6.83-6.72 (m, 2H), 5.54 (dd, 0.3H), 5.45 (dd, 0.7H), 4.42-3.90 (m, 4H), 3.81-3.64 (m , 5H), 3.633.45 (m, 2H), 3.15-2.95 (m, 2H), 2.85-2.70 (m, 1H), 1.03 (s, 2.7H), 0.84 (s, 6.3H).

Stage b. To a solution of the above intermediate (1 g, 1.6 mmol) in IMS (20 ml) was added 1-methyl-1,4-cyclohexadiene (1.8 g, 15.8 mmol) and Pd/C (20%; 0 .11 g, 0.16 mmol) and the reaction mixture was heated at 60°C for 18 hours. Additional 1-methyl-1,4-cyclohexadiene (3.6 g, 31.6 mmol) was added and the mixture was heated at 60° C for a further 36 hours. The mixture was filtered through a pad of Celite®, and washed with IMS (20 ml) and THF (20 ml), and the filtrate was concentrated in vacuo. Purification by flash column chromatography (10% MeOH in DCM) afforded tert-butyl-N)-8-(2-aminoethoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-3,4- Dihydroisoquinoline-2(III)carboxylate (352 mg, 49%). LCMS (method 4): 0.81 min, 452.4 [M+H]+.

Stage c. To a stirred solution of 5-methylisoxazole-3-carboxylic acid (19 mg, 0.15 mmol, CAS: 3405-77-4) in DMF (2 ml) was added 1,1'-carbonyldiimidazole (24 mg, 0.15 mmol, CAS: 530-62-1). After 5 min, a solution of the above intermediate (60 mg, 0.13 mmol) in DMF (1 ml) was added. The reaction mixture was stirred at room temperature. for 3 hours, diluted with water (10 ml) and extracted with EtOAc (2x10 ml). The combined organic layers were washed with water (20 ml), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (EtOAc) afforded tert-butyl-^)-1-((1,3dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazole-3-carboxamido)ethoxy) -3,4-dihydroisoquinoline2(III)-carboxylate (67 mg, 80%). LCMS (method 4): 0.93 min, 561.3 [M+H]+.

Stage d. A solution of the above intermediate (67 mg, 0.12 mmol) in HCl (4M in dioxane; 2 ml) was stirred at RT. for 1 hour. The reaction mixture was concentrated in vacuo to give ^)-K-(2-((1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8yl )oxy)ethyl)-5-methylisoxazole-3-carboxamide hydrochloride (59 mg, 100%), used without further purification. LCMS (method 4): 0.76 min, 461.3 [M+H]+.

Step f: To a stirred solution of the above intermediate (59 mg, 0.12 mmol) and triethylamine (82 µl, 0.59 mmol) in DCM (5 ml) at 0° C. was added a solution of intermediate 26 (50 mg, 0.59 mmol) in DCM (5 ml) at 0°C. 18 mmol) in DCM (1 ml). The reaction mixture was stirred at 0°C for

- 103 045906 15 min. DCM (6 ml) and saturated aqueous NaHCO3 (12 ml) were added. The layers were separated by passing through a phase separation cartridge and the organic layer was concentrated in vacuo. Purification by flash column chromatography (40-80% EtOAc in heptanes) gave benzyl-(1S,2R)2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8 -(2-(5-methylisoxazole-3-carboxamido)ethoxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (78 mg, 92%). LCMS (method 4): 0.98 min, 705.4 [M+H]+.

Stage f. To a solution of the above intermediate (78 mg, 0.11 mmol) in THF (5 ml) was added Pd/C (10%; 50 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature. under atmospheric pressure for 18 hours. The mixture was filtered through a pad of Celite®, washed with THF (15 ml) and the filtrate was concentrated in vacuo. Purification by reverse phase column chromatography (C18 cartridge with 12 g spherical beads, 15-80% MeCN in aqueous ammonium bicarbonate buffer pH 10) afforded the title compound (15 mg, 22%). LCMS (method 4a): 1.7 min, 615.1 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.68 (bs, 1H), 8.76 (t, 1H), 7.91-7.78 (m, 4H), 7.19 (t, 1H), 6.89 (d, 1H), 6.80 (d, 1H), 6.54 (m, 1H), 6.04 (dd, 1H), 4.28-4.03 (m, 3H ), 4.013.73 (m, 4H), 3.66 (m, 1H), 3.27 (m, 1H), 2.94-2.72 (m, 2H), 2.35 (m, 3H) , 2.21 (m, 1H), 1.83 (m, 1H), 1.601.42 (m, 2H), 1.41-1.18 (m, 2H), 0.94 (m, 1H), 0.82 (m, 1H), 0.15 (m, 1H).

Example 2. (1S,2R)-2-((S)-8-(2-(Benzo[d]oxαzol-2-carboxamugo)ethoxy)-1-((1,3-dioxoisoindolin2-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. Benzyl-(1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane- 1-Carboxylate (370 mg, 59%) was prepared from intermediate 10 (350 mg, 1.14 mmol) and intermediate 26 (351 mg, 1.25 mmol) using a procedure similar to that described for Example 1, step e. LCMS (method 4a): 2.86 min, 553.4 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) 9.86 (br s, 1H), 7.86-7.79 (m, 4H), 7.19-7.00 (m, 5H), 6.73 (d, 1H), 6.60 (d, 1H), 5.98 (dd, 1H), 4.77 (q, 2H), 4.22 (dd, 1H), 3.80 (d, 1H) , 3.75-3.60 (m, 2H), 3.29-3.24 (m, 1H), 2.73-2.69 (m, 1H), 2.40 (dt, 1H), 1 .84 (q, 1H), 1.68-1.60 (m, 1H), 1.50 (d, 1H), 1.36-1.23 (m, 3H), 1.00-0.76 (m,3H), 0.15 (q,1H).

Stage b. Benzyl-(1S,2R)-2-((S)-8-(2-((tert-butoxycarbonyl)amino)ethoxy)-1 -((1,3dioxoisoindolin-2-yl)methyl)-1,2, 3,4-Tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (380 mg, 43%) was prepared from the above intermediate and tert-butyl (2 bromoethyl) carbamate using a procedure similar to that described for Example 1, Step a. LCMS (method 4): 1.05 min, 713.6 [M+NH ₄ ]+.

Stage c. Benzyl-(1S,2R)-2-((S)-8-(2-((m-tert-butoxycarbonyl)amino)ethoxy)-1 -((1,3-dioxoisoindolin2-yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate was prepared from the above intermediate using a procedure similar to that described for Example 1, step d. LCMS (method 4): 0.93 min, 596.5 [M+H]+.

Stage d. To a solution of the above intermediate (105 mg, 0.16 mmol) and triethylamine (0.11 mL, 0.80 mmol) in DCM (2 mL) was added a solution of benzo^]oxazole-2-carbonyl chloride (43 mg, 0.26 mmol, CAS: 408538-63-6) in DCM (0.5 ml). The reaction mixture was stirred at room temperature. for 20 minutes, then quenched with saturated aqueous NaHCO ₃ (2 ml) and the mixture was passed through a phase separator. The DCM layer was concentrated in vacuo. Purification by flash column chromatography (30-60% EtOAc in heptanes) afforded benzyl-(1S,2R)-2-((S)-8-(2-(benzo[d]oxazole-2carboxamido)-ethoxy)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylate (104 mg, 88%). LCMS (method 4): 1.02 min, 741.6 [M+H]+.

Step f: To a solution of the above intermediate (104 mg, 0.14 mmol) in DCM (2 ml) cooled to -10°C, boron tribromide (1M in DCM; 1 ml) was added and the reaction mixture was allowed to warm to room temperature. T. After 2 hours, saturated aqueous NaHCO ₃ (2 ml) was added and the reaction mixture was concentrated in vacuo. Purification by preparative HPLC (method 6; 25-50% MeCN in aq NH ₄ CO ₃ H (pH 10)) gave the title compound (42 mg, 53%). LCMS (Method 4a): 1.80 min, 651.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ) δ 11.67 (bs, 1H), 9.31 (t, 1H), 7.88-7.77 (m, 4H), 7.72 (m, 1H ), 7.44 (m, 1H), 7.35-7.27 (m, 2H), 7.20 (t, 1H), 6.91 (d, 1H), 6.80 (d, 1H) , 6.09 (dd, 1H), 4.30-4.10 (m, 3H), 4.02 (m, 1H), 3.95-3.75 (m, 3H), 3.63 (m , 1H), 3.27 (m, 1H), 2.94-2.71 (m, 2H), 2.20 (m, 1H), 1.80 (m, 1H), 1.59-1, 41 (m, 2H), 1.40-1.16 (m, 2H), 0.93 (m, 1H), 0.79 (m, 1H), 0.14 (m, 1H).

Example 3.(1S,2R)-2-((S)-8-(((S)-1-Acetylpyrrolidin-3-yl)oxy)-1-((1,3-dioxoiso-indolin2-yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

- 104 045906

Stage a. A solution of DBAD (120 mg, 0.52 mmol, CAS: 870-50-8) in THF (2.0 ml) was added slowly over 10 min. to a stirred solution of intermediate 11 (180 mg, 0.40 mmol), (R)1-(3-hydroxypyrrolidin-1-yl)ethan-1-one (67.0 mg, 0.52 mmol, CAS: 916733- 17-0) and triphenylphosphine (136 mg, 0.52 mmol) in THF (3.0 ml) at RT. After stirring for 2 hours, the reaction mixture was concentrated in vacuo. Purification by flash column chromatography afforded tert-butyl-^)-8-((^)-1-acetylpyrrolidin-3-yl)oxy)-1-((1,3-dioxoisoindolin-2-yl)methyl) -3,4dihydroisoquinoline-2(III)-carboxylate (171 mg, 63%). LCMS (Method 4a): 2.38 min, 520.4 [M+H]+.

Stages bd. The title compound was synthesized from the above intermediate using procedures similar to those described for Example 1, steps d, e, f. LCMS (method 4a): 1.47 and 1.57 min (rotamers), 574.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ; rotamers observed, both reported) δ 11.67 (bs, 1H), 7.89-7.76 (m, 4H), 7.21 (m, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 5.98-5.89 (m, 1H), 5.15 (m, 0.5H), 5.11 (m , 0.5H), 4.11 (m, 1H), 3.98-3.71 (m, 4H), 3.71-3.52 (m, 3H), 3.25 (m, 1H), 2.94-2.71 (m, 2H), 2.54-2.09 (m, 3H), 2.03 (s, 1.5H), 2.01 (s, 1.5H), 1, 82 (m, 1H), 1.59-1.40 (m, 2H), 1.401.19 (m, 2H), 0.93 (m, 1H), 0.76 (m, 1H), 0.10 (m, 1H).

Example 4. (1S,2R)-2-((S)-1-((1,3-Dioxoisoindolin-2-yl)methyl)-8-((^)-1-(5-methylisoxazol-3carbonyl)pyrrolidine -3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. tert-butyl-^)-3-((^)-2-((^^)-2-((benzyloxy)carbonyl)-cyclohexane-1-carbonyl)-1-((1,3dioxoisoindolin-2-yl) Methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)pyrrolidine-1-carboxylate (4.3 g, 93%) was prepared from N)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 .78 g, 9.50 mmol, CAS: 103057-44-9) and benzyl-(1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)- 8-Hydroxy-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (from Example 2, Step a, 3.56 g, 6.40 mmol) using a similar procedure to Example 3, Step A. The crude product was purified by flash column chromatography (50-100% EtOAc in heptanes). LCMS (method 4): 1.07 min, 722.6 [M+H] ⁺ .

Stage b. Benzyl-(1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-pyrrolidin-3yl)oxy)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (1.8 g, 48%) was prepared from the above intermediate using a procedure similar to that described for Example 1, step d. LCMS (Method 4a): 2.85 min, 622.4 [M+H] ⁺ .

Stage c. To a suspension of 5-methylisoxazole-3-carboxylic acid (130 mg, 0.89 mmol, CAS: 3405-774) in DCM (5 ml) was added oxalyl chloride (0.5 ml) and THF (0.1 ml). After 30 min. Oxalyl chloride (0.5 ml) and DMF (0.05 ml) were added to the reaction mixture. After another 30 minutes. the reaction mixture was concentrated in vacuo, azeotroped twice with toluene to give 5methylisoxazole-3-carbonyl chloride (150 mg, 100%). To a stirred solution of benzyl-(1S,2R)-2-((S)1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((^)-pyrrolidin-3-yl)oxy)- 1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylate (92 mg, 0.14 mmol) and triethylamine (0.10 ml, 0.70 mmol) in DCM (1 ml) was added portionwise with a solution of 5- methylisoxazole-3-carbonyl chloride (150 mg, 0.91 mmol) in DCM (2 ml). After 30 min. saturated aqueous NaHCO ₃ (2 ml) was added and the organic layer was separated and dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was passed through an SCX-2 cartridge (1 g, methanolic ammonia) and concentrated in vacuo to give (1S,2R)-benzyl-2-((S)-1((1,3-dioxoisoindolin-2-yl)methyl) -8-((^)-1-(5-methylisoxazol-3-carbonyl)pyrrolidin-3-yl)oxy)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexanecarboxylate (34 mg, 33%), used without further purification. LCMS (Method 4a): 3.07 min, 748.6 [M+NH ₄ ] ⁺ .

Stage d. The title compound (5 mg, 17%) was prepared from the above intermediate (34 mg, 0.05 mmol) using a procedure similar to that described for Example 1, step f. The crude product was purified by preparative HPLC (method 6; 20-45% MeCN in aq NH4CO3H (pH 10)). LCMS (Method 4a): 1.62 and 1.76 min, 641.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ; rotamers observed, both reported) δ 11.50 (bs, 1H), 7.88-7.76 (m, 4H), 7.26-7.16 (m, 1H), 6.93 (d, 0.5H), 6.88 (d, 0.5H), 6.81 (m, 1H), 6.54 (m, 0.5H), 6. 53 (m, 0.5H), 5.92 (m, 1H), 5.19 (m, 1H),

- 105 045906

4.20-4.00 (m, 3H), 3.99-3.73 (m, 4H), 3.65 (m, 1H), 3.25 (m, 1H), 2.95-2, 71 (m, 2H), 2.60-2.24 (m, 5H), 2.19 (m, 1H), 1.82 (m, 1H), 1.60-1.40 (m, 2H) , 1.39-1.16 (m, 2h), 0.93 (m, 1H), 0.77 (m, 1H), 0.12 (m, 1H).

Examples 5 and 6. (1S,2R)-2-((S)-1-((1,3-Dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazol-5carbonyl) pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid and (1S,2R)-2-((S)-1-((1,3 -dioxoisoingolin-2-yl)methyl)-8-(((S)-1-(thiαzol-5-carbonyl)pyrrolidin-3yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane- 1-carboxylic acid.

Stage a. To a solution of benzyl-(1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)pyrrolidin-3-yl)oxy)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (example 4, Step b; 320 mg, 0.51 mmol) and triethylamine (0.27 ml, 2.06 mmol) in DCM ( 6 ml) thiazole-5carboxylic acid (75 mg, 0.61 mmol CAS: 14527-41-4]) and HATU (194 mg, 0.53 mmol; CAS: 148893-101) were added. The mixture was stirred at room temperature. for 8 hours, then diluted with water (10 ml). The product was extracted with DCM (3x15 ml). The combined organic layers were washed with saturated aqueous NaHCO ₃ (4 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (5-10% MeOH in EtOAc) afforded benzyl-(1S,2R)-2-((S)-1-((1,3dioxoisoindolin-2-yl)methyl)-8- ((^)-1-(thiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (120 mg, 32%). LCMS (Method 4): 0.92 min, 733.5 [M+H]+.

Stage b. The title compounds from Example 5, (1S,2R)-2-((S)-5-6pom-1-((1,3dioxoisoindolin-2-yl)methyl)-8-((^)-1-( thiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (6.1 mg, 5%), and from Example 6, (1S ,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiαzol-5-carbonyl)pyrrolidin-3yl)oxy )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (20 mg, 19%) was prepared from the above intermediate (120 mg, 0.16 mmol) using a procedure similar to that described for example 2, step e. The crude products were separated using preparative HPLC (method 6; 20-40% MeCN in aq NH4CO3H (pH 10)).

Example 5 LCMS (method 4a): 1.70 min, 721.3 and 723.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ) δ 11.63 (bs, 1H), 9.27 (s, 0.6H), 9.23 (s, 0.4H), 8.45 (s, 0 ,6H), 8.40 (s, 0.4H), 7.90-7.71 (m, 4H), 7.54 (m, 1H), 6.99 (m, 1H), 5.94 ( m, 1H), 5.23 (bm, 1H), 4.44-3.54 (m, 7H), 3.53-3.11 (m, 2H), 2.90-2.61 (bm, 2H), 2.61-2.10 (m, 3H), 1.78 (bm, 1H), 1.59-1.38 (bm, 2H), 1.38-1.17 (bm, 2H) , 1.00-0.65 (bm, 2H), 0.11 (bm, 1H).

Example 6. LCMS (method 4a): 1.52 min, 643.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d _6; rotamers observed, both reported) δ 11.51 (bs, 1H), 9.27 (s, 0.5H), 9.24 (s, 0.5H ), 8.45 (s, 0.5H), 8.40 (s, 0.5H), 7.87-7.75 (m, 4H), 7.26-7.16 (m, 1H), 6.98-6.88 (m, 1H), 6.85-6.75 (m, 1H), 5.96 (dd, 0.5H), 5.91 (dd, 0.5H), 5, 21 (m, 1H), 4.33 (dd, 0.5H), 4.26-3.55 (m, 7.5H), 3.24 (m, 1H), 2.97-2.69 ( m, 2H), 2.56-2.34 (m, 1H), 2.17 (m, 1H), 1.80 (m, 1H), 1.58-1.39 (m, 2H), 1 .38-1.17 (m, 2H), 0.91 (m, 1H), 0.76 (m, 1H), 0.11 (m, 1H).

Example 8. (1 S,2R)-2-((S)-1 -((1,3-Dioxoisoindolin-2-yl)methyl)-8-((1 -methyl-P 1-benzo[s1|[ 1,2,3]triazol5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. tert-butyl-(S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d][1,2,3]triαzol-5yl) methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (264 mg, 97%) was prepared from intermediate 11 (200 mg, 0.45 mmol) and 1-methyl-1H-benzo[1,2,3 ]triazol-5-yl)methanol (104 mg, 0.64 mmol, CAS: 120321-72-4) using a procedure similar to that described for example 3, step a. The crude product was purified by flash column chromatography (0-100% EtOAc in cyclohexane). LCMS (method 2): 1.61 min, 576.3 [M+Na] ⁺ .

Stage b. (S)-2-((8-((1-Methyl-1H-benzo[d][1,2,3]triαzol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1yl) Methyl)isoindoline-1,3-dione hydrochloride (234 mg, tentatively quantified) was prepared from the above intermediate (264 mg, 0.48 mmol) using a procedure similar to that described for Example 1, step d. The crude product was used without further purification. LCMS (Method 2): 0.90 min, 454.0 [M+H] ⁺ .

Stage c. To a stirred solution of the above intermediate (233 mg, 0.48 mmol) and cis-cyclohexanedicarboxyl anhydride (81 mg, 0.52 mmol, CAS: 85-42-7) in DCM

- 106 045906 (6 ml) triethylamine (0.17 ml, 1.19 mmol) was added and the reaction mixture was stirred at room temperature. for 24 hours. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method 1) to give the title compound (31 mg, 11%). LCMS (Method 3) 4.65 min, 608.3 [M+H]+. ^1H NMR (400 MHz, DMSO-d6) δ 11.62 (bs, 1H), 8.27 (m, 1H), 7.92 (d, 2H), 7.88-7.77 (m, 4H ), 7.20 (t, 1H), 7.07 (d, 1H), 6.81 (d, 1H), 6.15 (dd, 1H), 5.45 (d, 1H), 5.40 (d, 1H), 4.33 (s, 3H), 4.20 (dd, 1H), 3.90-3.75 (m, 2H), 3.69 (m, 1H), 3.50- 3.14 (m, 1H), 2.99-2.72 (m, 2H), 2.19 (m, 1H), 1.87 (m, 1H), 1.59 (m, 1H), 1 .48-1.19 (m, 3H), 0.92 (m, 1H), 0.67 (m, 1H), 0.12 (m, 1H).

Example 11. (1S,2R)-2-((S)-8-(((S)-1-Acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2yl )methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Br Br Br

Stage a. Triethylamine (7 .34 ml, 52.7 mmol) at room temperature. The reaction mixture was cooled to 0°C and methanesulfonyl chloride (4.23 mL, 52.7 mmol) was added dropwise. Allow the reaction mixture to warm to rt and stir for 18 hours. The reaction mixture is diluted with water (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were separated, dried over Na ₂ SO _4; filtered and concentrated in vacuo. Purification by flash column chromatography on Biotage Companion™ (220 g Puriflash cartridge, 80-100% MeOH in EtOAc) provided (I)-1-acetylpyrrolidin-3-yl methanesulfonate (4.09 g, 75%). 1H NMR (400 MHz, CDCl ₃ ) δ 5.38-5.28 (m, 1H), 3.96-3.52 (m, 4H), 3.05 (m, 3H), 2.50-2 .13 (m, 2H), 2.10 (m, 3H).

Stage b. The carbonate cesium (21.4 g, 65.8 mmol) and the mixture was stirred at room temperature. for 18 hours, then at 40°C for 7.5 hours. The reaction mixture was diluted with water (400 ml) and the crude product was extracted into ethyl acetate [400 + (2x300 ml)]. The combined organic layers were washed with brine (250 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 220 g silica gel, 0-20% MeOH in EtOAc) provided tert-butyl-^)-8-((^)-1-acetylpnrrolidine3- yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl-3,4-dihydroisoquinoline-2(III)-carboxylate (7.33 g, 93%). LCMS (method 2): 1.62 min, 620.2 [M+Na] ⁺ .

Stage c. To a solution of the above intermediate (7.32 g, 12.23 mmol) in DCM (33 ml) under argon was added TFA (33 ml, 428 mmol) and the resulting solution was stirred at room temperature. for 1 hour. The reaction mixture was concentrated in vacuo, dissolved in DCM (100 ml) and stirred quickly. Saturated NaHCO ₃ solution (48 ml) was then added in portions until the aqueous layer reached pH 9. The phases were separated and the aqueous layer was extracted with DCM (4x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in DCM (300 ml), and washed with water/saturated NaHCO ₃ solution (10:1, 55 ml), and the aqueous layer (pH 9) was extracted further with DCM (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 2-(((S)-8(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1,2 ,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione (4.94 g, 81%). LCMS (method 2): 0.97 min, 498.2 [M+H] ⁺ .

Stage d. To a solution of intermediate 28 (4.15 g, 12.9 mmol) in anhydrous DMF (66 mL) under argon was added HATU (4.9 g, 12.9 mmol; CAS: 148893-10-1), followed by DIPEA (2.24 ml, 12.9 mmol) and the resulting solution was stirred for 10 minutes. The solution was then added dropwise using a dropping funnel over 10 min. to a solution of the above intermediate (4.94 g, 9.91 mmol) in anhydrous DMF (33 ml) under argon and stirred at RT. for 48 hours, then at 40°C for 48 hours. The mixture was partitioned between water/saline (400 ml/50 ml) and EtOAc (400 ml). The aqueous layer was extracted further with EtOAc (2x200 ml) and the combined organic extracts were washed with saturated NaHCO3 (250 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 300 g silica gel, 0-20% MeOH in EtOAc) gave 2,4-dimethoxybenzyl(III^)-2-(^)-8- ((^)-1-acetylnirrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)cyclohexane -1-carboxylate (4.71 g, 59%). LCMS (Method 2): 1.74 min, 802.3 [M+H] ⁺ .

Step f: To a stirred solution of the above intermediate (4.56 g,

- 107 045906

5.68 mmol) in anhydrous DCM (100 mL), triethylsilane (4.54 mL, 28.4 mmol) was added under argon followed by TFA (4.38 mL, 56.8 mmol) and the resulting solution was stirred at .T. for 0.5 h. The mixture was poured into pH 5.2 buffer (100 ml) and the crude product was extracted into DCM (250 ml). The combined organic layers were dried over Na ₂ O ₄ , filtered and concentrated in vacuo. Purification by preparative HPLC (method below) gave the title compound (2.09 g, 55%). [Unique MDAP method: PMIG1-AUV-Quick40-60, 250 mAV threshold for collection. Gradient 40-60% ACN in H2O with 0.1% formic acid buffer over 12 min on a 5 µm XSelect PhenylHexyl column. Compound dissolved in formic acid]. LCMS (method 3): 4.61 min, 652.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ; rotamers observed, both reported) δ 11.65 (bs, 1H), 7.90-7.77 (m, 4H), 7.53 (m, 1H ), 6.92 (d, 1H), 5.94 (m, 1H), 5.17 (m, 0.5H), 5.12 (m, 0.5H), 4.09 (m, 1H) , 4.03-3.80 (m, 3.5H), 3.79-3.46 (m, 3.5H), 3.43-3.20 (m, 1H), 2.82 (dt, 1H), 2.69 (m, 1H), 2.57-2.42 (m, 0.5H), 2.41-2.27 (m, 1H), 2.27-2.12 (m, 1.5H), 2.03 (s, 1.5H), 2.01 (s, 1.5H), 1.82 (m, 1H), 1.54 (m, 1H), 1.45 (m , 1H), 1.39-1.20 (m, 2H), 0.94 (m, 1H), 0.75 (m, 1H), 0.13 (m, 1H).

Example 12 )methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

To a stirred solution of Example 3 (182 mg, 0.32 mmol) in DMF (2 ml) was added Nchlorosuccinimide (45 ml, 0.34 mmol) and the reaction mixture was stirred at room temperature. within 4 days. The reaction mixture was diluted with DCM (20 ml) and washed with water (2x5 ml), brine (5 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. A portion of the residue (94 mg) was purified by preparative HPLC (Method 1) to give the title compound (46 mg, 24%). LCMS (Method 3): 4.57 min, 608.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6; rotamers observed, both reported) δ 11.65 (bs, 1H), 7.90-7.77 (m, 4H), 7.37 (m, 1H) , 6.97 (m, 1H), 5.94 (m, 1H), 5.17 (m, 0.5H), 5.12 (m, 0.5H), 4.16-4.04 (m , 1H), 4.03-3.50 (m, 7H), 3.42-3.19 (m, 1H), 2.86 (dt, 1H), 2.73 (m, 1H), 2, 54-2.09 (m, 3H), 2.03 (s, 1.5H), 2.01 (s, 1.5H), 1.82 (m, 1H), 1.54 (m, 1H) , 1.45 (m, 1H), 1.38-1.20 (m, 2H), 0.94 (m, 1H), 0.75 (m, 1H), 0.13 (m, 1H).

Example 13. (1S,2R)-2-((S)-8-(((S)-1-Acetylpyrrolidin-3-yl)oxy)-5,7-dichloro-1-((1,3dioxoisoindoline-2 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

To a stirred solution of Example 3 (40 mg, 0.07 mmol) in DCM (3 ml) and DMF (2 ml) was added N-chlorosuccinimide (19 mg, 0.14 mmol) and the reaction mixture was refluxed for 24 h. Additional N-chlorosuccinimide (19 mg, 0.14 mmol) was added and the mixture was refluxed for 8 h. Additional N-chlorosuccinimide (19 mg, 0.14 mmol) was added and the mixture was refluxed for 16 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method 1) to give the title compound (8 mg, 18%). LCMS (method 3): 5.21 min, 642.4 [M+H]+. ^1H NMR (400 MHz, _DMSOd6 ; rotamers observed, both reported) δ 11.60 (bs, 1H), 7.91-7.79 (m, 4H), 7.69 (s, 0. 5H), 7.65 (s, 0.5H), 6.11 (m, 1H), 5.24 (m, 0.5H), 4.99 (m, 0.5H), 4.10-3 .50 (m, 8H), 3.50-3.12 (m, 1H), 2.91 (m, 1H), 2.75 (m, 1H), 2.60-2.43 (m, 0 ,5H), 2.37-2.08 (m, 2.5H), 1.94 (s, 3H), 1.88 (m, 1H), 1.57 (m, 1H), 1.461.18 ( m, 3H), 0.94 (m, 1H), 0.65 (m, 1H), 0.19 (m, 1H).

Example 15. (18^)-2-((8)-1-((1-Oxoisoindolin-2-yl)methyl)-8-(((8)-1-(thiazol-5-carbonyl)pyrrolidine3 -yl)oxy)-1,2,3,4-tetrachroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

- 108 045906

Stage a. Benzyl-(1S,2R)-2-((S)-8-hydroxy-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1- carboxylate (269 mg, 72%) was prepared from intermediate 14 (173 mg, 0.59 mmol) and intermediate 26 (250 mg, 0.88 mmol) using a procedure similar to that described for Example 1, Step e. Crude Product purified by flash column chromatography (75% EtOAc in heptanes, then 10% MeOH in EtOAc). LCMS (method 5): 2.18 min, 539.1 [M+H]+.

Stage b. tert-butyl-^)-3-((^)-2-((III^)-2-((benzyloxy)carbonyl)-cyclohexane-1-carbonyl)-1((1-oxoisoindolin-2-yl)methyl )-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)pyrrolidine-1-carboxylate (344 mg, 99%) was prepared from the above intermediate (265 mg, 0.49 mmol) and tert-butyl-^)- 3-hydroxypyrrolidine-1-carboxylate (111 mg, 0.59 mmol, CAS: 103057-44-9) using a procedure similar to that described for example 3, step a. The crude product was purified by flash column chromatography (20-75% EtOAc in heptanes). LCMS (Method 5): 2.49 min, 708.2 [M+H]+.

Stage c. A solution of the above intermediate (344 mg, 0.486 mmol) in HCl (4M in dioxane; 5 ml) was stirred at RT. for 3 hours. The reaction mixture was concentrated in vacuo to give benzyl-(1S,2R)-2-((S)-1-((1-oxoisoindolin-2-yl)methyl)-8-(((S)- npyrrolidin-3-yl)oxy)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate hydrochloride (313 mg, 100%), used without further purification. LCMS (method 5): 2.19 min, 608.2 [M+H]+

Stage d. Benzyl-(1S,2R)-2-((S)-1-((1-oxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazol-5carbonyl)pyrrolidin-3-yl )oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (210 mg, 60%) was prepared from the above intermediate (313 mg, 0.48 mmol) and thiazole-5-carboxylic acid ( 75 mg, 0.58 mmol, CAS: 14527-41-4) using a procedure similar to that described for example 5, step a. The crude product was purified by flash column chromatography (0-10% MeOH in EtOAc). LCMS (method 5): 2.13 min, 719.1 [M+H]+.

Step e: The title compound (30 mg, 16%) was prepared from the above intermediate (210 mg, 0.29 mmol) using a similar procedure to Example 2, Step e. The crude product was purified by flash column chromatography (0-20% MeOH in EtOAc). LCMS (Method 4a): 1.34 min, 629.4 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ; rotamers observed, both of which have been reported) δ 11.61 (bs, 1H), 9.33 (s, 0.5H), 9.23 (s, 0. 5H), 8.51 (s, 1H), 7.64-7.34 (m, 4H), 7.22 (m, 1H), 6.95 (m, 1H), 6.82 (m, 1H ), 5.93 (m, 1H), 5.23 (d, 0.5H), 5.16 (d, 0.5H), 4.66 (d, 0.5H), 4.57 (d, 0.5H), 4.29 (dd, 0.5H), 4.24-3.99 (m, 3.5H), 3.98-3.82 (m, 2H), 3.82-3, 62 (m, 2H), 3.52-3.20 (m, 2H), 2.92-2.72 (m, 2H), 2.43 (m, 1H), 2.31 (m, 1H) , 2.17 (m, 1H), 1.83 (m, 1H), 1.60-1.37 (m, 2H), 1.33-1.15 (m, 2H), 0.88 (m , 1H), 0.60 (m, 1H), 0.04 (m, 1H).

Example 16. (1S,2R)-2-((S)-8-([1,2,4]Triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((1 -oxoisoindolin2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. A mixture of intermediate 27 (2.51 g, 5.66 mmol) in EtOAc (70 mL) and citric acid (10 wt% aqueous solution; 25 mL, 5.14 mmol) was shaken until the entire biphasic mixture was clear. The organic layer was isolated, washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in DMF (50 ml) and intermediate 16 (1.92 g, 5.14 mmol) was added followed by DIPEA (2.64 ml, 15.43 mmol) and HATU (2.15 g, 5 .66 mmol; CAS: 148893-10-1). The resulting solution was stirred at room temperature. for 17 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Biotage SNAP column with 100 g silica gel, 0-100% EtOAc in DCM) gave 2,4-dimethoxybenzyl-(1S,2R)-2-((S) -5-bromo-8-hydroxy-1-((1-oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (1.34 g, 1. 98 mmol, yield 38%). LCMS (method 2): 1.64 min, 699.3 [M+Na]+.

Stage b. To a solution of N-pyridin-2-one hydrazone (1.0 g, 9.2 mmol, CAS: 4930-98-7) in ethanol (15 ml), 2-chloro-1,1,1-trimethoxyethane (2 47 ml, 18.3 mmol, CAS: 74974-54-2) and reaction

- 109 045906 the mixture was refluxed for 4 hours. The reaction mixture was cooled, concentrated in vacuo and purified using Biotage Companion™ flash column chromatography (80g Puriflash cartridge, 0-30% IPA in EtOAc) to give 3- (chloromethyl)-[1,2,4]triazolo[4,3-a]pyridine (128 mg, 8%). LCMS (method 2): 0.77 min, 168.1 [M+H]+.

Stage c. To a stirred solution of 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-bromo-8-hydroxy-1((1-oxoisoindolin-2-yl)methyl)-1,2,3, 4-tetrahydroisoquinoline-2-carbonyl)-cyclohexane-1-carboxylate (80 mg, 0.12 mmol) in DMF (2 ml) at 0°C was added sodium hydride (5.2 mg, 0.13 mmol; 60% dispersion in mineral oil) and the reaction mixture was stirred for 5 minutes. 3(chloromethyl)-[1,2,4]triazolo[4,3-a]pyridine (22 mg, 0.13 mmol) was added to it and the reaction mixture was stirred at 0°C for 0.5 h, then at k.t. for 1 hour. Water (10 ml) was added and the mixture was concentrated in vacuo to give 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-8-([1,2,4]triazolo[4 ,3-a]pyridin-3-ylmethoxy)5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)cyclohexane-1carboxylate (95 mg , estimated quantity) used without further purification. LCMS (method 2): 1.56 min, 808.4 [M+H] ⁺ .

Stage d. To a stirred solution of the above intermediate (95 mg, 0.12 mmol) in DCM (2 mL) was added TFA (200 μL, 2.7 mmol) and anisole (13 μL, 0.12 mmol). The crude product was azeotroped in vacuo with toluene and purified by preparative HPLC (Method 1) to give the title compound (35 mg, 44%). LCMS (Method 3): 3.92 min, 658.4 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) δ 11.65 (bs, 1H), 8.81 (dt, 1H), 7.93 (dt, 1H), 7.61 (d, 1H), 7.58 -7.49 (m, 3H), 7.42 (t, 1H), 7.37 (d, 1H), 7.26 (d, 1H), 7.15 (td, 1H), 5.94- 5.79 (m, 3H), 4.19 (d, 1H), 4.13 (dd, 1H), 3.99 (dd, 1H), 3.70 (m, 1H), 3.54 (d , 1H), 3.40-3.25 (m, 2H), 2.83 (dd, 1H), 2.67 (m, 1H), 2.18 (m, 1H), 1.83 (m, 1H), 1.54 (m, 1H), 1.41 (m, 1H), 1.31-1.17 (m, 2H), 0.89 (m, 1H), 0.60 (m, 1H ), 0.06 (m, 1H).

Example 17. (1 S,2R)-2-((S)-8-(( 1 -Isopropyl-III-1,2,3-triazol-4-yl)methoxy)-1 -((1 -oxoisoindolin- 2yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1 S,2R)-2-((S)-8-hydroxy-1-((1-oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2- Carbonyl)cyclohexane-1-carboxylate (331 mg, 94%) was prepared from intermediate 28 (216 mg, 0.62 mmol) and intermediate 14 (174 mg, 0.59 mmol) using a procedure similar to that described for Example 11 , stage d. The crude product was purified by flash column chromatography on a CombiFlash Rf 200™ (25 g silica gel column, 20-100% EtOAc in cyclohexane, then 0-10% MeOH in DCM). LCMS (Method 2): 1.56 min, 621.4 [M+Na] ⁺ .

Stage b. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-mriazol-4-yl)methoxy)-1((1-oxoisoindoline -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-cyclohexane-1-carboxylate (74 mg, 61%) was prepared from the above intermediate (100 mg, 0.17 mmol) and 4(bromomethyl)-1-isopropyltriazole (64 mg, 0.32 mmol, CAS: 1248068-91-8) using a procedure similar to that described for example 1, step a. The crude product was purified by flash column chromatography on a CombiFlash Rf 200™ (12 g silica gel column, 0-100% EtOAc in DCM). LCMS (method 2): 1.63 min, 722.5 [M+H] ⁺ .

Stage c. The title compound (47 mg, 81%) was prepared from the above intermediate (70 mg, 0.10 mmol) using a procedure similar to that described for Example 16, step d. The crude product was purified by flash column chromatography on a CombiFlash Rf 200™ (12 g silica gel column, 0-10% MeOH in DCM) to give a colorless solid. The residue was dissolved in MeCN-H ₂ O (3:2, 5 ml) and freeze-dried to give the title compound. LCMS (Method 3): 4.11 min, 572.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.63 (bs, 1H), 8.48 (s, 1H), 7.60 (m, 1H), 7.56 (td, 1H), 7 .50 (m, 1H), 7.44 (m, 1H), 7.23 (t, 1H), 7.09 (d, 1H), 6.83 (d, 1H), 5.96 (dd, 1H), 5.29-5.17 (m, 2H), 4.91 (m, 1H), 4.56 (d, 1H), 4.16-4.05 (m, 2H), 3.90 (m, 1H), 3.70 (m, 1H), 3.53 (dd, 1H), 3.42-3.21 (m, 1H), 2.93-2.76 (m, 2H), 2.17 (m, 1H), 1.85 (m, 1H), 1.59-1.41 (m, 8H), 1.331.18 (m, 2H), 0.89 (m, 1H), 0 .61 (m, 1H), 0.07 (m, 1H).

Example 22. (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)oxy)-1- ((1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

- 110 045906

Br

Stage a. A mixture of intermediate 27 (2.51 g, 5.66 mmol) in EtOAc (70 mL) and citric acid (10 wt% aqueous solution; 25 mL, 5.14 mmol) was shaken until the entire biphasic mixture was clear. The organic layer was isolated, washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in DMF (50 ml) and intermediate 16 (1.92 g, 5.14 mmol) was added, followed by DIPEA (2.64 ml, 15.43 mmol) and HATU (2.15 g, 5.66 mmol). The resulting solution was stirred at room temperature. for 17 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Biotage SNAP column with 100 g silica gel, 0-100% EtOAc in DCM) gave the title compound (1.339 g, 38%). LCMS (method 2): 1.64 min, 699.3 [M+NaJ+.Stadaya b. To a stirred solution of the above intermediate (81 mg, 0.12 mmol) and (R)-1-(5methylpyridazin-3-yl)pyrrolidin-3-ylmethanesulfonate (46 mg, 0.18 mmol) in anhydrous DMF (1 ml) Cesium carbonate (194 mg, 0.59 mmol) was added under argon and the mixture was stirred at room temperature. for 72 hours, then at 40°C for 24 hours. Additional ^)-1-(5-methylpyridazin-3yl)pyrrolidin-3-ylmethanesulfonate (15 mg, 0.06 mmol) was added and the reaction mixture was stirred at 40 °C for 24 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 12 g silica gel, 0-20% MeOH in EtOAc) to give 2,4dimethoxybenzyl-(1S,2R)-2-((S) -5-bromo-8-(((S)-1-(5-methylpyridαzin-3-yl)pyrrolidin-3-yl)oxy)-1-((1oxoisoindolin-2-yl)methyl)-1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (68 mg, 68%). LCMS (Method 2): 1.30 min, 838.5/840.2 [M+H]+, 860.4 [M+Na]+.

Stage c. To a stirred solution of the above intermediate (66 mg, 0.080 mmol) in anhydrous DCM (2 ml) under argon was added triethylsilane (0.06 ml, 0.390 mmol), followed by TFA (0.06 ml, 0.780 mmol) and the resulting the solution was stirred at room temperature. within 30 min. The mixture was diluted with pH 5.2 buffer (5 ml) and the crude product was extracted into DCM (3x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. MDAP purification (Method 1) gave the title compound (32 mg, 59%). LCMS (Method 3): 3.50 min, 688.0 [M+H]+. ^1H NMR (400 MHz, DMSOd6) δ 8.42 (d, 1H), 7.59-7.51 (m, 3H), 7.41 (t, 1H), 7.24 (d, 1H), 7.01 (d, 1H), 6.86 (m, 1H), 5.89 (dd, 1H), 5.28 (bm, 1H), 4.38 (d, 1H), 4.16 (dd , 1H), 4.04-3.90 (m, 2H), 3.82 (dd, 1H), 3.78-3.60 (m, 4H), 3.57-3.10 (m, 2H ), 2.83 (dd, 1H), 2.72-2.57 (m, 1H), 2.46-2.31 (m, 2H), 2.21 (s, 3H), 2.18 ( m, 1H), 1.79 (m, 1H), 1.58-1.40 (m, 2H), 1.32-1.13 (m, 2H), 0.88 (m, 1H), 0 .63 (m, 1H), 0.05 (m, 1H).

Example 29. (1 S,2R)-2-((S)-5-6pom-8-(( 1 -methyl-III-1,2,4-triazol-5-yl)methoxy)-1 -(( 1-oxoisoindolin-2yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Вг ΒιStage a. To a stirred solution of (1-methyl-1H-1,2,4-triazol-5-yl)methanol (16 mg, 0.14 mmol, CAS: 91616-36-3) in anhydrous DMF (1 ml) at 0° Triethylamine (0.02 mL, 0.14 mmol) and methanesulfonic anhydride (0.01 mL, 0.14 mmol) were added under argon and the reaction mixture was stirred at 0° C. for 0.5 h. This solution was added at drops to a stirred solution of 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-bromo-8-hydroxy-1-((1-oxoisoindolin-2-yl)methyl)-1,2, 3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (80 mg, 0.12 mmol) and cesium carbonate (96 mg, 0.29 mmol) in anhydrous DMF (1 ml) at 0°C under argon and reaction the mixture was stirred for 0.5 hours, then at room temperature. for 18 hours. To an additional portion of (1-methyl-III-1,2,4triazol-5-yl)methanol (16 mg, 0.14 mmol) in anhydrous DMF (1 ml) was added at 0°C under argon. triethylamine (0.02 ml, 0.14 mmol) and methanesulfonyl chloride (0.01 ml, 0.12 mmol) and the mixture was stirred

- 111 045906 for 0.5 hours at 0°C. It was added to the main part of the reaction mixture and the mixture was stirred at room temperature. for a further 18 hours. The mixture was concentrated in vacuo, diluted with water (10 ml) and extracted with DCM (30 ml). The organic layers were washed with water (5 ml), brine (5 ml), dried over Na2SO4, filtered and concentrated in vacuo to give 2,4-dimethoxybenzyl-(1S,2R)-2(^)-5-bromo-8- ((1-methyl-III-1,2,4-triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl) cyclohexane-1-carboxylate (88 mg, 96%). LCMS (method 2): 1.59 min, 772.4 [M+H]+.

Stage b. The title compound was synthesized from the above intermediate using a procedure similar to that described for Example 22, step d. LCMS (method 3): 4.01 min, 622.2 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.65 (bs, 1H), 8.03 (s, 1H), 7.64-7.53 (m, 4H), 7.44 (m, 1H), 7.12 (d, 1H), 6.01 (dd, 1H), 5.50-5.40 (m, 2H), 4.54 (d, 1H), 4.23-4.12 (m, 2H), 4.06-3.93 (m, 4H), 3.75 (m, 1H), 3.52 (dd, 1H), 3.44-3.22 (m, 1H), 2.85 (dd, 1H), 2.75-2.61 (m, 1H), 2.20 (m, 1H), 1.86 (m, 1H), 1.55 (m, 1H), 1 .42 (m, 1H), 1.33-1.19 (m, 2H), 0.90 (m, 1H), 0.59 (m, 1H), 0.09 (m, 1H).

Example 45 (1S,2R)-2-((1S)-5-6pom-8-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1 -( (1-oxoisoindolin-2yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Vg Vg

Stage a. Bromo(methyl)magnesium (1.4 M toluene/THF 3:1; 7.72 ml, 10.8 mmol) for 5 min. The reaction mixture was stirred at 0°C for 0.5 hours, heated to room temperature. and stirred at room temperature. for 1.5 hours. The reaction mixture was diluted with saturated aqueous NH ₄ Cl (15 ml) and extracted with EtOAc (2x50 ml). The combined organics were dried over MgSO ₄ , filtered and concentrated in vacuo. Purify by flash column chromatography on Biotage Companion™ (40g Puriflash cartridge, 0-10% MeOH in EtOAc) to give 1-(1-methyltriazol-4-yl)ethanol (467 mg, 41%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.46 (s, 1H), 5.12-5.06 (m,1H), 4.09 (s, 3H), 2.63 (d, 1H) , 1.59 (d, 3H).

Stage b. To a stirred solution of the above intermediate (140 mg, 1.1 mmol) in chloroform (2 ml) at room temperature. thionyl chloride (0.16 ml, 2.2 mmol) was added and the reaction mixture was stirred at room temperature. for 3 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether (3 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-(1-chloroethyl)-1-methyltriazole hydrochloride (142 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 5.45 (q, 1H), 4.03 (s, 3H), 1.83 (d, 3H).

Stages cd. The title compound was prepared using a procedure similar to that described for Example 22, steps c, d. LCMS (method 3): 4.18 min, 636.4 [M+H]+. 1H NMR (400 MHz, DMSOd ₆ ) δ 11.73 (bs, 1H), 8.25 (s, 1H), 7.67-7.60 (m, 2H), 7.58 (m, 1H), 7.49-7.41 (m, 2H), 6.99 (d, 1H), 6.05 (dd, 1H), 5.76 (m, 1H), 4.72 (d, 1H), 4 .37 (d, 1H), 4.11 (dd, 1H), 4.04-3.94 (m, 4H), 3.71 (m, 1H), 3.57 (dd, 1H), 3, 51-3.11 (m, 1H), 2.79 (dd, 1H), 2.73-2.58 (m, 1H), 2.18 (m, 1H), 1.87 (m, 1H) , 1.79 (d, 3H), 1.56 (m, 1H), 1.45 (m, 1H), 1.34-1.19 (m, 2H), 0.90 (m, 1H), 0.62 (m, 1H), 0.10 (m, 1H).

Example 49. (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2yl)methyl)-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-hydroxy-1-((1-oxoisoindolin-2yl)methyl)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)cyclohexane-1-carboxylate (1.4 g, 50%) was prepared from intermediate 27 (2.11 g, 4.76 mmol) and intermediate 18 (1.49 g, 4.53 mmol) with using a procedure similar to that described for example 16, step a. LCMS (method 2): 1.70 min, 655.4 [M+Na]+.

Stages b-c. The title compound (23 mg, 31%) was prepared from the above intermediate (80 mg, 0.126 mmol) and 3-(chloromethyl)-5-methylisoxazole (25 mg, 0.19 mmol, CAS: 35166-37-1) using procedures similar to those described for Example 22, steps c and d. LCMS (Method

- 112 045906

3): 4.62 min, 578.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 7.64-7.53 (m, 3H), 7.45 (m, 1H), 7.40 (d, 1H ), 7.09 (d, 1H), 6.54 (m, 1H), 6.02 (dd, 1H), 5.31 (d, 1H), 5.23 (d, 1H), 4.62 (d, 1H), 4.27 (d, 1H), 4.19 (dd, 1H), 4.01 (dd, 1H), 3.76 (m, 1H), 3.54 (dd, 1H) , 3.36-3.26 (m, 3H), 2.89 (dd, 1H), 2.69 (m, 1H), 2.522.47 (m, 1H), 2.20 (m, 1H), 1.87 (m, 1H), 1.56 (m, 1H), 1.42 (m, 1H), 1.33-1.18 (m, 2H), 0.90 (m, 1H), 0 .58 (m, 1H), 0.08 (m, 1H).

Example 56 -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. To a rapidly stirred solution of methyl 1-methylimidazole-4-carboxylate (500 mg, 3.57 mmol, CAS: 17289-19-9) and zinc difluoromethanesulfinate (1475 mg, 4.99 mmol) in DMSO (65 ml) was added one portion of tert-butyl hydroperoxide (70% in water; 1.62 mL, 11.8 mmol) and the resulting solution was stirred at room temperature. over 21 hours. An additional portion of zinc difluoromethanesulfinate (1476 mg, 4.99 mmol) was added followed by tert-butyl hydroperoxide (70% in water; 1.62 ml, 11.8 mmol) and the mixture was stirred at room temperature. for a further 72 hours. The mixture was carefully poured into saturated NaHCO ₃ -EDTA solution (200 ml) and the crude product was extracted into EtOAc (3x300 ml). The combined organic layers were washed with water (2x200 ml), brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 25 g silica gel, 0-10% MeOH in EtOAc) provided methyl 5-(difluoromethyl)-1-methyl-III-imidazole-4carboxylate ( 137 mg, 20%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.57 (t, 1H), 7.50 (s, 1H), 3.94 (s, 3H), 3.87 (s, 3H).

Stage b. To a stirred solution of the above intermediate (130 mg, 0.68 mmol) in EtOH (2 ml) and THF (1 ml) under argon was added lithium chloride (64 mg, 1.5 mmol) and NaBH ₄ (57 mg, 1 .5 mmol) and the resulting mixture was stirred at room temperature. for 18 hours. The mixture was diluted with 10% aqueous citric acid (5 ml) and extracted with DCM (3x10 ml). The aqueous layer was adjusted to pH 8 by adding saturated NaHCO ₃ solution (5 ml) and further extracted with DCM (9x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (5-(difluoromethyl)-1-methyl-III-imidazol-4yl)methanol (96.6 mg, 87%), used without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ 7.44 (s, 1H), 6.96 (t, 1H), 4.69 (t, 2H), 3.78 (s, 3H), 2.59 ( br s, 1H).

Stage c. To a stirred mixture of the above intermediate (96.4 mg, 0.59 mmol) in chloroform (2 ml) under argon, thionyl chloride (0.08 ml, 1.05 mmol) was added dropwise and the resulting solution was stirred at room temperature. T. for 1.5 hours. The reaction mixture was concentrated in vacuo to give 4-(chloromethyl)-5-(difluoromethyl)-1-methyl-III-imidazole hydrochloride (135 mg, estimated amount), used without further purification. 1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.42 (t, 1H), 4.81 (s, 2H), 3.76 (s, 3H).

Stages de. The title compound (47 mg, 71%) was prepared from 2,4-dimethoxybenzyl(1S,2R)-2-((S)-5-chloro-8-hydroxy-1-((1-oxoisoindolin-2-yl )methyl)-1,2,3,4-tetrahydroisoquinoline-2 carbonyl)cyclohexane-1-carboxylate (Example 45, step a; 80 mg, 0.13 mmol) and the above intermediate (41 mg, 0.19 mmol) using procedures similar to those described for Example 22, steps c and d. LCMS (Method 3): 4.15 min, 627.0 [M+H]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 11.66 (bs, 1H), 7.91 (s, 1H), 7.63-7.52 (m, 3H), 7.47 (t, 1H ), 7.44 (m, 1H), 7.38 (d, 1H), 7.17 (d, 1H), 5.92 (dd, 1H), 5.20 (d, 1H), 5.14 (d, 1H), 4.50 (d, 1H), 4.14 (dd, 1H), 4.06-3.94 (m, 2H), 3.79 (s, 3H), 3.71 ( m, 1H), 3.51 (dd, 1H), 3.44-3.18 (m, 1H), 2.87 (dd, 1H), 2.67 (m, 1H), 2.19 (m , 1H), 1.84 (m, 1H), 1.55 (m, 1H), 1.42 (m, 1H), 1.32-1.18 (m, 2H), 0.89 (m, 1H), 0.61 (m, 1H), 0.09 (m, 1H).

Example 58 -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

- 113 045906

Stage a. 2,4-Dimethoxybenzyl-(N,2H)-2-((M5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy) was loaded into a tube for microwave treatment -1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (from example 35; 200 mg, 0.25 mmol), potassium acetate ( 0.05 ml, 0.75 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)-phenyl]phosphane (5 mg, 0.010 mmol), X-Phos Pd G2 (4 mg, 0.005 mmol) and hypoboric acid (67 mg, 0.750 mmol).The tube was sealed and EtOH (2.5 ml) was added.The reaction mixture was degassed with argon for 10 minutes, heated at 60°C for 4 hours, cooled to room temperature. and concentrated in vacuo. The residue was dissolved in EtOAc (5 ml) and filtered through a Celite® plug. The filtrate was washed with water (10 ml) and the aqueous phase was extracted with EtOAc (3x10 ml). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain a 1: 1 mixture ((S)-2((1H^)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-cyclohexane-1-carbonyl )-8-(( 1 -isopropyl-1H-1,2,3 triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline -5-yl)boronic acid and 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl) methoxy)-1-((1 oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (170 mg), used in the next step without further purification. LCMS (method 2) 1.45 min, 766.5 [M+H] .

Stage b. A mixture of the above intermediate (85 mg, 0.06 mmol) and sodium hydroxide (2.2 mg, 0.06 mmol) in MeOH (1 ml) was stirred at room temperature. for 15 minutes, then cooled to 0°C and silver trifluoromethanesulfonate (43 mg, 0.17 mmol) was added in one portion. The mixture was stirred at 0°C for 30 minutes, then acetone (2 ml) was added and the reaction mixture was concentrated in vacuo at 0°C. The residue was azeotroped in vacuo at 0°C with acetone (2™1 ml). The residue was dissolved in acetone (0.5 ml) and 3 A molecular sieve powder (50 mg) was added followed by SelectFluor® (20.65 mg, 0.06 mmol). The mixture was stirred at room temperature. for 3 hours, then diluted with water and extracted in DCM. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a mixture of 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-fluoro-8-( (1-isopropyl1H-1,2,3-triazol-4-yl)methoxy)-1 -((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2carbonyl)cyclohexane-1 -carboxylate and 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3triazol-4-yl)methoxy)-1-((1 -oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbon)cyclohexane-1-carboxylate (67 mg), used in the next step without further purification. LCMS (method 2): 1.62 min, 740.5 [M+H] ⁺ .

Stage c. The title compound (10 mg, 37%) was prepared from the above crude reaction mixture (1:1 mixture with dehalogenated material) (67 mg, 0.045 mmol) using the method described for Example 22, step d. The crude product was purified using preparative HPLC (method 1). LCMS (Method 3), 4.18 min, 590.2 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ

11.69 (bs, 1H), 8.48 (s, 1H), 7.61 (m, 1H), 7.56 (td, 1H), 7.50 (m, 1H), 7.44 (m , 1H), 7.17-7.07 (m, 2H),5.96 (dd, 1H), 5.28-5.18 (m, 2H), 4.91 (m, 1H), 4, 54 (d, 1H), 4.20-4.05 (m, 2H), 3.98 (dd, 1H), 3.69 (m, 1H), 3.53 (dd, 1H), 3.48 -3.15 (m, 1H), 2.84 (m, 1H), 2.69 (m, 1H), 2.17 (m, 1H), 1.85 (m, 1H), 1.65- 1.48 (m, 7H),1.43 (m, 1H), 1.34-1.17 (m, 2H), 0.89 (m, 1H), 0.60 (m, 1H), 0 .09 (m, 1H).

Example 59 -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy was loaded into a vessel for microwave processing )-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (from example 35; 80 mg, 0.1 mmol), trimethylboroxine ( 0.02 ml, 0.15 mmol), cesium carbonate (65.1 mg, 0.2 mmol), Pd(dppf)Cl ₂ DCM (4.1 mg, 0.005 mmol) and washed with argon. The tube was sealed and 1,4-dioxane (0.7 ml) and water (0.1 ml) were added. The mixture was heated at 80°C for 18 hours, then cooled to room temperature, diluted with water and extracted into EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-8((1-isopropyl-1H -1,2,3-triazol-4-yl)methoxy)-5 -methyl-1 -((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)cyclohexane-1 -carboxylate (67 mg, 91%), used without further purification. LCMS (method 2): 1.67 min, 736.5 [M+H] ⁺ .

Stage b. The title compound (15 mg, 26%) was prepared from the above intermediate (67 mg, 0.091 mmol) using the method described for Example 22, step d. The crude product was purified using preparative HPLC (method 1). LCMS (method 3): 4.24

- 114 045906 min, 586.5 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.59 (bs, 1H), 8.47 (s, 1H), 7.60 (m, 1H), 7.55 (td, 1H), 7 .49 (m, 1H), 7.44 (m, 1H), 7.10 (d, 1H), 7.00 (d, 1H), 5.95 (dd, 1H), 5.25-5, 13 (m, 2H), 4.90 (m, 1H), 4.55 (d, 1H), 4.13 (dd, 1H), 4.07 (d, 1H), 3.97 (dd, 1H ), 3.71 (m, 1H), 3.51 (dd, 1H), 3.46-3.23 (m, 1H), 2.78-2.56 (m, 2H), 2.21- 2.10 (m, 4H), 1.84 (m, 1H), 1.59-1.50 (m, 7H), 1.45 (m, 1H), 1.32-1.17 (m, 2H), 0.88 (m, 1H), 0.60 (m, 1H), 0.08 (m, 1H).

Example 60 -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5bromo-8-(( 1 -isopropyl-1H-1,2,3-triazol-4-yl)methoxy was loaded into a vessel for microwave processing )-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (from example 35; 80 mg, 0.1 mmol), palladium- tetrakis(triphenylphosphine) (23 mg, 0.02 mmol) and zinc cyanide (0.02 ml, 0.3 mmol) and washed with argon. DMF (0.75 ml) was added, the tube was sealed and the mixture was heated at 100°C for 18 hours. The mixture was cooled to room temperature. and concentrated in vacuo. The residue was diluted with water and extracted into EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by Companion™ flash column chromatography (4 g silica gel column, 0-100% DCM in EtOAc) provided 2,4dimethoxybenzyl-(1S,2R)-2-((S)-5-cyano-8-(( 1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)cyclohexane- 1-carboxylate (35 mg, 46%). LCMS (method 2): 1.59 min, 747.5 [M+H]+.

Stage b. The title compound (12 mg, 97%) was prepared from the above intermediate (35 mg, 0.05 mmol) using the method described for Example 22, step d. The crude product was purified using preparative HPLC (method 1). LCMS (method 3): 4.02 min, 597.2 [M+H]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 11.66 (bs, 1H), 8.52 (s, 1H), 7.82 (d, 1H), 7.66-7.53 (m, 2H ), 7.50 (m, 1H), 7.44 (m, 1H), 7.32 (d, 1H), 5.94 (dd, 1H), 5.45-5.29 (m, 2H) , 4.91 (m, 1H), 4.50 (d, 1H), 4.16 (dd, 1H), 4.11-3.98 (m, 2H), 3.77 (m, 1H), 3.50 (dd, 1H), 3.39-3.27 (m, 1H), 3.06-2.81 (m, 2H), 2.20 (m, 1H), 1.84 (m, 1H), 1.62-1.48 (m, 7H), 1.43 (m, 1H), 1.33-1.16 (m, 2H), 0.90 (m, 1H), 0.62 (m, 1H), 0.09 (m, 1H).

Examples 61 and 62. (1S,2R)-2-((S)-8-((1-Isopropyl-1H-1,2,3-triαzol-4-ul)methoxy)-5-methoxy-1-( (1oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (61) and (1 S,2R)-2-((S)-8- (( 1 -isopropyl-III-1,2,3-triazol-4-yl)methoxy)-1 -((1-oxoisoindolin-2-yl)methyl)-5(trifluoromethyl)-1,2,3,4 -tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (62).

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl) was loaded into a microwaving tube. methoxy)-1 -((1-oxoisoind olin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (from example 35; 400 mg, 0.5 mmol), potassium acetate (147 mg, 1.5 mmol), bis(pinacolato)diboron (165 mg, 0.65 mmol) and Pd(dppf)Cl ₂ ) (21 mg, 0.02 mmol) and the tube was sealed, pumped out of it air, then filled with argon again. Anhydrous 1,4-dioxane (4 ml) was added and the mixture was heated at 80°C for 14 hours. The mixture was cooled to rt, then additional bis(pinacolato)diboron (127 mg, 0.5 mmol) was added and Pd(dppf)Cl ₂ (21 mg, 0.02 mmol) under nitrogen. The flask was resealed and heated for another 8 hours at 100°C before cooling to room temperature. The reaction mixture was filtered through a pad of Celite®, washed with DCM (50 ml). The filtrate was partitioned with water (50 ml) and the phases were separated. The aqueous layer was washed with DCM (25 ml) and the organic phases were combined and passed through a phase separator, then concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 24 g silica gel, 0-100% EtOAc in isohexane) gave 2,4dimethoxybenzyl-(1S,2R)-2-((S)-8 -((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindoline

- 115 045906

2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylate (397 mg, 94%). LCMS (method 2): 1.10 min, 848.5 [M+H]+.

Stage b. The microwave vessel was charged with the above intermediate (150 mg, 0.180 mmol), copper(II) acetate (32 mg, 0.18 mmol) and potassium trimethoxy(trifluoromethyl) boranuide (75 mg, 0.35 mmol). The flask was sealed and purged with oxygen gas. Anhydrous DMSO was added and the reaction mixture was heated at 60°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted into EtOAc/diethyl ether (1:1). The combined organic layers were filtered through a pad of Celite®, washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on Biotage Companion™ (12 g silica gel column, 0-100% DCM in EtOAc) gave a mixture of 2,4-dimethoxybenzyl-(^^)-2(^)-8-((1 -isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxy-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl )cyclohexane-1-carboxylate and 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-8-((1isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((1-oxoisoindolin-2-yl)methyl)-5 -(trifluoromethyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (16 mg, 11%), which was used without further purification . 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-Ίriazol-4-yl)methoxy)5 -methoxy-1 -( (1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylate: LCMS (method 2): 1.67 min, 774.5 [M+Na] +. 2,4-Dimethoxybenzyl-(^^)-2-(^)-8-((1-isopropyl1H-1,2,3-triazol-4-yl)methoxy)-1 -((1-oxoisoindoline-2- yl)methyl)-5-(trifluoromethyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate: LCMS (method 2): 1.73 min, 812.4 [M+Na]+.

Stage c. The title compounds of Example 61 (12 mg, 59%) and Example 62 (10 mg, 46%) were prepared from the above mixture (52 mg, 0.035 mmol) using the method described for Example 22, step d. The crude products were purified and separated by preparative HPLC (method 1).

Example 61 -2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid. LCMS (Method 3): 4.19 min, 602.13 [M+H]+. 1H NMR (400 MHz, MeOD) δ 8.30 (s, 1H), 7.69 (m, 1H), 7.58 (td, 1H), 7.51-7.42 (m, 2H), 6 .99 (d, 1H), 6.84 (d, 1H), 6.06 (dd, 1H), 5.24 (d, 1H), 5.19 (d, 1H), 4.94 (m, 1H), 4.72 (d, 1H), 4.27 (dd, 1H), 4.15 (d, 1H), 4.03 (dd, 1H), 3.88-3.75 (m, 4H ), 3.67 (dd, 1H), 3.41 (m, 1H), 2.90 (dd, 1H), 2.74 (m, 1H), 2.33 (m, 1H), 1.97 (m, 1H), 1.83-1.56 (m, 8H), 1.47-1.30 (m, 2H), 1.02 (m, 1H), 0.80 (m, 1H), 0.23 (m, 1H).

Example 62 )methyl)-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-cyclohexane-1-carboxylic acid. LCMS (Method 3): 4.52 min, 640.11 [M+H]+. ^1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.70 (m, 1H), 7.66 (d, 1H), 7.59 (m, 1H), 7.51- 7.42 (m, 2H), 7.21 (d, 1H), 6.13 (dd, 1H), 5.39 (d, 1H), 5.34 (d, 1H), 4.96 (m , 1H), 4.69 (d, 1H), 4.31 (dd, 1H), 4.13 (d, 1H), 4.08 (m, 1H), 3.90 (m, 1H), 3 .67 (dd, 1H), 3.41 (m, 1H), 3.153.05 (m, 2H), 2.34 (m, 1H), 1.96 (m, 1H), 1.78-1, 57 (m, 8H), 1.48-1.32 (m, 2H), 1.02 (m, 1H), 0.82 (m, 1H), 0.23 (m, 1H).

The compounds presented in table. 2 was synthesized using methods similar to those of the examples above.

table 2

Note Structure Name Analogue from example 1H NMR δ ppm LCMS 7 (15.25)-2-((5)-1-((1,3Dioxoisoindolin-2yl)methyl)-8-(((5)-1 -(2methylthiazol-5carbonyl)pyrrolid in-3 yl)oxy)- 1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 5 (400 MHz, DMSO-d ₆ ; rotamers observed, both reported) δ 8.14 (s, 1H), 7.88-7.71 (m, 4H), 7.20 (m, 1H), 6.91 (m, 1H), 6.78 (m, 1H), 5.94 (m, 1H), 5.21 (m, 0.5H), 5.17 (m, 0.5H), 4 .34-3.98 (m, 3H), 3.97-3.70 (m, 4H), 3.60 (m, 1H), 3.21 (m, 1H), 3.01 (m, 1H ), 2.80-2.20 (m, 6H), 1.96-1.72 (m, 2H), 1.52 (m, 1H), 1.38 (m, 1H), 1.30- 1.13 (m, 2H), 0.87 (m, 1H), 0.66 (m, 1H), 0.15 (m, 1H). Method 4a: 1.60 minutes, 657.4 [M+H] ⁺ 9 \ X) Ν-Ν Ο^/γ γ >4 _ο % 1 οθγθΗ (15.25)-2-((5)-1-((1.3- Dioxoisoindolin-2yl)methyl)-8-((1 -methyl-1H1,2,3-triazol-4-yl)methoxy)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 8 (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 8.45 (s, 1H), 7.91-7.75 (m, 4H), 7.22 (t, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.03 (dd, 1H), 5.33 (d, 1H), 5.25 (d, 1H), 4.18-4 .04 (m, 4H), 3.84 (m, 1H), 3.76 (dd, 1H), 3.67 (m, 1H), 3.47-3.14 (m, 1H), 2, 95-2.75 (m, 2H), 2.19 (m, 1H), 1.85 (m, 1H), 1.54 (m, 1H), 1.41 (m, 1H), 1.37 -1.20 (m, 2H), 0.92 Method 3: 4.26 minutes, 558.2 [M+H] ⁺ .

- 116 045906

(m, 1H), 0.68 (m, 1H), 0.09 (m, 1H). 10 V.....;·· . G- (15.2^)-2-((5)-1-((1.3- Dioxoisoindolin-2yl)methyl)-8-((1 -methyl-1HbenzoIimidazol-5yl)methoxy)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 3, stage a, 8, stages b, c (400 MHz, DMSO-d ₆ ) δ 11.69 (bs, 1H), 8.19 (s, 1H), 7.87-7.79 (m, 5H), 7.67-7.58 (m , 2H), 7.16 (t, 1H), 7.03 (d, 1H), 6.77 (d, 1H), 6.14 (dd, 1H), 5.44-5.34 (m, 2H), 4.21 (dd, 1H), 3.88-3.74 (m, 5H), 3.68 (m, 1H), 3.39-3.20 (m, 1H), 2.95 -2.77 (m, 2H), 2.20 (m, 1H), 1.87 (m, 1H), 1.54 (m, 1H), 1.44 (m, 1H), 1.39- 1.21 (m, 2H), 0.93 (m, 1H), 0.70 (m, 1H), 0.14 (m, 1H). Method 3: 3.68 minutes, 607.4 [M+H] ⁺ 14 ^N -1 , ^N A, \X ( O°Y ^OH Λ,',ν Cl (1 S,2R)-2-((S)-5 -chloro-1-((1,3Dioxoisoindolin-2yl)methyl)-8-(((5)-1 -(thiazol-5carbonyl)pyrrolid in-3 yl)oxy)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 12 (from example 6) (400 MHz, DMSO-d ₆ ; rotamers observed, both reported) δ 11.64 (bs, 1H), 9.26 (s, 0.6H), 9.23 (s, 0.4H), 8.44 (s, 0.6H), 8.39 (s, 0.4H), 7.88-7.73 (m, 4H), 7.38 (m, 1H), 7.04 (m, 1H), 5.97 (dd, 0.4H), 5.92 (dd, 0.6H), 5.23 (m, 1H), 4.33 (m, 0.6H), 4.243.58 (m , 7.4H), 3.48-3.17 (m, 1H), 2.86 (m, 1H), 2.73 (m, 1H), 2.62-2.24 (m, 2H), 2.19 (m, 1H), 1.81 (m, 1H), 1.60-1.39 (m, 2H), 1.38-1.19 (m, 2H), 0.92 (m, 1H), 0.75 (m, 1H), 0.13 (m, 1H). Method 3: 4.59 minutes, 677.3 [M+H] ⁺ 18 < b ^; %A (15.25)-2-((5)-8-((1-Methyl-1-benzo[5] [1,2,3]triazole-5 - yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 17 (400 MHz, DMSO-d ₆ ) δ 11.63 (bs, 1H), 8.28 (m, 1H), 8.00 (dd, 1H), 7.82 (dd, 1H), 7.61- 7.51 (m, 2H), 7.46-7.39 (m, 2H), 7.24 (t, 1H), 7.05 (d, 1H), 6.83 (d, 1H), 6 .07 (dd, 1H), 5.40 (d, 1H), 5.31 (d, 1H), 4.53 (d, 1H), 4.36 (s, 3H), 4.16 (dd, 1H), 4.03 (d, 1H), 3.91 (m, 1H), 3.80-3.66 (m, 1H), 3.56 (dd, 1H), 3.42-3.20 (m, 1H), 2.952.76 (m, 2H), 2.17 (m, 1H), 1.85 (m, 1H), 1.54 (m, 1H), 1.44 (m, 1H) , 1.32-1.17 (m, 2H), 0.88 (m, 1H), 0.58 (m, 1H), 0.06 (m, 1H). Method 3: 4.15 minutes, 594.5 [M+H] ⁺ 19 /* (15,25)-2-((5)-8-(((5)-1- Acetylpyrrolidin-3 yl)oxy)-5 -bromo-1-((1oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 15 (400 MHz, DMSO-d ₆ ; rotamers observed, both reported) δ 11.65 (bs, 1H), 7.64-7.50 (m, 4H), 7.45 (m, 1H), 6.96 (d, 0.5H), 6.93 (d, 0.5H), 5.95 (m, 1H), 5.19 (m, 0.5H), 5.09 (m, 0. 5H), 4.67 (m, 1H), 4.31 (d, 0.5H), 4.25 (d, 0.5H), 4.19 (dd, 1H), 4.01 (dd, 1H ), 3.86 (dd, 0.5H), 3.80-3.58 (m, 4H), 3.52-3.37 (m, 1.5H), 3.37-3.26 (m , 1H), 2.83 (m, 1H), 2.73-2.60 (m, 1H), 2.41-2.29 (m, 1H), 2.27-2.13 (m, 2H ), 2.06 Method 3: 4.02 minutes, 638.3 [M+H] ⁺

- 117 045906

rotamers, which

M+N

Method 3:

M+H carboxylic acid

M+N

Method 2:

M+H is, 1.5H), 2.01 (s, 1.5H), 1.86 (m, 1H).

1.55 (t, 1H), 1.47 (t, 1H), 1.34-1.18 (t.

2H), 0.91 (t, 1H), 0.63 (t, 1H), 0.10 (t.

(15.2l)-2-((5)-5-Bromo-8-(((0)-1(2-methylthiazol-5-carbonyl)pyrrolid in-3-yl)oxy)-1-((1oxoisoindoline -2-yl )methyl )1,2,3,4-tetrahydroisoquinoline2-carbonyl chlorohexane-1 carboxylic acid (15.27?)-2-((M-5-Bromo-8-(((M-1 (5 -methylthiazol-2yl)pyrrolidin-3 -yl)oxy)-1 ((1-oxoisoind olin-2 yl)methyl)-1,2,3,4tetrahydroisoquinoline-2carbonylschlorohexane-1 (15.2L)-2-((5 )-5-Bromo-8-((5methyl-1,2,4-oxadiazol-3 yl (methoxy)-1-((1oxoisoindolin-2-yl)methyl)1,2,3,42-carbonyl chlorohexane-1 carboxylic acid (15.2L)-2-((5)-5-Bromo-8-((4methyl-47/-1,2,4-triazol-3 yl)methoxy)-1-((1oxoisoindoline-2- yl)methyl)1,2,3,42-carbonyl chlorohexane - 1 carboxylic acid

400 MHz, DMSO-d ₆ :

observed reported) δ 11.63 (bs, 1H), 8.21 (s.

Sh), 7.64-7.51 (m, ZN), 7.50-7.39 (m.

2H), 7.00 (m, 1H), 5.94 (m, 1H), 5.25 (m.

0.5H), 5.17 (m, 0.5H), 4.62 (d, 0.5H), 4.55 d, 0.5H), 4.31-3.82 m, 6H), 3 ,81-3.64 m, 2H), 3.50-3.17 (m, 2H), 2.83 (m, 1H).

2.77-2.58 (m, 4H), 2.42 (m, 1H), 2.36-2.24 m, 1H), 2.18 (m, 1H), 1.83 (m, 1H ), 1.54 m, 1H), 1.45 (m, 1H), 1.33-1.14 (m, 2H).

0.89 (m, 1H), 0.61 (m, 1H), 0.07 (m, 1H),

NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (bs.

1H), 7.61-7.51 (m, 3H), 7.42 (t, 1H), 7.38 d, 1H), 6.98 (d, 1H), 6.87 (m, 1H) , 5.90 dd, 1H), 5.22 (m, 1H), 4.44 (d, 1H), 4.17 dd, 1H), 3.99 (dd, 1H), 3.87-3, 63 (m, 4H).

3.60-3.44 (m, 2H), 3.41-3.21 (m, 2H), 2.83 dd, 1H), 2.72-2.58 (m, 1H), 2.44 -2.34 (m.

2H), 2.22 (d, 3H), 2.19 (m, 1H), 1.82 (m.

1H), 1.54 (m, 1H), 1.45 (m, 1H), 1.34-1.14 m, 2H), 0.89 (m, 1H), 0.62 (m, 1H) , 0.05 m, 1H

400 MHz, DMSO-d ₆ ) δ 11.63 (bs, 1H).

8.60 (s, 1H), 7.64-7.53 (m, 4H), 7.44 (m.

1H), 7.18 (d, 1H), 5.99 (dd, 1H), 5.48 (d.

1H), 5.43 (d, 1H), 4.51 (d, 1H), 4.17 (dd.

1H), 4.10 (d, 1H), 4.00 (dd, 1H), 3.84 (s.

3H), 3.74 (m, 1H), 3.44 (dd, 1H), 3.413.21 (m, 1H), 2.85 (dd, 1H), 2.69 (m, 1H).

2.20 (m, 1H), 1.86 (m, 1H), 1.55 (m, 1H).

1.41 (m, 1H), 1.33-1.19 (m, 2H), 0.90 (m.

1H), 0.59 (m, 1H), 0.09 (m, 1H)

400 MHz, DMSO-d ₆ ) δ 11.57 (bs, 1H).

7.64-7.53 (m, 4H), 7.44 (m, 1H), 7.08 (d.

1H), 6.05 (dd, 1H), 5.45-5.33 (m, 2H).

4.68 (d, 1H), 4.35 (d, 1H), 4.20 (dd, 1H).

4.00 (dd, 1H), 3.75 (m, 1H), 3.63 (dd, 1H).

3.44-3.21 (m, 1H), 2.84 (dd, 1H), 2.762.63 (m, 4H), 2.18 (m, 1H), 1.86 (m, 1H).

1.55 (m, 1H), 1.42 (m, 1H), 1.32-1.18 (m.

2H), 0.89 (m, 1H), 0.58 (m, 1H), 0.07 (m.

- 118 045906

1H). 25 tji ο-γζρ HtAcF ₃ Ό / 0 °Υ ^ΟΗ Βγ (15.27?)-2-((5)-5-Bromo-8-((1methyl-1 //- and mid azol-4yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)1 ,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid-2,2,2- trifluoroacetic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.61 (bs, 1H), 8.97 (s, 1H), 7.84 (m, 1H), 7.65-7.52 (m, 4H), 7.45 (m, 1H), 7.10 (d, 1H), 5.97 (dd, 1H), 5.27 (d, 1H), 5.20 (d, 1H), 4.56 (d , 1H), 4.23-4.08 (m, 2H), 4.00 (dd, 1H), 3.90 (s, 3H), 3.74 (m, 1H), 3.52 (dd, 1H), 3.31 (m, 1H), 2.84 (dd, 1H), 2.68 (m, 1H), 2.21 (m, 1H), 1.85 (m, 1H), 1, 56 (m, 1H), 1.44 (m, 1H), 1.35-1.17 (m, 2H), 0.91 (m, 1H), 0.62 (m, 1H), 0.09 (m, 1H). Method 3: 3.36 minutes, 621.3 [M+H] ⁺ 26 b Τ NV Ό ( 0 °γ° ^Η ή'· ^α Вг (15.2R)-2-((5)-5-Bromine-8-((5- methylisoxazol-3 yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 16, stage c, 22, stage d (400 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 7.64-7.52 (m, 4H), 7.44 (m, 1H), 7.04 (d, 1H), 6.54 (m, 1H), 6.02 (dd, 1H), 5.31 (d, 1H), 5.23 (d, 1H), 4.62 (d, 1H), 4.27 (d , 1H), 4.19 (dd, 1H), 4.00 (dd, 1H), 3.76 (m, 1H), 3.53 (dd, 1H), 3.38-3.25 (m, 1H), 2.84 (dd, 1H), 2.75-2.61 (m, 1H), 2.532.47 (m, 3H), 2.20 (m, 1H), 1.87 (m, 1H ), 1.55 (m, 1H), 1.42 (m, 1H), 1.33-1.18 (m, 2H), 0.90 (m, 1H), 0.58 (m, 1H) , 0.08 (m, 1H). Method 3: 4.71 minutes, 622.2 [M+H] ⁺ 27 ~~\-Ν Гь νΛ к /»Υ ^Η Вг (15,2D)-2-((5)-5-Bromo-8-((2ethyl-2//-1,2,3-triazol-4yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 8.00 (s, 1H), 7.63-7.52 (m, 4H), 7.44 (m, 1H), 7.10 (d, 1H), 5.98 (dd, 1H), 5.31 (d, 1H), 5.25 (d, 1H), 4.58-4.46 (m, 3H), 4 .16 (dd, 1H), 4.13 (d, 1H), 3.99 (dd, 1H), 3.74 (m, 1H), 3.50 (dd, 1H), 3.44-3, 19 (m, 1H), 2.83 (dd, 1H), 2.74-2.61 (m, 1H), 2.18 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.48 (t, 3H), 1.41 (m, 1H), 1.31-1.18 (m, 2H), 0.89 (m, 1H), 0.59 ( m, 1H), 0.08 (m, 1H). Method 3: 4.68 minutes, 636.3 [M+H] ⁺ 28 O \ / -Ζ o—y u—sh (15,2D)-2-((5)-5-Bromo-8-((5methylthiazol-2-yl)methoxy)-1 ((1-oxoisoind olin-2yl)methyl)-1,2,3,4tetrahydroisoquinoline -2carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 7.65-7.53 (m, 5H), 7.45 (m, 1H), 7.07 (d, 1H), 6.10 (dd, 1H), 5.51 (d, 1H), 5.42 (d, 1H), 4.67 (d, 1H), 4.29 (d, 1H), 4.22 (dd , 1H), 4.00 (dd, 1H), 3.78 (m, 1H), 3.58 (dd, 1H), 3.37-3.28 (m, 1H), 2.86 (dd, 1H), 2.69 (m, 1H), 2.53 (d, 3H), 2.20 (m, 1H), 1.88 (m, 1H), 1.56 (m, 1H), 1, 38 (m, 1H), 1.25 (m, 2H), 0.90 (m, 1H), 0.54 (m, 1H), 0.06 (m, 1H). Method 3: 4.75 minutes, 638.1 [M+H] ⁺ .

- 119 045906

thirty О °Хр X f ^N °°Y ^0H ¢0 и Вг (15.27?)-2-((£)-5-Bromo-1-((1oxoisoindolin-2-yl)methyl)8-(pyridazin-3-ylmethoxy)1,2,3,4-tetrahydroisoquinoline2-carbonyl )cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 9.31 (dd, 1H), 8.03 (dd, 1H), 7.93 (dd, 1H), 7.65- 7.51 (m, 4H), 7.44 (m, 1H), 7.09 (d, 1H), 6.08 (dd, 1H), 5.56 (d, 1H), 5.49 (d , 1H), 4.57 (d, 1H), 4.29-4.11 (m, 2H), 4.01 (dd, 1H), 3.78 (m, 1H), 3.62 (dd, 1H), 3.32 (m, 1H), 2.86 (dd, 1H), 2.70 (m, 1H), 2.20 (m, 1H), 1.86 (m, 1H), 1, 56 (m, 1H), 1.42 (m, 1H), 1.34-1.16 (m, 2H), 0.91 (m, 1H), 0.57 (m, 1H), 0.06 (m, 1H). Method 3: 4.03 minutes, 619.4 [M+H] ⁺ . 31 D) V °γΜ ϊ Ν—' ^k o / ο°γ ^0Η s'-'; Br (15.27?)-2-((5)-5-Bromo-8-((1(cyclopropylmethyl)- 1H-1,2,3triazol-4-yl)methoxy)-1-((1oxoisoindolin-2- yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, CDC1 ₃ ) δ 7.79 (s, 1H), 7.70 (m, 1H), 7.48 (td, 1H), 7.46 (d, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 6.86 (d, 1H), 6.14 (dd, 1H), 5.28 (d, 1H), 5.21 (d, 1H), 4, 68 (d, 1H), 4.33 (dd, 1H), 4.26 (d, 2H), 4.12 (d, 1H), 4.04 (m, 1H), 3.86 (dd, 1H ), 3.62 (dd, 1H), 3.09-2.91 (m, 2H), 2.79 (m, 1H), 2.50 (m, 1H), 2.16 (m, 1H) , 1.64-1.14 (m, 6H), 1.12-0.81 (m, 2H), 0.72 (m, 2H), 0.46 (m, 2H). Method 3: 4.54 minutes, 662.5 [M+H] ⁺ . 32 X (15.27?)-2-((5)-5-Bromo-8(imidazo[1,2-a]pyridin-7ylmethoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.73 (bs, 1H), 8.67 (d, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.66- 7.51 (m, 4H), 7.50-7.40 (m, 2H), 7.12 (dd, 1H), 7.05 (d, 1H), 6.10 (dd, 1H), 5 .31 (d, 1H), 5.23 (d, 1H), 4.60 (d, 1H), 4.294.13 (m, 2H), 4.01 (dd, 1H), 3.78 (m, 1H), 3.58 (dd, 1H), 3.48-3.18 (m, 1H), 2.86 (dd, 1H), 2.69 (m, 1H), 2.20 (m, 1H ), 1.86 (m, 1H), 1.55 (m, 1H), 1.43 (m, 1H), 1.34-1.18 (m, 2H), 0.90 (m, 1H) , 0.59 (m, 1H), 0.08 (m, 1H). Method 3: 3.40 minutes, 657.2 [M+H] ⁺ . 33 4 / °°Y° ^H Br (15.27?)-2-((5)-5-Bromo-8-((1methyl-1R-benzo[b]imidazol-5yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl) 1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.70 (bs, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.70 (d, 1H), 7.60- 7.50 (m, 4H), 7.42 (t, 1H), 7.36 (d, 1H), 7.08 (d, 1H), 6.03 (dd, 1H), 5.36 (d , 1H), 5.27 (d, 1H), 4.44 (d, 1H), 4.19 (dd, 1H), 4.00 (dd, 1H), 3.91 (d, 1H), 3 .89 (s, 3H), 3.74 (m, 1H), 3.50 (dd, 1H), 3.453.20 (m, 1H), 2.84 (dd, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 1.83 (m, 1H), 1.54 (m, 1H), 1.44 (m, 1H), 1.32-1.16 (m, 2H ), 0.89 (m, 1H), 0.62 (m, 1H), 0.09 (m, 1H). Method 3: 3.60 minutes, 671.5 [M+H] ⁺ .

- 120 045906

34 -U ^k o / o°V ^OH fH Br (15.27?)-2-((5)-5-Bromo-8-((1methyl-1H-1,2,3-triazol-4yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 8.32 (s, 1H), 7.64-7.51 (m, 4H), 7.44 (m, 1H), 7.12 (d, 1H), 5.97 (dd, 1H), 5.35-5.22 (m, 2H), 4.54 (d, 1H), 4.21-4.05 (m, 5H), 3.99 (dd, 1H), 3.73 (m, 1H), 3.51 (dd, 1H), 3.43-3.23 (m, 1H), 2.83 (dd, 1H ), 2.66 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.42 (m, 1H), 1.33 -1.17 (m, 2H), 0.90 (m, 1H), 0.60 (m, 1H), 0.09 (m, 1H). Method 3: 4.08 minutes, 622.4 [M+H] ⁺ . 35 Хм-N /А) C'N X ί°°τ ^0Η fii Br (15,2D)-2-((5)-5-Bromo-8-((1isopropyl-III-1,2,3-triazol-4yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl) 1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 8.49 (s, 1H), 7.58 (m, 3H), 7.49 (d, 1H), 7.44 ( t, 1H), 7.13 (d, 1H), 5.95 (dd, 1H), 5.32-5.21 (m, 2H), 4.91 (m, 1H), 4.52 (d , 1H), 4.16 (dd, 1H), 4.07 (d, 1H), 4.00 (dd, 1H), 3.73 (m, 1H), 3.51 (dd, 1H), 3.393 .24 (m, 1H), 2.83 (dd, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 1.84 (m, 1H), 1.60-1, 50 (m, 7H), 1.44 (m, 1H), 1.33-1.18 (m, 2H), 0.89 (m, 1H), 0.62 (m, 1H), 0.09 (m, 1H) Method 3: 4.42 minutes, 650.4 [M+N] ⁺ 36 \=N Г II <C« Ά L /о°у ^he XX Br (15,2D)-2-((5)-5-Bromo-8-((5methyl-1,3,4-oxadiazol-2yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 7.64-7.54 (m, 4H), 7.45 (td, 1H), 7.11 (d, 1H), 6.04 (dd, 1H), 5.55 (d, 1H), 5.49 (d, 1H), 4.66 (d, 1H), 4.33 (d, 1H), 4.21 (dd , 1H), 4.01 (dd, 1H), 3.76 (m, 1H), 3.55 (dd, 1H), 3.44-3.21 (m, 1H), 2.85 (dd, 1H), 2.76-2.62 (m, 1H), 2.59 (s, 3H), 2.20 (m, 1H), 1.87 (m, 1H), 1.56 (m, 1H ), 1.42 (m, 1H), 1.33-1.18 (m, 2H), 0.90 (m, 1H), 0.59 (m, 1H), 0.08 (m, 1H) Method 3: 4.13 minutes, 623.3 [M+H] ⁺ . 37 \|-N X /о°у ^it ₁₇ ¹ ' ^L 1 W (15.2D)-2-((5)-5-Bromine-8-((7- methoxy-1 -methyl- 1Hbenzo[</][1,2,3]triazol-5yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 7.82 (m, 1H), 7.61-7.51 (m, 3H), 7.43 (m, 1H), 7.38 (m, 1H), 7.18 (d, 1H), 7.07 (d, 1H), 6.10 (dd, 1H), 5.38 (d, 1H), 5.31 (d , 1H), 4.51 (d, 1H), 4.43 (s, 3H), 4.21 (dd, 1H), 4.09-3.95 (m, 5H), 3.77 (m, 1H), 3.57 (dd, 1H), 3.44-3.19 (m, 1H), 2.85 (dd, 1H), 2.76-2.61 (m, 1H), 2.20 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.43 (m, 1H), 1.33-1.18 (m, 2H), 0.90 ( m, 1H), 0.61 (m, 1H), 0.10 (m, 1H). Method 3: 4.72 minutes, 702.5 [M+H] ⁺ .

- 121 045906

38 \-N % / ο °γ ^ΟΗ >> Br (15.27?)-2-((5)-5-Bromo-8-((1methyl-III- benzo[g/][1,2,3]triazole-5- yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.64 (bs, 1H), 8.29 (s, 1H), 8.00 (d, 1H), 7.82 (dd, 1H), 7.62- 7.51 (m, 3H), 7.46-7.36 (m, 2H), 7.09 (d, 1H), 6.05 (dd, 1H), 5.42 (d, 1H), 5 .33 (d, 1H), 4.47 (d, 1H), 4.36 (s, 3H), 4.20 (dd, 1H), 4.06-3.94 (m, 2H), 3, 75 (m, 1H), 3.54 (dd, 1H), 3.46-3.18 (m, 1H), 2.85 (dd, 1H), 2.76-2.62 (m, 1H) , 2.17 (m, 1H), 1.83 (m, 1H), 1.54 (m, 1H), 1.42 (m, 1H), 1.321.17 (m, 2H), 0.89 ( m, 1H), 0.59 (m, 1H), 0.08 (m, 1H). Method 3: 4.52 minutes, 672.5 [M+H] ⁺ . 39 eV _ο ^Ο _Ν Ν Ογγ L / ^Ν °°γ ^ΟΗ φόυ Br (15,2D)-2-((5)-5-Bromo-8-((1methyl-177-1,2,4-triazol-3 yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 8.55 (s, 1H), 7.62-7.55 (m, 3H), 7.54 (d, 1H), 7.44 (td, 1H), 7.10 (d, 1H), 6.00 (dd, 1H), 5.30-5.16 (m, 2H), 4.61 (d, 1H), 4 .26 (d, 1H), 4.17 (dd, 1H), 3.99 (dd, 1H), 3.92 (s, 3H), 3.73 (m, 1H), 3.64 (dd, 1H), 3.423.22 (m, 1H), 2.83 (dd, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1, 55 (m, 1H), 1.43 (m, 1H), 1.33-1.17 (m, 2H), 0.90 (m, 1H), 0.60 (m, 1H), 0.08 (m, 1H). Method 3: 4.03 minutes, 622.2 [M+H] ⁺ . 40 ζ-5 Ο-' χ Ν ζ (15.27?)-2-((5)-5-Bromo-8-((1isopropyl-17/-imidazol-2yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 7.62-7.51 (m, 4H), 7.49-7.39 (m, 2H), 7.22 (d , 1H), 7.00 (d, 1H), 5.95 (dd, 1H), 5.35 (d, 1H), 5.24 (d, 1H), 4.71 (m, 1H), 4 .48 (d, 1H), 4.17 (dd, 1H), 4.04-3.88 (m, 2H), 3.71 (m, 1H), 3.42 (dd, 1H), 3. 38-3.20 (m, 1H), 2.83 (dd, 1H), 2.73-2.60 (m, 1H), 2.19 (m, 1H), 1.84 (m, 1H) , 1.54 (m, 1H), 1.48 (d, 3H), 1.46-1.37 (m, 4H), 1.32-1.19 (m, 2H), 0.90 (m , 1H), 0.61 (m, 1H), 0.11 (m, 1H). Method 3: 3.62 minutes, 649.2 [M+H] ⁺ 41 Ν-Ν Γ ι'ι VV °vV ' Ν—/ 4 / ο°γ ^ΟΗ φΎ) Br (15.27?)-2-((5)-5-Bromo-8-((5(difluoromethyl)-1 -methyl-1H1,2,3-triazol-4-yl)methoxy)-1((1 -oxoisoin oline-gshOmetshTShchDZEtetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 7.63 (t, 1H), 7.62-7.52 (m, 4H), 7.44 (m, 1H), 7.15 (d, 1H), 5.93 (dd, 1H), 5.43-5.30 (m, 2H), 4.49 (d, 1H), 4.22 (s, 3H), 4 .15 (dd, 1H), 4.06-3.92 (m, 2H), 3.72 (m, 1H), 3.45 (dd, 1H), 3.40-3.22 (m, 1H ), 2.83 (dd, 1H), 2.67 (m, 1H), 2.18 (m, 1H), 1.84 (m, 1H), 1.54 (m, 1H), 1.39 (m, 1H), 1.31-1.17 (m, 2H), 0.89 (m, 1H), 0.57 (m, 1H), 0.06 (m, 1H). Method 3: 4.49 minutes, 672.0 [M+H] ⁺

- 122 045906

42 /=N //) Od \ * T N—/ H / ο °γ ^ΟΗ ¢6¾ Br (15.27?)-2-((5)-5-Bromo-8-((4ethyl-4/7-1,2,4-triazol-3 yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 8.70 (s, 1H), 7.64-7.52 (m, 4H), 7.48-7.40 (m , 1H), 7.19 (d, 1H), 5.97 (dd, 1H), 5.505.40 (m, 2H), 4.50 (d, 1H), 4.28-4.12 (m, 3H), 4.06 (d, 1H), 3.99 (dd, 1H), 3.73 (m, 1H), 3.44 (dd, 1H), 3.38-3.24 (m, 1H ), 2.84 (dd, 1H), 2.68 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.49 -1.35 (m, 4H), 1.32-1.19 (m, 2H), 0.89 (m, 1H), 0.58 (m, 1H), 0.08 (m, 1H). Method 3: 3.82 minutes, 636.1 [M+H] ⁺ 43 5?Х~У° ..... ^z₽J / \ . About z (15.2R)-2-((5)-5-Bromo-8-((5cyano-1-ethyl-1 H-i m idazol-4yl)methoxy)-1-((1- oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 8.18 (s, 1H), 7.60 (m, 1H), 7.56 (m, 3H), 7.44 ( m, 1H), 7.10 (d, 1H), 5.97 (dd, 1H), 5.22 (s, 2H), 4.59 (d, 1H), 4.28-4.10 (m , 4H), 3.99 (dd, 1H), 3.73 (m, 1H), 3.57 (dd, 1H), 3.41-3.23 (m, 1H), 2.83 (dd, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 1.84 (m, 1H), 1.54 (m, 1H), 1.49-1.35 (m, 4H ), 1.33-1.18 (m, 2H), 0.89 (m, 1H), 0.58 (m, 1H), 0.07 (m, 1H). Method 3: 4.44 minutes, 660.0 [M+N] ⁺ 44 —N -NN % _r 1 N - ? i Ci ⁰¹¹ C j 1 T ' ~ Br (15.27?)-2-((5)-5-Bromine-1-((1- oxoisoindolin-2-yl)methyl)- 8-((5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin3-yl)methoxy)-1,2,3,4- tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.55 (bs, 1H), 7.61 (m, 1H), 7.59-7.53 (m, 3H), 7.45 (m, 1H), 7.19 (d, 1H), 5.99 (dd, 1H), 5.42 (d, 1H), 5.37 (d, 1H), 4.53 (d, 1H), 4.22-4 .05 (m, 4H), 3.99 (dd, 1H), 3.75 (m, 1H), 3.46 (dd, 1H), 3.42-3.16 (m, 1H), 2, 97-2.77 (m, 3H), 2.69 (m, 1H), 2.18 (m, 1H), 2.06-1.76 (m, 5H), 1.55 (m, 1H) , 1.41 (m, 1H), 1.321.17 (m, 2H), 0.90 (m, 1H), 0.59 (m, 1H), 0.10 (m, 1H). Method 3: 3.75 minutes, 662.0 [M+H] ⁺ 46 ~Ci-N vn “yV IN—' -Ό / 0 °Y ^OH 00Y Br (15.27?)-2-((15)-5-Bromo-8-(1-(1isopropyl-177-1,2,3-triazol-4yl)ethoxy)-1-((1oxoisoindolin-2-yl )methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid (isomer 1) 45 (400 MHz, DMSO-d ₆ ) δ 11.68 (bs, 1H), 8.41 (s, 1H), 7.64-7.54 (m, 3H), 7.50-7.41 (m , 2H), 7.03 (d, 1H), 6.03 (dd, 1H), 5.75 (m, 1H), 4.79 (m, 1H), 4.68 (d, 1H), 4 .25 (d, 1H), 4.10 (dd, 1H), 3.99 (dd, 1H), 3.71 (m, 1H), 3.65-3.35 (m, 1H), 3. 31 (bm, 1H), 2.80 (dd, 1H), 2.64 (m, 1H), 2.20 (m, 1H), 1.86 (m, 1H), 1.78 (d, 3H ), 1.56 (m, 1H), 1.52-1.41 (m, 7H), 1.34-1.19 (m, 2H), 0.90 (m, 1H), 0.62 ( m, 1H), 0.08 (m, 1H). Method 3: 4.52 minutes, 664.1 [M+H] ⁺

- 123 045906

47 v ^ο ύΥ T N-/ A _o / _ο ο _γ θΗ C ^J Y Br (15.27?)-2-((15)-5-Bromo-8-(1-(1isopropyl-\H-1,2,3-triazol-4yl)ethoxy)-1-((1oxoisoindoline-2- yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid (isomer 2) 45 (400 MHz, DMSO-d ₆ ) δ 11.62 (bs, 1H), 8.40 (s, 1H), 7.62 (m, 1H), 7.60-7.55 (m, 2H), 7.52-7.40 (m, 2H), 7.11 (d, 1H), 5.96 (dd, 1H), 5.76 (m, 1H), 4.82 (m, 1H), 4 .64 (d, 1H), 4.40 (d, 1H), 4.20 (dd, 1H), 3.99 (dd, 1H), 3.85-3.42 (m, 2H), 3, 30 (m, 1H), 2.82 (dd, 1H), 2.63 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.78 (d, 3H ), 1.60-1.40 (m, 8H), 1.34-1.17 (m, 2H), 0.90 (m, 1H), 0.61 (m, 1H), 0.08 ( m, 1H). Method 3: 4.61 minutes, 664.1 [M+H] ⁺ 48 ^x nn 979 4 / o °Y ^OH ...... ^... Cl (15.2R)-2-((5)-5-Chloro-8-((1methyl-1//- benzoI[1,2,3]triazol-5yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 12 (from example 18) (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 8.29 (s, 1H), 8.00 (d, 1H), 7.82 (dd, 1H), 7.58 ( d, 1H), 7.55 (td, 1H), 7.46-7.36 (m, 3H), 7.14 (d, 1H), 6.05 (dd, 1H), 5.43 (d , 1H), 5.33 (d, 1H), 4.48 (d, 1H), 4.36 (s, 3H), 4.21 (dd, 1H), 4.07-3.95 (m, 2H), 3.76 (m, 1H), 3.54 (dd, 1H), 3.49-3.22 (m, 1H), 2.89 (m, 1H), 2.77-2.63 (m, 1H), 2.20 (m, 1H), 1.84 (m, 1H), 1.54 (m, 1H), 1.43 (m, 1H), 1.33-1.17 ( m, 2H), 0.89 (m, 1H), 0.60 (m, 1H), 0.07 (m, 1H). Method 3: 4.45 minutes, 628.4 [M+H] ⁺ 50 A °A 1 N—/ A / o°Y ^OH 9 ^U , Cl (15.27?)-2-((S)-8([1,2,4]Triazolo[4,3a\pyridin-3-ylmethoxy)-5 chloro-1 -((1-oxoisoind olin-2yl) methyl)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 8.81 (dt, 1H), 7.93 (dt, 1H), 7.58-7.49 (m, 3H), 7.47-7.35 (m, 3H), 7.31 (d, 1H), 7.16 (td, 1H), 5.95-5.77 (m, 3H), 4.20 (d, 1H), 4.13 (dd, 1H), 4.00 (dd, 1H), 3.70 (m, 1H), 3.55 (d, 1H), 3.39-3.25 (m, 1H ), 2.87 (dd, 1H), 2.68 (m, 1H), 2.55-2.45 (m, 1H), 2.19 (m, 1H), 1.83 (m, 1H) , 1.54 (m, 1H), 1.41 (m, 1H), 1.31-1.15 (m, 2H), 0.89 (m, 1H), 0.60 (m, 1H), 0.06 (m, 1H). Method 3: 1.23 minutes, 614 [M+H] ⁺ . 51 A /=\ oAQ p-\AD1 Yy ³ Arr ¢6 u Cl (15,277)-2-((5)-5-Chloro-1-((1oxoisoindolin-2-yl)methyl)8-((1-(2,2,2-trifluoroethyl)-1Iamidazol-2-yl)methoxy )- 1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 7.63-7.49 (m, 3H), 7.47-7.37 (m, 3H), 7.21 (d , 1H), 7.12 (d, 1H), 5.93 (dd, 1H), 5.365.19 (m, 4H), 4.47 (d, 1H), 4.15 (dd, 1H), 4 .00 (dd, 1H), 3.92 (d, 1H), 3.71 (m, 1H), 3.46 (dd, 1H), 3.38-3.25 (m, 1H), 2, 87 (dd, 1H), 2.70 (m, 1H), 2.19 (m, 1H), 1.84 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H ), 1.34-1.18 (m, 2H), 0.90 (m, 1H), 0.64 (m, 1H), 0.12 (m, 1H). Method 3: 4.01 minutes, 645 [M+H] ⁺ .

- 124 045906

52 f-VnCn ^ο γΜ T NV Ch) / ο°γ ^ΟΗ φό ^ΝΛ ύ Cl (15.27?)-2-((5)-5-Chlorine-8-((1- (2,2-difluoroethyl)- 1R- imide azol-2-yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.70 (bs, 1H), 7.64-7.50 (m, 3H), 7.48-7.33 (m, 3H), 7.23 (d , 1H), 7.06 (d, 1H), 6.42 (m, 1H), 5.95 (dd, 1H), 5.34-5.22 (m, 2H), 4.75 (m, 2H), 4.48 (d, 1H), 4.16 (dd, 1H), 4.06-3.93 (m, 2H), 3.72 (m, 1H), 3.45 (dd, 1H ), 3.413.22 (m, 1H), 2.88 (dd, 1H), 2.69 (m, 1H), 2.20 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.33-1.18 (m, 2H), 0.90 (m, 1H), 0.63 (m, 1H), 0.11 ( m, 1H). Method 3: 3.52 minutes, 627.1 [M+H] ⁺ . 53 N—N //1 ^F Ό / ^N O^OH Cl (15.27?)-2-((5)-5-Chlorine-8-((5- (difluoromethyl)-1 -methyl-\H1,2,3-triazol-4-yl)methoxy)-1((1-oxoisoind oline^wOmethyl)-!^^^tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 7.63 (t, 1H), 7.60 (m, 1H), 7.57-7.53 (m, 2H), 7.47-7.37 (m, 2H), 7.20 (d, 1H), 5.93 (dd, 1H), 5.41-5.31 (m, 2H), 4.49 (d, 1H), 4.22 (s, 3H), 4.15 (dd, 1H), 4.07-3.92 (m, 2H), 3.72 (m, 1H), 3.45 (dd, 1H ), 3.413.22 (m, 1H), 2.87 (dd, 1H), 2.68 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.54 (m, 1H), 1.39 (m, 1H), 1.32-1.16 (m, 2H), 0.89 (m, 1H), 0.57 (m, 1H), 0.06 ( m, 1H). Method 3: 4.44 minutes, 628.0 [M+H] ⁺ 54 NN Γ /1 yy ^{= F} T _n /*' CU,OH 0 ( 0 Y Cl (15,2R)-2-((5)-5-Chloro-8-((1methyl-5-(trifluoromethyl)-1H1,2,3-triazol-4-yl)methoxy)-1((1-oxoisoind olin^homethyl^D3^tetrahydroisoquinoline-2carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 7.63-7.52 (m, 3H), 7.48-7.38 (m, 2H), 7.21 (d , 1H), 5.93 (dd, 1H), 5.43 (d, 1H), 5.36 (d, 1H), 4.52 (d, 1H), 4.28 (d, 3H), 4 .17 (dd, 1H), 4.07 (d, 1H), 3.98 (dd, 1H), 3.73 (m, 1H), 3.44 (dd, 1H), 3.39-3, 23 (m, 1H), 2.87 (dd, 1H), 2.69 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H ), 1.37 (m, 1H), 1.31-1.16 (m, 2H), 0.88 (m, 1H), 0.54 (m, 1H), 0.04 (m, 1H) . Method 3: 4.68 minutes, 646.0 [M+H] ⁺ 55 d. o 4) / ο°γ ^ΟΗ Cl (15.27?)-2-((5)-5-Chloro-8-((1ethyl-1H-pyrazol-3 yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl)1,2, 3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 7.80 (d, 1H), 7.64-7.50 (m, 3H), 7.44 (m, 1H), 7.37 (d, 1H), 7.13 (d, 1H), 6.47 (d, 1H), 5.99 (dd, 1H), 5.16 (d, 1H), 5.11 (d , 1H), 4.55 (d, 1H), 4.22-4.06 (m, 4H), 4.00 (dd, 1H), 3.73 (m, 1H), 3.50 (dd, 1H), 3.43-3.20 (m, 1H), 2.87 (dd, 1H), 2.69 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H ), 1.55 (m, 1H), 1.47-1.32 (m, 4H), 1.32-1.18 (m, 2H), 0.90 (m, 1H), 0.60 ( m, 1H), 0.09 (m, 1H). Method 3: 4.52 minutes, 591.1 [M+H] ⁺ 57 /У) v “тУ ^k o / o°Y ^OH ¢6¾ Cl (15.27?)-2-((5)-5-Chloro-8-((1isopropyl-1R-1,2,3-triazol-4yl)methoxy)-1-((1oxoisoindolin-2-yl)methyl )1,2,3,4-tetrahydroisoquinoline2-carbonyl)cyclohexane-1 carboxylic acid 22 (400 MHz, DMSO-d ₆ ) δ 11.60 (bs, 1H), 8.49 (s, 1H), 7.60 (d, 1H), 7.57 (td, 1H), 7.49 ( d, 1H), 7.44 (t, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 5.95 (dd, 1H), 5.32-5.20 (m , 2H), 4.91 (m, 1H), 4.52 (d, 1H), 4.16 (dd, 1H), 4.07 (d, 1H), 4.01 (dd, 1H), 3 .73 (m, 1H), 3.51 (dd, 1H), 3.43-3.23 (m, 1H), 2.88 (dd, 1H), 2.68 (m, 1H), 2, 20 (m, 1H), 1.84 (m, 1H), 1.61-1.50 (m, 7H), 1.45 (m, 1H), 1.33-1.16 (m, 2H) , 0.90 (m, 1H), 0.62 (m, 1H), 0.08 (m, 1H). Method 3: 4.38 minutes, 606.1 [M+H] ⁺

Example 63. (1S,2R)-2-((S)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazol-5carbonyl) pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

- 125 045906

Stage a. A solution of intermediate 11 (3.30 g, 8.10 mmol) and hydrazine hydrate (5.4 mL, 110.2 mmol) in IMS (45 mL) was stirred at RT. for 18 hours. The reaction mixture was cooled at 0°C, filtered and rinsed with IMS (10 ml). The filtrate was concentrated in vacuo to give N)-tert-butyl-1-(aminomethyl)-8-hydroxy-3,4-dihydroisoquinoline-2(III)-carboxylate (2.25 g, estimated amount), used without further purification. LCMS (method 2): 0.92 min, 301.2 [M+Na]+.

Step B: A solution of the above intermediate (2.25 g, 8.10 mmol), Et ₃ N (2.80 ml, 20.2 mmol) and methyl 4-bromobutanoate (CAS: 4897-84-1; 1, 61 g, 8.90 mmol) in DMF (35 ml) was heated at 70°C for 18 hours. The reaction mixture was partitioned between EtOAc (25 ml) and water (25 ml) and the aqueous solution was further extracted with EtOAc (2x25 ml ). The combined organic layers were washed with water (50 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (25-85% EtOAc in heptanes) afforded (S)tert-butyl-8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (1.30 g, 46%). LCMS (method 4a): 1.84 min, 347.2 [M-H] ^- .

Stage c. A solution of the above intermediate (600 mg, 1.70 mmol) in HCl in dioxane (4 M; 5 ml) was stirred at room temperature. for 4 hours. The reaction mixture was concentrated in vacuo to give (S)-1-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one hydrochloride (0.49 g, estimated amount) used without further purification. LCMS (method 4): 0.49 min, 247.1 [M+H] ⁺ .

Stage d. To a solution of the above intermediate (490 mg, 1.70 mmol) and Et ₃ N (1.20 mL, 8.70 mmol) in DCM (6 mL) was added dropwise at 0° C. under argon a solution of intermediate 26 ( 490 mg, 1.70 mmol) in DCM (2 ml). The reaction mixture was heated to room temperature, stirred for 0.5 hours and diluted with a saturated aqueous solution of NaHCO ₃ (6 ml). The organic layer was isolated using a phase separation cartridge and concentrated in vacuo. Purify by flash column chromatography (50-100% EtOAc in heptanes) to give (1S,2R)benzyl-2-(^)-8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexanecarboxylate (579 mg, 69%). LCMS (method 4): 0.77 min, 491.3 [M+H]+.

Step f. ^)-tert-butyl 3-((^)-2-((^^)-2-((benzyloxy)carbonyl)cyclohexanecarbonyl)-1-((2oxopyrrolidin-1-yl)methyl)-1, 2,3,4-Tetrahydroisoquinolin-8-yl)oxy)-pyrrolidine-1-carboxylate (436 mg, 56%) was synthesized from the above intermediate (504 mg, 0.91 mmol) and (K)-tert-butyl-3- hydroxypyrrolidine-1-carboxylate (CAS: 103057-44-9; 331 mg, 1.33 mmol) using a procedure similar to that described for example 3, step a. LCMS (method 4): 0.93 min, 660.5 [M+H]+.

Stage f. (1S,2R)-Benzyl-2-((S)-1-((2-oxopyrrolidin-1-yl)methyl)-8-((S)-pyrrolidin-3-yloxy)1,2,3,4 α-tetrahydroisoquinoline-2-carbonyl)cyclohexanecarboxylate hydrochloride (390 mg, estimated amount) was synthesized from the above intermediate (436 mg, 0.66 mmol) using a procedure similar to that described for Example 4, step b. LCMS (Method 4a): 0.80 min, 560.3 [M+H]+.

Stage g. (1S,2R)-Benzyl-2-((S)-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazol-5carbonyl)pyrrolidin-3-yl )oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexanecarboxylate (316 mg, 72%) was synthesized from the above intermediate (390 mg, 0.65 mmol) and 2-methylthiazole-5carboxylic acid (CAS: 20485-41-0; 100 mg, 0.78 mmol) using a procedure similar to that described for example 5, step a. LCMS (Method 4a): 0.78 min, 671.2 [M+H]+.

Stage h. (^^)-2-(^)-1-((2-Oxopyrrolidin-1-yl)methyl)-8-((^)-1-(thiazol-5-carbonyl)pyrrolidin-3yl)oxy)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-carboxylic acid (83 mg, 30%) was synthesized from the above intermediate (316 mg, 0.47 mmol) using a procedure similar to that described for Example 2, step e LCMS (Method 4a): 1.10 min, 581.3 [M+H]+.

Stage i. To a stirred solution of the above intermediate (35 mg, 0.060 mmol) in DMF (2 ml) was added NBS (11 mg, 0.064 mmol, CAS: 128-08-5) and the reaction mixture was stirred at room temperature. for 24 hours. Additional NBS (6 mg, 0.03 mmol) was added and stirring was continued for another 24 hours. Brine was added and extracted with DCM. The organic layer was separated, washed with water, dried over MgSO ₄ , filtered and concentrated in vacuo. MDAP purification (Method 3) gave the title compound (22 mg, 55%). LCMS (Method 3) 3.69 min, 661.2 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ; rotamers observed, both reported) δ 11.70 (bs, 1H), 9.26 (m, 1H), 8.46 (s, 0.5H) , 8.42 (s, 0.5H), 7.51 (m, 1H), 6.95 (d, 1H), 5.80 (m, 1H), 5.19 (m, 0.5H), 5.13 (m, 0.5H), 4.25 (dd, 0.5H), 4.08-3.80 (m,

- 126 045906

4.5H), 3.75 (m, 0.5H), 3.68-3.50 (m, 2H), 3.50-3.14 (m, 1.5H), 3.04 (m, 1H), 2.95 (dd, 0.5H), 2.88 (dd, 0.5H), 2.83-2.57 (m, 2H), 2.44-1.94 (m, 6H) , 1.94-1.59 (m, 5H), 1.58-1.33 (m, 2H), 1.28-0.94 (m, 2H).

Example 64. (1S,2R)-2-((S)-8-([1,2,4]Triazolo[4,3-a]pyridin-3-ulmethoxy)-5-bromo-1-((2 -oxopyrrolidin1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-bromo-8-hydroxy-1 -((2-oxopyrrolidin-1 -yl)methyl)1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (1.097 g, 78%) was prepared from intermediate 21 (730 mg, 2.24 mmol) and intermediate 28 (872 mg, 2.71 mmol) using a procedure similar to described for example 11, stage d. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0-100% EtOAc in DCM). LCMS (Method 2): 1.62 min, 651.3 [M+Na]+.

Stage b. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-8-([1,2,4]mtriazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1( (2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (121 mg, estimated amount) was prepared from the above intermediate (100 mg, 0.16 mmol) and (3-(chloromethyl)-[1,2,4]triazolo[4,3-a]pyridine (from example 16 step b; 40 mg, 0.24 mmol) using a procedure similar to that described for example 11 , stage b. LCMS (Method 2): 1.45 min, 759 [M+H]+.

Stage c. The title compound (14 mg, 14%) was prepared from the above intermediate (121 mg, 0.16 mmol) using a procedure similar to that described for Example 11, Step e. The crude product was purified by preparative HPLC (Method 1). LCMS (Method 3): 3.42 min, 610.2 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.70 (bs, 1H), 8.71 (dt, 1H), 7.87 (dt, 1H), 7.58 (d, 1H), 7 .48 (m, 1H), 7.20 (d, 1H), 7.12 (td, 1H), 5.91-5.69 (m, 3H), 3.94 (dd, 1H), 3, 81 (dd, 1H), 3.57 (m, 1H), 3.41-3.23 (m, 1H), 3.05 (m, 1H), 2.87-2.73 (m, 2H) , 2.73-2.61 (m, 1H), 2.42-2.27 (m, 2H), 2.21-2.01 (m, 2H), 1.99-1.87 (m, 1H), 1.76-1.54 (m, 5H), 1.53-1.42 (m, 1H), 1.38 (m, 1H), 1.28-0.95 (m, 2H) .

Example 68. (1S,2R)-2-((S)-8-(benzo[d]isothiazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

ClCl

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-hydroxy-1 -((2-oxopyrrolidin-1 -yl)methyl)1,2,3,4- Tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (169 mg, 54%) was prepared from intermediate 28 (180 mg, 0.56 mmol) and intermediate 24 (150 mg, 0.53 mmol) using the method described for example 11, stage d. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash Rf 200™ (25 g silica gel column, 0-10% MeOH in DCM), then triturated with MeCN-diethyl ether. LCMS (method 2): 1.57 min, 607.4 [M+Na]+.

Stage b. 2,4-Dumethoxybenzyl-(1S,2R)-2-((S)-8-(benzo[d]uzotuazol-3-ulmethoxu)-5-chloro-1-((2oxopyrrolidin-1-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-cyclohexane-1-carboxylate (100 mg, 100%) was prepared from the above intermediate (81 mg, 0.14 mmol) and 3(bromomethyl)-1,2 -benzothiazole (47 mg, 0.21 mmol, CAS: 59057-83-9) using a procedure similar to that described for Example 11, Step b. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 12 g silica gel, 20-100% EtOAc in cyclohexane). LCMS (Method 2): 1.79 min, 754.3 [M+Na]+.

Stage c. The title compound (48 mg, 62%) was prepared from the above intermediate (98 mg, 0.13 mmol) using a procedure similar to that described for Example 11, Step e. The crude product was purified by preparative HPLC (Method 1). LCMS (Method 3): 4.71 min, 582.1 [M+H]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 11.70 (bs, 1H), 8.33 (m, 1H), 8.28 (m, 1H), 7.67 (m, 1H), 7. 58 (m, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 5.83 (dd, 1H), 5.68 (d, 1H), 5.61 (d, 1H ), 3.94 (dd, 1H), 3.84 (dd, 1H), 3.60 (m, 1H), 3.40-3.21 (m, 1H), 3.16 (m, 1H) , 2.98 (dd, 1H), 2.83 (dd, 1H), 2.69 (m, 1H), 2.54-2.44 (m, 1H), 2.33 (m, 1H), 2.20-2.01 (m, 2H), 1.94 (m, 1H), 1.80-1.56 (m, 5H), 1.49 (m, 1H), 1.39 (m, 1H), 1.270.97 (m, 2H).

Example 73. (1S,2R)-2-(( 1 S)-5-6pom-8-(( 1 -isopropyl-III-1,2,3-triazol-4-yl)methoxy)-1 -(( 3-methyl-2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid (isomer 1) and example 74. (1S,2R)-2-( (1S)-5-Bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1((3-methyl-2-oxopyrrolidin-1 -yl)methyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 - 127 045906 carboxylic acid (isomer 2).

Stage a. tert-Butyl-^)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-isopropyl-1H-1,2,3triazol-4-yl)methoxy) -3,4-dihydroisoquinoline-2(1H)-carboxylate (1.02 g, 81%) was synthesized from intermediate 8 (1.0 g, 2.05 mmol) and (1-isopropyltriazol-4-yl)methanol ( 377 mg, 2.67 mmol) using a procedure similar to that described for example 3, step a. LCMS (Method 2): 1.74 min, 610.2 [M+H]+.

Stage b. tert-butyl-^)-1-(aminomethyl)-5-bromo-8-((1-isopropyl-III-1,2,3-triazol-4-yl)methoxy)3,4-dihydroisoquinoline-2(III )-carboxylate (462 mg, 51%) was synthesized from the above intermediate using a procedure similar to that described for intermediate 19. LCMS (Method 2): 1.15 min, 480.3 [M+H] ⁺ .

Stage c. To a stirred solution of the above intermediate (20 mg, 0.420 mmol) in toluene (5 ml) was added methyl 4-bromo-2-methyl-butanoate (106 mg, 0.540 mmol; CAS: 58029-83-7) and triethylamine (0.087 ml, 0.62 mmol). The reaction mixture was heated at reflux for 24 hours, cooled to room temperature. and concentrated in vacuo. The mixture was diluted with water, extracted with ethyl acetate, isolated, and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC/Biotage SNAP column with 24 g silica gel, 0-100% EtOAc in cyclohexane) gave tert-butyl-(^)-5-bromo-8-((1 -isopropyl-1H-1,2,3-triazol-4yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate ( 176 mg, 76%) as a mixture of diastereoisomers. LCMS (method 2): 1.61 min, 562.3 [M+H] ⁺ .

Stage d. 1 -(((S)-5-6pom-8-(( 1 -isopropyl-III-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin1-yl)methyl )-3-methylpyrrolidin-2-one (mixture of diastereoisomers; 1.02 g, 81%) was synthesized from the above intermediate using a procedure similar to that described for Example 11, step c. LCMS (method 2): 0.92 and 0.94 min, 462.3 [M+H] ⁺ .

Step f. 2,4-Dimethoxybenzyl-(1S,2R)-2-((1S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy )1 -((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylate (mixture of diastereoisomers; 237 mg, 98%) was prepared from the above intermediate (145 mg, 0.31 mmol) and intermediate 28 (121 mg, 0.38 mmol) using a procedure similar to that described for Example 11, step d. LCMS (method 2): 1.64 and 1.67 min, 766 [M+H] ⁺ .

Stage f. (1S,2R)-2-((1S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triαzol-4-yl)methoxy)-1-((3-methyl- 2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-cyclohexane-1-carboxylic acid (mixture of diastereoisomers; 64 mg, 33%) was prepared from the above intermediate (237 mg, 0 .31 mmol) using a procedure similar to that described for Example 11, step e. The crude product was purified using MDAP (method 1). LCMS (Method 3): 4.20 min, 616.1 [M+H] ⁺ .

The isomer mixture was isolated using SFC (YMC Cellulose-SC 35/65 MeOH (0.1% DEA)/cO2, 15 ml/min, 120 bar, 40°C, 185 bar system, DAD 215 nM. Teacher: 1, 47 mg in 1.5 ml MeOH, 1 vial, approximately 31 mg/ml, injection 300 µl x 6; ST 3.75/0.5 min. After prep: SFC4 YMC Cellulose-SC 35/65 MeOH (0.1 % DEA)/CO2, 0.95 ml/min, 120 bar, 40° C. Isomers observed at 2.4 and 3.1 minutes after running Purification gave the compound of Example 73 (isomer 1; 13 mg , 20%) and example 74 (isomer 2; 15 mg, 23%).

Example 73 LCMS (Method 3): 4.19 min, 616.1 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.43 (s, 1H), 7.52 (d, 1H), 7.08 (d, 1H), 5.77 (dd, 1H), 5 .25-5.11 (m, 2H), 4.87 (m, 1H), 3.94 (dd, 1H), 3.86 (dd, 1H), 3.58 (m, 1H), 3. 47-3.19 (m, 2H), 3.02 (dd, 1H), 2.83-2.60 (m, 3H), 2.33 (m, 1H), 2.20-1.97 ( m, 3H), 1.77-1.61 (m, 3H), 1.57-1.30 (m, 9H), 1.25-1.09 (m, 2H), 0.99 (d, 3H).

Example 74 LCMS (Method 3): 4.20 min, 616.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ) δ 8.43 (s, 1H), 7.52 (d, 1H), 7.07 (d, 1H), 5.82 (dd, 1H), 5. 23-5.12 (m, 2H), 4.86 (m, 1H), 3.97 (m, 1H), 3.80 (dd, 1H), 3.59 (m, 1H), 3.50 -3.14 (m, 2H), 3.01 (dd, 1H), 2.87-2.63 (m, 3H), 2.36 (m, 1H), 2.26 (m, 1H), 2.14-1.99 (m, 2H), 1.761.61 (m, 3H), 1.59-1.44 (m, 7H), 1.42-1.10 (m, 4H), 0. 97 (d, 3H).

Example 79 -1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

- 128 045906

Stage a. To a stirred solution of ethyl 4,4-difluoro-3-oxobutanoate (4.01 g, 24.1 mmol, CAS: 352-24-9) and AcOH (1.38 ml, 24.1 mmol) in anhydrous chloroform ( 50 mL) under argon at 0°C, ethanamine (2.0 M in THF; 12.1 mL, 24.1 mmol) was added dropwise while maintaining the temperature < 10°C. The resulting solution was then refluxed for 21 hours. The mixture was allowed to cool to room temperature, then carefully poured into a saturated aqueous solution of NaHCO ₃ (80 ml). The mixture was diluted with water and extracted into EtOAc. The organic layer was washed with aqueous 5% NaHCO ₃ (30 ml), water (30 ml), brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain ethyl-^)-3-(ethylamino) -4,4-difluorobut-2-enoate (4.42 g, 95%) used without further purification. ^1H NMR (400 MHz, CDCl ₃ ; mixture of imine and enamine tautomers) δ 7.96 (s, 0.6H), 7.50 (t, 0.4H), 5.99 (t, 0.6H), 4.75 (s, 1.2H), 4.17-4.10 (m, 2H), 3.41-3.33 (m, 1.2H), 3.06 (m, 0.8H), 1.30-1.22 (m, 6H).

Stage b. To a stirred solution of the above intermediate (0.44 g, 2.27 mmol) in anhydrous MeCN (95 ml) under argon at -20°C was added DBU (1 ml, 6.8 mmol) followed by dropwise addition of methanesulfonyl azide solution (0.82 g, 6.8 mmol, CAS: 1516-70-7) in anhydrous MeCN (2 ml) for 15 min. maintaining temperature < -19°C. The resulting solution was slowly heated to room temperature. for 2 hours, then stirred at room temperature. for 18 hours. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc (15 ml) and saturated aqueous KHSO4 (10 ml). The aqueous layer was extracted with EtOAc (15 ml) and the combined organic layers were washed with saturated aqueous KHSO4 (4x10 ml), water (10 ml), brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf 200 (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in isohexane) gave ethyl 5-(difluoromethyl)-1-ethyl-III-1,2 ,3triazole-4-carboxylate (0.26 g, 53%). ^1H NMR (400 MHz; CDCl ₃ ) δ 7.53 (t, 1H), 4.64 (q, 2H), 4.47 (q, 2H), 1.62 (t, 3H), 1.45 (t, 3H).

Stage c. To a stirred solution of the above intermediate (257 mg, 1.17 mmol) in EtOH (3 ml) and THF (1.5 ml) under argon was added lithium chloride (110 mg, 2.58 mmol) and sodium borohydride (98 mg , 2.58 mmol) and the resulting mixture was stirred at room temperature. for 22 hours. The mixture was diluted with citric acid (10% aqueous solution; 5 ml) and extracted with DCM (5x10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methanol (205 mg, 98%) , used without further purification. ¹ H NMR (400 MHz; CDCl ₃ ) δ 7.10 (t, 1H), 4.92 (s, 2H), 4.55 (q, 2H), 2.20 (br s, 1H), 1, 59 (t, 3H).

Stage d. To a stirred solution of the above intermediate (204 mg, 1.15 mmol) in chloroform (5 ml) under argon was added thionyl chloride (0.17 ml, 2.31 mmol) dropwise and the resulting mixture was stirred at room temperature. for 2 hours. The reaction mixture was concentrated in vacuo to give 4-(chloromethyl)-5-(difluoromethyl)-1-ethyl-III-1,2,3-triazole (235 mg, estimated amount), used without further purification. ^1H NMR (400 MHz; CDCl3) δ 7.00 (t, 1H), 4.76 (s, 2H), 4.53 (q, 2H), 1.60 (t, 3H).

Stages e, f. The title compound (29 mg, 35%) was prepared from the above intermediate (69 mg, 0.35 mmol) and 2,4-dimethoxybenzyl-(^,2K)-2-(^)-5-chloro-8- Hydroxy-1-((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (from Example 68, step a; 81 mg, 0.14 mmol) using procedures similar to those described for Example 68, step b, c. LCMS (Method 3): 4.13 min, 594.1 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.66 (bs, 1H), 7.63 (t, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 5 .76 (dd, 1H), 5.38-5.22 (m, 2H), 4.56 (m, 2H), 3.95 (dd, 1H), 3.84 (dd, 1H), 3, 59 (m, 1H), 3.45-3.20 (m, 2H), 2.93 (dd, 1H), 2.88-2.61 (m, 3H), 2.33 (m, 1H) , 2.21-2.04 (m, 2H), 1.99 (m, 1H), 1.89-1.61 (m, 5H), 1.56-1.34 (m, 5H), 1 .15 (m, 2H).

Example 80 (1H)-yl)-3-methyl-4-oxobutanoic acid.

- 129 045906

Stage a. tert-butyl-^)-8-(benzoschizoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.58 g, 64%) was prepared from intermediate 23 (1.85 g, 4.86 mmol) and 3-(bromomethyl)-1,2-benzoxazole (1.24 g, 5.83 mmol, CAS: 37924-85- 9) using a procedure similar to that described for Example 68, Step b. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 10-90% EtOAc in isohexane). LCMS (Method 2): 1.62 min, 534.3 [M+Na]+.

Stage b. ^)-1-((8-(benzo^]isoxazol-3-ylmethoxy)-5-chloro-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)pyrrolidin-2-one hydrochloride (1.41 g, expected amount) was prepared from the above intermediate (1.58 g, 3.09 mmol) using a procedure similar to that described for Example 1, step d, and used without further purification. LCMS (method 2): 0.93 min, 412.2 [M-N] ^- .

Stage c. tert-Butyl (R)-4-(^)-8-(benzoschizoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1yl)methyl)-3,4-dihydroisoquinoline-2(1H) -yl)-3-methyl-4-oxobutanoate (153 mg, 82%) was prepared from the above intermediate (144 mg, 0.32 mmol) and (R)-4-(tert-butoxy)-2-methyl-4oxobutane acid (79 mg, 0.42 mmol, CAS: 185836-75-3) using a procedure similar to that described for example 11, step d. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 24 g silica gel, 0-5% MeOH in DCM). LCMS (method 2): 1.56 min, 582.4 [M+H] ⁺ .

Stage d. To a solution of the above intermediate (153 mg, 0.26 mmol) in DCM (5 ml) was added TFA (0.5 ml, 6.53 mmol) and the reaction mixture was stirred at room temperature. for 2.5 hours. The solvent was removed in vacuo and the residue was azeotroped in vacuo with toluene. Purification by preparative HPLC (Method 1) gave the title compound (79 mg, 56%). LCMS (Method 3): 4.04 min, 526.1 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.97 (bs, 1H), 8.04 (dt, 1H), 7.83 (dt, 1H), 7.72 (m, 1H), 7 .47 (m, 1H), 7.43 (d, 1H), 7.20 (d, 1H), 5.87 (dd, 1H), 5.71 (d, 1H), 5.62 (d, 1H), 4.05 (dd, 1H), 3.89 (dd, 1H), 3.64 (m, 1H), 3.42-3.21 (m, 1H), 3.16 (m, 1H ), 3.01 (dd, 1H), 2.91-2.71 (m, 2H), 2.62-2.45 (m, 2H), 2.22 (dd, 1H), 2.07 ( m, 1H), 1.93 (m, 1H), 1.64 (m, 2H), 0.93 (d, 3H).

Example 81 5-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one.

Stage a. To a stirred solution of Example 72 (372 mg, 0.66 mmol) in DMF (9 ml) was added DIPEA (0.57 ml, 3.29 mmol) and HATU (275 mg, 0.72 mmol; CAS: 148893-10 -1) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium chloride (105 mg, 1.97 mmol) was added to it and the reaction mixture was stirred at room temperature. under argon atmosphere for 18 hours. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ (40 ml) and EtOAc (40 ml), water (20 ml) and saline (20 ml). The aqueous layer was further extracted with EtOAc (2x40 ml) and the combined organic layers were washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (25 g silica gel column, 0-10% MeOH in DCM) to give (^,2R)-2-(^)-8-(benzoY]isoxazole-3 -ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxamide (356 mg, 0.63 mmol) . LCMS (method 2): 1.23 min, 587.3 [M+Na]+.

Stage b. Phosphorus oxychloride (0 .12 ml, 1.31 mmol) and the resulting mixture was stirred at -20°C for 35 minutes. The mixture was concentrated in vacuo and the residue was partitioned between 10% citric acid (20 ml) and DCM (50 ml). The aqueous layer was further extracted with DCM (30 ml) and the combined organic layers were washed with brine (40 ml),

- 130 045906 dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (4 g silica gel column, 0-10% MeOH in DCM) to give isoxazol-3-ylmethoxy)-5-chloro-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)cyclohexane-1-carbonitrile (193 mg, 68%) . LCMS (method 2): 1.38 min, 547.3 [M+H]+.

Stage c. To a solution of the above intermediate (61 mg, 0.11 mmol) in m-xylene (3 ml) in a reaction tube was added azidotri-n-butyltin(1U) (0.15 ml, 0.56 mmol; CAS: 1784668-3 ). The tube was sealed and the mixture was heated at 140°C for 19 hours. Additionally, azidotri-n-butyltin(1U) (0.09 mL, 0.33 mmol) was added and the mixture was heated at 140°C for an additional 23 hours. The reaction mixture poured into water (15 ml) and the crude product was extracted into DCM (2x20 ml). The combined organics were dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 4 g silica gel, 0-10% MeOH in DCM) followed by purification by preparative HPLC (method 3) afforded the title compound (43 mg , 65%). LCMS (Method 12): 2.96 min, 590.4 [M+H]+. Ί1 NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (m, 1H), 7.81 (m, 1H), 7.70 (m, 1H), 7.447.38 (m, 2H), 7, 16 (d, 1H), 5.77-5.62 (m, 2H), 5.57 (d, 1H), 4.01 (dd, 1H), 3.83 (dd, 1H), 3.61 (m, 1H), 3.53 (m, 1H), 3.15 (m, 2H), 2.97-2.70 (m, 3H), 2.60-2.42 (m, 1H), 2.26 (m, 1H), 2.09 (m, 1H), 2.02-1.76 (m, 4H), 1.691.54 (m, 3H), 1.48 (m, 1H), 1 .43-1.32 (m, 2H).

Example 84. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) -1((4-methyl-1H-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. To a stirred solution of 2-(3-methoxyphenyl)ethan-1-amine (5.0 g, 33.1 mmol, CAS: 2039-67-0) in acetic acid (50 ml) at room temperature. sulfuryl chloride (4.0 mL, 49.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature. for 4 hours. The mixture was concentrated in vacuo, the residue was diluted with NaHCO3 (100 ml) and extracted with EtOAc (3x100 ml). The combined organic extracts were washed with brine (100 ml) and dried (Na ₂ SO ₄ ). The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC/Biotage SNAP column with 40 g silica gel, 0-100% methanol ammonia in DCM (2 M; 20:1) in DCM) to give 2- (2-chloro-5-methoxyphenyl)ethan-1-amine (3.83 g, 62%). LCMS (method 2): 0.74 min, 168.9 [M+H] ⁺ .

Stage b. To a stirred solution of the above intermediate (3.79 g, 20.4 mmol) in DCM (30 ml) at 0° C., triethylamine (5.7 ml, 40.8 mmol) and 2chloroacetyl chloride (1.63 ml, 20.4 mmol CAS: 79-04-9) and the mixture was stirred at room temperature. for 2 hours. The reaction mixture was diluted with saturated ammonium chloride solution (200 ml), extracted with DCM (100 ml), and the organic layers were dried over MgSO4, and concentrated in vacuo. Purification by flash column chromatography on Biotage Companion (220 g Puriflash cartridge, 0-70% EtOAc in cyclohexane) gave 2-chloro-N-(2-chloro-5-methoxyphenethyl)acetamide (2.66 g, 50% ). LCMS (method 2): 1.26 min, 261.9 [M+H]+.

Stage c. To a stirred solution of the above intermediate (2.66 g, 10.2 mmol) in DMF (50 ml) was added 4-methyl-N-pyrazole (0.78 ml, 10.2 mmol, CAS: 7554-65-6) and cesium carbonate (16.5 g, 50.7 mmol) and the reaction mixture was stirred at RT. for 1 hour. The mixture was diluted with water (50 ml), and extracted with EtOAc (3x50 ml), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC/Biotage SNAP column with 120 g silica gel, 0-80% EtOAc in isohexane) provided N-(2-chloro^-methoxyphenethyl^-H-methyl- N-pyrazol1-yl)acetamide (1.59 g, 51%). LCMS (method 2): 1.39 min, 307.9 [M+H]+.

Stage d. 5-chloro-8-methoxy-1-((4-methyl-1H-pyrazol-1-yl)methyl)-3,4-dihydro-isoquinoline (1.37 g, 94%) was prepared from the above intermediate (1 .55 g, 5.04 mmol) using a procedure similar to that described for intermediate 4. The crude product was used without further purification. LCMS (method 2): 0.87 min, 289.9 [M+H]+.

Step f: 5-chloro-8-methoxy-1-((4-methyl-1H-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (1.03 g, 74%; mixture with 5-chloro-8-methoxy-1-((4-methyl-1H-pyrazol-1-yl)methyl)-3,4-dihydroisoquinoline2(III)-carbaldehyde) was prepared from the above intermediate (1.37 g, 4 .73 mmol) using a procedure similar to that described for intermediate 5. The crude product was purified by flash column chromatography (80 g silica gel column, 0-100% methanol ammonia in DCM (2 M; 20:1 ) in DCM). LCMS (method 2): 0.92 min, 291.9 [M+H]+.

Stage f. 5-chloro-1-((4-methyl-III-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-ol (1.01 g, estimated amount) was prepared from the above intermediate (1.03 g, 3.52 mmol) using a procedure similar to that described for intermediate 10. The crude product was used without further purification. LCMS (method 2): 0.83 min, 277.9 [M-N] ^-

Stage g. tert-Butyl-5-chloro-8-hydroxy-1 -((4-methyl-1H-pyrazol-1-yl)methyl)-3,4-dihydroisoquinoline2(III)-carboxylate (316 mg, 37%) was obtained from the above intermediate (627 mg, 2.26 mmol) and di-tert-butyl dicarbonate (493 mg, 2.26 mmol) using a procedure similar to that described for intermediate 8. The crude product was purified by Interchim flash column chromatography Puriflash® 4100 (Puriflash HC/Biotage SNAP column with 25 g silica gel, 0-100% EtOAc in DCM). LCMS (method 2): 1.53 min, 376.1 [M-N] ^- .

Stages h-j. 2,4-Dimethoxybenzyl-(1S,2R)-2-(5-chloro-8-((5-(diftΌrmethyl)-1 -methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -((4-methyl-N-pyrazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1 carboxylate (276 mg, mixture of diastereoisomers) was prepared from the above intermediate (316 mg, 0.84 mmol), 4-(chloromethyl)-5-(difluoromethyl)-1-methyltriazole (190 mg, 1.05 mmol, CAS: 2138555-232) and intermediate 27 (221 mg, 0.50 mmol ) using procedures similar to those described for example 11, stages b, c, d. The crude product was purified by Biotage Companion™ flash column chromatography (12 g silica gel column, 0-60% EtOAc in DCM). LCMS (method 2): 1.64 and 1.68 min, 727.2 [M+H]+.

Stage k. The title compound (30 mg, 13%) was prepared from the above intermediate (276 mg, 0.38 mmol) using a procedure similar to that described for Example 11, Step e. The crude product was purified by preparative HPLC (Method 1) followed by SFC (method 1). LCMS (Method 3): 4.65 min, 577.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.63 (t, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.08 (m, 2H), 5 .91 (dd, 1H), 5.36 (s, 2H), 4.37 (dd, 1H), 4.23 (dd, 1H), 4.19 (s, 3H), 3.97 (m, 1H), 3.58 (m, 1H), 3.52-3.18 (m, 1H), 2.80-2.63 (m, 2H), 2.23 (m, 1H), 2.06 -1.87 (m, 4H), 1.701.51 (m, 3H), 1.40 (m, 1H), 1.23 (m, 1H), 1.09 (m, 1H), 0.77 ( m, 1H).

Example 86 -1((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid.

Stage a. To a stirred solution of intermediate 23 (2.6 g, 6.83 mmol) in DMF (59 mL) was added 4-(chloromethyl)-5-(difluoromethyl)-1-methyltriazole (1.29 g, 7.09 mmol, CAS: 2138555-232) and cesium carbonate (8.01 g, 24.6 mmol) and the reaction mixture was stirred under argon at room temperature. for 19 hours. The reaction mixture was filtered and the solid was washed with EtOAc (20 ml) and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water, the organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0-10% MeOH in DCM) to give the title compound (0.63 g). The remainder of the cesium carbonate was partitioned between DCM/H ₂ O and the aqueous layer was extracted with DCM, the combined organic layers were dried over Mg ₂ SO ₄ , filtered and concentrated in vacuo to give another portion of the title compound (2.35 g). Batches were combined to give tert-butyl-^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1-((2- Oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate (2.98 g, 83%). LCMS (method 2): 1.42 min, 548.3 [M+Na]+.

Stage b. ^)-1-((5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinoline- 1-yl)methyl)pyrrolidin-2-one hydrochloride (2.46 g, estimated amount) was prepared from the above intermediate (2.35 g, 4.47 mmol) using a procedure similar to that described for Example 1, step d. and used without further purification. LCMS (Method 2): 0.80 min, 426.2 [M+H]+.

Stage c. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(diftΌrmethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy )-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1carboxylate (155 mg, estimated amount) was prepared from the above intermediate (100 mg, 0.22 mmol) and intermediate 31 (67 mg, 0.22 mmol) using a procedure similar to that described for Example 11, step d, and used without further purification. LCMS (Method 2): 1.46

- 132 045906 min, 738.3 [M+Na]+.

Stage d. (1 S,2R)-2-((S)-5 -chloro-8-((5 -(difluoromethyl)-1 -methyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-cyclopentane-1-carboxylic acid (33 mg, 27%) was prepared from the above intermediate (155 mg, 0 .22 mmol) using a procedure similar to that described for Example 22, step d. The crude product was purified using preparative chiral SFC (method 3). LCMS (Method 3): 3.73 min, 566.2 [M+H]+. ^1H NMR (400 MHz, _DMSOd6 ; rotamers observed, both reported) δ 7.75-7.43 (m, 1H), 7.39 (d, 0.8H), 7.31 (d, 0.2H), 7.15 (d, 0.8H), 7.08 (d, 0.2H), 5.72 (dd, 0.8H), 5.39-5.20 (m, 2H) , 5.15 (dd, 0.2H), 4.38 (m, 0.2H), 4.21-4.14 (m, 3H), 4.12-3.95 (m, 1H), 3 .84 (dd, 0.8H), 3.77-2.40 (m, 8H), 2.36-1.36 (m, 10H).

Example 87. (^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1 ((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid.

To a solution of ^)-1-((5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1,2,3, 4tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one hydrochloride (from example 86, step b; 0.10 g, 0.22 mmol) in DCM (2.5 ml) was added triethylamine (0.12 ml, 0. 87 mmol) and (3aR,6aS)-tetrahydro-1Hcyclopenta[c]furan-1,3(3aH)-dione (0.03 g, 0.24 mmol, CAS: 35878-28-5). The reaction mixture was stirred at room temperature. for 18 hours. The reaction mixture was partitioned between water and DCM, and the aqueous layer was acidified with dilute HCl and extracted with DCM. The combined organic layers were dried and concentrated in vacuo. A portion of the crude compound (40 mg) was purified by preparative HPLC (Method 3) to give the title compound (6 mg, 5%) and Example 86 (3 mg, 2%). LCMS: (method 1) 4.09 min., 566.2 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ; rotamers observed, both of which have been reported) δ 7.69 (t, 0.3H), 7.57 (t, 0.7H), 7.37 (d, 0.7H), 7.32 (d, 0.3H), 7.18-7.08 (m, 1H), 5.74 (dd, 0.7H), 5.40-5.20 (m, 2.3H), 4.44 (dd, 0.3H), 4.17 (s, 2.1H), 4.16 (s, 0.9H), 4.02 (m, 0.7H), 3.883 .54 (m, 2H), 3.50-2.40 (m, 7H), 2.37-1.38 (m, 10H).

Example 91 )-1 ((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1 S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1 -methyl-1H-1,2,3 triazol-4-yl )methoxy)-1 -((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylate (136 mg, 60%) was prepared from ^) -1-((5-chloro-8-((5-(difluoromethyl)-1-methyl1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-1- yl)methyl)pyrrolidin-2-one hydrochloride (Example 86, Step b; 131 mg, 0.31 mmol) and intermediate 29 (117 mg, 0.34 mmol) using a procedure similar to that described for Example 11, Step d . The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 12 g silica gel, 0-10% MeOH in EtOAc). LCMS (method 2): 1.54 min, 744.4/746.3 [M+H]+.

Stage b. The title compound (19 mg, 54%) was prepared from the above intermediate (130 mg, 0.17 mmol) using a procedure similar to that described for Example 22, step d. The crude product was purified using preparative HPLC (method 3). LCMS (Method 3): 4.34 min, 594.2 [M+H]+, 616.2 [M+Na]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.83 (bs, 1H), 7.58 (t, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5 .77 (dd, 1H), 5.29 (s, 2H), 4.18 (s, 3H), 3.93 (dd, 1H), 3.83 (dd, 1H), 3.57 (m, 1H), 3.47-3.15 (m, 1H), 3.00-2.93 (m, 2H), 2.91-2.65 (m, 3H), 2.28-2.10 ( m, 2H), 1.97 (m, 1H), 1.90-1.69 (m, 2H), 1.68-1.46 (m, 3H), 1.44-1.26 (m, 3H), 1.19 (bm, 1H), 1.08 (s, 3H).

Example 96 1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.1]heptane-2carboxylic acid.

- 133 045906

Solution of (S)-1 -((5-chloro-8-((5 -(difluoromethyl)-1 -methyl1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4 tetrahydroisoquinoline -1-yl)methyl)pyrrolidin-2-one hydrochloride (example 86, Step b; 100 mg, 0.22 mmol) and (3aR,4S,7R,7aS)-hexahydro-4,7-methanoisobenzofuran-1,3 -dione (35.9 mg, 0.22 mmol, CAS: 14166-28-0) in DIPEA (0.08 ml, 0.43 mmol) and THF (2 ml) were stirred at RT. for 20 hours. The mixture was diluted with water and extracted with DCM (x2). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo. Purification by preparative HPLC (method 3), followed by flash column chromatography on Puriflash (4 g, 0-75% methanol ammonia in DCM) and preparative HPLC (method 7; 5-20% MeCN in water (0.1% NH4OH)) gave the title compound (5 mg, 3%, mixture of diastereoisomers). LCMS (method 3) 4.06 min, 592.3 [M+H]+.

Example 101 1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluorocyclopentane-1 carboxylic acid.

Stage a. To a solution of 4-oxocyclopentane-cis-1,2-dicarboxylic acid dimethyl ester (0.5 g, 2.31 mmol, CAS: 28269-02-5) in anhydrous DCM (20 ml) was added DAST (0.76 ml , 5.78 mmol, CAS: 38078-09-0) and the reaction mixture was stirred at 40°C for 24 hours. An additional portion of DAST (0.76 ml, 5.78 mmol) was added and the mixture was stirred at 40°C in for another 48 hours. The reaction mixture was cooled to room temperature and poured into water and extracted with DCM. The organic layer was dried over (MgSO ₄ ) and concentrated in vacuo to give dimethyl 4,4-difluorocyclopentane-cis1,2-dicarboxylate (450 mg, 88%) used without further purification. ^1H NMR ( _CDCl3 ) 3.70 (s, 6H), 3.28 (m, 2H), 2.60 (m, 2H), 2.44 (m, 2H).

Stage b. To a solution of the above intermediate (200 mg, 0.9 mmol) in MeOH (5 ml) at 0°C, NaOH (108 mg, 2.7 mmol) and water (5 ml) were added and the mixture was stirred for 10 min at 0 °C, then heated to room temperature. and stirred for 18 hours. The mixture was concentrated in vacuo to remove the volatile solvent and the residue was cooled to 0°C, acidified with HCl and concentrated in vacuo. To the residue was added 5% MeOH in chloroform, which was then filtered and concentrated in vacuo to give 4,4-difluorocyclopentane-cis-1,2-dicarboxylic acid (180 mg, estimated amount), used without further purification. LCMS (method 2): 1.13 min, 217.1 [M+Na]+.

Stage c. A solution of the above intermediate (0.64 ml, 8.96 mmol) in acetyl chloride (0.6 ml) was refluxed for 3 hours. The solvent was concentrated in vacuo and the residue was azeotroped twice in vacuo with toluene and dried at high vacuum to give cis-5,5-difluorotetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (150 mg, 95%), used without further purification. 1H NMR (400 MHz; CDCl ₃ ) δ: 3.12-3.33 (m, 2H), 2.22-2.62 (m, 4H).

Stage d. To a solution of ^)-1-((5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)1,2,3,4 Triethylamine (0.25 ml, 1.76 mmol) and the above intermediate (124 mg, 0.7 mmol) and the mixture was stirred at 0°C for 1 hour, then warmed to room temperature. and stirred for 18 hours. The reaction mixture was partitioned between water (50 ml) and DCM (15 ml) and the layers were separated. The aqueous layer was acidified with dilute HCl and extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude material (155 mg). A portion of the crude material (55 mg) was purified by preparative HPLC (Method 3) to give the title compound (4.1 mg, 2%) and the alternative diastereoisomer (4.3 mg, 2%). LCMS (Method 3): 4.22 min, 602.21 [M+H]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.58 (t, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 5.79 (dd, 1H), 5, 30 (s, 2H), 4.17 (s, 3H), 4.14 (m, 1H), 3.82 (dd, 1H), 3.68-3.54 (m, 2H), 3.53 -3.15 (m, 1H), 3.07 (m, 1H), 3.01 (dd, 1H), 2.94-2.78 (m, 2H),

- 134 045906

2.78-2.63 (m, 1H), 2.60-1.95 (m, 6H), 1.88-1.64 (m, 2H).

Example 102. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) -1((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy )-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclopentane-1-carboxylate (136.4 mg, 61%) was prepared from (I )-1-((5-chloro-8-((5-(difluoromethyl)-1methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-1 -yl)methyl)pyrrolidin-2-one hydrochloride (Example 86, Step b; 141 mg, 0.31 mmol) and intermediate 32 (98 mg, 0.31 mmol) using a procedure similar to that described for Example 11, Step d. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (Puriflash HC column with 12 g silica gel, 0-5% MeOH in DCM). LCMS (method 2): 1.51 min, 730.3 [M+H]+.

Stage b. The title compound (12 mg, 7%) was prepared from the above intermediate (200 mg, 0.27 mmol) using a procedure similar to that described for Example 11, step e. The crude product was purified by preparative HPLC (method 9). LCMS (Method 3): 2.69 min, 580.5 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ) δ 10.77 (bs, 1H), 7.58 (t, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 5, 72 (dd, 1H), 5.29 (s, 2H), 4.18 (s, 3H), 3.98 (dd, 1H), 3.84 (dd, 1H), 3.56 (m, 1H ), 3.40 (m, 1H), 3.03 (m, 1H), 2.93 (dd, 1H), 2.89-2.76 (m, 2H), 2.69 (m, 1H) , 2.30 (m, 1H), 2.16 (m, 1H), 2.10-1.51 (m, 7H), 1.39 (m, 1H), 1.13 (s, 3H).

Example 104. (1 S,2R)-2-((S)-5-chloro-8-((1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1-(( 2-oxopyrrolidin-1 yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. tert-butyl-(R)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((2-oxopyrrolidin1-yl)methyl)- 3,4-Dihydroisoquinoline-2(1H)-carboxylate (240 mg, 87%) was prepared from intermediate 23 (220 mg, 0.58 mmol) and 4-(chloromethyl)-1-methyltriazole hydrochloride (58 mg, 0.58 mmol) 35 mmol, CAS: 327985-63-7) using a procedure similar to that described for example 11, Step b. Additional parts of cesium carbonate (355 mg, 1.09 mmol) and 4-(chloromethyl)-1-methyltriazole hydrochloride (58 mg, 0.35 mmol) were added and the reaction mixture was stirred at room temperature. within 5 days. The crude product was used without further purification. LCMS (method 1a): 2.84 min, 476 [M+H] ⁺ .

Stage b. ^)-1-((5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin1-yl)methyl) Pyrrolidin-2-one hydrochloride (210 mg, estimated amount) was prepared from the above intermediate (240 mg, 0.5 mmol) using a procedure similar to that described for Example 1, step d, and used without further purification. LCMS (method 2): 0.71 min, 376.2 [M+H] ⁺ .

Stage c. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1( (2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylate (40 mg, 77%) was prepared from the above intermediate (110 mg, 0.270 mmol) and intermediate 31 (100 mg, 0.32 mmol) using a procedure similar to that described for Example 11, step d. The crude product was purified by flash column chromatography on an Interchim Puriflash 4100 (25 g column, 0-2.5% MeOH in DCM). LCMS (method 2): 1.42 min, 680 [M+H] ⁺ .

Stage d. The title compound (30 mg, 27%) was prepared from the above intermediate (140 mg, 0.21 mmol) using a procedure similar to that described for Example 29, step d. The crude product was purified by preparative HPLC (method 7; 10-70% MeCN (with 0.1% HCO2H) in 0.1% aqueous formic acid). LCMS (Method 1): 3.55 min, 528.3 [M-N] ^- . 1H NMR (400 MHz, DMSO- _d6 ) δ 11.73 (bs, 1H), 8.24 (s, 1H), 7.35 (d, 1H), 7.12 (d, 1H), 5, 81 (dd, 1H), 5.26-5.15 (m, 2H), 4.07 (s, 3H), 3.95 (dd, 1H), 3.83 (dd, 1H), 3.60 (m, 1H), 3.48-3.13 (m, 2H), 3.03 (dd, 1H), 2.97 (m, 1H), 2.82 (dd, 1H), 2.69 ( m, 1H), 2.34 (m, 1H), 2.27-1.95 (m, 3H), 1.95-1.62 (m, 5H), 1.50 (m, 1H), 1 .42 (m, 1H),

- 135 045906

1.28-1.05 (m, 2H).

Example 105 -1((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-fluorocyclohexane-1 carboxylic acid.

a a

Stage a. To a stirred solution of intermediate 28 (193.4 mg, 0.6 mmol) in anhydrous THF (0.5 ml) cooled to -55°C under argon, a solution of lithium diisopropylamide (1.0 M in THF) was added dropwise /hexanes; 1.5 ml, 1.5 mmol) for 5 minutes. The solution was stirred at -45 to -25°C for 30 minutes, then treated dropwise with a solution of Nfluorobenzenesulfonimide (567.6 mg, 1.8 mmol) in anhydrous THF (2 ml). The reaction mixture was allowed to warm slowly to 5°C over 2 hours, then quenched with saturated aqueous NaHCO ₃ , then extracted with EtOAc. The aqueous layer was acidified with 10% aqueous citric acid (20 ml) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1S,2R)-2(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-fluorocyclohexane-1-carboxylic acid (204 mg, estimated amount) used without further purification. LCMS (method 2): 1.34, 363.2 [M+Na]+.

Stage b. 2,4-Dimethoxybenzyl-(III^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)- 1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-fluorocyclohexane-1-carboxylate (130 mg, estimated amount) was prepared from ^)-1- ((5-chloro-8-((5(difluoromethyl)-1 -methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1 yl)methyl )pyrrolidin-2-one hydrochloride (Example 86, Step b; 70 mg, 0.16 mmol) and the above intermediate (84 mg, 0.25 mmol) using a procedure similar to that described for Example 11, Step d, and used without additional cleaning. LCMS (method 2): 1.52 mass/charge 748.3 [M+H]+.

Stage c. The title compound was prepared from the above intermediate (176 mg, 0.24 mmol) using a procedure similar to that described for Example 29, step d. The crude product was purified by preparative HPLC (Method 6), then further purified by SFC (Method 3) and freeze-dried to give the title compound (3 mg, 8%). LCMS (Method 1): 4.00 min, mass/charge 598.4 [M+H]+. ^1H NMR (400 MHz, DMSOd6) δ 7.58 (t, 1H), 7.37 (d, 1H), 7.15 (d, 1H), 5.75 (dd, 1H), 5.36- 5.22 (m, 2H), 4.18 (s, 3H), 3.96 (m, 1H), 3.82 (dd, 1H), 3.55 (m, 1H), 3.47-3 ,13 (m, 2H), 2.95 (dd, 1H), 2.90-2.72 (m, 3H), 2.15 (m, 2H), 1.98 (m, 1H), 1.881, 70 (bm, 3H), 1.69-1.50 (bm, 3H), 1.49-1.30 (bm, 3H).

Example 108. (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy) -1((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

ClCl

Stage a. tert-Butyl-^A-chloro^-^bmethylADtrifluoromethyl^NDD-triazolL-yl^ethoxy)^((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (157 mg , 99%) was prepared from intermediate 23 (100 mg, 0.26 mmol) and 4-(chloromethyl)-1-methyl-5-(trifluoromethyl)triazole (63 mg, 0.32 mmol, CAS: 2169203-94- 3) using a procedure similar to that described for Example 11, Step b. The crude product was purified by flash column chromatography (4% MeOH in DCM). LCMS (Method 4): 0.99 min, 444.2 [M-CO ₂ ' ^Bu +H] ⁺ . 1H NMR (300 MHz, CDCl ₃ ) δ 7.23-7.26 (m, 1H), 6.95 (d, 1H), 5.49-5.53 (m, 1H), 5.26-5 .32 (m, 2H), 4.22 (s, 3H), 3.98-4.16 (m, 2H), 3.77-3.85 (m, 1H), 3.373.55 (m, 1H ), 3.04-3.18 (m, 2H), 2.71-2.88 (m, 2H), 2.17-2.35 (m, 2H), 1.93-2.06 (m , 2H), 1.43 (s, 9H).

Stage b. ^-G^-chloro^-^Gmethyl^Dtrifluoromethyl^NHDD-triazol^-yl^ethoxy)1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one hydrochloride (143 mg, 97% ) was prepared from the above intermediate (157 mg, 0.26 mmol) using a procedure similar to that described for Example 1, step d, and used without further purification. LCMS (Method 4): 0.73 min, 444.2 [M+H] ⁺ . 1H NMR (300 MHz, DMSO- _d6 ) δ 9.67 (s, 1H), 8.73 (d, 1H), 7.50 (d, 1H), 7.24 (d, 1H),

- 136 045906

5.35 (dd, 2H), 4.60 (d, 1H), 4.10-4.22 (m, 4H), 3.93 (dd, 1H), 3.53-3.63 (m, 1H), 3.48-3.35 (m, 1H), 2.82-3.12 (m, 4H), 2.12-2.33 (m, 2H), 1.80-1.97 ( m, 2H).

Stage c. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3triazol-4-yl)methoxy )-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylate (42 mg, 30%) was prepared from the above intermediate ( 86 mg, 0.15 mmol) and intermediate 29 (56 mg, 0.17 mmol) using a procedure similar to that described for Example 11, step d. The crude product was purified by reverse phase column chromatography on a Biotage Isolera (60 g, C18, 30-90% MeCN column in pH 10 ammonium carbonate buffer). LCMS (method 4): 1.06 min, 762.4 [M+H]+. ^1H NMR (300 MHz, CDCl ₃ ) δ 6.99 (d, 1H), 6.86-6.91 (m, 1H), 6.45 (q, 1H), 6.31 (d, 1H) , 6.22 (dd, 1H), 5.94 (dd, 1H), 5.22-5.32 (m, 2H), 5.03-5.10 (m, 2H), 4.69 (d , 1H), 4.22 (s, 3H), 3.93-4.01 (m, 1H), 3.81 (t, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.04-3.14 (m, 2H), 2.82-2.86 (m, 2H), 2.58 (s, 1H), 2.17-2.36 (m, 4H) , 1.91 (t, 2H), 1.63-1.70 (m, 2H), 1.23-1.34 (m, 4H), 1.18 (s, 3H).

Step c, method 2. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H1,2,3-triazole -4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (5.3 g, 66 %) was prepared from the above intermediate (4.69 g, 10.6 mmol) and intermediate 33 (4.80 g, 10.6 mmol) using a procedure similar to that described for Example 143, step c.

Stage d. The title compound (24 mg, 84%) was prepared from the above intermediate (42 mg, 0.05 mmol) using a procedure similar to that described for Example 29, Step b. The crude product was purified by flash column chromatography twice (4% MeOH in DCM). LCMS (Method 8): 1.35 min, 612.4 [M+H]+. 1H NMR (300 MHz, CDCy δ 7.30 (d, 1H), 7.02 (d, 1H), 5.97 (m, 1H), 5.29 (m, 2H), 4.22 (s, 3H), 4.11-3.61 (m, 4H), 3.24-2.98 (m, 3H), 2.74 (m, 1H), 2.56 (d, 1H), 2.46 -2.08 (m, 3H), 2.04-1.18 (m, 8H), 1.17-0.87 (m, 4H) The above reaction was repeated with 4.5 g of the above intermediate and yield 1.25 g (35%).

Example 109 -1((^)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclopentane-1-carboxylic acid.

\

Stage a. A solution of (4R)-4-methyltetrahydrofuran-2-one (875 mg, 8.74 mmol, CAS: 65284-00-6) in hydrogen bromide (33% in acetic acid; 6.1 ml, 35 mmol) was heated at 80° C for 16 hours. The mixture was cooled to room temperature. and MeOH (5 ml) was added. The reaction mixture was stirred at room temperature. for 16 hours and concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ . The aqueous layer was extracted with ethyl acetate (x2). The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give methyl (N)-4-bromo-3-methylbutanoate (790 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 3.64-3.72 (m, 3H), 3.36-3.50 (m, 2H), 2.45-2.69 (m, 1H), 2, 19-2.42 (m, 2H), 1.021.12 (m, 3H).

Stage b. tert-Butyl-^)-5-chloro-8-((5 -(difluoromethyl)-1 -methyl-1H-1,2,3-triazol-4-yl)methoxy)-1 ((1,3-dioxoisoindoline -2-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate (2.95 g, 97%) was prepared from intermediate 12 (2.2 g, 4.97 mmol) and 4-(chloromethyl )-5-(difluoromethyl)-1-methyltriazole (1.07 g, 5.51 mmol, CAS: 2138555-23-2) using a procedure similar to that described for Example 11, Step b, and used without further purification. LCMS (method 4): 1.08 min, 488.2 [M-CO ₂ ® ^u +H] ⁺ .

Stage c. To a solution of the above intermediate (2.9 g, 4.74 mmol) in EtOH (98 ml) was added hydrazine hydrate (1.61 ml, 33.15 mmol). The reaction mixture was heated at 65°C for 18 hours. The suspension was filtered and the solid was rinsed with ice-cold EtOAc. The filtrate was concentrated in vacuo. The residue was washed with diethyl ether and filtered. The filtrate was concentrated in vacuo to give tert-butyl-N)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1methyl-III-1,2,3-triazol-4-yl)methoxy )-3,4-dihydroisoquinoline-2(III)-carboxylate (2.2 g, 93%). LCMS (Method 4): 0.90 min, 458.2 [M+H]+.

Stage d. Mixture of tert-butyl-^)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-3,4 -dihydroisoquinoline-2(III)-carboxylate (step c; 520 mg, 1.14 mmol), methyl

- 137 045906 (I)-4-bromo-3-methylbutanoate (step a; 300 mg, 1.48 mmol) and triethylamine (0.24 ml, 1.7 mmol) in MeCN (10.6 ml) were heated at reflux refrigerator for 16 hours. Additional parts of methyl (I)4-bromo-3-methylbutanoate (100 mg, 0.5 mmol) and triethylamine (0.08 ml, 0.57 mmol) were added and the reaction mixture was stirred at room temperature. T. for 24 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (66% EtOAc in hexanes) afforded tert-bugyl-^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazole -4-yl)methoxy)-1-(((I)-4-methyl2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (252 mg, 41%). LCMS (Method 6a): 0.98 min; 537.75 [M-N]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.55 (t, 1H), 7.34-7.42 (m, 1H), 7.12 (d, 1H), 5.18-5.33 (m, 3H), 3.70-4.15 (m, 5H), 3.19-3.37 (m, 2H), 2.46-3.06 (m, 4H), 2.21-2 .33 (m, 2H), 1.63-1.70 (m, 1H), 0.93-1.39 (m, 12H).

Step f. (I)-1-((^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1 ,2,3,4tetrahydroisoquinolin-1-yl)methyl)-4-methylpyrrolidin-2-ono hydrochloride (237 mg, estimated amount) was prepared from the above intermediate (252 mg, 0.47 mmol) using a procedure similar to that described for example 1, stage d. The crude product was ground into powder with diethyl ether and used without further purification. LCMS (method 6a): 0.44 min; 439.87 [M+H]+.

Stage f. 2,4-Dimethoxybenzyl-(^,2H)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy) -1-(((I)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1-carboxylate (14 mg, 7% ) was prepared from the above intermediate (119 mg, 0.24 mmol) and intermediate 32 (132 mg, 0.29 mmol, 70% purity) using a procedure similar to that described for Example 11, step d. Additional portions of intermediate 32 (60 mg, 0.13 mmol, 70% purity) and HATU (50 mg, 0.13 mmol; CAS: 148893-10-1) were added and the mixture was stirred for a further 4 hours at room temperature. T. The crude product was purified by reverse phase column chromatography (C18 column, 30 g, e20-100% MeCN in 0.1 M NH4HCO ₃ buffer pH 10), then further purified by flash column chromatography (40-66% EtOAc in heptanes). LCMS (method 9): 1.01 min, 744.4 [M+H]+.

Stage g. The title compound (2.5 mg, 21%) was prepared from the above intermediate (14 mg, 0.02 mmol) using a procedure similar to that described for Example 11, step e. The crude product was purified by reverse phase chromatography ( 10-45% MeCN in 0.1% formic acid in water), then triturated with diethyl ether. LCMS (Method 10a): 2.74 min, 594.3 [M+H]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 11.42 (bs, 1H), 7.59 (t, 1H), 7.38 (d, 1H), 7.14 (d, 1H), 5, 69 (m, 1H), 5.29 (s, 2H), 4.18 (s, 3H), 3.97 (dd, 1H), 3.86 (dd, 1H), 3.57 (m, 1H ), 3.37-3.19 (m, 1H), 3.09-2.96 (m, 2H), 2.91-2.79 (m, 3H), 2.75-2.17 (m , 4H), 2.12-1.97 (m, 1H), 1.68-1.59 (m, 3H), 1.40 (m, 1H), 1.14 (s, 3H), 1, 01-0.94 (d, 3H).

Example 110 1((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclopentane-1-carboxylic acid.

Stage a. Mixture of tert-butyl-^)-1-(aminomethyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-3,4 -dihydroisoquinoline-2(1H)-carboxylate (example 109, step c; 320 mg, 0.7 mmol), triethylamine (0.15 ml, 1.05 mmol) and methyl 2-(1-(bromomethyl)cyclopropyl) acetate (376 mg, 0.91 mmol, CAS: 855473-50-6) in MeCN (6.5 ml) was refluxed for 72 hours. The mixture was concentrated in vacuo. Purification by reverse phase column chromatography (C18 column, 30 g, 10-80% MeCN in 0.1 M NH4HCO ₃ buffer pH 10) gave tert-butyl-^)-5-chloro-8-(( 5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-3, 4-dihydroisoquinoline-2(1H)-carboxylate (223 mg, 58%). LCMS (Method 4): 0.97 min, 452.2 [M-CO ₂ ' ^Bu +H] ⁺ .

Stage b. ^)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinoline- 1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (198 mg, 99%) was prepared from the above intermediate (223 mg, 0.4 mmol) using a procedure similar to that described for Example 1. step d and used without further purification. LCMS (method 4): 0.73 min, 452.2 [M+H] ⁺ .

Stage c. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2

- 138 045906 carbonyl)-1-methylcyclopentane-1-carboxylate (94 mg, 23% yield) was prepared from the above intermediate (198 mg, 0.4 mmol) and intermediate 32 (220 mg, 0.48 mmol, purity 70 %) using a procedure similar to that described for example 11, stage d. The crude product was purified by flash column chromatography (40 g Zip sphere column, 0-80% EtOAc in heptanes). LCMS (method 9): 1.02 min, 756.4 [M+H]+.

Stage d. The title compound (16 mg, 21%) was prepared from the above intermediate (94 mg, 0.12 mmol) using a procedure similar to that described for Example 29, Step b. The crude product was purified by reverse phase column chromatography (30-60% MeCN in 0.1% formic acid in water). LCMS (Method 9a): 0.99 min, 606.3 [M+H]+. 1H NMR (300 MHz, DMSO- _d6 ) δ 11.42 (bs, 1H), 7.57 (t, 1H), 7.38 (d, 1H), 7.14 (d, 1H), 5. 70 (m, 1H), 5.28 (s, 2H), 4.17 (s, 3H), 4.09-3.88 (m, 2H), 3.56 (m, 1H), 3.36 (d, 1H), 3.06 (m, 1H), 2.98-2.77 (m, 2H), 2.67 (m, 1H), 2.58-2.43 (m, 1h), 2.42-2.23 (m, 1H), 2.23-1.96 (m, 3H), 1.64 (m, 3H), 1.40 (m, 1H), 1.14 (s, 3H), 0.63-0.37 (m, 4H).

Example 111. (1 S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 1-(((R)-4methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy )-1-((^)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (84 mg, 18% ) were obtained from ^)-1-((^)-5-chloro-8-((5(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1,2 ,3,4-tetrahydroisoquinolin-1-yl)methyl)-4methylpyrrolidin-2-one hydrochloride (example 109, step e, 119 mg, 0.24 mmol) and intermediate 29 (120.5 mg, 0.29 mmol, purity 80%) using a procedure similar to that described for example 11, step d. Additional portions of intermediate 29 (60 mg, 0.14 mmol, 80% purity) and HATU (50 mg, 0.13 mmol; CAS: 148893-10-1) were added and the mixture was stirred at RT. for an additional 16 hours. The crude product was purified by reverse phase column chromatography (C18 column, 30 g, 20-75% MeCN in 0.1 M NH4HCO3 buffer, pH 10), then further purified by flash column chromatography (10 g Zip sphere column, 0-80% EtOAc in heptanes). LCMS (method 9): 1.06-1.09 min, 758.4 [M+H]+.

Stage b. The title compound (4.9 mg, 18%) was prepared from the above intermediate (82 mg, 0.04 mmol) using a procedure similar to that described for Example 11, step d. The crude product was purified by preparative HPLC (method 5; 60% MeOH in 0.1% formic acid in water). The isolated fractions were concentrated in vacuo, and partitioned between DCM (5 ml) and HCl (2 M aq, 5 ml), and the mixture was passed through a phase separator (repeated twice more), and the organic layer was concentrated in vacuo. LCMS (method 9a): 1.04 min, 608.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.92 (bs, 1H), 7.58 (t, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5.75 (m, 1H), 5.30 (s, 2H), 4.16 (s, 3H), 3.94 (dd, 1H), 3.86 (dd, 1H), 3.60 (m, 1H) , 3.03-2.86 (m, 4H), 2.85-2.63 (m, 2H), 2.38-2.13 (m, 3H), 1.751.17 (m, 8H), 1 .14-1.08 (m, 3H), 0.97 (d, 3H).

Step b, Method 2 The title compound (641 mg, 48%) was prepared from the above intermediate (1.65 mg, 1.06 mmol) using a procedure similar to that described for Example 135, Step b. The reaction mixture was concentrated in vacuo, triturated with MeOH and the supernatant was concentrated in vacuo. The crude product was then purified on Isolera (Biotage C18 SNAP 120 g, 5-30% MeCN in water, 0.1% ammonia). Fractions containing product were combined, freeze-dried and repurified on Isolera (Silicycle Silica SiliaPrep 120 g, 0-4% MeOH in DCM) to give the title compound (391 mg, 30%). LCMS (Method 13): 2.48 min, 608.1 [M+H]+.

Example 112. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) -1-(((R)3 -methyl-2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid.

- 139 045906

Stage a. To a stirred solution of tert-butyl-^)-1-(aminomethyl)-5-chloro-8-((5(difluoromethyl)-1 -methyl-1H-1,2,3-triazol-4-yl)methoxy)- 3,4-dihydroisoquinoline-2(1H)-carboxylate (Example 109, step c; 1.04 g, 2.27 mmol) and methyl 4-bromo-2-methylbutanoate (0.71 g, 3.63 mmol , CAS: 58029-83-7) triethylamine (0.6 mL, 4.32 mmol) was added to MeCN (45 mL). The solution was refluxed and stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (66% EtOAc in heptanes) followed by chiral flash column chromatography (Chiralpak IC, 15% EtOH in heptanes and 0.1% diethylamine) gave tert-butyl-(b)-5- chloro8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((^)-3-methyl-2-oxopyrrolidin-1yl)methyl) -3,4-dihydroisoquinoline-2(III)-carboxylate (200 mg, 16%) and tert-butyl-^)-5-chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2 ,3-triazol-4-yl)methoxy)-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)3,4-dihydroisoquinoline-2(III)-carboxylate (218 mg, 18%).

tert-Butyl-^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1-((^)-3 -methyl-2oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.257.15 (m, 1H), 7.02-6 .89 (m, 2H), 5.49-5.22 (m, 3H), 4.19-4.08 (m, 4H), 3.91 (dd, 1H), 3.63-3.35 (m, 3H), 3.21-2.68 (m, 4H), 2.40 (q, 1H), 2.18-2.10 (m, 1H), 1.43 (s, 9H), 1.18-1.14 (m, 3H).

tert-Butyl-^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1-((^)-3 -methyl-2oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate: 1H NMR (400 MHz, CDCl ₃ ) δ 7.257.15 (m, 1H), 7.02-6, 89 (m, 2H), 5.49-5.22 (m, 3H), 4.19-3.91 (m, 5H), 3.70-3.45 (m, 3H), 3.14- 3.01 (m, 2H), 2.86-2.71 (m, 2H), 2.36-2.16 (m, 2H), 1.42 (s, 9H), 1.20-1, 14 (m, 3H).

Stage b. ^)-1-((^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1,2,3 ,4tetrahydroisoquinolin-1-yl)methyl)-3-methylpyrrolidin-2-one hydrochloride (188 mg, 92%) was prepared from the above intermediate tert-butyl-^)-5-chloro-8-((5-(difluoromethyl) -1-methyl-1H1,2,3-triazol-4-yl)methoxy)-1-((^)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline2(III) -carboxylate (218 mg, 0.4 mmol) using a procedure similar to that described for Example 1, step d, and used without further purification. LCMS (Method 6): 0.63 min, 439.8 [M+H]+.

Stage c. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy )-1-((^)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (91 mg, 23% ) was prepared from the above intermediate (94 mg, 0.2 mmol) and intermediate 29 (122 mg, 0.25 mmol) using a procedure similar to that described for Example 11, step d. The crude product was purified by flash column chromatography (2-4% MeOH in DCM). LCMS (method 6b): 2.86 min, 757.7 [M-H] ^- .

Stage d. The title compound (15.4 mg, 56%) was prepared from the above intermediate (91 mg, 0.04 mmol) using a procedure similar to that described for Example 29, Step b. The crude product was purified by flash column chromatography (2% MeOH in DCM). LCMS (Method 10): 2.50 min, 608.5 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 6.94 (t, 1H), 5.94 (m, 1H), 5.31 ( d, 1H), 5.26 (d, 1H), 4.20 (s, 3H), 4.10-3.92 (m, 2H), 3.90-3.80 (m, 1H), 3 .60 (m, 1H), 3.17 (dd, 1H), 3.11-2.98 (m, 2H), 2.81-2.69 (m, 1H), 2.55 (m, 1H ), 2.40 (m, 1H), 2.28-2.10 (m, 2H), 1.82 (m, 2H), 1.68-1.19 (m, 5H), 1.13- 1.08 (m, 6H), 1.01 (m, 1H).

Example 117. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triαzol-4-yl)methoxy) -1((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclohexane-1 carboxylic acid.

Stage a. To a stirred solution of intermediate 28 (400 mg, 1.24 mmol) in THF (10 ml) at -30°C under argon was added LDA (2M in THF, heptane, ethylbenzene) (1.61 ml, 3.23 mmol ) for 5 min. The resulting solution was stirred for 0.5 hours and heated to -20°C. Iodoethane (0.3 mL, 3.72 mmol) was added to this solution and the resulting solution was stirred for 2 hours while maintaining the internal temperature at 10°C. The solution was stirred for another 1 hour and diluted with a saturated aqueous solution of ammonium chloride. The mixture was partitioned between EtOAc and water and further extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give (1S,2S)-2(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-ethylcyclohexane-1-carboxylic acid (300 mg , purity 69%,

- 140 045906 ~70%), used without additional purification. LCMS (method 15): 1.65 min, mass/charge 373.1 [M+Na]+.

Stages b-c. The title compound (25 mg, 13%) was prepared from the above intermediate (148 mg, 0.42 mmol) using procedures similar to those described for Example 91, steps a, b. LCMS (Method 3): 4.52 min, 606.1 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.93 (bs, 1H), 7.59 (t, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 5 .78 (dd, 1H), 5.29 (s, 2H), 4.17 (s, 3H), 3.95 (dd, 1H), 3.85 (dd, 1H), 3.59 (m, 1H), 3.41-3.26 (m, 1H), 3.03 (m, 1H), 2.98 (dd, 1H), 2.92-2.77 (m, 2H), 2.76 -2.62 (m, 1H), 2.33-2.10 (m, 2H), 2.04-1.93 (m, 1H), 1.92-1.60 (m, 4H), 1 .55-1.35 (m, 5H), 1.33-1.05 (m, 2H), 0.72 (t, 3H).

Example 123 )-1 -((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (501 mg, 20 %) was obtained from ^)-5-((5-chloro-8-((5(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1,2,3 ,4-tetrahydroisoquinolin-1-yl)methyl)-5azaspiro[2.4]heptan-6-one hydrochloride (1.92 g, 3.26 mmol; Example 110, Step b) and intermediate 29 (1.65 g, 5 .00 mmol) using a procedure similar to that described for example 11, step d. The crude product was purified by Biotage Isolera flash column chromatography (45 g column, 0-4% MeOH in DCM) followed by further purification (60 g column, 20-80% 0.1% formic acid in MeCN). LCMS (method 9a): 2.85 min, 770.3 [M+H]+. This purification also directly provided the compound of Example 123 (155 mg, 7%).

Step a, method 2. Mixture of ^)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4yl)methoxy)-1,2 ,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (12.4 g, 25.4 mmol; Example 110, Step b), intermediate 33 (17, 3 g, 38.1 mmol) and DIPEA (8.85 ml, 50.8 mmol) in DMF (30 ml) were stirred under nitrogen at room temperature. within 6 days. The mixture was diluted with water (120 ml) and extracted with ethyl acetate. The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column 330 g silica gel, 0-5% MeOH in DCM) followed by further purification on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column 330 g silica gel, 0-5% MeOH in DCM) 0-5% MeOH in DCM) to give 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8((5-(difluoromethyl)-1-methyl-1H-1, 2,3-triazol-4-yl)methoxy)-1 -((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl) 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)- 1-methylcyclohexane-1-carboxylate (14.7 g, 75%). LCMS (method 15): 1.71 min, 770.5 [M+H]+.

Stage b. A solution of the above intermediate (500 mg, 0.65 mmol) in hydrogen chloride in dioxane (4 M; 25 ml, 100 mmol) was stirred at room temperature. within 10 min. and concentrated in vacuo to give the title compound (160 mg, 39%). LCMS (Method 10): 2.52 min, 620.3 [M+H]+. ^1H NMR (300 MHz, DMSO-de) δ 11.84 (bs, 1H), 7.57 (t, 1H), 7.38 (d, 1H), 7.14 (d, 1H), 5. 77 (m, 1H), 5.28 (s, 2H), 4.16 (s, 3H), 4.04-3.86 (m, 2H), 3.59 (m, 1H), 3.38 -3.24 (m, 1H), 3.06-2.90 (m, 2H), 2.84 (m, 1H), 2.77-2.65 (m, 1H), 2.61 (d , 1H), 2.37-2.15 (m, 2H), 2.10 (d, 1H), 1.75-1.16 (m, 7H), 1.10 (s, 3H), 0.670, 32 (m, 4H).

Step b, method 2: To a stirred solution of the above intermediate (14.7 g, 19.1 mmol) in DCM (92 ml) was added triethylsilane (3.05 ml, 19.1 mmol) followed by dropwise addition of TFA (1 .76 ml, 22.9 mmol). The resulting solution was stirred for 1.5 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to ~5 ml. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 220 g silica gel, 0-3% MeOH in DCM). The product was then dissolved in 10 ml of warm EtOH, and allowed to cool to room temperature, and the resulting precipitate was collected by filtration, and the precipitate was washed with cold EtOH. The material was then suspended in MeCN (30 mL) and collected by filtration to give the title compound (9.45 g, 15.0 mmol, 78%). LCMS (method 3): 4.57 min, 620.4 [M+H]+.

Example 123A. (1 S,2R)-2-((S)-5 -chloro-8-((5 -(difluoromethyl)-1 -methyl-1H-1,2,3 -triazol-4-yl)methoxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; potassium salt.

- 141 045906

ClCl

The compound of Example 123 (1.2 g, 1.94 mmol) was dissolved in 1,4-dioxane (100 ml) and potassium hydroxide (3.84 ml, 1.94 mmol) was added to obtain a clear solution. Water (100 ml) was added to the solution and the resulting solution was filtered through a coarse frit. The solution was freeze-dried overnight, suspended in water, and freeze-dried again overnight to remove residual dioxane to give the title compound (1.2 g, 94%). LCMS (method 3): 4.56 min, 620.4 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.59 (t, 1H), 7.34 (d, 1H), 7.11 (d, 1H), 5.75 (dd, 1H), 5 .25 (m, 2H), 4.16 (s, 3H), 4.00-3.81 (m, 2H), 3.53-3.23 (m, 2H), 3.03 (m, 1H ), 2.96-2.86 (m, 2H), 2.69 (m, 1H), 2.56-2.45 (m, 1H), 2.36-2.20 (m, 1H), 2.11 (m, 2H), 1.63-1.06 (m, 7H), 0.93 (s, 3H), 0.61-0.45 (m, 3H), 0.41 (m, 1H).

Example 135 heptan-5 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid.

Stage a. 2,4-Dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)-pyrimidin-5yl)methoxy)-1-((6-oxo-5- Azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylate (17 mg, 6%) was prepared from 5-(chloromethyl)-4- (difluoromethyl)pyrimidine (31 mg, 0.17 mmol) and intermediate 37 (71 mg, 0.11 mmol) using a procedure similar to that described for Example 11, Step b, used without further purification. LCMS (method 9c): 1.54 min, 767.4 [M+H] ⁺ .

Stage b. A solution of 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5yl)methoxy)-1-((6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylate (17.4 mg, 0.020 mmol) in HCl in dioxane (4 M; 0.46 ml, 1.83 mmol) was stirred at room temperature. within 10 min. The reaction mixture was concentrated in vacuo and the crude material was purified using MDAP (10-35% acetonitrile in 0.1% ammonium hydroxide method) and selected fractions were freeze-dried to give the title compound (1.4 mg, 10%). LCMS (Method 9b): 1.51 min, 617.2 [M+H]+. 1H NMR (300 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 9.09 (s, 1H), 7.33 (d, 1H), 6.82 (d, 1H), 6.66 ( t, 1H), 6.10 (dd, 1H), 5.43 (m, 1H), 5.32 (m, 1H), 4.20 (dd, 1H), 4.11-3.84 (m , 2H), 3.49 (d, 1H), 3.19-3.05 (m, 2H), 3.01 (d, 1H), 2.79 (m, 1H), 2.62 (m, 1H), 2.48-2.36 (m, 2H), 2.12 (d, 1H), 1.90-1.76 (m, 2H), 1.71-1.22 (m, 4H) , 1.15 (s, 3H), 1.04 (m, 1H), 0.73-0.47 (m, 4H).

Example 140. pH^A-^A-chloro^-^-CifluoromethylA-methyl-III-AD-triazol^-yl^ethoxyA((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2Hpyran-3-carboxylic acid.

Cl

To a stirred solution ^)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1,2,3,4 -tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (389 mg, 0.80 mmol; Example 110, Step b) and DIPEA (0.69 ml, 3.98 mmol) to MeCN (8.943 ml) add tetrahydro-2H-furo[3,4-b]pyran-5,7-dione (Example 140, intermediate; 249 mg, 0.80 mmol) in DCM. The reaction mixture was stirred at room temperature. for 30 min., concentrated in vacuo and purified using Isolera (Biotage C18 SNAP 30 g, 5-30% MeCN in water, 0.1% ammonia) followed by preparative HPLC (method 6) to give the title compound ( 23 mg, 5%). LCMS

- 142 045906 (Method 13): 2.19 min, 608.1 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ; rotamers observed, both reported) δ 7.40-6.82 (m, 3H), 5.83 (dd, 0.7H), 5.74 (dd, 0 ,3H), 5.37-5.16 (m, 2H), 4.78 (m, 0.3H), 4.72-4.61 (m, 1H), 4.33 (dd, 0.7H ), 4.18 (s, 0.9H), 4.14 (s, 2.1H), 4.08 (dd, 0.7H), 3.84-3.09 (m, 5.3H), 3.06 (d, 0.3H), 3.01 (d, 0.7H), 2.97-2.83 (m, 1H), 2.82-2.65 (m, 2H), 2. 45-2.33 (m, 1H), 2.32-2.10 (m, 2H), 2.01-1.40 (m, 3H), 0.68-0.42 (m, 4H).

Example 141. ^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1-( (2oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.2]octane-1 carboxylic acid.

Stage a. To a solution of triphenylphosphine (749 mg, 2.85 mmol) in toluene (4 ml) was added dropwise tert-butyl-(E)-4-bromobut-2-enoate (631 mg, 2.85 mmol, CAS: 86606-04 -4) and the resulting mixture was stirred at room temperature. for 66 hours. The resulting precipitate was collected by filtration, washed with toluene and dried in vacuo at 50°C for 5 hours to give (E)-(4-(tert-butoxy)-4-oxobut- 2-en-1-yl)triphenylphosphonium bromide (874 mg, 63%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92-7.77 (m, 9H), 7.74-7.65 (m, 6H), 6.70-6.44 (m, 2H), 5.30-5.21 (m, 2H), 1.42 (s, 9H).

Stage b. (+)-Camphor-10-sulfonic acid (14 mg, 0.06 mmol, CAS: 3144-169) and the resulting mixture was stirred for 0.5 h to obtain acrolein. To a solution of the above intermediate (873 mg, 1.81 mmol) in DCM (14 ml) was added saturated aqueous sodium bicarbonate (11 ml, 1.81 mmol), followed by the above solution containing acrolein, and the resulting mixture was stirred at k.t. under argon atmosphere for 48 hours. The organic phase was isolated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica gel column, 100% DCM) to give tert-butylcyclohexa-1,3-diene-1carboxylate (191 mg, 59%). 1H NMR (400 MHz, CDCl ₃ ) δ 6.91 (dd, 1H), 6.13-6.01 (m, 2H), 2.44-2.37 (m, 2H), 2.28-2 .21 (m, 2H), 1.50 (s, 9H).

Stage c. A closed vial containing tert-butylprop-2-enoate (0.35 ml, 2.39 mmol, CAS: 249535-4) and the above intermediate (220 mg, 1.59 mmol) was heated at 140°C under argon. for 18 hours. The reaction mixture was cooled to RT, diluted with DCM and purified by flash column chromatography on Teledyne ISCO CombiFlash® Rf+ (25 g silica gel, 010% EtOAc in cyclohexane) to give 2-benzyl-1 -(tert-butyl)-bicyclo[2.2.2]oct-5-ene-1,2dicarboxylate (146 mg, 53%). 1H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.29 (m, 5H), 6.63-6.47 (m, 1H), 6.29-6.14 (m, 1H), 5 .14-4.99 (m, 2H), 3.14-3.00 (m, 1H), 2.78-2.61 (m, 1H), 2.06-1.99 (m, 1H) , 1.90-1.23 (m, 14H).

Stage d. A solution of the above intermediate (146 mg, 0.43 mmol) and Pd/C (10%; 12 mg, 0.11 mmol) in EtOAc (4 ml) was stirred under hydrogen atmosphere at atmospheric pressure at room temperature. for 18 hours. The catalyst was removed by filtration through Celite® and the filtrate was concentrated in vacuo to give the title compound (101 mg, 93%) as a mixture of 1-(tert-butoxycarbonyl)bicyclo[2.2.2]octane-2-carboxylic acid and 4-(tert-butoxycarbonyl)bicyclo[2.2.2]octane-2-carboxylic acid. 1H NMR (400 MHz, CDCl ₃ ) δ 2.99 (m, 0.6H), 2.71-2.65 (m, 0.4H), 2.16-1.49 (m, 11H), 1 .42 (s, 3.6H), 1.41 (s, 5.4H).

Step f: To a stirred solution of the above intermediate (101 mg, 0.40 mmol) and HATU (166 mg, 0.44 mmol; CAS: 148893-10-1) in DMF (1 ml) was added DIPEA (0.08 ml , 0.48 mmol) and the reaction mixture was stirred at room temperature. under argon for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica gel column, 0-100% EtOAc in cyclohexane) gave 2(3H-[1,2,3]triαzolo[4,5-b]pyridine -3-yl) 1-(tert-butyl)-bicyclo[2.2.2]octane-1,2-dicarboxylate (69 mg,

47%). LCMS (Method 16): 1.54 min, 373.3 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 8.71 (dd, 1H), 8.40 (dd, 1H), 7.42 (dd, 1H), 3.49 (ddd, 1H), 2.33- 2.20 (m, 2H), 2.11-2.05 (m, 1H), 1.93-1.80 (m, 4H), 1.73-1.61 (m, 4H),

1.46(s,9H).

Stage f. To a stirred solution ^)-1-((5-chloro-8-((5-(difluoromethyl)-1 -methyl-1H-1,2,3triazol-4-yl)methoxy)-1,2,3,4 -tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one hydrochloride (Example 86, Step b; 94 mg, 0.20 mmol) and the above intermediate (69 mg, 0.19 mmol) in DMF (1.3 ml ) DIPEA (0.04 ml, 0.22 mmol) was added and the reaction mixture was stirred at RT. V

- 143 045906 argon atmosphere for 18 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica gel column, 0-100% EtOAc in cyclohexane) gave tert-butyl-2-(^)-5-chloro-8-((5- (difluoromethyl)-1-methyl1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl) bicyclo[2.2.2]octane-1-carboxylate as a mixture of diastereoisomers (101 mg, 82%). LCMS (method 16): 1.50 min, 684.5 [M+Na]+ and 1.56 min, 684.5 [M+Na]+.

Stage g. To a stirred solution of the above intermediate (101 mg, 0.15 mmol) in DCM (1 ml) was added TFA (0.01 ml, 0.15 mmol) and the resulting mixture was stirred at room temperature. for 18 hours. An additional aliquot of TFA (0.01 ml, 0.15 mmol) was added and the resulting mixture was stirred at room temperature. for another 30 minutes. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica gel column, 0-5% MeOH in DCM) followed by reverse phase preparative UPLC (X-Select CSH 5 µm C18 19x250 mm, 10-98% MeCN in 0.1% aqueous formic acid) gave the title compound (13 mg, 14%). LCMS (Method 3): 4.16 min, 606.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.59 (t, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 5.75 (dd, 1H), 5 .29 (s, 2H), 4.18 (s, 3H), 4.03 (dd, 1H), 3.84 (dd, 1H), 3.54 (m, 1H), 3.46-3, 26 (m, 1H), 3.10 (m, 1H), 2.94 (dd, 1H), 2.892.77 (m, 2H), 2.68 (m, 1H), 2.58-2.36 (m, 1H), 2.18 (m, 1H), 2.05-1.43 (m, 11H), 1.37 (m, 1H), 1.21 (m, 1H).

Example 142. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triαzol-4-yl)methoxy) -1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic-4,4D ₂ acid.

Stage a. To a stirred solution ^)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-1,2,3,4 -tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (165 mg, 0.340 mmol; Example 110, Step b) and 2-(3H- |1.2.3|τρ^;· βολο|4.5-0|pyridin-3-yl)-1-methyl(^^)-1-methylcyclohexane-1,2-dicarboxylate-4,4D2 (130 mg, 0.41 mmol) in DMF (1.4 ml ) DIPEA (0.12 mL, 0.680 mmol) was added and the resulting mixture was stirred at RT. in an argon atmosphere for 2 days. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(1S,2R)-2-((S)-5 -chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5 -yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate-4,4D2 (112 mg, 52%). LCMS (method 2): 1.45 min, 636.3 [M+H]+.

Stage b. To a solution of the above intermediate (105 mg, 0.17 mmol) in MeOH (2.4 ml) was added sodium hydroxide solution (3 M; 0.55 ml, 1.65 mmol) and the resulting mixture was heated at 100°C under microwave conditions for 15 hours. The solution was cooled and concentrated in vacuo. The residue was diluted with water, acidified to pH 4 using 5% citric acid solution and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by reverse phase flash column chromatography on InterChim 4125 (C18 InterChim HP, 80 g, 5-70% MeCN in water + 0.1% HCOOH buffer) to give the title compound (50 mg, 47% ). LCMS (method 3): 4.56 min, 622.5 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 15.23 (bs, 1H), 7.30 (d, 1H), 6.98 (d, 1H), 6.92 (t, 1H), 5.95 ( dd, 1H), 5.36-5.20 (m, 2H), 4.17 (m, 3H), 4.11 (dd, 1H), 4.00 (m, 1H), 3.88 (m , 1H), 3.44 (d, 1H), 3.15 (m, 1H), 3.11-3.01 (m, 2H), 2.75 (m, 1H), 2.59 (dd, 1H), 2.46-2.35 (m, 2H), 2.12 (d, 1H), 1.82 (m, 1H), 1.70-1.40 (m, 3H), 1.13 (s, 3H), 1.02 (m, 1H), 0.74-0.45 (m, 4H).

Example 143. (^^)-2-(^)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1 -((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid.

- 144 045906

Stage a. Mixture of intermediate 50 (142 mg, 0.33 mmol), 4-(chloromethyl)-1,5-dimethyl1H-1,2,3-triazole (63 mg, 0.430 mmol) and cesium carbonate (327 mg, 1 mmol) in DMF (1 ml) was stirred under nitrogen atmosphere at RT. over 18 hours. Additional 4-(chloromethyl)-1,5dimethyl-III-1,2,3-triazole (32 mg, 0.22 mmol) and cesium carbonate (163 mg, 0.5 mmol) were added and the mixture stirred for another 5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) gave tert-butyl-^)-5-chloro-8-(( 1.5 -dimethyl-1 H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1 -((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-3,4- Dihydroisoquinoline-2(III)-carboxylate (150 mg, 84%). LCMS (method 2): 1.64 min, 534.2 [M+H] ⁺ .

Stage b. Add hydrochloric acid (4M in dioxane; 1.4 mL, 5.62 mmol) to the above intermediate (150 mg, 0.28 mmol) and allow the resulting reaction mixture to stir at room temperature. for 0.5 h. The reaction mixture was concentrated in vacuo and subjected to azeotropic distillation with toluene to obtain ^)-5-((5-chloro-8-((1,5-dimethyl-III,2,3-triazol- 4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6one hydrochloride (146 mg, estimated amount). LCMS (Method 2): 0.97 min, 434.1 [M+H]+.

Stage c. To a stirred solution of the above intermediate (132 mg, 0.280 mmol) and intermediate 33 (113 mg, 0.250 mmol) in DMF (1 ml) was added DIPEA (0.1 ml, 0.560 mmol) and the resulting mixture was stirred at room temperature. T. in an argon atmosphere for 4 days. The reaction mixture was diluted with EtOAc and saturated sodium bicarbonate and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl-(1S,2R)-2(^)- 5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro-[2.4] heptan-5yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (119 mg, 56%). LCMS (method 2): 1.77 min, 752.4 [M+H]+.

Stage d. To a stirred solution of the above intermediate (119 mg, 0.16 mmol) in DCM (1.5 ml) was added triethylsilane (0.03 ml, 0.160 mmol) followed by the addition of TFA (0.01 ml, 0.160 mmol) and the resulting As a result, the mixture was stirred at room temperature. within 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 15 μm, 05% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeCN/water (1:1) and freeze-dried to give the title compound (72 mg, 73%). LCMS (method 3a): 3.01 min, 602.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.88 (bs, 1H), 7.52 (d, 1H), 5.46 (dd, 1H), 5.27 (d, 1H), 5.08 (dd, 1H), 4.00-3.82 (m, 5H), 3.53 (m, 1H), 3.06 (d, 1H), 2.97 (t, 1H), 2.92 ( dd, 1H), 2.83-2.71 (m, 2H), 2.62 (m, 1H), 2.38-2.16 (m, 2H), 2.13 (s, 3H), 2 .05 (d, 1H), 1.71-1.49 (m, 3H), 1.48-1.14 (m, 4H), 1.11 (s, 3H), 0.65-0.40 (m, 4H).

Example 144 (4,5,6,7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane- 1-carboxylic acid.

Stage a. Mixture of intermediate 50 (142 mg, 0.33 mmol), 3-(chloromethyl)-4,5,6,7tetrahydro-[1,2,3]triazolo[1,5-a]pyridine (75 mg, 0.430 mmol ) and cesium carbonate (327 mg, 1 mmol) in DMF (1 ml) were stirred under nitrogen at room temperature. over 18 hours. Additional 3-(chloromethyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine (38 mg, 0.22 mmol) was added and carbonate

- 145 045906 cesium (163 mg, 0.5 mmol) and the mixture was stirred for a further 5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) gave tert-butyl-^)-5-chloro-7-fluoro-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3 -yl)methoxy)-3,4dihydroisoquinoline-2(III)-carboxylate (139 mg, 74%). LCMS (method 2): 1.71 min, 560.3 [M+H] ⁺ .

Stage b. Add hydrochloric acid (4M in dioxane; 1.2 mL, 4.96 mmol) to the above intermediate (139 mg, 0.25 mmol) and allow the resulting reaction mixture to stir at room temperature. for 0.5 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give ^)-5-((5-chloro-7-fluoro-8-((4,5,6,7tetrahydro-[1 ,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5azaspiro[2.4]heptan-6-one (136 mg, estimated amount). LCMS (method 2): 1.02 min, 460.2 [M+H] ⁺ .

Stage c. To a stirred solution of the above intermediate (123 mg, 0.250 mmol) and intermediate 33 (169 mg, 0.37 mmol) in DMF (1 ml) was added DIPEA (0.09 ml, 0.50 mmol) and the resulting mixture stirred at room temperature. in an argon atmosphere for 4 days. The reaction mixture was diluted with EtOAc and saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl-(1S,2R)-2-((S )-5chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2, 3]triazolo[1,5a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylate (103 mg, 53%). LCMS (method 2): 1.81 min, 778.4 [M+H] ⁺ .

Stage d. To a stirred solution of the above intermediate (103 mg, 0.13 mmol) in DCM (1.2 ml) was added triethylsilane (0.02 ml, 0.13 mmol) followed by the addition of TFA (0.01 ml, 0.13 mmol ) and the resulting mixture was stirred at room temperature. within 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 15 μm, 05% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeCN/water (1:1) and freeze-dried to give the title compound (56 mg, 73%). LCMS (method 3a): 3.25 min, 628.5 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.88 (bs, 1H), 7.51 (d, 1H), 5.58 (dd, 1H), 5.26 (dd, 1H), 5 .09 (dd, 1H), 4.28 (m, 2H), 4.00-3.84 (m, 2H), 3.55 (m, 1H), 3.13 (d, 1H), 3, 06-2.56 (m, 7H), 2.35-2.16 (m, 2H), 2.08 (d, 1H), 2.03-1.92 (m, 2H), 1.88- 1.72 (m, 2H), 1.70-1.48 (m, 3H), 1.47-1.19 (m, 4H), 1.10 (s, 3H), 0.65-0, 42 (m, 4H).

Example 146 -yl)methoxy)7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1 -carboxylic acid.

Stage a. Mixture of intermediate 50 (133 mg, 0.31 mmol), 3-(chloromethyl)-5,6-dihydro4H-pyrrolo[1,2-c]triazole (64 mg, 0.41 mmol) and cesium carbonate (306 mg , 0.94 mmol) in DMF (1 ml) was stirred under nitrogen at room temperature. over 3.5 hours. Additional 3(chloromethyl)-5,6-dihydro-4H-pyrrolo[1,2-c]triazole (47 mg, 0.30 mmol) and cesium carbonate (153 mg, 0.30 mmol) were added. 47 mmol) and the mixture was stirred for another 66 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0100% EtOAc in cyclohexane) gave tert-butyl-((S)-5-chloro-8-((5.6 -dihydro-4H-pyrrolo[1,2с][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl )methyl)-3,4dihydroisoquinoline-2(III)-carboxylate (128 mg, 75%) LCMS (method 2): 1.65 min, 546.2 [M+H] ⁺ .

Stage b. Add hydrochloric acid (4M in dioxane; 1.2 mL, 4.69 mmol) to the above intermediate (128 mg, 0.23 mmol) and allow the resulting reaction mixture to stir at room temperature. for 0.5 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give ^)-5-((5-chloro-8-((5,6-dihydro-4H

- 146 045906 pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5azaspiro[ 2.4]heptan-6-one hydrochloride (128 mg, estimated amount). LCMS (method 2): 0.97 min, 446.2 [M+H]+.

Stage c. To a stirred solution of the above intermediate (113 mg, 0.23 mmol) and intermediate 33 (160 mg, 0.35 mmol) in DMF (1 ml) was added DIPEA (0.08 ml, 0.47 mmol) and the resulting As a result, the mixture was stirred at room temperature. in an argon atmosphere for 4 days. The reaction mixture was diluted with EtOAc and saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl-(A2K)-2-(^)-5chloro -8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5azaspiro [2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylate (109 mg, 61%). LCMS (method 2): 1.81 min, 764.4 [M+H]+.

Stage d. To a stirred solution of the above intermediate (109 mg, 0.14 mmol) in DCM (1.2 ml) was added triethylsilane (0.02 ml, 0.14 mmol) followed by TFA (0.01 ml, 0.14 mmol ) and the resulting mixture was stirred at room temperature. within 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeCN/water (1:1) and freeze-dried to give the title compound (65 mg, 71%). LCMS (Method 3): 4.45 min, 614.3 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.87 (bs, 1H), 7.51 (d, 1H), 5.52 (dd, 1H), 5.27 (m, 1H), 5 .10 (dd, 1H), 4.36-4.20 (m, 2H), 4.00-3.85 (m, 2H), 3.54 (m, 1H), 3.14 (d, 1H ), 2.97 (m, 2H), 2.90-2.55 (m, 7H), 2.35-2.15 (m, 2H), 2.08 (d, 1H), 1.71- 1.49 (m, 3H), 1.48-1.18 (m, 4H), 1.10 (s, 3H), 0.64-0.42 (m, 4H).

Example 147 (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) -7fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

Stage a. A solution of intermediate 49 (240 mg, 0.73 mmol), methyl 4-bromobutanoate (0.11 mL, 0.80 mmol; CAS: 4897-84-1) and triethylamine (0.15 mL, 1.09 mmol ) in toluene (3.4 ml) was heated at reflux for 24 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 layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, eluting with 0-100% ethyl acetate in cyclohexane) to give tert-butyl-^)-5-chloro-7-fluoro- 8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)3,4-dihydroisoquinoline-2(III)-carboxylate (162 mg, 56%). LCMS (method 2): 1.59 min, 421.1 [M+Na]+.

Stage b. Mixture of the above intermediate (162 mg, 0.41 mmol), 4-(chloromethyl)5-(difluoromethyl)-1-methyl-1H-1,2,3-triazole (96 mg, 0.53 mmol) and cesium carbonate (397 mg, 1.22 mmol) in DMF (1.2 ml) was stirred under nitrogen at room temperature. for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) gave tert-butyl-^)-5-chloro-8-((5-( difluoromethyl)-1-methyl1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H )carboxylate (130 mg, 59%). LCMS (method 2): 1.68 min, 566.2 [M+Na]+.

Stage c. Add hydrochloric acid (4M in dioxane; 1.19 mL, 4.78 mmol) to the above intermediate (130 mg, 0.24 mmol) and allow the resulting reaction mixture to stir at RT. for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with toluene to give ^)-1-((5-chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2,3 -triazol-4-yl)methoxy)-7-fluoro-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)pyrrolidin-2-one hydrochloride (128 mg, estimated amount). LCMS (method 2): 1.00 min, 444.1 [M+H] ⁺ .

Stage d. DIPEA was added to a stirred solution of the above intermediate (115 mg, 0.24 mmol) and intermediate 33 (163 mg, 0.36 mmol) in DMF (1 mL).

- 147 045906 (0.08 ml, 0.48 mmol) and the resulting mixture was stirred at room temperature. in an argon atmosphere for 5 days. The reaction mixture was diluted with EtOAc and saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl-(1S,2R)-2(^)- 5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin1-yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (90 mg, 49%). LCMS (method 2): 1.82 min, 762.3 [M+H] ⁺ .

Step f: To a stirred solution of the above intermediate (90 mg, 0.12 mmol) in DCM (1.1 ml) was added triethylsilane (0.02 ml, 0.12 mmol) followed by TFA (0.01 ml, 0 .12 mmol) and the resulting mixture was stirred at room temperature. within 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 15 μm, 05% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeCN/water (1:1) and freeze-dried to give the title compound (53 mg, 71%). LCMS (Method 3): 4.51 min, 612.3 [M+H]+. 1H NMR (400 MHz, DMSO- _d6 ) δ 11.90 (bs, 1H), 7.53 (d, 1H), 7.36 (t, 1H), 5.47 (dd, 1H), 5, 41 (d, 1H), 5.24 (d, 1H), 4.14 (s, 3H), 3.97-3.78 (m, 2H), 3.54 (m, 1H), 3.42 -3.20 (m, 1H), 3.06-2.86 (m, 3H), 2.78 (dd, 1H), 2.62 (m, 1H), 2.25-2.09 (m , 2H), 1.98 (m, 1H), 1.92-1.68 (m, 2H), 1.67-1.49 (m, 3H), 1.48-1.29 (m, 3H ), 1.28-1.13 (m, 1H), 1.08 (s, 3H).

Example 151. 1-((^)-5-Chloro-8-((5-(difluoromethyl)-1-methyl-1H-1, 2,3-triazol-4-yl)methoxy)-2((1R, 2S)-2-methyl-2-(2H-tetrazol-5-yl)cyclohexan-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)pyrrolidin-2-one.

Stage a. (1 S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1 -methyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxamide (60 mg, 0.10 mmol) was prepared from Example 91 (160 mg, 0.27 mmol) using a procedure similar to that described for example 81, step a. LCMS (method 10b): 0.74 min, 593.2 [M+H]+.

Stage b. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carbonitrile (65 mg, estimated amount) was prepared from the above intermediate (60 mg, 0. 10 mmol) using a procedure similar to that described for example 81, step b. LCMS (method 9): 0.92 min, 575.2 [M+H]+.

Stage c. The title compound (2.2 mg, 0.004 mmol, 3.507% yield) was prepared from the above intermediate (58 mg, 0.10 mmol) using a procedure similar to that described for Example 81 step c. 1H NMR (400 MHz, methanol^ ₃ ) δ: 7.05-7.36 (m, 3H), 5.74 (d, J=9.2 Hz, 1H), 5.25 (d, J=12 .4 Hz, 2H), 4.09-4.25 (m, 4H), 3.90-4.00 (dd, 1H), 3.66-3.77 (m, 1H), 3.48 ( td, J=8.9, 5.0 Hz, 1H), 3.10 (dd, J=14.0, 2.5 Hz, 1H), 2.99 (q, J=8.l Hz, 3H ), 2.46-2.54 (m, 1H), 2.16-2.33 (m, 2H), 1.72-1.95 (m, 6H), 1.57-1.65 (m , 3H), 1.39 (s, 3H). LCMS (method 14): 1.24 min, 618.1 [M+H]+.

Example 152. (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy) -1-((4,4dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

To a stirred solution of Example 123 (100 mg, 0.160 mmol) in acetic acid (10 ml) was added sodium acetate (40 mg, 0.48 mmol) and platinum oxide (PO) (13 mg, 0.05 mmol) and the mixture was stirred in hydrogen atmosphere at room temperature at atmospheric pressure for 2 hours. Add additional platinum oxide (PO) (13 mg, 0.05 mmol, CAS: 1314-15-4), and after another 2 hours of stirring, add until

- 148 045906 additional platinum(IV) oxide (13 mg, 0.05 mmol), and the reaction mixture was stirred for another 1 hour. After the mixture had stood for 18 hours, additional platinum(IV) oxide (13 mg) was added , 0.05 mmol), and the reaction mixture was stirred under a hydrogen atmosphere for 3 hours, after which additional platinum oxide (25 mg, 0.10 mmol) was added and the reaction mixture was stirred for 1 hour. The mixture was filtered through Celite®, washed with EtOAc (50 ml). The organic layer was washed with water (50 ml) and the aqueous layer was re-extracted with EtOAc (50 ml). The combined organic layers were washed with saturated Na ₂ CO ₃ and brine, dried over MgSO ₄ and concentrated in vacuo. Purification on Biotage Isolera (C18 SNAP, 30 g, 5-95% MeCN in 0.1% aqueous formic acid) followed by MDAP (method 5, 20% MeCN in 0.1% ammonium hydroxide) afforded the title compound (4 mg, 4%). LCMS (method 12): 1.34 min, 622.2 [M+H]+. ^1H NMR (300 MHz, CDCl ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 6.95 (t, 1H), 5.91 (dd, 1H), 5.36 -5.22 (m, 2H), 4.19 (s, 3H), 4.13-3.80 (m, 3H), 3.43 (d, 1H), 3.13-2.98 (m , 2H), 2.83-2.65 (m, 2H), 2.56 (m, 1H), 2.40 (m, 1H), 2.17-1.98 (m, 2H), 1, 91-1.76 (m, 2H), 1.69-1.20 (m, 4H), 1.12 (s, 3H), 1.10 (s, 3H), 1.08 (s, 3H) , 1.01 (m, 1H).

Example 156. (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

Stage a. To a stirred solution of intermediate 35 (500 mg, 1.23 mmol) and 4(chloromethyl)-1,5-dimethyl-III-1,2,3-triazole (268 mg, 1.47 mmol) in DMF (8 ml ) cesium carbonate (1.44 g, 4.42 mmol) was added and the reaction mixture was stirred at 50°C for 5 hours, followed by stirring for 16 hours. The reaction mixture was cooled to room temperature. and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water (x3), brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (4% MeOH in DCM) to give tert-butyl-N)-5-chloro-8-((1,5-dimethyl-III-1,2,3-triazol- 4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan5-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate (640 mg, 79%). LCMS (method 9): 0.94 min, 516.2 [M+H] ⁺ . The above reaction was repeated with 5.0 g of intermediate 35 to yield 5.4 g (85%) tert-butyl-(S)-5-chloro-8-((1,5-dimethyl-1H-1,2, 3-triazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(III)-carboxylate.

Stage b. (S)-5-((5-chloro-8-((1,5-dimethyl-1H-1,2,3-mriazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin1-yl )Methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (560 mg, 86%) was prepared from the above intermediate (640 mg, 1.2 mmol) using the method described for example 1, step d, used without additional cleaning. LCMS (Method 9): 0.68 min, 416.2 [M+H] ⁺ . This reaction was repeated with the above intermediate (5.4 g, 10.5 mmol) to yield 4.8 g (expected amount) of ^)-5-((5-chloro-8-((1,5-dimethyl- Ш-1,2,3-triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinolin-1 -yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride.

Stage c. To a stirred solution of the above intermediate (560 mg, 1.24 mmol), intermediate 29 (541 mg, 1.61 mmol) and DIPEA (1.29 mL, 7.43 mmol) in DMF (1.8 mL) HATU (706 mg, 1.86 mmol; CAS: 148893-10-1) and the reaction mixture was stirred at RT. within 5 days. The mixture was partitioned between water and EtOAc, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with water (x3), brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (4% MeOH in DCM) to give the title compound (530 mg, 50%). LCMS (method 9a): 1.66 min, 735.0 [M+H] ⁺ .

Step c, Method 2: To a stirred solution of the above intermediate (5.36 g, 11.84 mmol) in DMF (28 ml) was added intermediate 33 (9.69 g, 21.32 mmol) and DIPEA (5.16 ml, 29.61 mmol) and the reaction mixture was stirred under nitrogen atmosphere for 4 days. The mixture was diluted with water (120 ml) and extracted with EtOAc. The combined organic layers were concentrated in vacuo and the crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 220 g silica gel, 0-4% MeOH in DCM) to give 2,4-dimethoxybenzyl-(1S,2R) -2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4 ]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylate (6.5 g, 75%). LCMS (method 2): 1.74 min, 734.4 [M+H] ⁺ .

Stage d. Into a flask containing the above intermediate (530 mg, 0.72 mmol) at room temperature. add hydrogen chloride (4M in dioxane; 3.0 mL, 12 mmol) and stir the reaction mixture

- 149 045906 Vali at k.t. within 5 min. The mixture was concentrated in vacuo and the crude product was purified by reverse phase column chromatography on Biotage Isolera (C18 column, 60 g, 5-40% MeCN in 0.1% aqueous ammonia). LCMS (method 12, 2% B with 5% C, and from 93% A to 50% B with 5% C, and 45% A at 3.00 min., temp to 95% B with 5% C to 4, 50 min Held at 95% B until 5.00 min) 1.39 min, 584.2 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 7.29 (d, 1H), 7.00 (d, 1H), 5.95 (dd, 1H), 5.28-5.02 (m, 2H), 4 .11 (dd, 1H), 4.05-3.82 (m, 5H), 3.39 (d, 1H), 3.18 (dd, 1H), 3.12-2.94 (m, 2H ), 2.73 (m, 1H), 2.59 (m, 1H), 2.49-2.26 (m, 5H), 2.12 (d, 1H), 1.92-1.74 ( m, 2H), 1.73-1.45 (m, 3H), 1.44-1.21 (m, 1H), 1.12 (s, 3H), 1.02 (m, 1H), 0.710 .43 (m, 4H).

Step d, method 2: To a stirred solution of the above intermediate (6.5 g, 8.88 mmol) in DCM (40 ml) was added triethylsilane (1.42 ml, 8.88 mmol) followed by dropwise addition of 2.2 ,2-trifluoroacetic acid (0.82 ml, 10.7 mmol). The reaction mixture was stirred for 1 hour and the precipitate was removed by filtration through a PTFE frit. The filtrate was diluted with toluene and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 220 g silica gel, 0-3% MeOH in DCM) followed by reverse phase flash column chromatography on an InterChim 4125 (320 g, C18 InterChim HP, 20-80% CH ₃ CN in water with 0.1% HCOOH). The product containing fractions was combined, concentrated to half volume in vacuo and freeze-dried. The product was further purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 330 g silica gel, 5-90% methyl acetate in DCM) to give the title compound (1.91 g, 37% yield). LCMS (Method 3) 4.15 min, 584.4 [M+H]+. ^1H NMR (400 MHz, CDCl3) δ 15.33 (bs, 1H), 7.29 (d, 1H), 7.00 (d, 1H), 5.95 (dd, 1H), 5.19 ( d, 1H), 5.11 (d, 1H), 4.11 (dd, 1H), 4.04-3.93 (m, 4H), 3.89 (m, 1H), 3.39 (d , 1H), 3.18 (dd, 1H), 3.07 (m, 1H), 3.01 (d, 1H), 2.74 (m, 1H), 2.59 (dd, 1H), 2 .46-2.34 (m, 2H), 2.33 (s, 3H), 2.12 (d, 1H), 1.90-1.77 (m, 2H), 1.71-1.44 (m, 3H), 1.42-1.21 (m, 1H), 1.12 (s, 3H), 1.02 (m, 1H), 0.67-0.47 (m, 4H).

Example 170. (A2K)-2-(^)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid.

Stage a. Cesium carbonate (1.28 g, 3.93 mmol) was added to a stirred suspension of intermediate 35 (400 mg, 0.98 mmol) in DMF (4 mL) and the mixture was stirred at room temperature. within 3 min. To this was added a solution of 3-(chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine (253 mg, 1.47 mmol) in DMF (4 ml). The reaction mixture was stirred at room temperature. for 16 hours. An additional portion of intermediate 35 (253 mg, 1.47 mmol) was added and the reaction mixture was stirred at 45°C for 26 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by flash column chromatography on an Interchim Puriflash® 4100 (120 g silica gel column, 0-100% EtOAc in DCM followed by 10% MeOH in DCM), then further purified by flash column chromatography on an Interchim Puriflash ® 4100 (120 g silica gel column, 0-10% MeOH in DCM) followed by further purification by reverse phase column chromatography on Interchim Puriflash® 4100 (80 g C18, 5-95% MeCN in water, 0.1% buffer NH4OH) to obtain tert-butylA)-5-chloro-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-dihydroisochopnoline-2(III)-carboxylate (250 mg, 47%). LCMS (method 2): 1.46 min, 541.7 [M+H]+.

Stage b. ^)-5-((5-chloro-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1 ,2,3,4tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (225 mg, estimated amount) was prepared from the above intermediate (250 mg, 0.46 mmol) using the procedure similar to that described for example 1, step d, and used without further purification. LCMS (method 17): 1.49 min, 442.2 [M+H]+.

Stage c. To a stirred solution of intermediate 29 (186 mg, 0.55 mmol) in DMF (1.5 ml) at RT. HATU (262 mg, 0.69 mmol; CAS: 148893-10-1), the above intermediate (220 mg, 0.46 mmol) and DIPEA (0.4 ml, 2.3 mmol) were added and the reaction mixture was stirred at k.t. for 16 hours. Additional intermediate 29 (186 mg, 0.55 mmol), HATU (262 mg, 0.69 mmol) and DIPEA (0.4 ml, 2.3 mmol) were added and the reaction mixture was stirred for another 24 hours. Saturated aqueous NaHCO ₃ and EtOAc were added to it. The aqueous layer was further extracted with EtOAc (x2). The combined organic layers were washed with water and

- 150 045906 saline solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on an Interchim Puriflash® 4100 (120 g silica gel column, 0-100% EtOAc in cyclohexane, followed by 5% MeOH in DCM), then further purified by flash column chromatography on an Interchim Puriflash® 4100 (40 g silica gel column, 05% MeOH in DCM) to give 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-1-((6-oxo-5azaspiro[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-carboxylate (273 mg, 78%). LCMS (method 2): 1.59 min, 759.7 [M+H]+.

Stage d. To a stirred solution of the above intermediate (283 mg, 0.37 mmol) in DCM (2.7 mL) was added triethylsilane (0.06 mL, 0.37 mmol) followed by TFA (0.03 mL, 0.37 mmol ) and the reaction mixture was stirred at room temperature. within 15 min. Additional triethylsilane (0.01 mL, 0.07 mmol) and TFA (0.01 mL, 0.07 mmol) were added thereto, and the reaction mixture was stirred for 30 minutes, concentrated in vacuo, and azeotroped with toluene (x2), and concentrated in vacuo. The crude product was purified by flash column chromatography on Interchim Puriflash® 4125 (40 g silica gel column, 0-5% MeOH in DCM) and further purified by flash column chromatography on Interchim Puriflash® 4125 (40 g silica gel column, 0-10% MeOH in toluene) to give the title compound (28 mg, 12%). LCMS (Method 3): 4.37 min, 610.1 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 15.32 (bs, 1H), 7.29 (d, 1H), 6.99 (d, 1H), 5.98 (dd, 1H), 5.20 (d, 1H), 5.12 (d, 1H), 4.35 (t, 2H), 4.12 (dd, 1H), 4.00 (m, 1H), 3.89 (m, 1H) , 3.41 (d, 1H), 3.18 (dd, 1H), 3.07 (m, 1H), 3.02 (d, 1H), 2.93-2.67 (m, 3H), 2.59 (dd, 1H), 2.46-2.33 (m, 2H), 2.13 (d, 1H), 2.09-2.00 (m, 2H), 1.97-1, 77 (m, 4H), 1.67-1.47 (m, 3H), 1.42-1.21 (m, 1H), 1.12 (s, 3H), 1.02 (m, 1H) , 0.65-0.47 (m, 4H).

Example 174. (1S,2R)-1-Methyl-2-((S)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triαzol-4yl) methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane1-carboxylic acid

To a stirred solution of Example 108 (44 mg, 0.072 mmol) in 1,4-dioxane (1 ml) and water (0.2 ml) was added XPhos Pd G2 (0.79 mg, 0.001 mmol, CAS: 1310584-14- 5), XPhos (1.43 mg, 0.003 mmol, CAS: 564483-18-7), potassium carbonate (30 mg, 0.22 mmol) and trimethylboroxine (50% in THF, 0.02 ml, 0.072 mmol, CAS : 823-96-1) and the reaction mixture was heated at 90°C under microwave radiation for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash column with 12 g silica gel, 15 μm, 0-8% MeOH in DCM) followed by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash column with 4 g silica gel, 15 µm, 0-4% MeOH in DCM) to give the title compound (10 mg, 22%). LCMS (Method 3) 4.42 min, 592.3 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 15.53 (bs, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 5.97 (dd, 1H), 5.28 ( m, 2H), 4.21 (m, 3H), 4.10-3.92 (m, 2H), 3.84 (m, 1H), 3.71 (m, 1H), 3.223.09 (m , 2H), 2.83 (m, 1H), 2.68 (m, 1H), 2.56 (dd, 1H), 2.40 (m, 1H), 2.28 (m, 1H), 2 .20-2.10 (m, 4H), 1.981.77 (m, 4H), 1.68-1.44 (m, 3H), 1.41-1.17 (m, 1H), 1.12 (s, 3H), 1.00 (m, 1H).

Example 178. (1S,2R)-2-((S)-5-Fluoro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triαzol-4-yl)methoxy) -1((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid.

Stage a. Stirred solution of 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((1-methyl-5(trifluoromethyl)-III-1,2,3-triazol-4- yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (100 mg, 0.13 mmol, example 108, step c), potassium acetate (39 mg, 0.39 mmol), XPhos Pd G2 (2 mg, 0.003 mmol, CAS: 1310584-14-5),

- 151 045906

XPhos (2.5 mg, 0.05 mmol, CAS: 564483-18-7) and tetrahydroxydiboron (35 mg, 0.39 mmol) in EtOH (1.3 ml) were degassed with argon for 10 min, and then heated at 80°C for 3 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (^)-2-((^^)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl) -2methylcyclohexan-1-carbonyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1-yl)methyl )-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid (105 mg, 52%). LCMS (method 15): 1.49 min, 772.4 [M+H]+.

Stage b. Sodium hydroxide (3.7 mg, 0.09 mmol) was added to a stirred solution of the above intermediate (105 mg, 0.090 mmol) in MeOH (1 mL) under argon. The reaction mixture was stirred at room temperature. for 15 minutes, cooled to 0°C and silver trifluoromethanesulfonate (70 mg, 0.27 mmol, CAS: 2923-28-6) was added thereto. The reaction mixture was stirred for 0.5 hours and concentrated in vacuo at 0°C. Acetone (1 ml) was added and the reaction mixture was again concentrated in vacuo at 0°C (repeated twice). The residue was dissolved in acetone (0.5 ml) and powdered molecular sieves (3 A; 50 mg) were added, followed by the addition of 1-chloromethyl-4fluoro-1,4-diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate) ( 34 mg, 0.10 mmol, CAS: 140681-55-6) and the reaction mixture was stirred at room temperature. for 3 hours. The reaction mixture was filtered, diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on an Interchim Puriflash® 4100 (InterChim HP column with 40 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl-(1S,2R)-2-((S )5-fluoro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate (25 mg, 24%). LCMS (method 15): 1.68 min, 746.4 [M+H]+.

Stage c. The title compound was prepared from the above intermediate (25 mg, 0.034 mmol) using a procedure similar to that described for Example 29, Step b. The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (x2). The residue was purified by flash column chromatography on an Interchim Puriflash® 4125 (Puriflash HP column with 25 g, 15 μm, silica gel, 0-5% MeOH in DCM) followed by flash column chromatography on an Interchim Puriflash® 4125 (80 g, 15 µm, C18 Puriflash HP, 10-80% MeCN in 0.1% aqueous formic acid) to obtain the title compound as a white solid (6.7 mg, 33%). LCMS (Method 3): 4.39 min, 596.0 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 15.28 (bs, 1H), 7.03-6.91 (m, 2H), 5.94 (dd, 1H), 5.28 (m, 2H), 4.21 (m, 3H), 4.03 (dd, 1H), 3.94 (m, 1H), 3.84 (m, 1H), 3.70 (m, 1H), 3.24-3 .11 (m, 2H), 3.00 (m, 1h), 2.72 (m, 1H), 2.55 (m, 1H), 2.40 (m, 1H), 2.29 (m, 1H), 2.16 (m, 1H), 1.99-1.87 (m, 2H), 1.87-1.77 (m, 2H), 1.68-1.44 (m, 3H) , 1.35 (m, 1H), 1.12 (s, 3h), 1.01 (m, 1h).

Example 180 ,6,7tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclopentane-1-carboxylic acid .

Stage a. To a stirred solution of intermediate 36 (299 mg, 0.87 mmol) and intermediate 34 (767 mg, 1.74 mmol) in DMF (3 ml) was added DIPEA (0.3 ml, 1.74 mmol) and the reaction mixture stirred at room temperature. under argon for 18 hours. The reaction mixture was diluted with EtOAc and the solid was removed by filtration. The filtrate was diluted with saturated sodium bicarbonate solution and the crude product was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4dimethoxybenzyl-(1S,2R)-2-((S) -5-chloro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1 -carboxylate (190 mg, 36%). LCMS (method 16): 1.46 min, 633.4 [M+Na]+.

Stage b. 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-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-2carbonyl)-1- Methylcyclopentane-1-carboxylate (196 mg, 84%) was prepared from the above intermediate (190 mg, 0.31 mmol) and 3-(chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine (71 mg, 1.3 mmol, example 170) using a procedure similar to that described for example 156, step b. Not

- 152 045906 the purified product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (25 g silica gel column, 0-5% MeOH in DCM). LCMS (method 16): 1.53 min, 746.6 [M+H]+.

Stage c. The title compound (48 mg, 29%) was prepared from the above intermediate (196 mg, 0.26 mmol) using a procedure similar to that described for Example 29, Step b. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (12 g silica gel column, 0-2.5% MeOH in DCM) then by reverse phase preparative HPLC (X-Select CSH 5 µm C18 19x250 mm, 10-98% MeCN in 0.1% aqueous formic acid LCMS (LCMS Method 3): 4.02 min, 596.3 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ 11 .44 (bs, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5.72 (dd, 1H), 5.21-5.09 (m, 2H), 4, 30 (t, 2H), 4.02 (dd, 1H), 3.94 (dd, 1H), 3.57 (m, 1H), 3.42-3.28 (m, 1H), 3.06 (m, 1H), 2.95 (dd, 1H), 2.87-2.77 (m, 3H), 2.75-2.60 (m, 2H), 2.35 (m, 1H), 2.22-1.92 (m, 5H), 1.82 (m, 2H), 1.72-1.59 (m, 3H), 1.40 (m, 1H), 1.15 (s, 3H), 0.63-0.40 (m, 4H).

Example 190. (1S,2R)-1-Methyl-2-((S)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triαzol-4-yl)methoxy) 1 -((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid.

Stage a. Potassium carbonate suspension (82 mg, 0.59 mmol), XPhos Pd G3 (6.7 mg, 0.01 mmol, CAS: 1445085-55-1), XPhos (7.5 mg, 0.02 mmol, CAS: 564483-18-7) and 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3- triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-1-methylcyclohexane-1-carboxylate (150 mg, 0 , 20 mmol, example 108, step c) in EtOH (2 ml) under argon was stirred at 90°C for 18 hours. The reaction mixture was diluted with water and the crude product was extracted into EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was combined with another batch (0.13 mmol and purified by flash column chromatography on an Interchim Puriflash® 4100 (40 g silica gel column, 0-5% MeOH in DCM) to give 2,4-dimethoxybenzyl-(1S ,2R)-1 -methyl-2-(^)-8-(( 1 -methyl-5-(trifluoromethyl)- 1H-1,2,3triazol-4-yl)methoxy)-1-((2-oxopyrrolidine -1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylate (101 mg). LCMS (method 2): 1.53 min, 728.5 [M+H]+.

Stage b. The title compound (62 mg, 77%) was prepared from the above intermediate using a procedure similar to that described for Example 29, step b. LCMS (Method 3): 4.22 min, 578.4 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 15.49 (bs, 1H), 7.22 (t, 1H), 7.02 (d, 1H), 6.82 (d, 1H), 5.99 ( dd, 1H), 5.30 (m, 2H), 4.22 (m, 3H), 4.03 (dd, 1H), 3.96 (m, 1H), 3.82-3.67 (m , 2H), 3.223.10 (m, 2H), 3.00-2.84 (m, 2H), 2.55 (dd, 1H), 2.40 (m, 1H), 2.28 (m, 1H), 2.16 (m, 1H), 1.99-1.77 (m, 4H), 1.67-1.45 (m, 3H), 1.34 (m, 1H), 1.11 (s, 3H), 1.00 (m, 1H).

Example 194 (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triαzol-4-yl)methoxy) -1((^)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxylic acid.

Stage a. To a stirred solution of tert-butyl-^)-1-(aminomethyl)-5-chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 0.11 mmol; example 109, step c) and 4-oxopentanoic acid (13 mg, 0.11 mmol, CAS: 123-76-2) in DMSO (0.5 ml), formic acid (0.02 ml, 0.55 mmol) and triethylamine (0.02 ml, 0.11 mmol) were added. The reaction mixture was degassed with argon for 5 min. and heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature. and NaOH (2 M, aqueous solution) was added and the mixture was extracted with DCM (x3). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash column chromatography (100% EtOAc) afforded tert-butyl-^)-5-chloro-8-((5-(difluoromethyl)-1methyl-1H-1,2,3-triazol-4-yl )methoxy)-1-((^)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-3,4dihydroisoquinoline-2(III)-carboxylate (12 mg, 19%), LCMS (method 9): 1.00 min, 540.6 [M+H]+ and tert-butyl-(8)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazole-4 -yl)methoxy)-1-(((8)-2-methyl-5

- 153 045906 oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (10 mg, 7%), LCMS (method 9): 0.98 min, 440.5 [M+H -CO ₂ ]+.

Stage b. The title compound (12 mg, 32%) was prepared from tert-butyl-^)-5-chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl )methoxy)-1-((A)-2-methyl-5-oxopyrrolidin-1-yl)methyl)3,4-dihydroisoquinoline-2(1H)-carboxylate and intermediate 29 using a procedure similar to that described for Example 123 The crude product was purified by MDAP (Method 5, 40-55% MeCN in 0.1% aqueous formic acid) and further purified by flash column chromatography (2-4% MeOH in DCM). LCMS (Method 9b): 1.52 min, 608.3 [M+H] ⁺ . 1H NMR (300 MHz, CDCl ₃ ) δ 7.29 (d, 1H), 6.98 (d, 1H), 6.93 (t, 1H), 5.89 (dd, 1H), 5.36- 5.22 (m, 2H), 4.26-4.10 (m, 4H), 3.92-3.77 (m, 2H), 3.45 (m, 1H), 3.21 (dd, 1H), 3.05 (m, 1H), 2.72 (m, 1H), 2.58 (m, 1H), 2.40 (m, 1H), 2.252.13 (m, 2H), 2, 04 (m, 1H), 1.91-1.74 (m, 2H), 1.69-1.27 (m, 5H), 1.18-0.94 (m, 7H).

Example 195 -1-(((S)2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid.

The title compound (5 mg, 28%) was prepared from tert-butyl-^)-5-chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl )methoxy)-1-((^)-2-methyl-5-oxopyrrolidin-1-yl)methyl)3,4-dihydroisoquinoline-2(1H)-carboxylate and intermediate 29 using a procedure similar to that described for Example 123 The crude product was purified by MDAP (Method 5, 40-55% MeCN in 0.1% aqueous formic acid) and further purified by flash column chromatography (3% MeOH in DCM). LCMS (Method 9b): 1.53 min, 608.3 [M+H] ⁺ . 1H NMR (300 MHz, CDCl ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 6.92 (t, 1H), 5.88 (dd, 1H), 5.36 ( d, 1H), 5.24 (d, 1H), 4.19 (s, 3H), 4.102.96 (m, 6H), 2.73 (m, 1H), 2.56 (m, 1H), 2.47-2.22 (m, 2H), 2.21-1.98 (m, 2H), 1.90-1.72 (m, 2H), 1.72-0.69 (m, 12H ).

Example 196. (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro[1,2,3 ]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid.

1.6 mmol), methyl-2-(2Step a. Solution of intermediate 22 (500 mg, iodoethoxy)acetate (507.11 mg, 2.08 mmol, CAS: 84424-42-0) and triethylamine (0.33 ml, 2.4 mmol) in toluene (6 ml) was refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and 5% citric acid. The organic phase was isolated and the aqueous layer was further extracted with DCM (x2) The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo Purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in cyclohexane) gave tert-butyl-^)-5-chloro-8-hydroxy-1-((3-oxomorpholino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (503 mg , 79%). LCMS (method 16): 1.28 min, 419.3 [M+Na] ⁺ .

Stage b. ^)-4-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-morpholin-3-one hydrochloride (422 mg, estimated amount) was prepared from the above intermediate (503 mg, 1.27 mmol) using a procedure similar to that described for Example 1, step d, and used without further purification. LCMS (method 16): 0.68 min, 297.1 [M+H] ⁺ .

Stage c. To a stirred solution of the above intermediate (422 mg, 1.27 mmol) and intermediate 33 (691 mg, 1.52 mmol) in DMF (5 ml) was added DIPEA (0.44 ml, 2.53 mmol) and the resulting As a result, the mixture was stirred at room temperature. in an argon atmosphere for 5 days. The reaction mixture was diluted with EtOAc, diluted with saturated sodium bicarbonate solution and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in cyclohexane) to give 2,4-dimethoxybenzyl- 154 045906 (1S,2R)-2- ((S)-5-chloro-8-hydroxy-1-((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylate (387 mg, 50% ). LCMS (method 16): 1.45 min, 637.3 [M+Na]+.

Stage d. 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)-methyl)-8-((4,5,6,7tetrahydro-[1, 2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylate (252 mg, estimated amount) was prepared from the above intermediate (190 mg, 0.31 mmol) and 3-(chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5a]pyridine (71 mg, 0.41 mmol) using a procedure similar to that described for example 22, stage c. The crude product was used without further purification. LCMS (method 16): 1.49 min, 750.4 [M+H] ⁺ .

Step f: The title compound (126 mg, 63%) was prepared from the above intermediate (232 mg, 0.31 mmol) using a procedure similar to that described for Example 156. The crude product was purified by Teledyne ISCO flash column chromatography CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-5% MeOH in DCM). LCMS (Method 3): 4.21 min, 600.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.78 (bs, 1H), 7.37 (d, 1H), 7.15 (d, 1H), 5.85 (dd, 1H), 5 .22-5.13 (m, 2H), 4.39-4.26 (m, 3H), 4.04-3.89 (m, 2H), 3.85-3.55 (m, 4H) , 3.43 (m, 1H), 2.98 (m, 1H), 2.932.77 (m, 5H), 2.69 (m, 1H), 2.26 (m, 1H), 2.02- 1.92 (m, 2H), 1.87-1.77 (m, 2H), 1.70-1.47 (m, 3H), 1.44-1.20 (m, 4H), 1. 10 (s, 3H).

Example 201 -1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1 carboxylic acid.

Stage a. Mixture of intermediate 36 (2.16 g, 6.29 mmol), intermediate 40 (1.99 g, 6.29 mmol) and DIPEA (2.19 mL, 12.59 mmol), in DMF (39 mL) stirred under nitrogen atmosphere at room temperature. for 28 hours. The reaction mixture was diluted with ethyl acetate, washed with brine and the combined organic layers were concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0-10% MeOH in DCM) gave methyl-(1S,6R)-6-[(1S)-5-chloro -8-hydroxy-1-[(6-oxo-5azaspiro[2.4]heptan-5-yl)methyl]-3,4-dihydro-III-isoquinoline-2-carbonyl]-1-methylcyclohex-3-ene-1carboxylate (1.64 g, 53%) and O2-[(^)-5-chloro-2-[(^^)-6-methoxycarbonyl-6-methylcyclohex-3-ene-1carbonyl]-1-[(6- oxo-5-azaspiro[2.4]heptan-5-yl)methyl]-3,4-dihydro-III-isoquinolin-8-yl]-O1-methyl (1S,2R)-1-methylcyclohex-4-en-1 ,2-dicarboxylate (1.22 g, 29%). Methyl-(1S,6R)-6-[(1S)-5-chloro-8hydroxy-1-[(6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl]-3,4-dihydro- III-isoquinoline-2-carbonyl]-1methylcyclohex-3-ene-1-carboxylate: LCMS (Method 18): 1.43 min, 487.3 [M+H] ⁺ . О2-[(^)-5-chloro-2[(^^)-6-methoxycarbonyl-6-methylcyclohex-3-ene-1-carbonyl]-1-[(6-oxo-5-azaspiro[2.4]heptane -5yl)methyl]-3,4-dihydro-1H-isoquinolin-8-yl]-01-methyl-(1S,2R)-1-methylcyclohex-4-ene-1,2dicarboxylate: LCMS (method 16): 1.66 min, 667.3 [M+H] ⁺ .

Stage b. To a solution of lithium hydroxide monohydrate (305 mg, 7.26 mmol) in THF (20 ml) was added O2[(1S)-5-chloro-2-[(1R,6S)-6-methoxycarbonylcyclohex-3-ene-1- carbonyl]-1-[(6-oxo-5-azaspiro[2.4]gentan-5yl)methyl]-3,4-dihydro-1H-isoquinolin-8-yl]-O1-methyl-1-methylcyclohex-4-ene -1,2-dicarboxylate (1.210 g, 0.92 mmol) in water (5 ml) and the reaction was stirred at room temperature. for 3 days, then concentrated in vacuo. The residue was diluted with citric acid (10% aq) and extracted with EtOAc. The combined organic layers were dried (MgSO ₄ , filtered and concentrated in vacuo and the crude material was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC/Biotage SNAP column with 40 g silica gel, 0-8% MeOH in DCM) with by preparing methyl-(1S,6R)-6-[(1S)-5-chloro-8-hydroxy-1-[(6-oxo-5-azaspiro[2.4]gengan-5-yl)methyl]-3,4 -dihydroIII-isoquinoline-2-carbonyl]-1-methylcyclohex-3-ene-1-carboxylate (655 mg, 79%) LCMS (Method 16): 1.32 min, 487.2 [M+H] ⁺ .

Stage c. Methyl-(1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)meΊΌoxy)- 1((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3ene-1-carboxylate (2.03 g, 95%) was prepared from the above intermediate (1.64 g, 3.37 mmol) using a procedure similar to that described for Example 22, step c. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® (Puriflash HC column with 80 g silica gel, 0-4% MeOH in DCM). LCmS (method 16): 1.42 min, 632.3 [M+H] ⁺ .

Stage d. To a stirred solution of the above intermediate (503 mg, 0.800 mmol) in methanol (8 ml) was added a solution of sodium hydroxide (334 mg, 7.96 mmol) in water (2 ml) and the reaction vial was sealed and heated under microwave radiation at 100° C for 4 hours. The residue was diluted with citric acid (10% aq) and extracted with EtOAc. Unite

- 155 045906 The resulting organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC/Biotage SNAP column (15 µM) with 40 g silica gel, 0-2% MeOH in DCM) and freeze-dried to give the title compound ( 362 mg, 69%). LCMS (method 3) 4.48 min, 618.3 [M+H] ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 14.93 (bs, 1H), 7.30 (d, 1H), 6.99 (d, 1H), 6.93 (t, 1H), 5.98 (dd, 1H), 5.77-5.69 (m, 1H), 5.68-5.59 (m, 1H), 5.38-5.15 (m, 2H), 4.22-3 .91 (m, 6H), 3.44 (d, 1H), 3.16 (dd, 1H), 3.11-2.99 (m, 3H), 2.93 (dd, 1H), 2. 76 (m, 1H), 2.42 (d, 1H), 2.37-2.23 (m, 2H), 2.13 (d, 1H), 1.83 (m, 1H), 1.21 (s, 3H), 0.74-0.46 (m, 4H).

Example 203 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid.

Stage a. To a stirred solution of intermediate 48 (racemic; 700 mg, 1.52 mmol) and cesium carbonate (1.78 g, 5.47 mmol) in DMF (25 ml) was added -4-(chloromethyl)-5(difluoromethyl)- 1-methyltriazole hydrochloride (380 mg, 1.74 mmol). The reaction mixture was left stirring at room temperature. for 18 hours overnight, then heated at 50°C for 24 hours, then cooled to room temperature. The mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g Silicycle silica gel column, 0-2% MeOH in DCM) to give tert-butyl-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H- 1,2,3-triazol-4yl)methoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.91 g, 96%). LCMS (method 9a): 2.99 min, 506.1 [M+H-CO ₂ ' ^Vi ]+.

Stage b. To a stirred solution of the above intermediate (0.91 g, 1.5 mmol) in EtOH (25 ml) was added hydrazine hydrate (0.37 ml, 7.51 mmol; CAS: 10217-52-4) and the reaction mixture was stirred at 65 °C for 18 hours, then cooled to room temperature. The reaction mixture was filtered, the filter cake was washed with EtOH and the filtrate was concentrated in vacuo. Et ₂ O was added to it and the precipitate was removed by filtration and washed with Et 2 O. The filtrate was concentrated in vacuo to give tert-butyl-1-(aminomethyl)-5-chloro-8-((5-(diphΌrmethyl)-1-methyl-1H-1,2,3-triαzol-4yl)meΊΌoxy)-7 -fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (581 mg, 71%). LCMS (method 9a): 2.41 min, 476.2 [M+H] ⁺ .

Stage c. To a solution of the above intermediate (575 mg, 1.21 mmol) and methyl 2(1-(bromomethyl)cyclopropyl) acetate (325 mg, 1.57 mmol CAS: 855473-50-6) in MeCN (42 ml) was added triethylamine (0.25 ml, 1.81 mmol) and the reaction mixture was heated at 90°C for 48 hours, then the temperature was raised to 95°C for another 7 hours. The reaction mixture was diluted with water, extracted with EtOAc and washed using water, saline, dried (Mg ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by silica gel chromatography (Biotage ZIP sphere, 80 g, 0-3% methanol in dichloromethane) to give tert-butyl-5-chloro-8-((5-(difluoromethyl)-1methyl-1H-1, 2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4dihydroisoquinoline-2(III)-carboxylate (541 mg, 77%). LCMS (method 9a): 2.67 min, 470.2 [M-CO ₂ ^Shi +H] ⁺ .

Stage d. A solution of the above intermediate (540 mg, 0.950 mmol) in hydrogen chloride (4M in dioxane; 5.0 mL, 20 mmol) was stirred at RT. for 1.5 hours and concentrated in vacuo to give 5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy )-7-fluoro1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one (454 mg, 92%), used without further purification. LCMS (method 9): 0.81 min, 470.2 [M+H]+.

Step f: To a solution of the above intermediate (454 mg, 0.90 mmol), intermediate 29 (392 mg, 1.17 mmol) and DIPEA (0.94 mL, 5.38 mmol) in DMF (3 mL) HATU (409 mg, 1.08 mmol; CAS: 148893-10-1) and the reaction mixture was stirred at RT. within 6 days. The mixture was diluted with water, extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Biotage Isolera One™ (diode array detector, 200-400 nm; 45 g silica gel column, 0-4% MeOH in DCM) followed by reverse phase column chromatography on a Biotage Isolera One™ ( diode array detector 200-400 nm, column with 60 g C18, 30-80% MeCN in 0.1% aqueous ammonia) to obtain two products. Mixed fractions were also collected, freeze-dried and purified again using reverse phase column chromatography on a Biotage Isolera One™ (diode array detector, 200-400 nm, C18 column,

- 156 045906 g, 30-80% MeCN in 0.1% ammonia solution). The pure fractions were combined with the corresponding product from the first purification and each was freeze-dried overnight to obtain two products: a first eluting isomer (isomer 1, 105 mg) and a second eluting isomer (isomer 2, 156 mg). Isomer 1: 2,4-dimethoxybenzyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methylIII-1,2,3-triazol-4- yl)methoxy)-7-fluoro-G((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1- carboxylate (105 mg, 13%), LCMS (Method 9a): 2.95 min, 788.3 [M+H]+. Isomer 2: 2,4-dimethoxybenzyl-(1S,2R)-2-((R)-5-chloro-8-((5-(difluoromethyl)1-methyl-III-1,2,3-triazole-4 -yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane- 1-Carboxylate (156 mg, 21%), LCMS (method 9a): 3.02 min, 788.3 [M+H]+. The absolute stereochemistry of the diastereoisomers was confirmed by low molecular weight X-ray crystallography of the carboxylic acid formed from enantiomer 2.

Stage f. A mixture of the above intermediate (isomer 1, 120 mg, 0.13 mmol) and hydrogen chloride (4M in dioxane; 15 mL, 60 mmol) was stirred at RT. for 2 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by reverse phase chromatography (Biotage C18 SNAP 60 g, 5-50% MeCN in 0.1% aqueous ammonia) to give the title compound (29 mg, 33%). LCMS (method 14 - specific gradient: MeCN with 5% D2 and 93% water to 50% MeCN with 5% D2 and 45% water in 3.00 min. Temp to 95% MeCN with 5% D2 in 4.50 min. ): 1.76 min., 638.22 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) 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), 2.99 (m, 1H), 2.67 (m, 1H), 2.57 (dd, 1H), 2.47-2.36 (m, 2H), 2.07 (d, 1H), 1.85-1.72 (m, 2H), 1.70-1.43 (m, 3H), 1. 41-1.23 (m, 1H), 1.12 (s, 3H), 1.03 (m, 1H), 0.69-0.50 (m, 4H).

Example 207. (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl) methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3methylbicyclo[4.1.0]heptane-3 -carboxylic acid.

Cl ci Cl

Stage a. Intermediate 39 (1.5 g, 7.57 mmol) was dissolved in DMF (15 ml) and potassium carbonate (1.57 g, 11.4 mmol), bromomethylbenzene (1.35 ml, 11.35 mmol; CAS) was added : 100-39-0) and potassium iodide (37 mg, 1.51 mmol). The solution was stirred at room temperature. for 2 hours. The reaction mixture was partitioned between EtOAc and brine, the organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 120 g silica gel, 0-2% MeOH in DCM) to give 2-benzyl-1methyl-(1S,2R)-1-methylcyclohex- 4-ene-1,2-dicarboxylate (1.7 g, 74% yield). 1H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.29 (m, 5H), 5.67-5.58 (m, 2H), 5.10-5.04 (m, 2H), 3 .58-3.57 (m, 3H), 3.03 (dd, 1H), 2.81-2.73 (m, 1H), 2.62-2.55 (m, 1H), 2.43 -2.34 (m, 1H), 2.08-2.02 (m, 1H), 1.24 (s, 3H).

Stage b. To a solution of diethylzinc (13.87 ml, 13.87 mmol) in DCM (30 ml) at -5°C under argon, TFA (0.85 ml, 11.1 mmol) was added dropwise over 10 min. followed by dropwise addition of diiodomethane (1.12 mL, 13.87 mmol) over 15 min. The solution was then stirred at -5°C for 15 minutes. A solution of the above intermediate (800 mg, 2.77 mmol) in DCM (3 ml) was added dropwise to this at -15° C. over 15 minutes. and the solution was slowly heated to room temperature. and stirred for 16 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude residue was then purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g Puriflash HC/Biotage SNAP silica gel column, dry load, 0-20% THF in cyclohexane) to give a colorless oil (725 mg). The mixture was diluted in DCM and treated with 3chloroperbenzoic acid (430 mg, 1.92 mmol) and the resulting solution was stirred at room temperature. for 16 hours. The reaction mixture was diluted with DCM, washed with water, saturated NaHCO ₃ and saline. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on Interchim Puriflash® 4125 (Puriflash InterChim column with 120 g silica gel, 0-30% THF in cyclohexane) to give 4-benzyl-3-methyl-(3S,4R)-3-methylbicyclo [4.1.0]heptane-3,4

- 157 045906 dicarboxylate (310 mg, 70%) in the form of a mixture of diastereoisomers. LCMS (method 2): 1.33 min, no ions observed in the mass spectrometer.

Stage c. To a solution of the above intermediate (242 mg, 0.80 mmol) in EtOH (4 ml) was added Pd/C (10%; 26 mg, 0.24 mmol) and the resulting mixture was stirred under a hydrogen atmosphere at ambient pressure of for 16 hours. The reaction mixture was diluted using IMS and filtered through Celite®. The filtrate was concentrated in vacuo to give (3R,4S)-4(methoxycarbonyl)-4-methylbicyclo[4.1.0]heptane-3-carboxylic acid (263 mg, estimated amount) as a mixture of diastereoisomers. LCMS (method 2): 1.23 min, 213.1 [M+H]+.

Stage d. To a stirred solution of the above intermediate (262 mg, 1.23 mmol) in DMF (3 ml) was added HATU (516 mg, 1.36 mmol; CAS: 148893-10-1) and the resulting mixture was stirred at room temperature. in an argon atmosphere for 5 minutes. DIPEA (0.24 mL, 1.36 mmol) was added and the resulting mixture was stirred for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HP column with 40 g silica gel, 0-50% EtOAc in cyclohexane) to give 4-(3H-[1,2,3]triazolo[4,5 -b]pyridin-3-yl)-3-methyl(3S,4R)-3-methylbicyclo[4.1.0]heptane-3,4-dicarboxylate (353 mg, 87%) as a mixture of diastereomers. LCMS (method 2): 1.51 and 1.52 min, 331.0 [M+H]+.

Step e. To solution ^)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1,2, 3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (200 mg, 0.41 mmol, Example 110, Step b) and the above intermediate (162 mg, 0.41 mmol, 49 mmol) in DMF (1.6 ml) was added DIPEA (0.14 ml, 0.820 mmol) and the resulting mixture was stirred at room temperature. in an argon atmosphere for 18 hours. Additionally, 4-(3H-[1,2,3]triazolo[4,5b]pyridin-3-yl)-3-methyl-(3S,4R)-3-methylbicyclo[4.1] was added .0]heptane-3,4-dicarboxylate (80 mg, 0.24 mmol) and DIPEA (0.08 ml, 0.47 mmol) and the reaction mixture was stirred for an additional 24 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0100% EtOAc in cyclohexane) to give methyl-(III^^^)-4-(^)-5-chloro -8-((5-(difluoromethyl)-1methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl) methyl)-1,2,3,4tetragsdroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylate (173 mg, 65%) and methyl(^^^^)-4-(^) -5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptane- 5-yl)methyl)-1,2,3,4-tetrahydroisocholine-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3carboxylate (43 mg, 16%). Methyl-(^^^^)-4-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-1- ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-3-methylbicyclo[4.1.0]heptan-3-carboxylate: LCMS ( method 15): 1.62 min, 646.4 [M+H]+. Methyl(^^^^)-4-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1 -((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisocnoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptan-3 carboxylate: LCMS ( method 15): 1.61 min, 646.4 [M+H]+.

Step f To a stirred solution of methyl-(1R,3S,4R,6S)-4-((S)-5-xnop-8-((5-(difluoromethyl)-1methyl-1H-1,2,3-triazol- 4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0 ]heptane-3-carboxylate (173 mg, 0.27 mmol) in MeOH (3 ml), sodium hydroxide solution (3 M; 0.89 ml, 2.68 mmol) was added and the resulting mixture was heated at 100°C at microwave radiation for 3 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water, acidified to pH 4 using 5% citric acid solution and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by reverse phase flash column chromatography on InterChim 4125 (C18 InterChim HP, 80 g, 5-70% MeCN in water with 0.1% HCOOH buffer). Fractions containing the desired product were combined and freeze-dried to give the title compound (116 mg, 66%). LCMS (Method 11): 4.72 min, 632.3 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 15.03 (bs, 1H), 7.30 (d, 1H), 6.98 (d, 1H), 6.91 (t, 1H), 5.93 ( dd, 1H), 5.43-5.13 (m, 2H), 4.20-3.98 (m, 6H), 3.43 (d, 1H), 3.19-3.01 (m, 3H), 2.90 (d, 1H), 2.75 (m, 1H), 2.62 (dd, 1H), 2.42 (d, 1H), 2.25 (m, 1H), 2, 17 (d, 1H), 1.67-1.42 (m, 2H), 1.08 (s, 3H), 1.03 (m, 1H), 0.86 (m, 1H), 0.70 -0.49 (m, 5H), 0.26 (dd, 1H).

Example 208. (1S,3S,4R,6R)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl) methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3methylbicyclo[4.1.0]heptane-3 -carboxylic acid.

- 158 045906

To a stirred solution of methyl-(1S,3S,4R,6R)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1R1,2,3-triazol-4- yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-3-methylbicyclo[4.1.0]heptane -3-carboxylate (43 mg, 0.03 mmol; Example 207, step e) in MeOH (0.8 ml) was added sodium hydroxide solution (3 M; 0.22 ml, 0.33 mmol) and the resulting the mixture was heated at 100° C. under microwave radiation for 15 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water, acidified to pH 4 using 5% citric acid solution and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by reverse phase flash column chromatography on InterChim 4125 (C18 InterChim HP, 40 g, 5-70% MeCN in water with 0.1% HCOOH buffer). Fractions containing the desired product were combined and freeze-dried to give the title compound (7 mg, 33%). LCMS (method 11): 4.92 min, 632.3 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 7.18 (m, 1H), 6.91 (t, 1H), 6.86 (d, 1H), 5.85 (m, 1H), 5.23 ( d, 1H), 5.17 (d, 1H), 4.31 (bm, 1H), 4.16 (m, 3H), 4.04 (m, 1H), 3.71-3.50 (m , 2H), 2.97 (m, 1H), 2.92-2.70 (m, 3H), 2.69-2.50 (m, 2H), 2.20 (d, 1H), 2, 08 (m, 1H), 1.93 (m, 1H), 1.82-1.51 (m, 2H), 1.39 (s, 3H), 1.06-0.95 (m, 1H) , 0.94-0.77 (m, 1H), 0.73-0.63 (m, 2H), 0.62-0.47 (m, 2H), 0.47-0.37 (m, 1H), 0.03-0.04 (m, 1H).

Example 210. (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl) methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohexane-1-carboxyl-4, 5^ ₂ acid.

To a stirred solution of Example 201 (300 mg, 0.49 mmol) in MeOH (10 mL) was added Pd/C (10%; 5.2 mg, 0.05 mmol). Deuterium gas was bubbled through the reaction mixture using a balloon and the reaction mixture was stirred at room temperature. for 16 hours. During this time, two additional parts of Pd/C (5.2 mg) and deuterium gas were continuously bubbled through the mixture. After this time, the reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and additional Pd/C (10%; 5.17 mg, 0.050 mmol) was added and deuterium gas was bubbled through the reaction mixture via a balloon and the reaction mixture was stirred at room temperature. for 6 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo, then purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC/Biotage SNAP column with 12 g silica gel, 0-1.5% MeOH in DCM ) followed by flash column chromatography on Interchim Puriflash® 4100 (C18 Puriflash HP with 80 g, 5-70% MeCN in water with 0.1% formic acid) to give the title compound (82 mg, 26%). LCMS (method 3): 4.57 min, 622.4 [M+H] ⁺ . ^1H NMR (400 MHz, CDCh) δ 15.27 (bs, 1H), 7.30 (d, 1H), 6.98 (d, 1H), 6.92 (t, 1H), 5.95 ( dd, 1H), 5.50-5.13 (m, 2H), 4.18 (m, 3H), 4.11 (dd, 1H), 4.00 (m, 1H), 3.88 (m , 1H), 3.44 (d, 1H), 3.21-3.02 (m, 3H), 2.76 (m, 1H), 2.59 (m, 1H), 2.46-2, 35 (m, 2H), 2.12 (d, 1H), 1.88-1.74 (m, 2H), 1.641.47 (m, 2H), 1.13 (s, 3H), 1.01 (t, 1H), 0.74-0.47 (m, 4H).

Example 212 -1((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid (isomer 1).

Stage a. Ethyl (E)-4,4,4-trifluoro-3-methyl-but-2-enoate mixture (2.0 g, 11.0 mmol; CAS: 24490-03-7),

- 159 045906

NBS (2.15 g, 12.08 mmol) and AIBN (0.09 g, 0.50 mmol) in carbon tetrachloride (16 ml) were refluxed with a halogen lamp for 4 hours, then without a halogen lamp! for 16 hours. Saturated aqueous sodium bicarbonate was added to the mixture and the mixture was extracted with Et ₂ O. The combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo to give ethyl-^)-3-(bromomethyl)-4 ,4,4-trifluoro-but-2-enoate (2.58 g, 81%). ¹ H NMR (301 MHz, CDCl ₃ ) δ 6.45 (d, 1H), 4.52 (s, 2H), 4.33-4.22 (m, 2H), 1.36-1.29 ( m, 3H).

Stage b. To a stirred solution of intermediate 58 (1.88 g, 5.75 mmol) in MeCN (35 ml) was added the above intermediate (1.58 g, 6.04 mmol) and triethylamine (0.96 ml, 6.9 mmol ) and the mixture was heated at 80°C for 25 minutes. The mixture was concentrated in vacuo and the crude product was purified by automated reverse phase column chromatography on a Biotage Isolera One™ (diode array detector, 200-400 nm, C18 column, 10 g, 2065% MeCN in water, 0.1% ammonia in throughout the entire stage) to obtain tert-butyl-^)-5-chloro-8-methoxy-1-((2oxo-4-(trifluoromethyl)-2,5-dihydro-III-pyrrol-1-yl)methyl)- 3,4-dihydroisoquinoline-2(III)-carboxylate (940 mg, 30%). LCMS (Method 9a): 2.96 min, 361.1 [M+H-CO ₂ ^tBu ]+.

Stage c. To a solution of the above intermediate (940 mg, 2.04 mmol) in IPA (70 ml) was added Pd/C (10%; 98 mg, 0.92 mmol). The mixture was stirred under a hydrogen atmosphere at ambient pressure! for 7 hours. The mixture was filtered through Celite® and the filter cake was washed with IPA. The filtrate was concentrated in vacuo and the crude product was purified by automated reverse phase column chromatography on a Biotage Isolera One (diode array detector, 200-400 nm, Zip sphere column, 45 g, 0-40% EtOAc in heptanes) to give tert. butyl(^)-5-chloro-8-methoxy-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline2(1C)-carboxylate in the form of two separate diastereoisomers . Diastereoisomer 1 (256 mg, 26%), LCMS (Method 9a): 2.86 min, 363.1 [M+H-CO2tBu] ⁺ .

Diastereoisomer 2 (348 mg, 35%), LCMS (method 9a): 2.82 min, 363.1 [M+H-CO ₂ tBu] ⁺ .

Stage d. To a solution of the above intermediate (diastereoisomer 1; 256 mg, 0.55 mmol) in DCM (34 ml) was added boron tribromide (1 M in DCM; 11.1 ml, 11.1 mmol). The reaction mixture was stirred at room temperature. Over 16 hours, cool in an ice bath (0-5°C) and slowly add MeOH (~10 ml). The mixture was concentrated in vacuo, further MeOH was added and the mixture was concentrated again in vacuo to give 1-((^)-5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1yl)methyl)-4-(trifluoromethyl )pyrrolidin-2-one hydrobromide (isomer 1; 237 mg, 82%), used without further purification. LCMS (method 9): 0.65 min, 349.1 [M+H] ⁺ .

Step f: To a stirred solution of the above intermediate (isomer 1; 217 mg, 0.51 mmol) in DMF (2.5 ml) was added intermediate 33 (230 mg, 0.51 mmol) and DIPEA (0.18 ml, 1.01 mmol) and the reaction mixture was stirred at room temperature. for 96 hours. The mixture was combined with the mixture from the smaller scale test (same conditions for 20 mg of the above intermediate), diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by automated reverse phase column chromatography on a Biotage Isolera OneTM (diode array detector, 200-400 nm, C18 column, 30 g, 2080% MeCN in water, 0.1% ammonia throughout) to give 2 ,4-dimethoxybenzyl-(1S,2R)-2-((1S)5-chloro-8-hydroxy-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylate (isomer 2; 120 mg, 26%). LCMS (method 9): 1.02 min, 665.2 [M-N] ^- .

Stage f. The title compound (22 mg, 44%) was prepared from the above intermediate (22 mg, 0.027 mmol) using a procedure similar to that described for Example 1, step d. LCMS (Method 4a): 1.29 min, 662.6 [M+H] ⁺ . ^1H NMR (400 MHz, CDCE) δ 7.32 (d, 1H), 6.98 (d, 1H), 6.95 (t, 1H), 5.92 (dd, 1H), 5.33- 5.22 (m, 2H), 4.18 (s, 3H), 4.05 (dd, 1H), 3.96-3.76 (m, 3H), 3.15 (dd, 1H), 3 .11-3.02 (m, 2H), 2.96 (m, 1H), 2.75 (m, 1H), 2.56 (dd, 1H), 2.51-2.32 (m, 3H ), 1.88-1.75 (m, 2H), 1.731.42 (m, 3H), 1.35 (m, 1H), 1.12 (s, 3H), 1.03 (m, 1H) .

Example 213 -1((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid (isomer 2).

Stage a. To a solution of tert-butyl-(^)-5-chloro-8-methoxy-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Example 212, step c, diastereoisomer 2; 333 mg, 0.72 mmol) boron tribromide (1M in DCM; 14.4 mL, 14.4 mmol) was added to DCM (44 mL). Reactionary

- 160 045906 the mixture was stirred at room temperature. for 16 h, cooled in an ice bath (0-5°C) and slowly added MeOH (~3 ml). The mixture was concentrated in vacuo, additional MeOH was added and the mixture was concentrated again in vacuo. The crude product was dissolved in DMSO and 33% aqueous ammonia (0.1 ml) was added. The mixture was left to stand for 5 minutes, then filtered through a filter pad. The crude residue was purified by automated reverse phase column chromatography on Biotage Isolera one (diode array detector: 200-400 nm, C18 column, 30 g, 10-40% MeCN in water containing 0.1% ammonia throughout the step) to give 1-(((S)-5chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-4-(trifluoromethyl)pyrrolidin-2-one (isomer 2; 250 mg, quantitation).

Stage b. To a stirred solution of the above intermediate (isomer 2; 250 mg, 0.72 mmol) in DMF (2.5 ml) was added intermediate 33 (326 mg, 0.72 mmol) and DIPEA (0.25 ml, 1.43 mmol) and the reaction mixture was stirred at room temperature. for 96 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by automated reverse phase column chromatography on Biotage Isolera One™ (diode array detector: 200-400 nm, C18 column, 30 g, 20-80% MeCN in water; 0.1% ammonia throughout) yielding two products, 2,4-dimethoxybenzyl-(1S,2R)-2-((1S)-5-chloro-8hydroxy-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (isomer 2; 51 mg, 9% yield), LCMS (method 9): 1.17, 667.3 [M+ H]+. 2-((^)-5-chloro-2-((^^)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclohexane-1carbonyl)-1-((2-oxo- 4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)-1(2,4-dimethoxybenzyl) (1S,2R)-1-methylcyclohexane-1,2 -dicarboxylate (63 mg, 7% yield), LCMS (method 9): 1.36 min, 986.5 [M+H]+.

Stage c. To a stirred solution of 2-((1S)-5-x.top-2-((1R,2S)-2-(((2,4dimethoxybenzyl)oxy)carbonyl)-2-methylcyclohexane-1-carbonyl)-1- ((2-oxo-4-(trifluoromethyl)pyrrolidin1 -yl)methyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)-1 -(2,4-dimethoxybenzyl) (1 S,2R)-1 -methylcyclohexane-1,2dicarboxylate (63 mg, 0.064 mmol) in THF (2 ml), a solution of lithium hydroxide (15 mg, 0.64 mmol) in water (0.5 ml) was added and the reaction mixture was stirred at room temperature. for 16 hours. The reaction mixture was extracted with EtOAc and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by automated reverse phase column chromatography on Biotage Isolera one (diode array detector: 200-400 nm, C18 column, 12 g, 20-70% MeCN in water; 0.1% ammonia throughout) to give 2,4-dimethoxybenzyl-(1S,2R)-2-((1S)5-chloro-8-hydroxy-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1, 2,3,4-Tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (isomer 2; 25 mg, 52%) LCMS (method 9a): 2.67 min, 665.2 [M-H] ^- .

Stage d. 2,4-Dimethoxybenzyl-(1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy )-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1-carboxylate (isomer 2, 22 mg , 64%) was prepared from the above intermediate (isomer 2; 25 mg, 0.037 mmol)) using a procedure similar to that described for Example 143, step c. (LCMS (method 9a): 2.96 min, 812.3 [M+H]+.

Step e The title compound (8 mg, 44%) was prepared from the above intermediate (22 mg, 0.027 mmol) using a procedure similar to that described for Example 1, Step d. LCMS (Method 4a): 1.28 min, 662.56 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, 1H), 7.10-6.81 (m, 2H), 5.93 (dd, 1H), 5.30 (m, 1H) , 5.23 (m, 1H), 4.18 (s, 3H), 4.08 (dd, 1H), 3.95-3.83 (m, 2H), 3.76 (dd, 1H), 3.22-3.11 (m, 2H), 3.10-2.95 (m, 2H), 2.83-2.68 (m, 1H), 2.55 (dd, 1H), 2. 49 (dd, 1H), 2.41 (dt, 1H), 2.34 (dd, 1H), 1.88-1.75 (m, 2H), 1.71-1.40 (m, 3H) , 1.33 (m, 1H), 1.11 (s, 3H), 1.01 (m, 1H).

Example 217.(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-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)-4,4-difluoro-1methylcyclohexane-1-carboxylic acid .

Stage a. Solution of methyl-(1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4yl)methoxy)-1 -((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methyl-4-oxocyclohexane-1-carboxylate (Example 219, step j; 199 mg, 0.31 mmol) in DCM (4 ml) was added dropwise to a stirred solution of DAST (0.11 ml, 0.80 mmol; CAS: 38078-09-0) in DCM (4 ml) at 0°C in an argon atmosphere and the reaction mixture was stirred at room temperature. within 24 hours Reaction

- 161 045906 the mixture was cooled in an ice bath and quenched by adding dropwise water (4 ml), heated to room temperature. and extracted with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(1S,2R)-2-((S)-5- chloro8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluoro-1-methylcyclohexane-1-carboxylate (132 mg, 64%). LCMS (method 2): 1.76 min, 670.3 [M+H] ⁺ .

Stage b. To a solution of the above intermediate (132 mg, 0.20 mmol) in MeOH (2 ml) was added a solution of sodium hydroxide (79 mg, 1.97 mmol) in water (0.50 ml) and the resulting mixture was heated at 100° C under microwave conditions for 12 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water and acidified to pH 4 using 10% aqueous citric acid. The resulting precipitate was collected by filtration and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in 1:1 MeCN/water and freeze-dried overnight to give the title compound (70 mg, 53%). LCMS (method 3): 4.56 min, 656.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- _d6 ) δ 12.10 (bs, 1H), 7.57 (t, 1H), 7.40 (d, 1H), 7.16 (d, 1H), 5, 74 (dd, 1H), 5.37-5.22 (m, 2H), 4.15 (s, 3H), 4.03-3.85 (m, 2H), 3.69 (m, 1H) , 3.45-3.20 (m, 1H), 3.11 (dd, 1H), 2.94 (dd, 1H), 2.87 (dd, 1H), 2.70 (m, 1H), 2.58-2.29 (m, 2H), 2.26-1.81 (m, 6H), 1.60 (m, 1H), 1.05 (s, 3H), 0.66-0, 31 (m, 4H).

Example 218 )methoxy)1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoro-1methylcyclohexane-1-carboxylic acid.

Stage a. To a stirred solution of methyl-(1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1methyl-1H-1,2,3-triazol-4-yl) methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylate (example 219, step i; 250 mg, 0.38 mmol) a solution of Deoxo-Fluor® (50% in THF; 0.37 ml, 1 mmol) was added dropwise to DCM (7 ml) at 0°C under argon and the reaction mixture was stirred at room temperature. for 20 hours. The reaction mixture was cooled in an ice bath and quenched by adding water dropwise, heated to room temperature. and extracted with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on an InterChim 4125 (40 g Puriflash HP silica gel column, 15 μM, 0-5% MeOH in DCM) to give the title compound (132 mg, 53%). LCMS (method 2): 1.42 min, 674.3 [M+Na]+.

Stage b. To a stirred solution of the above intermediate (22 mg, 0.03 mmol) in MeCN (0.400 ml) under argon was added sodium iodide (13 mg, 0.08 mmol) followed by dropwise addition of chlorotrimethylsilane (11 mg, 0.10 mmol ; CAS: 75-77-4). The reaction mixture was heated at 60°C in a sealed tube for 3 hours, diluted with water and extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on InterChim 4125 (C18 InterChim HP, 40 g, 5-75% MeCN in water with 0.1% formic acid buffer), then freeze-dried to give the title compound (5 .5 mi-).LCMS (method 3) 4.56 min, 638.4 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 15.28 (bs, 1H), 7.31 (d, 1H), 6.98 (d, 1H), 6.92 (t, 1H), 5.94 (dd, 1H), 5.35-5.21 (m, 2H), 4.95 (m, 1H), 4.18 (m, 3H), 4.11 (dd, 1H), 4.07- 3.88 (m, 2H), 3.43 (d, 1H), 3.20-3.04 (m, 3H), 3.01 (d, 1H), 2.77 (m, 1H), 2 .39 (d, 1H), 2.33-2.17 (m, 2H), 2.10 (d, 1H), 2.01-1.63 (m, 3H), 1.44 (m, 1H ), 1.19 (s, 3H), 0.73-0.45 (m, 4H).

Example 219 )methoxy)-1 ((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic-4M acid.

- 162 045906

Stage a. To a solution of intermediate 39 (250 mg, 1.26 mmol) in DCM (5 ml) was added portionwise N-iodosuccinimide (295 mg, 1.31 mmol; CAS: 516-12-1) and the resulting mixture was stirred at .T. in an argon atmosphere for 3 hours. The reaction mixture was diluted with DCM and washed with saturated solutions of sodium thiosulfate and sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-50% EtOAc in cyclohexane) to give methyl-(1K^^^)-4-iodo-2-methyl- 7-oxo-6oxabicyclo[3.2.1]octane-2-carboxylate (131 mg, 32%). ^1H NMR (400 MHz, CDCl ₃ ) δ 4.87-4.84 (m, 1H), 4.51-4.47 (m, 1H), 3.75 (s, 3H), 3.01- 2.90 (m, 3H), 2.43-2.34 (m, 1H), 2.18 (d, 1H), 1.65 (s, 3H). LCMS (method 16): 1.16 min, 324.9 [M+H]+.

Stage b. A stirred solution of the above intermediate (1.91 g, 5.89 mmol) in toluene (17.5 ml) was degassed with argon for 5 minutes. To this solution was added a solution of tris(trimethylsilyl)silane (1.82 ml, 5.89 mmol; CAS: 1873-77-4) and AIBN (97 mg, 0.59 mmol; CAS: 7867-1) in degassed toluene ( 2.9 ml) and the reaction mixture was heated at 60°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with 5% aqueous citric acid and extracted with EtOAc. The combined organic layers were washed with water, saturated aq. rast. sodium bicarbonate and saline, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(1K^.5K)-2-methyl-7-oxo- 6-oxabicyclo[3.2.1]octane-2-carboxylate (787 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 4.77 (t, 1H), 3.75 (s, 3H), 2.96 (d, 1H), 2.32-2.16 (m, 2H), 2 .08 (d, 1H), 2.06-1.99 (m, 1H), 1.741.62 (m, 2H), 1.36 (s, 3H).

Stage c. To a solution of the above intermediate (390 mg, 1.97 mmol) in THF (8 mL) and water (8 mL) cooled in an ice bath was added lithium hydroxide monohydrate (91 mg, 2.16 mmol) and the resulting mixture stirred for 1 hour. The reaction mixture was acidified to pH 3 using 5% citric acid and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1K^.5K)-5-hydroxy-2-(methoxycarbonyl)-2methylcyclohexane-1-carboxylic acid (241 mg, 57%). The aqueous layers obtained from the extraction were combined and further extracted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) to obtain a second batch of (1R,2S,5R)-5-hydroxy-2(methoxycarbonyl) -2-methylcyclohexane-1-carboxylic acid (153 mg, 36%). Combined product (394 mg, 93%). 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 4.59 (s, 1H), 3.56 (s, 3H), 3.51-3.43 (m, 1H) , 2.33 (dd, 1H), 2.00-1.74 (m, 3H), 1.63-1.57 (m, 1H), 1.38-1.26 (m, 2H), 1 .25 (s, 3H).

Stage d. Benzyl bromide (0.16 ml, 1.35 mmol; CAS: 100-39-0) was added to a mixture of the above intermediate (265 mg, 1.23 mmol) and potassium carbonate (186 mg, 1.35 mmol) in DMF (3 ml) under argon atmosphere and the resulting mixture was stirred at RT. for 2 hours. The reaction mixture was diluted with water, extracted with EtOAc, ethyl acetate and the combined organics were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) to give 2-benzyl-1-methyl (1S,2R,4R)-4- Hydroxy-1-methylcyclohexane-1,2-gucarboxylate (339 mg, 90%). 1H NMR (400 MHz, CDClj) δ: 7.36-7.30 (m, 5H), 5.13 (s, 2H), 3.77-3.68 (m, 1H), 3.58 (s , 3H), 2.51 (dd, 1H), 2.25-2.15 (m, 2H), 2.10-2.01 (m, 1H), 1.84-1.75 (m, 1H ), 1.59-1.56 (m, 1H), 1.46-1.39 (m, 1H), 1.35 (s, 3H).

Step f: To a solution of the above intermediate (339 mg, 1.11 mmol) in DMF (4.8 ml) under argon was added imidazole (226 mg, 3.32 mmol) and tert-butyl(chloro)diphenylsilane (0. 63 ml, 2.43 mmol; CAS: 58479-61-1) and the reaction mixture was stirred at room temperature. under argon for 2 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-10% EtOAc in cyclohexane) to give 2-benzyl-1-methyl-(18.2K,4K)- 4-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexane-1,2-163 045906 dicarboxylate (1.03 g, conditionally quantitative). LCMS (Method 2): 2.01 min, 545.3 [M+H]+.

Stage f. To a solution of the above intermediate (602 mg, 1.11 mmol) in EtOH (10 ml) was added Pd/C (10%; 100 mg, 0.94 mmol) and the reaction mixture was stirred under hydrogen atmosphere at ambient pressure for 18 h. Additional Pd/C (10%; 100 mg, 0.94 mmol) was added and the resulting mixture was heated at 40°C for 4 s under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with IMS and filtered through Celite®. The filtrate was concentrated in vacuo and purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-50% EtOAc in cyclohexane) to give (1R,2S,5R)-5-((tert -butyldiphenylsilyl)oxy)-2-(methoxycarbonyl)-2-methylcyclohexane-1-carboxylic acid (412 mg, 82%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.67-7.63 (m, 4H), 7.44-7.34 (m, 6H), 3.73 (s, 3H), 3.713.66 ( m, 1H), 2.39-2.36 (m, 1H), 2.22-2.01 (m, 2H), 1.60-1.53 (m, 1H), 1.44-1, 34 (m, 1H), 1.26-1.23 (m, 4H), 1.22-1.17 (m, 1H), 1.03 (s, 9H). LCMS (method 2): 1.77 min, 477.2 [M+Na]+.

Stage g. To a stirred solution of the above intermediate (412 mg, 0.91 mmol) in DMF (2 ml) was added HATU (379 mg, 1.0 mmol) and the reaction mixture was stirred at room temperature. in an argon atmosphere for 5 minutes. DIPEA (0.17 mL, 1 mmol) was added to this mixture and the mixture was stirred for 2 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-50% EtOAc in cyclohexane) to give 2-(3H-[1,2,3]triazolo[4,5-b ]pyridin-3-yl)-1-methyl-(1S,2R,4R)-4((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexane-1,2-dicarboxylate (471 mg, 91%). LCMS (method 2): 1.88 min, 595.2 [M+Na]+.

Stage h. To a stirred solution ^)-5-((5-xdor-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-1,2,3,4 -tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (Example 110, Step b; 525 mg, 1.08 mmol) and the above intermediate (739 mg, 1.29 mmol) in DMF (4.4 ml) DIPEA (0.37 ml, 2.15 mmol) was added and the reaction mixture was stirred at room temperature. in an argon atmosphere for 4 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc and the combined organic layers 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+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(1S,2R,4R)-4-((tert-butyldiphenylsilyl )oxy)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H1,2,3-triazol-4-yl)methoxy)-1-((6- Oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline2-carbonyl)-1-methylcyclohexane-1-carboxylate (669 mg, 70%). LCMS (method 2): 1.96 min, 910.3 [M+Na]+.

Stage i. To a stirred solution of the above intermediate (669 mg, 0.75 mmol) in THF (12.8 ml) was added a solution of tetrabutylammonium fluoride (1M in THF; 6.5 ml, 6.5 mmol; CAS: 429-41-4) and the reaction mixture was heated at 60°C for 3 hours. The reaction mixture was allowed to cool to RT, diluted with water, extracted into EtOAc and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo . The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-5% MeOH in DCM) to give methyl(^^^)-2-(^)-5-chloro- 8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1methylcyclohexane-1-carboxylate (406 mg, 83%). LCMS (method 2): 1.25 min, 650.3 [M+H]+.

Stage j. To a solution of the above intermediate (400 mg, 0.62 mmol) in DCM (6 ml) was added Dess-Martin periodinane (339 mg, 0.800 mmol; CAS: 87413-09-0) and the reaction mixture was stirred at room temperature. under argon for 1 hour. The reaction mixture was diluted with sodium thiosulfate solution, extracted with EtOAc and the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(^^)-2-(^)-5-chloro- 8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methyl-4-oxocyclohexane1-carboxylate (365 mg, 92%). LCMS (method 2): 1.30 min, 648.3 [M+H]+.

Stage k. To a solution of the above intermediate (150 mg, 0.23 mmol) in methane.ge-d.-i (3.0 ml) at 0°C was added sodium borodeuteride (12 mg, 0.28 mmol; CAS: 15681-89 -7) and the reaction mixture was stirred under argon for 0.5 h. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-5% MeOH

- 164 045906 in DCM) to obtain methyl-(1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3 -triazol-4yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4hydroxy-1- methylcyclohexane-1-carboxylate-4^(131 mg, 87%). LCMS (method 2): 1.27 min, 651.3 [M+H]+.

Step 1: To a solution of the above intermediate (80 mg, 0.12 mmol) in THF (4 ml) at 0°C under argon was added a solution of carbon disulfide (5 M in THF; 0.06 ml, 0.310 mmol; CAS: 75 -15-0) followed by the addition of sodium hydride (60% dispersion in mineral oil; 12 mg, 0.31 mmol; CAS: 75-15-0) and the reaction mixture was stirred for 0.5 h, heated to room temperature. T. and stirred for an additional 0.5 hours. The reaction mixture was cooled to 0°C, treated with iodomethane (0.02 ml, 0.310 mmol), warmed to room temperature. and stirred for 1 hour. The reaction mixture was diluted with saturated ammonium chloride solution, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(1S,2R,4R)-2-((S)- 5-chloro-8-((5-(difluoromethyl)-1methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methyl-4-(((methylthio)carbonothioyl)oxy)cyclohexane-1-carboxylate-4d (77 mg, 85%) . LCMS (method 2): 1.60 min, 741.3 [M+H] ⁺ .

Stage m. Tris(trimethylsilyl)silane (0 .09 ml, 0.280 mmol; CAS: 1873-77-4) and the reaction mixture was heated at 100°C in a sealed vial for 2 hours. The reaction mixture was cooled to room temperature, diluted with a 5% aqueous solution of citric acid, extracted with EtOAc and the combined organic layers were washed with water, saturated aq. rast. sodium bicarbonate and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 0-100% EtOAc in cyclohexane) with producing methyl-(1S,2R,4S)-2-((S)-5-chloro-8-((5(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate-4^( 122 mg, 81%). LCMS (method 2): 1.46 min, 635.3 [M+H]+.

Stage n. To a solution of the above intermediate (122 mg, 0.190 mmol) in MeOH (2 ml) was added a solution of sodium hydroxide (77 mg, 1.92 mmol) in water (0.5 ml) and the reaction mixture was heated at 100°C under microwave conditions. radiation for 30 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water and acidified to pH 4 using 10% aqueous citric acid. The mixture was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 25 g silica gel, 15 μm, 0-100% EtOAc in cyclohexane). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in 1:1 MeCN/water and freeze-dried overnight to give the title compound (55 mg, 45%). LCMS (Method 3): 4.56 min, 621.4 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 15.26 (bs, 1H), 7.30 (d, 1H), 6.98 (d, 1H), 6.92 (t, 1H), 5.95 (dd, 1H), 5.37-5.21 (m, 2H), 4.18 (m, 3H), 4.11 (dd, 1H), 4.00 (m, 1H), 3.88 ( m, 1H), 3.44 (d, 1H), 3.20-3.02 (m, 3H), 2.76 (m, 1H), 2.59 (dd, 1H), 2.47-2 .35 (m, 2H), 2.12 (d, 1H), 1.83 (m, 1H), 1.69-1.47 (m, 3H), 1.39-1.21 (m, 1H ), 1.13 (s, 3H), 1.02 (m, 1H), 0.72-0.48 (m, 4H).

Example 220. (1S,2R,4S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) methoxy)1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1methylcyclohexane-1-carboxylic acid .

Stage a. To a solution of methyl-(1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy )-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-4-hydroxy-1-methylcyclohexane-1-carboxylate ( example 219, step i, 100 mg, 0.15 mmol), 4-nitrobenzoic acid (51 mg, 0.31 mmol) and triphenylphosphine (80.79 mg, 0.31 mmol) in THF (2 ml) under argon dropwise add DIAD (0.06 ml, 0.310 mmol; CAS: 2446-83-5) and reaction

- 165 045906 the mixture was stirred at room temperature. for 2 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 40 g silica gel, 0-100% EtOAc/IMS (3:1) in cyclohexane). The crude product was further purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-100% EtOAc in cyclohexane) to give (^,3R^)-3-(^)-5-chloro -8-((5-(difluoromethyl)-1-methyl-III-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)-4(methoxycarbonyl)-4-methylcyclohexyl-4-nitrobenzoate (95 mg, 77%). LCMS (method 2): 1.58 min, 799.3 [M+H]+.

Stage b. To a solution of the above intermediate (95 mg, 0.12 mmol) in MeOH (1.6 ml) was added a solution of sodium hydroxide (48 mg, 1.19 mmol) in water (0.40 ml) and the reaction mixture was heated at 100° C under microwave conditions for 18 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with water and acidified to pH 4 using 10% aqueous citric acid and extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in 1:1 MeCN/water and freeze-dried overnight to give the title compound (47 mg, 59%). LCMS (method 3): 3.96 min, 636.5 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.92 (bs, 1H), 7.57 (t, 1H), 7.38 (d, 1H), 7.14 (d, 1H), 5 .76 (dd, 1H), 5.39-5.22 (m, 2H), 4.35 (d, 1H), 4.16 (s, 3H), 4.02-3.88 (m, 2H ), 3.62 (m, 1H), 3.50 (m, 1H), 3.42-3.25 (m, 1H), 3.16 (m, 1H), 2.99 (dd, 1H) , 2.83 (dd, 1H), 2.78-2.63 (m, 2H), 2.43-2.19 (m, 2H), 2.14 (d, 1H), 1.78-1 .63 (m, 2H), 1.62-1.44 (m, 2H), 1.30 (m, 1H), 1.12 (s, 3H), 0.66-0.35 (m, 4H ).

Example 221. (1R,2R,6S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) methoxy)1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1methylcyclohexane-1-carboxylic acid .

Cl

Example 222. (1R,2R,6R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) methoxy)1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1methylcyclohexane-1-carboxylic acid .

\

N—N

C.I.

Example 223 )1 -((6-oxo-5 -azaspiro[2.4]heptan-5 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5 -hydroxy-1 methylcyclohexane-1-carboxylic acid .

Stage a. To a stirred solution of (1K.^)-6-methoxycarbonylcyclohex-3-ene-1-carboxylic acid (5.00 g, 27.2 mmol; CAS: 88335-93-7) in toluene (70 ml) under argon at While heating to 110°C, 1,1-di-tert-butoxy-XX-dimethylmethylamine (5.52 g, 27.2 mmol; CAS: 3680597-7) was added dropwise and the resulting mixture was stirred at 110°C under atmosphere argon for 4 hours. The reaction mixture was cooled to room temperature. and successively washed with water, sat. NaHCO ₃ solution and saline solution. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to obtain

- 166 045906 nium 1-(tert-butyl) 2-methyl-(1K^)-cyclohex-4-ene-1.2-dicarboxylate (4.17 g, 63%). ^1H NMR (400 MHz, CDCl ₃ ) δ 5.67 (d, 2H), 3.69 (s, 3H), 3.03-2.93 (m, 2H), 2.55-2.45 ( m, 2H), 2.36-2.24 (m, 2H), 1.43 (s, 9H).

Stage b. To a solution of the above intermediate (4.17 g, 17.4 mmol) in THF (82 ml) was added a solution of lithium hydroxide monohydrate (728 mg, 17.4 mmol) in water (82 ml) and the resulting mixture was stirred at .T. under argon atmosphere for 16 hours. The reaction mixture was acidified to pH ~3 using 10% aqueous citric acid and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1S,6R)-6-(tert-butoxycarbonyl)cyclohex-3-ene-1-carboxylic acid (3.16 g, 76%). ^1H NMR (400 MHz, CDCl ₃ ) δ 11.11 (br. s, 1H), 5.70-5.67 (m, 2H), 3.05-2.97 (m, 2H), 2, 59-2.47 (m, 2H), 2.38-2.28 (m, 2H), 1.43 (s, 9H).

Stage c. To a solution of the above intermediate (3.9 g, 17.2 mmol) in DCM (45 ml) was added portionwise N-iodosuccinimide (4.03 g, 17.9 mmol) and the resulting mixture was stirred at room temperature. under argon atmosphere for 4 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give tert-butyl (1S,2R,4R,5R)-4-iodo-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylate (4, 43 g, 69%). LCMS (method 2): 1.38 min, 374.9 [M+Na]+.

Stage d. To a stirred solution of the above intermediate (4.43 g, 12.6 mmol) in toluene (128 ml), degassed with argon (over 5 min), was added a solution of tris(trimethylsilyl)silane (3.88 ml, 12 .6 mmol; CAS: 1873-77-4) and AIBN (206 mg, 1.26 mmol; CAS: 7867-1) in degassed toluene (8 ml). The reaction mixture was heated at 60°C for 4 hours, cooled to RT, diluted with 5% aqueous citric acid and extracted with EtOAc. The combined organic layers were separated, washed with water, saturated aqueous sodium bicarbonate and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on an InterChim 4125 (Puriflash HP column with 120 g silica gel, 0-100% EtOAc in cyclohexane) to give tert-butyl-(1S,2R,5S)-1oxo-6-oxabicyclo[3.2. 1]octane-2-carboxylate (2.2 g, 76%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.80 (t, 1H), 3.04 (d, 1H), 2.58-2.46 (m, 2H), 2.14-1.87 ( m, 3H), 1.77 (d, 1H), 1.56-1.55 (m, 1H), 1.47 (s, 9H).

Step f: To a solution of the above intermediate (1.48 g, 6.54 mmol) in THF (26 mL) and water (26 mL) cooled in an ice bath, lithium hydroxide monohydrate (302 mg, 7.19 mmol) was added. and the resulting mixture was stirred for 1 hour. The reaction mixture was acidified to pH 3 using 5% aqueous citric acid, extracted with EtOAc and the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1S,2R,5S)-2-(tert-butoxycarbonyl)-5hydroxycyclohexane-1-carboxylic acid (1.74 g, 98%). LCMS (method 2): 0.88 min, 243.1 [M-N] ^- .

Stage f. To a stirred solution of the above intermediate (1.0 g, 4.09 mmol) in DMF (10 ml) under argon was added iodomethane (0.28 ml, 4.5 mmol) and potassium carbonate (622 mg, 4.5 mmol ) and the reaction mixture was stirred at room temperature. for 2 hours. Additional potassium carbonate (622 mg, 4.5 mmol) and iodomethane (0.28 ml, 4.5 mmol) were added and the reaction mixture was stirred for 2 hours. Additional potassium carbonate (622 mg, 4.5 mmol) was added. 5 mmol) and iodomethane (0.28 ml, 4.5 mmol) and the reaction mixture was stirred for an additional 2 hours. Additional potassium carbonate (622 mg, 4.5 mmol) and iodomethane (0.28 ml, 4.5 mmol) were added and the reaction mixture was stirred for an additional 14 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0-100% EtOAc in cyclohexane) to give 1-(tert-butyl)-2-methyl (1R,2S,4S )-4hydroxycyclohexane-1,2-dicarboxylate (860 mg, 77%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.62 (d, 1H), 3.57-3.57 (m, 3H), 3.46-3.36 (m, 1H), 2, 87 (q, 1H), 2.58 (d, 1H), 1.99-1.98 (m, 2H), 1.65-1.45 (m, 3H), 1.36 (s, 9H) , 1.09 (td, 1H).

Stage g. To a solution of the above intermediate (850 mg, 3.29 mmol) in DMF (11 ml) under argon was added imidazole (717 mg, 10.5 mmol) and tert-butyl(chloro)diphenylsilane (1.37 ml, 5. 26 mmol; CAS: 58479-61-1) and the reaction mixture was stirred at room temperature. under argon for 2 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on InterChim 4125 (InterChim HP column with 80 g silica gel, 0-10% EtOAc in cyclohexane) to give 1-(tert-butyl)-2-methyl-(^^^)-4- ((tert-butyldiphenylsilyl)oxy)cyclohexane-1,2-dicarboxylate (950 mg, 56%). LCMS (method 2): 1.99 min, 519.3 [M+Na]+.

Stage h. To a stirred solution of the above intermediate (810 mg, 1.63 mmol) in DCM (60.353 mL) under argon at 0°C was added 2,6-lutidine (3.61 mL, 31.0 mmol; CAS:

- 167 045906

108-48-5) followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (2.8 ml, 15.49 mmol; CAS: 27607-77-8) and the reaction mixture was stirred at temperatures from 0° C. to RT. under argon atmosphere for 2 hours. The reaction mixture was cooled to 0°C, diluted with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with 10% citric acid, water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1K^^)-4-((tert-butyldiphenylsilyl)oxy)-2-(methoxycarbonyl )cyclohexane-1carboxylic acid (695 mg, 92%). ^1H NMR (400 MHz, CDCl ₃ ) δ 11.44-9.47 (br. s, 1H), 7.68-7.64 (m, 4H), 7.44-7.34 (m, 6H ), 3.76-3.66 (m, 1H), 3.63 (s, 3H), 2.86 (s, 1H), 2.60 (s, 1H), 2.29-2.10 ( m, 2H), 2.05-2.04 (m, 2H), 1.59-1.41 (m, 2H), 1.06-1.05 (m, 9H).

Stage i. To a stirred solution of the above intermediate (690 mg, 1.57 mmol) in anhydrous THF (6 ml) cooled to -25°C under argon, a solution of lithium diisopropylamide (1.0 M in THF/hexane mixture; 3.92 ml, 3.92 mmol; CAS: 4111-54-0) and the reaction mixture was stirred at -25°C for 30 minutes. To this mixture was added dropwise iodomethane (0.29 mL, 4.7 mmol) and the solution was allowed to warm slowly to 15° C. over 3 hours. The reaction mixture was diluted with saturated NH ₄ Cl solution, extracted with EtOAc and the combined organic layers were washed using 10% aqueous citric acid, saline, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1R,2S,4S)-4((tert-butyldiphenylsilyl)oxy)-2-(methoxycarbonyl)- 2-methylcyclohexane-1-carboxylic acid (720 mg, 99%). 1H NMR (400 MHz, CDCl ₃ ) δ 10.66 (br. s, 1H), 7.69-7.65 (m, 4H), 7.44-7.35 (m, 6H), 3.83 -3.75 (m, 1H), 3.61 (s, 3H), 2.63 (t, 1H), 2.28-2.13 (m, 2H), 1.78-1.56 (m , 3H), 1.49-1.32 (m, 2H), 1.06 (s, 11H).

Stage j. To a stirred solution of the above intermediate (709 mg, 1.56 mmol) in DMF (3 ml) at RT. HATU (652 mg, 1.72 mmol) was added under argon and the reaction mixture was stirred for 5 minutes. DIPEA (0.3 mL, 1.72 mmol) was added to this mixture and the mixture was stirred for 16 hours. The reaction mixture was diluted with water, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on an InterChim 4125 (Puriflash HP column with 80 g silica gel, 0-50% EtOAc in cyclohexane) to give 2-(3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl)-1-methyl-(1S,2R,5S)-5-((tert-butyldiphenylsilyl)oxy)-1-methylcyclohexane-1,2-dicarboxylate (630 mg, 67%). 1H NMR (400 MHz, CDCl ₃ ) δ 8.72 (dd, 1H), 8.41 (dd, 1H), 7.70-7.66 (m, 4H), 7.45-7.35 (m , 7H), 3.87-3.81 (m, 1H), 3.73 (s, 3H), 3.13 (dd, 1H), 2.46-2.39 (m, 1H), 2, 25 (dd, 1H), 1.96-1.82 (m, 1H), 1.76-1.70 (m, 1H), 1.66-1.56 (m, 2H), 1.18 ( s, 3H), 1.05 (s, 9H).

Stage k. To a stirred solution ^)-5-((5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-1,2,3,4 -tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride (Example 110, Step b; 310 mg, 0.63 mmol) in DMF (13 ml) was added the above intermediate (436 mg , 0.76 mmol) and DLPEA (0.27 ml, 1.52 mmol) and the reaction mixture was stirred at RT. in an argon atmosphere for 3.5 days. The reaction mixture was diluted with saturated sodium bicarbonate solution, extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on an InterChim 4125 (Puriflash HP column with 80 g silica gel, 0-100% EtOAc in cyclohexane) to give methyl-(1S,2R,5S)-5-((tert-butyldiphenylsilyl)oxy)-2 -(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6oxo-5-azaspiro[ 2.4]getan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylate (880 mg, conditionally quantitative). 1H NMR (400 MHz, CDCl ₃ ) δ 7.70-7.65 (m, 4H), 7.44-7.33 (m, 6H), 7.24 (d, 1H), 6.98-6 .92 (m, 2H), 5.84 (dd, 1H), 5.27 (dd, 2H), 4.19 (s, 3H), 4.07 (dd, 1H), 3.82-3, 78 (m, 2H), 3.72-3.63 (m, 1H), 3.48 (d, 1H), 3.27 (s, 3H), 3.11-3.04 (m, 2H) , 2.92-2.72 (m, 3H), 2.56 (t, 1H), 2.41 (d, 1H), 2.22 (d, 1H), 1.83 (dd, 1H), 1.69-1.52 (m, 2H), 1.46-1.37 (m, 2H), 1.09 (s, 9H), 0.92 (s, 3H), 0.79-0, 70 (m, 2H), 0.66-0.55 (m, 2H).

Step 1: To a stirred solution of the above intermediate (60 mg, 0.07 mmol) in MeOH (4.2 ml) was added a solution of sodium hydroxide (32 mg, 0.81 mmol) in water (0.48 ml) and the reaction mixture heated at 100°C under microwave conditions for 15 hours, then concentrated in vacuo. The residue was diluted with water, acidified to pH 4 using 5% aqueous citric acid, and the resulting precipitate was collected by filtration. The crude product was purified by reverse phase flash column chromatography on InterChim 4125 (C18 InterChim HP, 40 g, 5-70% MeCN in water with 0.1% HCOOH buffer). Fractions containing the desired product were combined and freeze-dried overnight to give the title compound (16 mg, 36%). LCMS (Method 3): 3.70 min, 636.4 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 7.30 (d, 1H), 6.99 (d, 1H), 6.93 (t, 1H), 5.96 (dd, 1H), 5.37- 5.17 (m, 2H), 4.18 (m, 3H), 4.16-3.96 (m, 3H), 3.85 (m, 1H), 3.42 (d, 1H), 3 .16 (dd, 1H), 3.12-3.02 (m, 2H), 2.86-2.67 (m, 2H), 2.60 (m, 1H), 2.41 (d, 1H ), 2.14 (d, 1H), 2.06-1.90 (m, 2H), 1.87-1.22 (m, 3H), 1.17 (s, 3H), 0.73- 0.49 (m, 4H).

Example 224. (1S,2R,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) methoxy) - 168 045906

1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1methylcyclohexane-1-carboxylic acid.

Stage a. To a stirred solution of a mixture of intermediate 36 (2.16 g, 6.29 mmol) in DMF (39 ml) was added intermediate 40 (1.99 g, 6.29 mmol), DIPEA (2.19 ml, 12.6 mmol) and the reaction mixture was stirred at room temperature. under nitrogen atmosphere for 28 hours. The reaction mixture was diluted with brine, extracted with EtOAc and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 80 g silica gel, 0-10% MeOH in DCM) gave methyl-(^.6K)-6-(^)-5-chloro- 8-hydroxy-1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene1-carboxylate ( 1.64 g, 53%). LCMS (method 18): 1.43 min, 487.3 [M+H]+.

Stage b. Methyl-(^,6K)-6-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4yl)methoxy)-1 -( (6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1 methylcyclohex-3-ene-1-carboxylate (2.03 g , 95%) was prepared from the above intermediate (1.64 g, 3.37 mmol) using a procedure similar to that described for Example 11, step b. LCMS (method 16): 1.42 min, 632.3 [M+H]+.

Stage c. To a stirred solution of methyl-(^,6K)-6-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III,2,3-triazol-4-yl)methoxy)- 1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohex-3-ene-1-carboxylate (Example 201 , step c; 304 mg, 0.48 mmol) in THF (2 ml) at 0° C., borane dimethyl sulfide complex (0.09 ml, 0.96 mmol; CAS: 1329287-0) was added dropwise and the mixture was stirred for 1 hour at 0°C. To this mixture was added dropwise sodium hydroxide (0.8 ml, 2.4 mmol) followed by the addition of hydrogen peroxide solution (30 wt% in water; 0.24 ml, 2.4 mmol; CAS: 7722-84-1) . The mixture was stirred for 4 hours, then diluted with water, extracted with EtOAc and the combined organic layers were washed with sodium bisulfite, brine, dried (MgSO ₄ ) and evaporated. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 0-2% MeOH in DCM) to give methyl-(^,2K,5K)-2-(^)-5 -chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylate (50 mg, 12%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.26 (d, 1H), 6.99 (t, 1H), 6.95 (d, 1H), 5.89 (dd, 1H), 5.25 (q, 2H), 4.18 (s, 3H), 4.26-4.19 (m, 1H), 4.12-4.04 (m, 1H), 3.90-3.83 (m , 2H), 3.55 (s, 2H), 3.49 (d, 1H), 3.14-3.07 (m, 1H), 3.03-2.89 (m, 2H), 2, 81-2.68 (m, 1H), 2.66-2.59 (m, 1H), 2.37 (d, 1H), 2.30-2.22 (m, 1H), 2.23 ( d, 1H), 2.09-1.91 (m, 3H), 1.44-1.31 (m, 2H), 1.291.24 (m, 1H), 1.21 (s, 3H), 0 .67-0.52 (m, 4H).

Stage d. To a solution of the above intermediate (45 mg, 0.070 mmol) in MeOH (0.80 ml) was added a solution of sodium hydroxide (28 mg, 0.69 mmol) in water (0.20 ml) and the reaction mixture was heated at 100°C in microwave conditions for 15 hours. The mixture was concentrated in vacuo, diluted with water, and acidified to pH 4 using 5% aqueous citric acid, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by reverse phase flash column chromatography on InterChim 4125 (C18 InterChim HP, 40 g, 5-70% MeCN in water with 0.1% HCOOH buffer). Fractions containing the desired product were combined and freeze-dried overnight to give the title compound (15 mg, 33%). LCMS (Method 3): 3.91 min, 636.4 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 15.36 (bs, 1H), 7.31 (d, 1H), 6.98 (d, 1H), 6.92 (t, 1H), 5.95 ( dd, 1H), 5.39-5.21 (m, 2H), 4.17 (m, 3H), 4.11 (dd, 1H), 4.07-3.81 (m, 3H), 3 .42 (d, 1H), 3.16 (dd, 1H), 3.13-3.02 (m, 2H), 2.76 (m, 1H), 2.64 (m, 1H), 2. 56 (dd, 1H), 2.41 (d, 1H), 2.17-2.04 (m, 2H), 1.94 (m, 1H), 1.78-1.44 (m, 1H) , 1.33 (m, 1H), 1.18 (s, 3H), 1.05 (dd, 1H), 0.75-0.47 (m, 4H).

Example 225. (1S,2R,4R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl) methoxy)1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1methylcyclohexane-1-carboxylic acid .

- 169 045906

To a stirred solution of methyl-(N,2H,4H)-4-((tert-butyldiphenylsilyl)oxy)-2-((R)-5-chloro-8-((5(difluoromethyl)-1-methyl-1H- 1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl) -1-methylcyclohexane-1-carboxylate (example 219, step h; 50 mg, 0.06 mmol) in MeOH (3.5 ml) was added a solution of sodium hydroxide (23 mg, 0.56 mmol) in water (0.50 ml) and the reaction mixture was heated at 100°C under microwave conditions for 17 hours. The reaction mixture was concentrated in vacuo, diluted with water, acidified to pH 4 using 5% aqueous citric acid and the resulting precipitate was collected by filtration. The precipitate was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (Puriflash HC column with 12 g silica gel, 15 μm, 0-5% MeOH in DCM). Fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in 1:1 MeCN/water and freeze-dried overnight to give the title compound (14 mg, 38%). LCMS (method 3): 4.08 min, 636.4 [M+H]+. ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.91 (bs, 1H), 7.57 (t, 1H), 7.40 (d, 1H), 7.17 (d, 1H), 5 .78 (dd, 1H), 5.41-5.23 (m, 2H), 4.62 (d, 1H), 4.15 (s, 3H), 4.05 (dd, 1H), 3, 97 (dd, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 3.44-3.19 (m, 1H), 3.05-2.78 (m, 3H) , 2.77-2.57 (m, 2H), 2.22-2.09 (m, 2H), 1.93-1.44 (m, 5H), 1.33 (m, 1H), 0 .94 (s, 3H), 0.67-0.35 (m, 4H).

Example 226 1((6-oxo-5-azaspuro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2Rpyran-2-carboxylic acid.

Cl Cl

Stage a. Benzyl alcohol (0.17 ml, 1.67 mmol) was added to a solution of tetrahydro-2H-furo[3,4CpyranAD-dione (intermediate for Examples 140 and 226; 260 mg, 1.67 mmol) in toluene (6.5 ml). The reaction mixture was stirred at 100°C for 18 hours and concentrated in vacuo. The crude material was purified on Isolera (Biotage Silica ZIPSphere, 10 g, 0-80% EtOAc in heptane) to give 2-((benzyloxy)carbonyl)tetrahydro-2H-pyran-3-carboxylic acid (340 mg, 70%). ^1H NMR (300 MHz, CDCl ₃ ) δ 7.37-7.32 (m, 5H), 5.29-5.18 (q, 2H), 4.25 (d, 1H), 4.14- 4.05 (m, 1H), 3.62-3.55 (m, 1H), 3.17 (m, 1H), 2.34-2.28 (m, 1H), 1.92-1, 72 (m, 2H), 1.56-1.50 (m, 1H).

Stage b. To a stirred solution of HATU (110 mg, 0.29 mmol) and DIPEA (0.24 mL, 1.36 mmol) in DMF (3 mL) was added ^)-5-((5-chloro-8-((5- (difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]-heptan- 6-one hydrochloride (Example 110, Step b; 123 mg, 0.23 mmol) and the above intermediate (60 mg, 0.230 mmol). The reaction mixture was stirred at room temperature. for 5 days, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (method 6; 0.1% NH4OH 63% to 44% in MeCN for 12 min) to give benzyl-3-((R)-5-chloro-8-((5(difluoromethyl )-1-methyl-III-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)tetrahydro-2H-pyran-2-carboxylate in the form of two isomers. Isomer 1 (34 mg, 21% yield): LCMS (method 9a): 2.32 min, 698.31 [M+H]+. Isomer 2 (56 mg, 35% yield): LCMS (method 9a): 2.41 min, 698.32 [M+H]+.

Stage c. TJM-003-096. To a stirred solution of the above intermediate (isomer 1) (34 mg, 0.05 mmol) in EtOH (2 ml) was added Pd/C (10%; 3 mg, 0.02 mmol) and the reaction mixture was stirred under hydrogen atmosphere at atmospheric pressure for 40 minutes. The reaction mixture was filtered through Celite® and the filter cake was further washed using IMS. The combined organic layers were concentrated under reduced pressure and the crude product was purified by preparative HPLC (Method 6) to give the title compound (1.4 mg, 5%). UPLC (method 13): 1.94 min., 608.2 [M+H]+. 1H NMR (300 MHz, CDCl ₃ ) δ 7.27-7.20 (m, 1H),

- 170 045906

6.94 (t, 1H), 6.91 (d, 1H), 5.88 (dd, 1H), 5.40-5.16 (m, 2H), 4.23-3.70 (m, 8H), 3.66-3.41 (m, 2H), 3.30 (m, 1H), 3.08 (dd, 1H), 2.96 (m, 1H), 2.88 (m, 1H ), 2.78 (m, 1H), 2.27 (m, 2H), 2.11-1.14 (m, 4H), 0.78-0.43 (m, 4H).

Example 227 )1 -((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1 methylcyclohexane-1-carboxylic acid .

Example 228. (^^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-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)-3-hydroxy-1 methylcyclohexane-1-carboxylic acid.

The compounds presented in Table 3 were synthesized by methods similar to those of the examples above.

Table 3

Note Structure Name Analogue from example 1H NMR δ ppm LCMS 65 b Y) X, (о°у ^he φύ ^ΝΛ 0 Вг (15,25)-2-((5)-5-bromo-8-((5methylthiazol-2-yl)methoxy)-1 -((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline -2carbonyl)cyclohexane-1-carbonic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.64 (bs, 1H), 7.54 (m, 1H), 7.52 (d, 1H), 7.02 (d, 1H), 5.93 ( dd, 1H), 5.44 (d, 1H), 5.36 (d, 1H), 4.01-3.85 (m, 2H), 3.65 (m, 1H), 3.56 (m , 1H), 3.38-3.22 (m, 1H), 3.17-3.03 (m, 2H), 2.78 (dd, 1H), 2.67 (m, 1H), 2, 48 (d, 3H), 2.36 (m, 1H), 2.26-1.98 (m, 3H), 1.971.63 (m, 5H), 1.58-1.38 (m, 2H) , 1.29-1.09 (m, 2H). Method 3: 4.20 minutes, 590.0 [M+H] ⁺ 66 Ny.N % Γζ° _γ ° ^Η ХА, Br (15.25)-2-((5)-5-bromo-8-((5isopropyl-1,2,4-oxadiazol-3 yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl)- 1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.70 (bs, 1H), 7.54 (d, 1H), 7.04 (d, 1H), 5.88 (dd, 1H), 5.36 ( d, 1H), 5.29 (d, 1H), 4.02-3.84 (m, 2H), 3.69-3.51 (m, 2H), 3.41-3.26 (m, 2H), 3.17 (m, 1H), 3.10 (dd, 1H), 2.77 (dd, 1H), 2.67 (m, 1H), 2.35 (m, 1H), 2.251, 96 (m, 3H), 1.95-1.77 (m, 2H), 1.77-1.64 (m, 3H), 1.57-1.38 (m, Method 3: 4.48 minutes, 603.0 [M+H] ⁺

- 171 045906

2H), 1.36-1.32 (m, 6H), 1.27-1.07 (m, 2H). 67 Ohl °V) ζ ( ^Ν ο°γ ^ΟΗ Βγ (15.27?)-2-((5)-8-(benzoIisoxazol- 3 -ylmethoxy)-5 -bromo-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carboxylic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 8.05 (m, 1H), 7.83 (m, 1H), 7.72 (m, 1H), 7.57 ( d, 1H), 7.48 (m, 1H), 7.14 (d, 1H), 5.87 (dd, 1H), 5.71 (d, 1H), 5.62 (d, 1H), 3.95 (dd, 1H), 3.87 (dd, 1H), 3.62 (m, 1H), 3.43-3.15 (m, 2H), 2.99 (dd, 1H), 2 .80 (dd, 1H), 2.69 (m, 1H), 2.59 (m, 1H), 2.34 (m, 1H), 2.20-2.02 (m, 2H), 1, 95 (m, 1H), 1.82-1.57 (m, 5H), 1.49 (m, 1H), 1.40 (m, 1H), 1.30-1.01 (m, 2H) . Method 1: 4.57 minutes, 610.0 [M+H] ⁺ 69 % f ο°γ ^ΟΗ ΑΝ'' CI (15.2D)-2-((5)-5-chloro-1-((2- oxopyrrolidin-1 -yl)methyl)-8(pyridin-2-ylmethoxy)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.72 (bs, 1H), 8.61 (m, 1H), 7.92 (td, 1H), 7.63 (m, 1H), 7.39 ( m, 1H), 7.35 (d, 1H), 7.04 (d, 1H), 5.94 (dd, 1H), 5.26-5.17 (m, 2H), 3.97 (dd , 1H), 3.90 (dd, 1H), 3.65 (m, 1H), 3.49 (m, 1H), 3.41-3.20 (m, 1H), 3.15 (m, 1H), 3.02 (m, 1H), 2.84 (dd, 1H), 2.71 (m, 1H), 2.36 (m, 1H), 2.26- Method 3: 3.62 minutes, 526.1 [M+H] ⁺ 1.96 (m, 3H), 1.94-1.62 (m, 5H), 1.52 (m, 1H), 1.42 (m, 1H), 1.281.08 (m, 2H). 70 k / ο°γ ^ΟΗ ' ^Λ 1 CI (15.2R)-2-((5)-5-chloro-8-((5- methylisothiazol-3 -yl)methoxy)-1 -((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carbonic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.71 (bs, 1H), 7.35 (d, 1H), 7.30 (m, 1H), 7.02 (d, 1H), 5.89 ( dd, 1H), 5.23 (d, 1H), 5.17 (d, 1H), 3.96 (dd, 1H), 3.88 (dd, 1H), 3.63 (m, 1H), 3.50 (m, 1H), 3.44-3.20 (m, 1H), 3.15-3.01 (m, 2H), 2.83 (dd, 1H), 2.70 (m, 1H), 2.59 (d, 3H), 2.35 (m, 1H), 2.27-2.08 (m, 2H), 2.03 (m, 1H), 1.96-1.62 (m, 5H), 1.51 (m, 1H), 1.42 (m, 1H), 1.29-1.08 (m, 2H). Method 3: 4.34 minutes, 546.1 [M+H] ⁺ 71 % / ο°γ ^ΟΗ λΉ α (15.27?)-2-((5)-5-chloro-8-(isothiazol-3ylmethoxy)-1 -((2-oxopyrrolidin-1yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carbonic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.71 (bs, 1H), 9.16 (d, 1H), 7.56 (d, 1H), 7.36 (d, 1H), 7.05 ( d, 1H), 5.89 (dd, 1H), 5.33 (d, 1H), 5.26 (d, 1H), 3.96 (dd, 1H), 3.88 (dd, 1H), 3.63 (m, 1H), 3.46 (m, 1H), 3.40-3.25 (m, 1H), 3.09 (dd, 1H), 3.00 (m, 1H), 2 .84 (dd, 1H), 2.70 (m, 1H), 2.35 (m, 1H), 2.24-2.08 (m, 2H), 2.02 (m, 1H), Method 3: 4.12 minutes, 532.1 [M+H] ⁺

- 172 045906

1.95-1.62 (m, 5H), 1.52 (m, 1H), 1.43 (m, 1H), 1.28-1.07 (m, 2H). 72 4 Ζο°γ ^ΟΗ ί,όΥ Cl (15.27?)-2-((5)-8-(benzo[</]isoxazole- 3 -ylmethoxy)-5 -chloro-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carboxylic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.71 (bs, 1H), 8.05 (m, 1H), 7.83 (m, 1H), 7.72 (m, 1H), 7.48 ( m, 1H), 7.42 (d, 1H), 7.19 (d, 1H), 5.87 (dd, 1H), 5.71 (d, 1H), 5.62 (d, 1H), 3.95 (dd, 1H), 3.87 (dd, 1H), 3.62 (m, 1H), 3.39-3.27 (m, 1H), 3.23 (m, 1H), 2 .99 (dd, 1H), 2.84 (dd, 1H), 2.782.64 (m, 1H), 2.60 (m, 1H), 2.35 (m, 1H), 2.19-2, 03 (m, 2H), 1.95 (m, 1H), 1.82-1.57 (m, 5H), 1.50 (m, 1H), 1.40 (m, 1H), 1.28 -1.01 (m, 2H). Method 1: 4.50 minutes, 566 [M+H] ⁺ 75 h Ν-Ν ογγ. to z ^N o°Y ^OH Br (15.2D)-2-((5)-5-bromo-8-((1- isopropyl-III-1,2,3-triazol-4yl)methoxy)-1 -(((7?)-4-methyl-2oxopyrrolidin-1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carbonic acid 64 (400 MHz, DMSO-d ₆ ) δ 11.70 (bs, 1H), 8.43 (s, 1H), 7.52 (d, 1H), 7.07 (d, 1H), 5.76 ( dd, 1H), 5.25-5.10 (m, 2H), 4.87 (m, 1H), 3.95 (dd, 1H), 3.86 (dd, 1H), 3.61 (m , 1H), 3.393.24 (m, 1H), 3.02-2.87 (m, 3H), 2.82-2.61 (m, 2H), 2.40-2.18 (m, 3H ), 2.10 (m, 1H), 1.81-1.61 (m, Method 3: 4.14 minutes, 616 [M+H] ⁺ 4H), 1.57-1.32 (m, 8H), 1.31-1.10 (m, 2H), 0.96 (d, 3H). 76 A Ν-Ν Vn o^y\ to ζ ^Ν Χθν ^0Η Br (15,2R)-2-((5)-5-bromo-8-((1isopropyl-III-1,2,3-triazol-4yl)methoxy)-1 -((6-oxo-5azaspiro[2.4] heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 135 (400 MHz, DMSO-d ₆ ) δ 11.71 (bs, 1H), 8.39 (s, 1H), 7.52 (d, 1H), 7.07 (d, 1H), 5.79 ( dd, 1H), 5.23-5.10 (m, 2H), 4.84 (m, 1H), 4.04-3.87 (m, 2H), 3.62 (m, 1H), 3 .41-3.24 (m, 2H), 3.04 (dd, 1H), 2.84-2.73 (m, 2H), 2.66 (m, 1H), 2.33 (m, 1H ), 2.27-2.04 (m, 3H), 1.81-1.62 (m, 3H), 1.58-1.31 (m, 8H), 1.30-1.10 (m , 2H), 0.59 (m, 1H), 0.55-0.47 (m, 2H), 0.44 (m, 1H). Method 3: 4.21 minutes, 628 [M+H] ⁺ 77 A NN M>°vy·' ¹ 4 / o V ^H ¢0% Br (15.2D)-2-((5)-5-bromo-8-((1- isopropyl-III-1,2,3-triazol-4yl)methoxy)-1 -(((5)-4-methyl-2oxopyrrolidin-1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carbonic acid 64 separated at the last stage from the connection from the example 75 (400 MHz, DMSO-d ₆ ) δ 11.14 (bs, 1H), 8.41 (s, 1H), 7.52 (d, 1H), 7.08 (d, 1H), 5.77 ( dd, 1H), 5.24-5.10 (m, 2H), 4.87 (m, 1H), 3.95 (dd, 1H), 3.83 (dd, 1H), 3.58 (m , 1H), 3.44 (m, 1H), 3.40-3.20 (m, 1H), 2.96 (dd, 1H), 2.82-2.56 (m, 2H), 2, 55-2.42 (m, 1H), 2.33 (m, 1H), 2.24-2.02 (m, 3H), 1.82 (m, 1H), 1.76-1.62 ( m, 3H), 1.56-1.33 (m, 8H), 1.15 (m, Method 3: 4.12 minutes, 616 [M+H] ⁺ .

- 173 045906

2H), 0.96 (d, ZN). 78 z=Z cAvaO Ab Λ ζ (15.27?)-2-((5)-5-chloro-1 -((2oxopyrrolidin-1 -yl)methyl)-8(pyrridin-3 -ylmethoxy)-1,2,3,4tetrahydroisoquinoline-2carbonyl )cyclohexane-1-carboxylic acid 68 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 8.76 (d, 1H), 8.60 (dd, 1H), 7.97 (dt, 1H), 7.49 ( m, 1H), 7.39 (d, 1H), 7.08 (d, 1H), 5.87 (dd, 1H), 5.23 (d, 1H), 5.14 (d, 1H), 3.96 (dd, 1H), 3.88 (dd, 1H), 3.63 (m, 1H), 3.43-3.27 (m, 2H), 3.02 (dd, 1H), 2 .89-2.79 (m, 2H), 2.70 (m, 1H), 2.34 (m, 1H), 2.26-2.04 (m, 2H), 2.00 (m, 1H ), 1.91-1.62 (m, 5H), 1.50 (m, 1H), 1.42 (m, 1H), 1.271.05 (m, 2H). Method 3: 3.17 minutes, 526.2 [M+H] ⁺ 82 Ν-Ν ¹ - * No- , F ϊ A ο i υ °'< ^ϋΗ 1 IL 1 i Г ^N 1 T ~ Cl (15.27?)-2-((5)-5-chloro-8-((5(difluoromethyl)-1-methyl-1R-1,2,3triazol-4-yl)methoxy)-1 -(( 2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 68 (400 MHz, DMSO-d ₆ ) δ 7.58 (t, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 5.75 (dd, 1H), 5.29 ( s, 2H), 4.18 (s, 3H), 3.93 (dd, 1H), 3.82 (dd, 1H), 3.56 (m, 1H), 3.48-3.27 (m , 2H), 2.95 (dd, 1H), 2.90-2.65 (m, 3H), 2.23-2.08 (m, 3H), 1.99 (m, 1H), 1, 90-1.62 (m, 5H), 1.52-1.31 (m, 2H), 1.29-1.10 (m, 2H). Method 3: 3.93 minutes, 580.2 [M+H] ⁺ 83 J yo NN 0¾ IN— ' ” О OH ⁰ ( Ί 1 jj ;i Cl (15.27?)-2-((5)-5-chloro-8-((5isopropyl-1,2,4-oxadiazol-3 yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl) -1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 68 (400 MHz, DMSO-d ₆ ) δ 11.71 (bs, 1H), 7.38 (d, 1H), 7.09 (d, 1H), 5.88 (dd, 1H), 5.37 ( d, 1H), 5.29 (d, 1H), 4.02-3.85 (m, 2H), 3.68-3.52 (m, 2H), 3.43-3.24 (m, 2H), 3.17 (m, 1H), 3.10 (dd, 1H), 2.83 (dd, 1H), 2.76-2.63 (m, 1H), 2.34 (m, 1H ), 2.25-2.08 (m, 2H), 2.02 (m, 1H), 1.95-1.77 (m, 2H), 1.77-1.64 (m, 3H), 1.51 (m, 1H), 1.42 (m, 1H), 1.34 (m, 6H), 1.25-1.10 (m, 2H). Method 3: 4.39 minutes, 559.3 [M+H] ⁺ 85 N^N A % / ο°γ ^ΟΗ ¢0 U Cl (15.27?)-2-((5)-5-chloro-1-((2oxopyrrolidin-1-yl)methyl)-8(pyrimidin-5-ylmethoxy)-1,2,3,4tetrahydroisoquinoline-2carbonyl) cyclohexane-1-carbonic acid AND (400 MHz, DMSO-d ₆ ) δ 11.65 (bs, 1H), 9.23 (s, 1H), 9.02 (s, 2H), 7.41 (d, 1H), 7.09 ( d, 1H), 5.86 (dd, 1H), 5.26 (d, 1H), 5.17 (d, 1H), 3.97 (dd, 1H), 3.87 (dd, 1H), 3.63 (m, 1H), 3.48-3.12 (m, 2H), 3.03 (dd, 1H), 2.91-2.78 (m, 2H), 2.71 (m, 1H), 2.33 (m, 1H), 2.23-2.05 (m, 2H), 1.99 (m, 1H), 1.91-1.63 (m, 5H), 1.51 (m, 1H), 1.41 (m, 1H), 1.271.06 (m, 2H). Method 3: 3.62 minutes, 527.2 [M+H] ⁺

- 174 045906

88 Π NyJ % / ο°γ ^ΟΗ Cl (15.27?)-2-((5)-5-chloro-1-((2- oxopyrrolidin-1 -yl)methyl)-8(pyridazin-3 -ylmethoxy)-1,2,3,4tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carbonic acid AND (400 MHz, DMSO-d ₆ ) δ 11.66 (bs, 1H), 9.26 (dd, 1H), 7.94 (dd, 1H), 7.84 (dd, 1H), 7.38 ( d, 1H), 7.11 (d, 1H), 5.91 (dd, 1H), 5.48 (d, 1H), 5.42 (d, 1H), 3.97 (dd, 1H), 3.88 (dd, 1H), 3.64 (m, 1H), 3.43 (m, 1H), 3.39-3.24 (m, 1H), 3.12 (dd, 1H), 2 .97 (m, 1H), 2.85 (dd, 1H), 2.71 (m, 1H), 2.35 (m, 1H), 2.25-2.07 (m, 2H), 2. 01 (m, 1H), 1.93-1.62 (m, 5H), 1.52 (m, 1H), 1.42 (m, 1H), 1.27-1.08 (m, 2H) . Method 3: 3.57 minutes, 527.2 [M+H] ⁺ 89 ο o ^z V-9¾ .2 o >=< _z Qa/ ^o ~V> ³ ζ=^ (15',27?)-2-((5)-5-chloro-8-((3-methyl-3-imidazo[4,5-/>]pyridin-6yl)methoxy)-1 -((2-oxopyrrolidine1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid AND (400 MHz, DMSO-d ₆ ) δ 11.76 (bs, 1H), 8.57 (d, 1H), 8.47 (s, 1H), 8.28 (d, 1H), 7.38 ( d, 1H), 7.13 (d, 1H), 5.86 (dd, 1H), 5.34 (d, 1H), 5.26 (d, 1H), 3.95 (dd, 1H), 3.91-3.81 (m, 4H), 3.62 (m, 1H), 3.48-3.16 (m, 2H), 3.03 (dd, 1H), 2.84 (dd, 1H), 2.79-2.63 (m, 2H), 2.32 (m, 1H), 2.20-2.03 (m, 2H), 1.96 (m, 1H), 1.77 -1.60 (m, 5H), 1.49 (m, 1H), 1.40 (m, 1H), 1.26-1.05 (m, 2H). Method 3: 3.55 minutes, 580.3 [M+H] ⁺ 90 ν-ν! Ν « 7 Ο, - , Γ nJ ^{1 Ν} Ο ₄ ,ΟΗ •,'ΑΤ CI (15.27?)-2-((5)-5-chloro-8-(( 1 -methyl- 1HbenzoI[1,2,3]triazol-5yl)methoxy)-1 -((2-oxopyrrolidin1 -yl )methyl)-1,2,3,4- tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid AND (400 MHz, DMSO-d ₆ ) δ 11.70 (bs, 1H), 8.20 (s, 1H), 7.93 (dd, 1H), 7.73 (dd, 1H), 7.38 ( d, 1H), 7.10 (d, 1H), 5.92 (dd, 1H), 5.35 (d, 1H), 5.27 (d, 1H), 4.33 (s, 3H), 3.96 (dd, 1H), 3.89 (dd, 1H), 3.63 (m, 1H), 3.48-3.18 (m, 2H), 3.08 (dd, 1H), 2 .93-2.79 (m, 2H), 2.78-2.64 (m, 1H), 2.31 (m, 1H), 2.20-2.06 (m, 2H), 1.98 (m, 1H), 1.80-1.63 (m, 5H), 1.49 (m, 1H), 1.41 (m, 1H), 1.24-1.09 (m, 2H). Method 11: 1.25 minutes, 578.0 [M-N]- 92 Ρ'ν W VN Ο=Ζ% Χ _ο / ο °γ ^ΟΗ Cl (15',27?)-2-((5)-5-chloro-8-(imidazo[1,2a\pyrimidin-2-ylmethoxy)-1 -((2oxopyrrolidin-1-yl)methyl)-1, 2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid AND (400 MHz, DMSO-d ₆ ) δ 11.72 (bs, 1H), 9.02 (dd, 1H), 8.55 (dd, 1H), 8.03 (s, 1H), 7.35 ( d, 1H), 7.13 (d, 1H), 7.07 (dd, 1H), 5.92 (dd, 1H), 5.33 (s, 2H), 3.96 (dd, 1H), 3.87 (dd, 1H), 3.62 (m, 1H), 3.49 (m, 1H), 3.44-3.24 (m, 1H), 3.21 (dd, 1H), 3 .07 (m, 1H), 2.83 (m, 1H), 2.74 (m, 1H), 2.31 (m, 1H), 2.23-2.07 (m, 2H), 2, 01 (m, 1H), 1.87-1.65 (m, 5H), 1.50 (m, 1H), 1.42 (m, 1H), Method 3: 3.26 minutes, 566.2 [M+H] ⁺

- 175 045906

1.24-1.10 (m, 2H).

α (15.27?)-2-((5)-5-chloro-8(isoxazolo[5,4-th]pyridin-3ylmethoxy)-1 -((2-oxopyrrolidin-1yl)methyl)-1, 2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid

(400 MHz, DMSO-d ₆ ) δ 11.73 (bs, 1H), 8.74 (dd, 1H), 8.57 (dd, 1H), 7.60 (dd, 1H), 7.41 ( d, 1H), 7.17 (d, 1H), 5.89 (dd, 1H), 5.71 (d, 1H), 5.63 (d, 1H), 3.96 (dd, 1H), 3.87 (dd, Method 11 3.18 And 1H), 3.63 (m, 1H), 3.45-3.19 (m, minutes, 2H), 3.01 (dd, 1H), 2.84 (dd, 1H), 567.3 2.78-2.64 (m, 2H), 2.33 (m, 1H), 2.22-2.05 (m, 2H), 1.96 (m, 1H), 1.79-1, 61 (m, 5H), 1.50 (m, 1H), 1.41 (m, 1H), 1.26-1.06 (m, 2H). [M+H] ⁺

(15.27?)-2-((5)-8-([1,2,4]triazolo[4,3a\pyridin-3-ylmethoxy)-5-chloro-1 ((2-oxopyrrolidine-1 - yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid (400 MHz, DMSO-d ₆ ) δ 11.69 (bs, 1H), 8.72 (dt, 1H), 7.86 (dt, 1H), 7.48 (m, 1H), 7.42 (d, 1H), 7.25 (d, 1H), 7.12 (td, 1H), 5.81-5 .68 (m, 3H), 3.95 (dd, 1H), 3.80 (dd, 1H), 3.57 (m, 1H), 3.50-3.18 (m, 1H),

Method 3: 2.87 minutes, 566.3 [M+H] ⁺

3.06 (m, 1H), 2.87-2.77 (m, 2H), 2.69 (m, 1H), 2.41-2.25 (m, 2H), 2.15-2, 02 (m, 2H), 1.92 (m, 1H), 1.76-1.56 (m, 5H), 1.47 (m, 1H), 1.37 (m, 1H), 1.25 -0.99 (m, 2H).

Cl

a (15.27?)-2-((5)-5-chloro-8-((3methylisoxazolo[5,4-/>]pyridin-6yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl )-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid

3-((8)-5-chloro-8-((5-(difluoromethyl)-1methyl-\H-1,2,3-triazol-4yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl )-1,2,3,4tetrahydroisoquinoline-2carbonyl)tetrahydrofuran-2carboxylic acid

AND (400 MHz, DMSO-d ₆ ) δ 11.75 (bs, 1H), 8.53 (d, 1H), 7.72 (d, 1H), 7.36 (d, 1H), 7.04 ( d, 1H), 6.00 (dd, 1H), 5.48-5.33 (m, 2H), 4.04-3.82 (m, 2H), 3.66 (m, 1H), 3 .57 (m, 1H), 3.46-3.27 (m, 1H), 3.24 (dd, 1H), 3.15 (m, 1H), 2.90-2.68 (m, 2H ), 2.60 (s, 3H), 2.31 (m, 1H), 2.27-1.96 (m, 3H), 1.96-1.62 (m, 5H), 1.52 ( m, 1H), 1.43 (m, 1H), 1.28-1.08 (m, 2H). Method 11: 3.26 minutes, 581.3 [M+H] ⁺ Method 3: 3.43 226 minutes, 566.2 [M-N]-

- 176 045906

98 CW Ma Ch / ο °Υ ^ΟΗ Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-1-indazol-3-yl)methoxy)-1-((2oxopyrrolidin-1-yl)methyl)-1, 2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid AND (400 MHz, DMSO-d ₆ ) δ 11.72 (bs, 1H), 7.91 (m, 1H), 7.67 (m, 1H), 7.44 (m, 1H), 7.38 ( d, 1H), 7.28-7.17 (m, 2H), 5.78 (dd, 1H), 5.50 (d, 1H), 5.44 (d, 1H), 4.07 (s , 3H), 3.93 (dd, 1H), 3.82 (dd, 1H), 3.59 (m, 1H), 3.45-3.20 (m, 1H), 3.13 (m, 1H), 2.95 (dd, 1H), 2.82 (dd, 1H), 2.762.62 (m, 1H), 2.44 (m, 1H), 2.31 (m, 1H), 2, 16-2.01 (m, 2H), 1.99-1.86 (m, 1H), 1.77-1.55 (m, 5H), 1.47 (m, 1H), 1.38 ( m, 1H), 1.13 (m, 2H). Method 3: 4.62 minutes, 577.2 [M-H]- 99 Ν=Λ % / _Ο °γ ^ΟΗ ' ¹ Cl (15.27?)-2-((5)-5-chloro-8-((3-methyl-3Namidazo[4,5-/>]pyridin-5yl)methoxy)-1 -((2-oxopyrrolidine1 - yl)methyl)-1,2,3,4tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 29 (400 MHz, DMSO-d ₆ ) δ 11.67 (bs, 1H), 8.45 (s, 1H), 8.18 (d, 1H), 7.54 (d, 1H), 7.35 ( d, 1H), 7.09 (d, 1H), 5.96 (dd, 1H), 5.37 (d, 1H), 5.31 (d, 1H), 3.97 (dd, 1H), 3.91 (dd, 1H), 3.85 (s, 3H), 3.64 (m, 1H), 3.45 (m, 1H), 3.41-3.23 (m, 1H), 3 .19 (dd, 1H), 2.92 (m, 1H), 2.84 (dd, 1H), 2.79-2.65 (m, 1H), 2.32 (bm, 1H), 2, 22-2.05 (m, 2H), 2.00 (m, 1H), 1.86-1.63 (m, 5H), 1.51 (bm, 1H), Method 3: 3.52 minutes, 578.3 [M-N] 1.42 (bm, 1H), 1.18 (bm, 2H). 100 VLn _ο γχ % Γο°γ ^ΟΗ Λ X'l α (15.27?)-2-((5)-8-(benzoIisoxazol- 3 -ylmethoxy)-5 -chloro-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.84 (bs, 1H), 8.04 (dt, 1H), 7.83 (dt, 1H), 7.72 (m, 1H), 7.48 ( m, 1H), 7.41 (d, 1H), 7.18 (d, 1H), 5.88 (dd, 1H), 5.71 (d, 1H), 5.63 (d, 1H), 3.95 (dd, 1H), 3.87 (dd, 1H), 3.61 (m, 1H), 3.24 (m, 1H), 3.04-2.95 (m, 2H), 2 .84 (dd, 1H), 2.79-2.65 (m, 1H), 2.61 (m, 1H), 2.24 (m, 1H), 2.10 (m, 1H), 1, 95 (m, 1H), 1.73-1.60 (m, 3H), 1.60-1.45 (m, 2H), 1.45-1.27 (m, 3H), 1.26- 1.12 (m, 1H), 1.09 (s, 3H). Method 3: 4.90 minutes, 580.2 [M+H] ⁺ 103 ¥= ^ν , - ^Ν γ ^Ν ο=^ % Λ _Ο °γ ^ΟΗ Α'-Γ α (15.2R)-2-((5)-5-chloro-8-((4.5- d imethyl-4R-1,2,4-triazol-3 yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carboxylic acid 29 (400 MHz, DMSO-d ₆ ) δ 11.73 (bs, 1H), 7.38 (d, 1H), 7.19 (d, 1H), 5.82 (m, 1H), 5.40- 5.25 (m, 2H), 3.96 (dd, 1H), 3.85 (dd, 1H), 3.70-3.53 (m, 4H), 3.53-3.06 (m, 2H), 3.002.87 (m, 2H), 2.82 (dd, 1H), 2.71 (m, 1H), 2.40-2.26 (m, 4H), 2.23-1.94 (m, 3H), 1.93-1.60 (m, 5H), 1.51 (m, 1H), 1.42 (m, 1H), 1.27-1.06 (m, Method 1: 3.14 minutes, 545.1 [M+H] ⁺

- 177 045906

2H). 106 \ Ν-Ν Ϋ°Ό k g o _h .on o / ⁰ Υ G ζόυ Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-1R1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1 -yl )methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.76 (bs, 1H), 8.24 (s, 1H), 7.35 (d, 1H), 7.13 (d, 1H), 5.81 ( dd, 1H), 5.26-5.16 (m, 2H), 4.07 (s, 3H), 3.95 (dd, 1H), 3.83 (dd, 1H), 3.59 (m , 1H), 3.42 (m, 1H), 3.08-2.92 (m, 3H), 2.82 (dd, 1H), 2.69 (m, 1H), 2.30-2, 09 (m, 2H), 2.01 (m, 1H), 1.94-1.71 (m, 2H), 1.71-1.47 (m, 3H), 1.46-1.28 ( m, 3H), 1.28-1.13 (m, 1H), 1.10 (s, 3H). Method 3: 3.93 minutes, 544.3 [M+H] ⁺ 107 O—O Ζ'“ ^ζ t (15.2R)-2-((5)-5-chloro-8-((1.5- dimethyl-1R-1,2,3-triazole-4- yl)methoxy)-1 -((2-oxopyrrolidine- 1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 1-methylcyclohexane-1-carboxylic acid 105 (300 MHz, CDC1 ₃ ) δ 7.29 (d, 1H), 7.00 (d, 1H), 5.95 (m, 1H), 5.20 (d, 1H), 5.11 (d, 1H), 4.11-3.53 (m, 7H), 3.24-2.98 (m, 3H), 2.74 (m, 1H), 2.57 (m, 1H), 2.47 -2.06 (m, 6H), 1.98-0.89 (m, 12H). Method 8: 1.10 minutes, 558.4 [M+H] ⁺ 113 Ν-Ν | ^F k/ ^Y O-.LN O/O V UO YU CI (15.27?)-2-((15)-5-chloro-8-((5(difluoromethyl)-1-methyl-1R-1,2,3triazol-4-yl)methoxy)-1 -(( (7?)-3 methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3,4- 112 (400 MHz, CDC1 ₃ ) δ 7.31-7.21 (m, 1H), 7.13-6.81 (m, 2H), 5.89 (m, 1H), 5.33-5.20 (m, 2H), 4.19 (s, 3H), 4.01 (m, 1H), 3.89 (m, 2H), 3.55 (m, 1H), 3.12 (m, 1H) , 2.99 (m, 2H), Method 10: 2.28 minutes, 594.5 [M+H] ⁺ tetrahydroisoquinoline-2-carbonyl)1-methylcyclopentane-1-carboxylic acid 2.79 (m, 2H), 2.53 (m, 1H), 2.24 (m, 1H), 2.13 (m, 2H), 1.74 (m, 1H), 1.52 (m , 1H), 1.41 (m, 1H), 1.311.22 (m, 4H), 1.18-1.06 (m, 4H). 114 Ν-Ν 1 νγο<) F 1 Ν—* _η ^h o / o V ^0H /ku Cl (15.2R)-2-((15)-5-chloro-8-((5- (difluoromethyl)-1 -methyl-1R-1,2,3triazol-4-yl)methoxy)-1 -(((5)-3 methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3, 4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclopentane-1-carboxylic acid 112 (400 MHz, CDC1 ₃ ) δ 7.27 (d, 1H), 6.97 (t, 1H), 6.95 (d, 1H), 5.91 (dd, 1H), 5.32-5, 21 (m, 2H), 4.19 (s, 3H), 3.99 (dd, 1H), 3.90 (m, 2H), 3.50 (td, 1H), 3.08 (dd, 1H ), 3.04-2.95 (m, 2H), 2.84-2.70 (m, 2H), 2.54 (m, 1H), 2.34 (m, 1H), 2.13 ( m, 2H), 1.92-1.33 (m, 3H), 1.31-1.21 (m, 4H), 1.15-1.06 (m, 4H). Method 10: 2.26 minutes, 594.2 [M+H] ⁺ 115 b , ..... Ν-Ν 1 ^F y4yN o=y> ^F to / o°y ^he 7 · '· CI (15.27?)-2-((15)-5-chloro-8-((5(difluoromethyl)-1-methyl-1R-1,2,3triazol-4-yl)methoxy)-1 -(( (5)-3 methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 112 (400 MHz, CDC1 ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 6.95 (t, 1H), 5.95 (dd, 1H), 5.35-5, 22 (m, 2H), 4.20 (s, 3H), 4.07-3.94 (m, 2H), 3.86 (m, 1H), 3.52 (td, 1H), 3.16 -2.96 (m, 3H), 2.75 (m, 1H), 2.54 (m, 1H), 2.442.29 (m, 2H), 2.20-2.11 (m, 1H), 1.86-1.73 (m, 2H), 1.70-1.15 (m, 5H), 1.12 (s, 3H), 1.08 (d, 3H), 1.01 (m, 1H). Method 10: 2.50 minutes, 608.5 [M+H] ⁺

- 178 045906

116 NN F 1 N-^ _o % / q uon ¢0 u Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -methyl- 1H-1,2,3triazol-4-yl)methoxy)-1 -(((5)-4methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3,4 - tetrahydroisoquinoline-2-carbonyl)1-methylcyclopentane-1-carboxylic acid 111 (300 MHz, DMSO-d ₆ ) δ 7.60 (t, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 5.84 (m, 1H), 5.31 ( s, 2H), 4.18 (s, 3H), 3.83 (m, 1H), 3.48 (m, 2H), 3.38-1.33 (m, 15H), 0.99-0 .95 (m, 6H). Method 10: 2.28 minutes, 594.2 [M+H] ⁺ 118 ⁴ NN ^F yAyN o=uch FTN—' _o ⁴ O / 0 ΥθΗ W' Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -methyl- 1H-1,2,3triazol-4-yl)methoxy)-1 -((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)1 - ethylcyclopentane-1-carboxylic acid 117 (400 MHz, DMSO-d ₆ ) δ 11.43 (bs, 1H), 7.59 (t, 1H), 7.39 (d, 1H), 7.15 (d, 1H), 5.72 ( dd, 1H), 5.29 (s, 2H), 4.18 (s, 3H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.66-3.51 (m , 1H), 3.40 (m, 1H), 3.07 (m, 1H), 2.96-2.89 (dd, 1H), 2.89-2.78 (m, 2H), 2, 75-2.60 (m, 1H), 2.25-2.10 (m, 2H), 2.021.89 (m, 2H), 1.89-1.66 (m, 2H), 1.63- 1.38 (m, 6H), 0.75 (t, 3H). Method 3: 4.23 minutes, 592.5 [M+H] ⁺ 119 'X-AJn Osa/Y ^F L / oV Vv Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -ethyl-1H-1,2,3triazol-4-yl)methoxy)-1 -((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)- 102 (400 MHz, DMSO-d ₆ ) δ 11.44 (bs, 1H), 7.63 (t, 1H), 7.40 (d, 1H), 7.15 (d, 1H), 5.70 ( dd, 1H), 5.28 (s, 2H), 4.55 (m, 2H), 3.99 (dd, 1H), 3.85 (dd, 1H), 3.56 (m, 1H), 3.47-3.20 Method For: 2.75 minutes, 592.4 [M-N]' 1-methylcyclopentane-1-carboxylic acid (m, 1H), 3.03 (m, 1H), 2.90 (dd, 1H), 2.84 (dd, 1H), 2.76-2.60 (m, 2H), 2.36- 2.23 (m, 1H), 2.23-1.51 (m, 8H), 1.50-1.34 (m, 4H), 1.14 (s, 3H). 120 N~N ' ,- ^J N θ ^F Г°°Г i'V ΐ ^Λ 1 1 '' (1X.27?)-2-((5)-5-chloro-8-((5(difluoromethyl)-1-ethyl-1H-1,2,3triazol-4-yl)methoxy)-1 -(( 2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz; DMSO-d ₆ ) δ: 11.81 (bs, 1H), 7.62 (t, 1 H), 7.41 (d, 0.07 H), 7.38 (d, 0. 93 H), 7.19 (d, 0.07 H), 7.14 (d, 0.93 H), 5.76 (dd, 0.75 H), 5.01 (dd, 0.25 H) , 5.29 (s, 2 H), 4.56 (q, 2 H), 3.95 (dd, 1 H), 3.83 (dd, 1H), 3.65-3.51 (m, 1 H), 2.98-2.91 (m, 2 H), 2.80-2.66 (m, 3 H), 2.262.11 (m, 3 H), 2.02-1.94 ( m, 1 H), 1.85-1.71 (m, 2 H), 1.64-1.49 (m, 3 H), 1.46 (t, 3 H), 1.42-1, 32 (m, 3H), 1.21-1.14 (m, 1H), 1.09 (s, 3H). Method For: 3.00 minutes, 608.5 [M+N] ⁺ 121 A N—N ^F yA> ^F % / o°Y ^OH c'C ^F Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -isopropyl-1H1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)1 - methylcyclohexane-1-carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.81 (bs, 1H), 7.64 (t, 1H), 7.39 (d, 1H), 7.14 (d, 1H), 5.75 ( dd, 1H), 5.32-5.24 (m, 2H), 4.92 (m, 1H), 3.95 (dd, 1H), 3.84 (dd, 1H), 3.57 (m , 1H), 3.413.17 (m, 1H), 2.97 (m, 1H), 2.90 (dd, 1H), 2.82 (dd, 1H), 2.76-2.63 (m, Method 3: 4.79 minutes, 622.0 [M+H] ⁺

- 179 045906

2H), 2.30-2.08 (m, 2H), 1.97 (w, 1H), 1.84-1.67 (m, 2H), 1.66-1.45 (m, 9H) , 1.44-1.26 (w, ZN), 1.241.00 (m, 4N). 122 4 NN ^F -yA> ^F to / o ^Q Y° ^H Cl (15.2R)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -isopropyl-1H1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)1 - methylcyclopentane-1-carboxylic acid 102 (400 MHz, DMSO-d ₆ ) δ 11.45 (bs, 1H), 7.64 (t, 1H), 7.40 (d, 1H), 7.14 (d, 1H), 5.68 ( dd, 1H), 5.40-5.22 (m, 2H), 4.92 (m, 1H), 3.99 (dd, 1H), 3.86 (dd, 1H), 3.55 (m , 1H), 3.473.20 (m, 1H), 3.03 (m, 1H), 2.912.76 (m, 2H), 2.72-2.58 (m, 2H), 2.35-2, 24 (m, 1H), 2.21-1.83 (m, 3H), 1.80-1.50 (m, 11H), 1.44-1.34 (m, 1H), 1.14 ( s, 3H). Method For: 2.64 minutes, 608.5 [M+H] ⁺ 124 _4n _r - 1 , ^N >, о OH ΐ 1 11' Г !i J Ί J T ~ Cl (15.2D)-2-((5)-5-chloro-8-((4.5- d imethylisoxazol-3 -yl)methoxy)-1 ((2-oxopyrrolidin-1 -yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.82 (bs, 1H), 7.37 (d, 1H), 7.09 (d, 1H), 5.86 (dd, 1H), 5.24 ( d, 1H), 5.18 (d, 1H), 3.96 (dd, 1H), 3.88 (dd, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.06-2.93 (m, 3H), 2.83 (dd, 1H), 2.78-2.64 (m, 1H), 2.35 (s, 3H), 2.30-2, 10 (m, 2H), 2.06-1.94 (m, 4H), 1.94-1.72 (m, 2H), 1.71-1.47 (m, 3H), 1.45- 1.28 Method 2: 4.69 minutes, 556.4 [M-N]- (m, 3H), 1.27-1.14 (m, 1H), 1.10 (s, 3H). 125 U ^O ^| O.. ΟΙ-Ά^Ν γ-\ % f ^N ^°Y ^OH c'-v Cl (15.27?)-2-((5)-5-chloro-8-((4-chloro-5methylisoxazol-3 -yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1, 2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.84 (bs, 1H), 7.38 (d, 1H), 7.10 (d, 1H), 5.87 (dd, 1H), 5.32 ( d, 1H), 5.23 (d, 1H), 3.95 (dd, 1H), 3.88 (dd, 1H), 3.60 (m, 1H), 3.51 (m, 1H), 3.10-2.92 (m, 3H), 2.87-2.65 (m, 2H), 2.47 (s, 3H), 2.30-2.11 (m, 2H), 2. 00 (m, 1H), 1.94-1.73 (m, 2H), 1.71-1.47 (m, 3H), 1.46-1.13 (m, 4H), 1.08 ( s, 3H). Method 1: 4.87 minutes, 578.4 [M+H]- 126 _N °UL t~0 f ^N /°Y ^OH Cl (15.2R)-2-((5)-5-chloro-8-((4- methylisoxazol-5 -yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.80 (bs, 1H), 8.52 (s, 1H), 7.40 (d, 1H), 7.09 (d, 1H), 5.82 ( dd, 1H), 5.35-5.26 (m, 2H), 3.96 (dd, 1H), 3.89 (dd, 1H), 3.60 (m, 1H), 3.44 (m , 1H), 3.032.90 (m, 3H), 2.83 (dd, 1H), 2.782.65 (m, 1H), 2.31-2.12 (m, 2H), 2.09 (s, 3H), 2.00 (m, 1H), 1.94-1.72 (m, 2H), 1.71-1.47 (m, 3H), 1.461.27 (m, 3H), 1.27 -1.13 (m, 1H), 1.10 (s, 3H). Method 2: 4.43 minutes, 544.4 [M+H] ⁺

- 180 045906

127 A Al _o<) s Lo°a Cl (15.27?)-2-((5)-5-chloro-8-((5(methoxymethyl)-1 -methyl- 1H-1,2,3 triazol-4-yl)methoxy)-1 -( (2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 123 (300 MHz, CDC1 ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 5.94 (m, 1H), 5.24 (d, 1H), 5.14 (d, 1H), 4.61-4.48 (m, 2H), 4.07 (s, 3H), 4.05-3.80 (m, 3H), 3.59 (m, 1H), 3.37 (s, 3H), 3.17 (dd, 1H), 3.11-2.99 (m, 2H), 2.73 (m, 1H), 2.57 (m, 1H), 2.40 ( m, 1H), 2.352.04 (m, 2H), 2.00-1.73 (m, 4H), 1.71-1.43 (m, 3H), 1.42-1.22 (m, 1H), 1.11 (s, 3H), 1.01 (m, 1H). Method 10: 1.96 minutes, 588.3 [M+H] ⁺ 128 \ \ NN °AJ o^X L /.......ov ^h ¢0+5 Cl (15,2^)-2-((1)-5-chloro-8-((5-(2methoxyethyl)-1 -methyl-177-1,2,3triazol-4-yl)methoxy)-1 -( (2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 123 (300 MHz, CDC1 ₃ ) δ 7.30 (d, 1H), 7.00 (d, 1H), 5.95 (dd, 1H), 5.20 (d, 1H), 5.10 (d, 1H), 4.09-3.82 (m, 6H), 3.62-3.45 (m, 3H), 3.27 (s, 3H), 3.17 (dd, 1H), 3.11 -2.90 (m, 4H), 2.74 (m, 1H), 2.58 (dd, 1H), 2.40 (m, 1H), 2.33-2.20 (m, 1H), 2.19-2.08 (m, 1H), 1.97-1.76 (m, 4H), 1.69-1.42 (m, 3H), 1.41-1.25 (m, 1H ), 1.11 (s, 3H), 1.01 (m, 1H). Method 10: 2.00 minutes, 602.4 [M+H] ⁺ 129 \ N-N Cl (15.27?)-2-((5)-5-chloro-8-((5cyclopropyl-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-1 -((2oxopyrrolidine-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 123 (300 MHz, CDC1 ₃ ) δ 7.29 (d, 1H), 7.06 (d, 1H), 5.97 (dd, 1H), 5.225.12 (m, 2H), 4.09-3, 92 (m, 5H), 3.86 (m, 1H), 3.62 (m, 1H), 3.19 (dd, 1H), 3.14-3.01 (m, 2H), 2.74 (m, 1H), 2.57 (m, 1H), 2.40 (m, 1H), 2.34-2.21 (m, 1H), 2.20-2.10 (m, 1H), 1.99-1.77 (m, 4H), 1.71 (m, 1H), 1.67-1.43 (m, 3H), 1.41-1.22 (m, 1H), 1. 14-1.06 (m, 5H), 1.01 (m, 1H), 0.85-0.73 (m, 2H). Method 10: 2.09 minutes, 584.3 [M+H] ⁺ 130 EA 1 _f AA ⁿ o=L ^F l A o OH o / o 'V ¢¢+ Cl (1 S,2R)-2-((S)-5 -chloro-1 -(((5)-3 -methyl2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 methyl-5 -(trifluoromethyl )- 1H-1,2,3 triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 112 (400 MHz, DMSO-d ₆ ) δ 12.02 (bs, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 5.80 (dd, 1H), 5.41- 5.25 (m, 2H), 4.24 (m, 3H), 3.96 (dd, 1H), 3.84 (dd, 1H), 3.59 (m, 1H), 2.99-2 .88 (m, 2H), 2.87-2.68 (m, 3H), 2.27 (m, 1H), 2.21-2.03 (m, 2H), 1.71-1.45 (m, 3H), 1.43-1.19 (m, 6H), 1.07 (s, 3H), 0.96 (d, 3H). Method 13: 2.69 minutes, 626.5 [M+H] ⁺

- 181 045906

131 _F NN ΐ CI (1 S,2R)-2-((S)-5 -chloro-1 -(((/()-3 -methyl2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 methyl-5 -( trifluoromethyl)-177-1,2,3triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 112 (300 MHz, DMSO-d ₆ ) δ 11.83 (bs, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 5.77 (dd, 1H), 5.45- 5.24 (m, 2H), 4.24 (m, 3H), 4.03-3.79 (m, 2H), 3.58 (m, 1H), 3.04-2.89 (m, 2H), 2.89-2.63 (m, 3H), 2.31-1.99 (m, 3H), 1.731.12 (m, 9H), 1.08 (s, 3H), 0.99 (d, 3H). Method 13: 2.70 minutes, 626.3 [M+H] ⁺ 132 \ NN _F yy'N ^F 1. , ^NJ O^OH -:7°) Cl (1X,27?)-2-((5)-5-chloro-1-(((7?)-4-methyl2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 methyl-5 -( trifluoromethyl)-177-1,2,3triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (300 MHz, DMSO-d ₆ ) δ 7.38 (d, 1H), 7.16 (d, 1H), 5.76 (m, 1H), 5.41-5.24 (m, 2H), 4.25 (m, 3H), 4.02-3.81 (m, 2H), 3.61 (m, 1H), 3.08-2.70 (m, 6H), 2.36-2, 13 (m, 3H), 1.77-1.18 (m, 8H), 1.08 (s, 3H), 0.98 (d, 3H). Method 13: 2.67 minutes, 626.2 [M+H] ⁺ 133 _F NN oyy ^F % /oV yy Cl (1X,25)-2-((5)-5-chloro-1-(((7?)-4-methyl2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 methyl-5 -(trifluoromethyl )-177-1,2,3triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid Selected from 132 (300 MHz, CDC1 ₃ ) δ 7.31-7.18 (m, 1H), 6.95 (d, 1H), 5.94 (dd, 1H), 5.34-5.16 (m, 2H ), 4.20 (m, 3H), 4.09-3.88 (m, 2H), 3.87-3.72 (m, 1H), 3.33 (dd, 1H), 3.19 ( m, 1H), 3.13-3.00 (m, 2H), 2.98-2.72 (m, 2H), 2.51-2.26 (m, 2H), 1.96-1, 19 (m, 12H), 1.07 (d, 3H). Method 13: 2.63 minutes, 626.2 [M+H] ⁺ 134 d NN ^>N O ₄ ' T \ / ^{r 1 N} o OH ? J ϊ Ί 1 ( ^N I 1 Cl (15.27?)-2-((5)-5-chloro-8-((1- cyclopropyl-5 -(difluoromethyl)-1771,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin-1-yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1 -methylcyclohexane-1-carboxylic acid 91 (400 MHz, CDC1 ₃ ) δ 15.08 (bs, 1H), 7.29 (d, 1H), 7.05 (t, 1H), 7.00 (d, 1H), 5.97 (dd, 1H), 5.28 (s, 2H), 4.09-3.91 (m, 2H), 3.86 (m, 1H), 3.74-3.60 (m, 2H), 3.18 (dd, 1H), 3.13-3.00 (m, 2H), 2.74 (m, 1H), 2.56 (dd, 1H), 2.40 (m, 1H), 2.28 ( m, 1H), 2.15 (m, 1H), 1.98-1.76 (m, 4H), 1.69-1.45 (m, 3H), 1.44-1.18 (m, 5H), 1.12 (s, 3H), 1.01 (m, 1H). Method 3: 4.57 minutes, 620.0 [M+H] ⁺ 136 Z'° b I (18.2K)-2-((8)-5-chloro-8-((5.5- d imethyl-4,5-dihydroisoxazol-3 yl)methoxy)-1 -((6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 170 (300 MHz, methanol-b ₃ ) δ 7.32 (m, 1H), 6.97 (m, 1H), 6.05 (m, 1H), 5.02-4.67 (m, 2H), 4.22-3.96 (m, 2H), 3.91-3.53 (m, 2H), 3.47-3.18 (m, 1H), 3.16-2.17 (m, 9H ), 1.901.06 (m, 16H), 0.83-0.51 (m, 4H). Method 14 (up to 50% A 3 minutes): 1.77 minutes, 586.1 [M+H] ⁺ 137 -Xn X (%v iW Cl (15,2R)-2-((5)-5-chloro-8-((4methylisoxazol-3 -yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinoline -2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz, CDC1 ₃ ) δ 15.21 (bs, 1H), 8.24 (m, 1H), 7.31 (d, 1H), 6.92 (d, 1H), 6.03 (dd, 1H), 5.22 (d, 1H), 5.13 (d, 1H), 4.06 (dd, 1H), 3.98 (m, 1H), 3.88 (m, 1H), 3, 69 (m, 1H), 3.17-3.01 (m, 3H), 2.76 (m, 1H), Method 3: 4.48 minutes, 544.1 [M+H] ⁺

- 182 045906

2.57 (dd, 1H), 2.41 (m, 1H), 2.28 (w, 1H), 2.21-2.09 (m, 4H), 1.98-1.77 (m, 4H), 1.68-1.44 (w, ZN), 1.34 (w, 1H), 1.13 (s, ZN), 1.02 (m, 1H). 138 GUYa ν-Λγ °=а to Ζ ^Ν- 1 CK TH O / O Y ύ Ά Cl (15.27?)-2-((5)-5-chloro-1 -((2oxopyrrolidin-1 -yl)methyl)-8((4,5,6,7- tetrahydrobenzo[I]isoxazol-3yl)methoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 91 (400 MHz, DMSO-d ₆ ) δ 11.84 (bs, 1H), 7.37 (d, 1H), 7.08 (d, 1H), 5.86 (dd, 1H), 5.26 ( d, 1H), 5.19 (d, 1H), 4.02-3.82 (m, 2H), 3.61 (m, 1H), 3.50 (m, 1H), 3.08-2 .93 (m, 3H), 2.88-2.64 (m, 4H), 2.56-2.41 (m, 2H), 2.30-2.11 (m, 2H), 2.01 (m, 1H), 1.94-1.48 (m, 9H), 1.47-1.28 (m, 3H), 1.21 (m, 1H), 1.10 (s, 3H). Method 3: 4.89 minutes, 584.1 [M+H] ⁺ 139 % _F NN ykk _Ο γ\ ^F A z ^N k CR.OH o / ° Y or k 1 Cl (15.2D)-2-((5)-8-((2.5- bis(difluoromethyl)-2R-1,2,3-triazol4-yl)methoxy)-5-chloro-1 -((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl) 1-methylcyclohexane-1-carboxylic acid 193 (300 MHz, CDC1 ₃ ) δ 7.33 (t, 1H), 7.32 (d, 1H), 6.90 (t, 1H), 6.90 (d, 1H), 6.07 (dd, 1H), 5.39-5.23 (m, 2H), 4.14 (dd, 1H), 4.02 (m, 1H), 3.90 (m, 1H), 3.54 (d, 1H ), 3.23 (dd, 1H), 3.16-3.02 (m, 2H), 2.76 (m, 1H), 2.59 (m, 1H), 2.47-2.34 ( m, 2H), 2.13 (d, 1H), 1.92-1.76 (m, 2H), 1.74-1.21 (m, 4H), 1.13 (s, 3H), 1 .09-0.95 (m, 1H), 0.73-0.45 (m, Method 9b: 1.80 minutes, 656.3 [M+H] ⁺ 4H). 145 o _F NN kV θΥ ^F / // V ^H AV a (15.2R)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -(2-methoxyethyl)1H-1,2,3-triazol-4-yl)methoxy)-1 ((2-oxopyrrolidin-1 -yl)methyl)1,2,3,4-tetrahydroisoquinoline -2carbonyl)-1-methylcyclohexane-1 carboxylic acid 91 (400 MHz, CDC1 ₃ ) δ 15.31 (bs, 1H), 7.30 (d, 1H), 7.12 (t, 1H), 7.01 (d, 1H), 5.98 (dd, 1H), 5.30 (s, 2H), 4.62 (m, 2H), 4.08-3.91 (m, 2H), 3.86 (m, 1H), 3.77 (t, 2H ), 3.67 (m, 1H), 3.31 (s, 3H), 3.22 (dd, 1H), 3.16-3.01 (m, 2H), 2.74 (m, 1H) , 2.56 (dd, 1H), 2.40 (m, 1H), 2.27 (m, 1H), 2.15 (m, 1H), 1.99-1.76 (m, 4H), 1.68-1.44 (m, 3H), 1.34 (m, 1H), 1.12 (s, 3H), 1.01 (m, 1H). Method 3: 4.45 minutes, 638.1 [M+H] ⁺ 148 1 FL X ¹ 0. Λ 'ο Λη”.™ J ' to 1 1 1 ^N I ϊ ' a (15.27?)-2-((5)-5-chloro-8-((1-methyl-2oxo-1,2-dihydropyridin-4yl)methoxy)-1 -((6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 135 (400 MHz, CDC1 ₃ ) δ 7.35-7.21 (m, 2H), 6.70 (d, 1H), 6.58 (s, 1H), 6.196.08 (m, 2H), 4, 99-4.86 (m, 2H), 4.19 (dd, 1H), 4.03 (m, 1H), 3.91 (dd, 1H), 3.64 (d, 1H), 3.53 (s, 3H), 3.26 (d, 1H), 3.20 (dd, 1H), 3.09 (dd, 1H), 2.78 (m, 1H), 2.63 (m, 1H) , 2.51-2.36 (m, 2H), 2.15 (d, 1H), 1.89-1.76 (m, 2H), 1.73-1.45 (m, 3H), 1 .44-1.27 (m, 1H), 1.15 (s, 3H), 1.11-0.99 (m, 1H), 0.78-0.53 (m, Method 9b: 1.39 minutes, 596.3 [M+H] ⁺

- 183 045906

4H). 149 \ _F nn ^F 1-0 (- ^N O°Y ^OH Cl (15.25)-2-((5)-5-chloro-8-((5(difluoromethyl)-1 -methyl-1H-1,2,3triazol-4-yl)methoxy)-1 -((( 7?)-4methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid Isolated during synthesis from example 111 (400 MHz, DMSO-d ₆ ) δ 7.59 (t, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5.78 (m, 1H), 5.45- 5.17 (m, 2H), 4.18 (s, 3H), 4.01 (dd, 1H), 3.85 (dd, 1H), 3.60 (m, 1H), 3.14-2 .63 (m, 6H), 2.382.17 (m, 2H), 1.80-0.71 (m, 15H) Method 9a: 0.97 minutes, 608.3 [M+H] ⁺ 150 _F nn ^F to ₍ -%V ^H ¢64 Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-5(methyl trifluoro)-1H-1,2,3-triazol-4yl)methoxy)-1 -( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 112 (300 MHz, CDC1 ₃ ) δ: Ή NMR (300 MHz, CDC1 ₃ ) δ 7.29 (d, 1H), 7.01 (d, 1H), 5.95 (dd, 1H), 5.36- 5.24 (m, 2H), 4.20 (m, 3H), 4.11 (dd, 1H), 4.05-3.79 (m, 2H), 3.48 (d, 1H), 3 .17 (dd, 1H), 3.13-2.99 (m, 2H), 2.74 (m, 1H), 2.58 (m, 1H), 2.48-2.34 (m, 2H ), 2.12 (d, 1H), 1.92-1.75 (m, 2H), 1.74-1.45 (m, 3H), 1.35 (m, 1H), 1.12 ( s, 3H), 1.01 (m, 1H), 0.76-0.45 (m, 4H). Method 13* 2.41 minutes, 638.2 [M+H] ⁺ . Separately specified gradient: from 20% B with 80% C to 70% B with 30% C for 3 minutes, to 95% B with 5% From up to 4.5 min.) 153 \ NN Ρ-γΧΧ °</y\ ^F L )n-% OH o / ο γ φ'% Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-5(methyl trifluoro)-1H-1,2,3-triazol-4yl)methoxy)-1 -( (6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclopentane-1 carboxylic acid 112 (300 MHz, CDC1 ₃ ) δ 7.26 (d, 1H), 6.99 (d, 1H), 5.93 (dd, 1H), 5.355.17 (m, 2H), 4.19 (s, 3H), 4.09 (dd, 1H), 3.91 (m, 2H), 3.63-3.40 (m, 1H), 3.23-2.89 (m, 3H), 2.88 -2.65 (m, 2H), 2.57 (m, 1H), 2.37 (d, 1H), 2.27-2.03 (m, 2H), 1.93-1.60 (m , 3H), 1.50-1.32 (m, 1H), 1.28 (s, 3H), 0.73-0.42 (m, 4H). Method 13: 2.53 minutes, 624.2 [M+H] ⁺ . 154 θγ*γ! ^F I ° V ¢60 Cl (15.27?)-2-((5)-5-chloro-8-((5-methyl-4(trifluoromethyl)isoxazol-3 yl)methoxy)-1 -((6-oxo-5azaspiro[2.4] heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 135 (300 MHz, CDC1 ₃ ) δ 7.29 (d, 1H), 6.91 (d, 1H), 6.05 (dd, 1H), 5.275.12 (m, 2H), 4.13 (dd, 1H), 4.083.81 (m, 2H), 3.57 (d, 1H), 3.27-3.14 (m, 2H), 3.08 (m, 1H), 2.76 (m, 1H ), 2.64-2.52 (m, 4H), 2.49-2.34 (m, 2H), 2.13 (d, 1H), 1.92-1.75 (m, 2H), 1.71-1.18 (m, 4H), 1.13 (s, 3H), 1.02 (m, 1H), 0.76-0.50 (m, 4H). Method 14: 3.04 minutes, 638.2 [M+H] ⁺ .

- 184 045906

155 ^F 'r _F NN yA N oyy f ζθ _N J fi u Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -(2,2,2- trifluoroethyl)-1H-1,2,3-triazol-4yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 127 (300 MHz, CD ₃ OH) δ 7.38 (t, 1H), 7.35 (d, 1H), 7.11 (d, 1H), 5.89 (m, 1H), 5.56-5 .43 (m, 2H), 5.42-5.26 (m, 2H), 4.13-3.66 (m, 3H), 3.613.48 (m, 1H), 3.18 (dd, 1H ), 3.102.74 (m, 4H), 2.45-2.09 (m, 3H), 2.03-1.26 (m, 9H), 1.21 (s, 3H). Method 10: 2.41 minutes, 662.3 [M+H] ⁺ 157 ^F A /-у™ Λ - °' Cl (1A,27?)-2-(($)-5-chloro-8-((4- (difluoromethyl)-5 -methylisoxazol-3 yl)methoxy)-1 -((6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 156 (300 MHz, CDC1 ₃ ) δ 7.28 (d, 1H), 6.90 (d, 1H), 6.68 (t, 1H), 6.05 (dd, 1H), 5.29-5, 16 (m, 2H), 4.12 (dd, 1H), 4.07-3.77 (m, 2H), 3.56 (d, 1H), 3.27-3.13 (m, 2H) , 3.07 (m, 1H), 2.76 (m, 1H), 2.59 (dd, 1H), 2.52 (t, 3H), 2.47-2.35 (m, 2H), 2.13 (d, 1H), 1.95-1.45 (m, 5H), 1.35 (m, 1H), 1.13 (s, 3H), 1.02 (m, 1H), 0 .74-0.48 (m, 4H). Method 9b: 1.76 minutes, 620.2 [M+H] ⁺ 158 NN An _o yA 4 Λο°γ ^ΟΗ ·· Cl (15.27?)-2-((5)-5-chloro-8-(( 1 -methyl- 1H1,2,3-triazol-4-yl)methoxy)-1-((6oxo-5-azaspiro [2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 156 (300 MHz, CDC1 ₃ ) δ 7.61 (s, 1H), 7.28 (d, 1H), 6.91 (d, 1H), 5.99 (dd, 1H), 5.24 (d, 1H), 5.18 (d, 1H), 4.184.06 (m, 4H), 4.05-3.83 (m, 2H), 3.44 (d, 1H), 3.20 (m, 1H ), 3.12-3.00 Method 9b: 1.44 minutes, 570.2 [M+H] ⁺ 1-methylcyclohexane-1-carboxylic acid (m, 2H), 2.73 (m, 1H), 2.60 (dd, 1H), 2.48-2.32 (m, 2H), 2.12 (d, 1H), 1.92- 1.74 (m, 2H), 1.72-1.46 (m, 3H), 1.35 (m, 1H), 1.13 (s, 3H), 1.02 (m, 1H), 0 .72-0.47 (m, 4H). 159 \NN ^-X.'n oyyA L _Z ^N CR.OH U / 0 J fo and Cl (15.27?)-2-((5)-5-chloro-8-((5cyclopropyl-1-methyl-1H-1,2,3triazol-4-yl)methoxy)-1 -((6-oxo -5 azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 156 (300 MHz, CDC1 ₃ ) δ 7.29 (d, 1H), 7.04 (d, 1H), 5.96 (dd, 1H), 5.235.10 (m, 2H), 4.17-3, 82 (m, 6H), 3.39 (d, 1H), 3.17 (dd, 1H), 3.06 (m, 1H), 2.99 (d, 1H), 2.74 (m, 1H ), 2.58 (m, 1H), 2.46-2.30 (m, 2H), 2.12 (d, 1H), 1.91-1.75 (m, 2H), 1.74- 1.46 (m, 4H), 1.33 (m, 1H), 1.17-0.93 (m, 6H), 0.88-0.68 (m, 2H), 0.66-0, 46 (m, 4H). Method 9b: 1.64 minutes, 610.3 [M+H] ⁺ . 160 \NN ^°\^OOn 1 , ^N 0. .OH 0 / 0 V :6% Cl (15.27?)-2-((5)-5-chloro-8-((5(methoxymethyl)-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-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 5.94 (dd, 1H), 5.24 (d, 1H), 5.13 (d, 1H), 4.53 (d, 1H), 4.49 (d, 1H), 4.10 (dd, 1H), 4.05 (s, 3H), 4.04-3.85 (m, 2H ), 3.38 (d, 1H), 3.36 (s, 3H), 3.16 (dd, 1H), 3.07 (m, 1H), 2.95 (d, 1H), 2.74 (m, 1H), 2.59 (dd, 1H), 2.46-2.31 (m, 2H), 2.12 (d, 1H), Method 12: 1.43 minutes, 614.8 [M+N] ⁺

- 185 045906

1.90-1.76 (m, 2H), 1.70-1.49 (w, ZN), 1.45-1.19 (m, 1H), 1.12 (s, ZN), 1, 02 (m, 1H), 0.69-0.46 (m, 4H). 161 N-N ψόχ) Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-1R1,2,3-triazol-4-yl)methoxy)-1-(((/?)4 -methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (300 MHz, CDC1 ₃ ) δ 7.66 (s, 1H), 7.27 (d, 1H), 6.91 (d, 1H), 5.96 (dd, 1H), 5.25 (d, 1H), 5.16 (d, 1H), 4.12 (s, 3H), 4.10-3.80 (m, 3H), 3.25 (dd, 1H), 3.20-3.09 (m, 2H), 3.04 (m, 1H), 2.72 (m, 1H), 2.56 (m, 1H), 2.48-2.23 (m, 3H), 1.94- 1.70 (m, 3H), 1.68-1.44 (m, 3H), 1.42-1.20 (m, 1H), 1.17-0.92 (m, 7H). Method 9b: 1.25 minutes, 558.2 [M+H] ⁺ 162 NN AA.N X , ^N o^si Cl (15.2D)-2-((5)-5-chloro-8-((5- (methoxymethyl)-1 -methyl-1//-1,2,3triazol-4-yl)methoxy)-1 -(((7?)-4methyl-2-oxopyrrolidin-1 yl)methyl)-1,2, 3.4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (300 MHz, CDC1 ₃ ) δ 7.30 (d, 1H), 6.98 (d, 1H), 5.93 (m, 1H), 5.26 (d, 1H), 5.14 (d, 1H), 4.61-4.48 (m, 2H), 4.13-3.80 (m, 6H), 3.38 (s, 3H), 3.21 (dd, 1H), 3.16 -3.00 (m, 3H), 2.73 (m, 1H), 2.56 (m, 1H), 2.49-2.24 (m, 3H), 1.95-1.73 (m , 3H), 1.71-1.19 (m, 4H), 1.11 (s, 3H), 1.08-0.94 (m, 4H). Method 9b: 1.53 minutes, 602.3 [M+H] ⁺ 163 NN --- ^J N ¢)^ y* Ί o OH ΥΙΌ Г Г ? Ύ j T '' Cl (15.2R)-2-((5)-5-chloro-8-((5- cyclopropyl-1 -methyl- 1H-1,2,3triazol-4-yl)methoxy)-1 -(((7?)-4methyl-2-oxopyrrolidin-1 yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (300 MHz, CDC1 ₃ ) δ 7.29 (d, 1H), 7.03 (d, 1H), 5.94 (m, 1H), 5.24-5.10 (m, 2H), 4, 19-3.79 (m, 6H), 3.292.97 (m, 4H), 2.72 (m, 1H), 2.55 (d, 1H), 2.48-2.24 (m, 3H) , 1.98-0.92 (m, 17H), 0.89-0.70 (m, 2H). Method 10a: 2.44 minutes, 598.3 [M+H] ⁺ 164 F CjX°n ογ^ I o. He X>/ΟY ¢6^ Cl (15.2D)-2-((5)-5-chloro-8-((7- fluorobenzoI isoxazole-3 - yl)methoxy)-1 -((2-oxopyrrolidine- 1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (400 MHz, DMSO-d ₆ ) δ 11.82 (bs, 1H), 7.87 (dd, 1H), 7.66 (m, 1H), 7.48 (td, 1H), 7.42 ( d, 1H), 7.18 (d, 1H), 5.89 (dd, 1H), 5.75 (d, 1H), 5.67 (d, 1H), 3.95 (dd, 1H), 3.88 (dd, 1H), 3.62 (m, 1H), 3.36-3.22 (m, 1H), 3.06-2.94 (m, 2H), 2.84 (dd, 1H), 2.78-2.64 (m, 2H), 2.24 (m, 1H), 2.12 (m, 1H), 1.96 (m, 1H), 1.85-1.46 (m, 5H), 1.45-1.28 (m, 3H), 1.19 (m, 1H), 1.10 (s, 3H). Method 3: 4.97 minutes, 598.1 [M+H] ⁺

- 186 045906

165 L, ^N 0. OH o / ο YV ^U Cl (15.27?)-2-((5)-5-chloro-8-((6.7- difluorobenzo|X]isoxazol-3yl)methoxy)-1 -((2-oxopyrrolidin1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (400 MHz, CDC1 ₃ ) δ 15.04 (bs, 1H), 7.54 (m, 1H), 7.33 (d, 1H), 7.31-7.22 (m, 1H), 6, 94 (d, 1H), 6.10 (dd, 1H), 5.55 (d, 1H), 5.45 (d, 1H), 4.12-3.94 (m, 2H), 3.88 (m, 1H), 3.50 (m, 1H), 3.14-3.02 (m, 2H), 2.88 (m, 1H), 2.77 (m, 1H), 2.59 ( m, 1H), 2.41 (m, 1H), 2.26 (m, 1H), 2.14 (m, 1H), 1.92-1.77 (m, 3H), 1.70-1 .43 (m, 4H), 1.34 (m, 1H), 1.13 (s, 3H), 1.02 (m, 1H). Method 3: 5.07 minutes, 616.0 [M+H] ⁺ 166 YY L / ^N o v ^h □ '°: Cl (15.2R)-2-((5)-5-chloro-8-((5- methylisoxazol-3 -yl)methoxy)-1-((2oxopyrrolidin-1 -yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 109 (400 MHz, CDC1 ₃ ) δ 15.18 (bs, 1H), 7.29 (d, 1H), 6.84 (d, 1H), 6.10 (m, 1H), 6.06 (dd, 1H), 5.18 (d, 1H), 5.10 (d, 1H), 4.07 (dd, 1H), 3.98 (m, 1H), 3.89 (m, 1H), 3, 77 (m, 1H), 3.22-3.12 (m, 2H), 3.07 (m, 1H), 2.75 (m, 1H), 2.58 (dd, 1H), 2.45 (d, 3H), 2.41 (m, 1H), 2.29 (m, 1H), 2.18 (m, 1H), 2.00-1.89 (m, 2H), 1.89- 1.77 (m, 2H), 1.69-1.46 (m, 3H), 1.35 (m, 1H), 1.14 (s, 3H), 1.02 (m, 1H). Method 3: 4.50 minutes, 544.1 [M+H] ⁺ 167 NyO Q^X L I O _h OH o / ο Y φό'-Ό Cl (15.27?)-2-((5)-5-chloro-8-((3-methyl1,2,4-oxadiazol-5-yl)methoxy)-1 ((2-oxopyrrolidin-1 -yl) methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 109 (400 MHz, DMSO-d ₆ ) δ 11.80 (bs, 1H), 7.38 (d, 1H), 7.03 (d, 1H), 5.94 (dd, 1H), 5.59 ( d, 1H), 5.53 (d, 1H), 4.02-3.86 (m, 2H), 3.72-3.54 (m, 2H), 3.24 (m, 1H), 3 .14 (dd, 1H), 3.00 (t, 1H), 2.85 (dd, 1H), 2.72 (m, 1H), 2.39 (s, 3H), 2.30-2, 12 (m, 2H), 2.03 (m, 1H), 1.97-1.75 (m, 2H), 1.72-1.48 (m, 3H), 1.48-1.29 ( m, 3H), 1.22 (m, 1H), 1.11 (s, 3H). Method 3: 4.24 minutes, 545.0 [M+H] ⁺ 168 ν° Ν ,Ν Ο^ΖΥ 1 , ^Ν o. he Ο / Ο Υ Φ6 ^νΛ ο CI (15.27?)-2-((5)-5-chloro-8-((5-methyl1,2,4-oxadiazol-3-yl)methoxy)-1 ((2-oxopyrrolidin-1-yl) methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 109 (400 MHz, DMSO-d ₆ ) δ 11.81 (s, 1H), 7.37 (d, 1H), 7.08 (d, 1H), 5.89 (dd, 1H), 5.36 ( d, 1H), 5.30 (d, 1H), 4.01-3.83 (dd, 2H), 3.68-3.52 (m, 2H), 3.20 (m, 1H), 3 .14 (dd, 1H), 2.98 (m, 1H), 2.84 (dd, 1H), 2.772.60 (m, 4H), 2.30-2.11 (m, 2H), 2, 02 (m, 1H), 1.97-1.74 (m, 2H), 1.72-1.48 (m, 3H), 1.47-1.29 (m, 3H), 1.28- 1.14 (m, 1H), 1.10 (s, 3H). Method 3: 4.24 minutes, 545.2 [M+H] ⁺

- 187 045906

169 _F o ^F >' _N ^h . J o OH ϊ 1 Ϊ f Ϊ Cl (15.25)-2-((5)-5 -chloro-8-(( 1 -methyl-5 (methyl trifluoro)- 1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidine- 1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid Isolated during synthesis from example 108 (400 MHz, CDC1 ₃ ) δ 7.25-7.20 (d, 1H), 6.94 (d, 1H), 5.97 (dd, 1H), 5.24 (m, 2H), 4, 19 (m, 3H), 4.063.91 (m, 2H), 3.85-3.64 (m, 2H), 3.19-2.99 (m, 3H), 2.91 (dd, 1H) , 2.80 (m, 1H), 2.36-2.10 (m, 2H), 1.95-1.84 (m, 2H), 1.80 (m, 1H), 1.73-1 .43 (m, 6H), 1.41-1.28 (m, 4H). Method 3: 4.39 minutes, 612.0 [M+H] ⁺ 171 N^N , ^F f T / o°y ^oh ό'-'Λ Cl (15.27?)-2-((5)-5-chloro-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-8((4-(trifluoromethyl)pyrimidin-5yl )methoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 14.91 (bs, 1H), 9.37 (s, 1H), 9.17 (s, 1H), 7.34 (d, 1H), 6.80 (d, 1H), 6.10 (dd, 1H), 5.38 (d, 1H), 5.27 (d, 1H), 4.21 (dd, 1H), 4.04 (m, 1H), 3, 92 (m, 1H), 3.49 (d, 1H), 3.16-3.06 (m, 2H), 3.03 (d, 1H), 2.80 (m, 1H), 2.62 (m, 1H), 2.47-2.38 (m, 2H), 2.13 (d, 1H), 1.87-1.77 (m, 2H), 1.69-1.46 (m , 3H), 1.43-1.28 (m, 1H), 1.15 (s, 3H), 1.04 (m, 1H), 0.73-0.48 (m, 4H). Method 3: 4.86 minutes, 635.0 [M+N] ⁺ 172 ^NN ^F yA _/ 'n Ог/γ ^F I. , ^NO ^ ^OH ¢0¾ Cl (15,2R)-2-((5)-5-chloro-8-((1cyclopropyl-5 -(methyl difluoro)- 1H1,2,3-triazol-4-yl)methoxy)-1-((6oxo -5-azaspiro[2.4]heptan-5yl)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 15.34 (bs, 1H), 7.29 (d, 1H), 7.04 (t, 1H), 7.00 (d, 1H), 5.97 (dd, 1H), 5.36-5.20 (m, 2H), 4.10 (dd, 1H), 3.99 (m, 1H), 3.88 (m, 1H), 3.67 (m, 1H ), 3.45 (d, 1H), 3.18 (dd, 1H), 3.11-3.01 (m, 2H), 2.75 (m, 1H), 2.58 (dd, 1H) , 2.48-2.34 (m, 2H), 2.12 (d, 1H), 1.91-1.76 (m, 2H), 1.68-1.50 (m, 3H), 1 .47-1.21 (m, 5H), 1.13 (s, 3H), 1.02 (m, 1H), 0.71-0.47 (m, 4H). Method 3: 4.80 minutes, 646.0 [M+N] ⁺ 173 / -N NN CJn _Ο =^Λ l, I o. he O / Ο Υ Cl (15.27?)-2-((5)-5-chloro-8-((1-(2(dimethylamino)ethyl)-177-1,2,3triazol-4-yl)methoxy)-1 -( (6-oxo-5 azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 156 (400 MHz, DMSO-d ₆ ) δ 11.93 (bs, 1H), 8.27 (s, 1H), 7.35 (d, 1H), 7.11 (d, 1H), 5.81 ( dd, 1H), 5.26-5.12 (m, 2H), 4.46 (t, 2H), 4.03-3.83 (m, 2H), 3.58 (m, 1H), 3 .45-3.24 (m, 1H), 3.08-2.95 (m, 2H), 2.86-2.72 (m, 3H), 2.67 (t, 2H), 2.36 -2.24 (m, 1H), 2.22-2.04 (m, 8H), 1.73-1.45 (m, 3H), 1.44-1.17 (m, 4H), 1 .08 (s, 3H), 0.67-0.39 (m, 4H). Method 3: 3.10 minutes, 627.4 [M+H] ⁺

- 188 045906

175 /= ^N -Nγ-Ν O^QA L /A 0. OH φό ^ΝΛ ο Cl (15.27?)-2-((5)-5-chloro-8-((4-methyl-4R1,2,4-triazol-3-yl)methoxy)-1-((6oxo-5-azaspiro [2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 156 (400 MHz, DMSO-d ₆ ) δ 11.82 (bs, 1H), 8.55 (s, 1H), 7.39 (d, 1H), 7.16 (d, 1H), 5.82 ( dd, 1H), 5.39 (d, 1H), 5.34 (d, 1H), 4.04-3.90 (m, 2H), 3.74 (s, 3H), 3.61 (m , 1H), 3.38-3.29 (m, 1H), 3.02 (m, 1H), 2.96 (dd, 1H), 2.84 (dd, 1H), 2.77-2, 62 (m, 2H), 2.30 (m, 1H), 2.23-2.06 (m, 2H), 1.73-1.47 (m, 3H), 1.45-1.18 ( m, 4H), 1.11 (s, 3H), 0.62-0.41 (m, 4H). Method 3: 3.68 minutes, 569.9 [M+H] ⁺ 176 Mon1 /.A VN^NO=AA k> / o °Y° ^H s*g ^t Cl (15,25)-2-((5)-5-chloro-8-((5,6dihydro-8R-[1,2,4]triazolo[3,4c][1,4]oxazin-3-yl )methoxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 14.96 (bs, 1H), 7.31 (d, 1H), 7.02 (d, 1H), 6.02 (dd, 1H), 5.37 (d, 1H), 5.27 (d, 1H), 4.94 (s, 2H), 4.27-3.96 (m, 6H), 3.91 (m, 1H), 3.40 (d, 1H ), 3.14-3.01 (m, 2H), 2.99 (d, 1H), 2.78 (m, 1H), 2.62 (dd, 1H), 2.47-2.33 ( m, 2H), 2.15 (d, 1H), 1.88-1.75 (m, 2H), 1.67-1.49 (m, 3H), 1.37 (m, 1H), 1 .25 (s, 3H), 1.13 (m, 1H), 0.72-0.48 (m, 4H). Method 3: 3.71 minutes, 612.3 [M+H] ⁺ 177 \=N p^-N .N ΟγγΑ L L CL ΌΗ O i Ο Y φό ^ΝΑ ύ Cl (15.25)-2-((5)-5-chloro-8-((4cyclopropyl-5-methyl-4R-1,2,4triazol-3-yl)methoxy)-1 -((6-oxo- 5 azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 14.98 (bs, 1H), 7.31 (d, 1H), 7.07 (d, 1H), 6.03 (dd, 1H), 5.32 (s, 2H), 4.14 (dd, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.38 (d, 1H), 3.15-3.05 (m, 3H ), 3.02 (d, 1H), 2.77 (m, 1H), 2.60 (m, 1H), 2.50 (s, 3H), 2.45-2.34 (m, 2H) , 2.14 (d, 1H), 1.89-1.77 (m, 2H), 1.71-1.48 (m, 3H), 1.43-0.93 (m, 9H), 0 .68-0.49 (m, 4H). Method 3: 3.84 minutes, 610.4 [M+H] ⁺ 179 ¥a /^A ^-N^N Og/uD L, ^N o. _z OH o / ο Y Φ0 ^νΛ Ο Cl (15.27?)-2-((5)-5-chloro-8-((4,5d imethyl-4R-1,2,4-triazol-3 yl)methoxy)-1 -((6-oxo -5azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 15.13 (bs, 1H), 7.31 (d, 1H), 7.06 (d, 1H), 6.00 (dd, 1H), 5.32 (d, 1H), 5.24 (d, 1H), 4.14 (dd, 1H), 4.00 (m, 1H), 3.91 (m, 1H), 3.64 (s, 3H), 3, 39 (d, 1H), 3.14-3.02 (m, 2H), 2.97 (d, 1H), 2.76 (m, 1H), 2.60 (m, 1H), 2.47 -2.34 (m, 5H), 2.14 (d, 1H), 1.90-1.77 (m, 2H), 1.70-1.48 (m, 3H), 1.43-1 .21 (m, 1H), 1.13 (s, 3H), 1.03 (m, 1H), 0.68-0.49 (m, 4H). Method 3: 3.58 minutes, 584.3 [M+H] ⁺

- 189 045906

181 C^NN _l Μζ;Ν ογ%Δ % / ο V >Χ·'· CI (15.25)-2-((5)-5-chloro-8-((5,6d ihydro-4R-pyrrolo[1,2- c][1,2,3]triazol-3-yl)methoxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 135 (400 MHz, DMSO-d ₆ ) δ 11.84 (bs, 1H), 7.35 (d, 1H), 7.10 (d, 1H), 5.81 (dd, 1H), 5.18 ( s, 2H), 4.29 (m, 2H), 4.02-3.87 (m, 2H), 3.61 (m, 1H), 3.39 (d, 1H), 3.07-2 .97 (m, 2H), 2.91-2.78 (m, 4H), 2.75-2.63 (m, 3H), 2.34-2.24 (m, 1H), 2.21 (d, 1H), 2.12 (d, 1H), 1.74-1.46 (m, 3H), 1.46-1.19 (m, 4H), 1.11 (s, 3H), 0.64-0.46 (m, 4H). Method 3: 4.17 minutes, 596.3 [M+H] ⁺ 182 /ιμ-ν VL ν ο % Λο°γ ^ΟΗ ν: > F (15,25)-2-((5)-5-fluoro-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-8((4,5,6,7-tetrahydro - [1,2,3]triazolo[1,5-a]pyridine-3 - yl)methoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 178 (400 MHz, CDC1 ₃ ) δ 15.33 (bs, 1H), 7.05-6.90 (m, 2H), 5.97 (dd, 1H), 5.18 (d, 1H), 5, 10 (d, 1H), 4.36 (t, 2H), 4.11 (m, 1H), 4.02-3.82 (m, 2H), 3.42 (d, 1H), 3.20 (dd, 1H), 3.08-2.96 (m, 2H), 2.93-2.65 (m, 3H), 2.59 (m, 1H), 2.47-2.33 (m , 2H), 2.13 (d, 1H), 2.10-2.00 (m, 2H), 1.93 (m, 2H), 1.83 (m, 2H), 1.691.46 (m, 3H), 1.36 (m, 1H), 1.12 (s, 3H), 1.02 (m, 1H), 0.69-0.47 (m, 4H). Method 3: 4.18 minutes, 594.5 [M+H] ⁺ 183 rN —Ν Ν _r _ 1 ^Ν Α ° ^he ° ι V Г J ?\ 1 CI (15.25)-2-((5)-5-chloro-8-((6,7dihydro-5R-pyrrolo[2,1 - c][1,2,4]triazol-3-yl)methoxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 156 (400 MHz, CDC1 ₃ ) δ 15.15 (bs, 1H), 7.29 (d, 1H), 6.99 (d, 1H), 6.05 (dd, 1H), 5.33-5, 22 (m, 2H), 4.15 (dd, 1H), 4.10-3.86 (m, 4H), 3.45 (d, 1H), 3.15-3.05 (m, 3H) , 2.99-2.92 (m, 2H), 2.84-2.71 (m, 3H), 2.62 (m, 1H), 2.46-2.36 (m, 2H), 2 .15 (d, 1H), 1.89-1.78 (m, 2H), 1.70-1.50 (m, 3H), 1.43-1.26 (m, 1H), 1.13 (s, 3H), 1.04 (m, 1H), 0.68-0.52 (m, 4H). Method 3: 3.76 minutes, 596.4 [M+H] ⁺ 184 -Ν ,Ν О=^у4 1 ₀ / ο °γ ^ΟΗ О > ι CI (15.25)-2-((5)-5-chloro-8-((5cyclopropyl-4-methyl-4R-1,2,4triazol-3-yl)methoxy)-1 -((6-oxo- 5 azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 176 (400 MHz, CDC1 ₃ ) δ 15.18 (bs, 1H), 7.31 (d, 1H), 7.03 (d, 1H), 6.00 (dd, 1H), 5.32 (d, 1H), 5.20 (d, 1H), 4.13 (dd, 1H), 4.06-3.86 (m, 2H), 3.74 (s, 3H), 3.38 (d, 1H ), 3.14-3.00 (m, 2H), 2.93 (d, 1H), 2.76 (m, 1H), 2.61 (m, 1H), 2.42 (m, 1H) , 2.37 (d, 1H), 2.14 (d, 1H), 1.90-1.78 (m, 2H), 1.73 (m, 1H), 1.69-1.49 (m , 3H), 1.42-1.25 (m, 1H), 1.17-0.96 (m, 8H), 0.670.49 (m, 4H). Method 3: 3.87 minutes, 610.4 [M+N] ⁺

- 190 045906

185 d XF _O O _Y OH □ s/ Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-1-imidazol-4-yl)methoxy)-1 -((6-oxo5 -azaspiro[2.4] heptane-5 -yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 176 (400 MHz, DMSO-d ₆ ) δ 11.78 (bs, 1H), 8.76 (s, 1H), 7.72 (s, 1H), 7.38 (d, 1H), 7.09 ( d, 1H), 5.81 (dd, 1H), 5.16 (d, 1H), 5.11 (d, 1H), 3.99 (dd, 1H), 3.91 (dd, 1H), 3.82 (s, 3H), 3.61 (m, 1H), 3.52-3.22 (m, 1H), 3.08 (dd, 1H), 3.01 (m, 1H), 2 .89-2.75 (m, 2H), 2.69 (m, 1H), 2.35-2.18 (m, 2H), 2.12 (d, 1H), 1.73-1.47 (m, 3H), 1.46-1.18 (m, 4H), 1.11 (s, 3H), 0.65-0.45 (m, 4H). Method 3: 3.32 minutes, 569.4 [M+H] ⁺ 186 z- ^z O-D T (15.27?)-2-((5)-5-Chloro-1-((6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)-8- ((5,6,7,8-tetrahydro- [ 1,2,4]triazolo[4,3 -a]pyr idin-3 - yl)methoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 176 (400 MHz, CDC1 ₃ ) δ 15.19 (bs, 1H), 7.31 (d, 1H), 7.04 (d, 1H), 6.02 (dd, 1H), 5.32 (d, 1H), 5.22 (d, 1H), 4.203.85 (m, 5H), 3.38 (d, 1H), 3.14-2.91 (m, 5H), 2.77 (m, 1H ), 2.61 (m, 1H), 2.46-2.33 (m, 2H), 2.14 (d, 1H), 2.08-1.98 (m, 2H), 1.97- 1.87 (m, 2H), 1.87-1.77 (m, 2H), 1.70-1.48 (m, 3H), 1.35 (m, 1H), 1.12 (s, 3H), 1.03 (m, 1H), 0.66-0.49 (m, 4H). Method 3: 3.78 minutes, 610.4 [M+N] ⁺ 187 o —S=° _l A C ^O <Х \ XN OH / O V Cl (15.27?)-2-((5)-5-chloro-8-(((5)-1- (methylsulfonyl)pyrrolidin-3 yl)oxy)-1 -((b-oxo-5 - azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 176 and I (400 MHz, CDC1 ₃ ) δ 14.96 (bs, 1H), 7.29 (d, 1H), 6.64 (d, 1H), 6.02 (m, 1H), 5.00 (m, 1H), 4.17 (m, 1H), 4.09-3.86 (m, 2H), 3.69-3.44 (m, 5H), 3.34 (d, 1H), 3.19 -3.01 (m, 2H), 2.86-2.69 (m, 4H), 2.61 (d, 1H), 2.48-2.37 (m, 2H), 2.36-2 .25 (m, 2H), 2.17 (d, 1H), 1.83 (m, 2H), 1.71-1.47 (m, 3H), 1.43-1.21 (m, 1H ), 1.12 (s, 3H), 1.03 (m, 1H), 0.79-0.57 (m, 4H). Method 3: 4.37 minutes, 622.4 [M+H] ⁺ 188 Ts ογΥΑ XX I X o^yun 1 ο γ ¢7% Cl (15.2D)-2-((5)-8-(((5)-1- acetylpyrrolide in-3 -yl)oxy)-5 chloro-1-((6-oxo-5- azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 176 and I (400 MHz, CDC1 ₃ ; rotamers have been observed, both of which have been reported) b 15.08 (bs, 1H), 7.29 (d, 0.4H), 7.27 (d, 0.6H), 6, 71 (d, 0.4H), 6.67 (d, 0.6H), 5.99 (dd, 0.4H), 5.95 (dd, 0.6H), 5.00 (w, 0. 4H), 4.96 (w, 0.6H), 4.15 (m, 1H), 4.05-3.85 (m, 2H), 3.84-3.46 (w, 5H), 3 .16 (m, 1H), 3.12-2.97 (w, 2H), 2.82-2.69 (m, 1H), 2.65-2.56 (t, 1H), 2.47 -2.01 (t, 8N), 1.901.76 (t, 2N), 1.69-1.50 (t, ZN), Method 3: 4.04 minutes, 586.4 [M+H] ⁺

- 191 045906

1.42-1.26 (m, 1H), 1.16 (s, 1.8H), 1.13 (s, 1.2H), 1.08-0.98 (m, 1H), 0. 78-0.55 (m, 4H). 189 ГЦм-N _A '^AyN k / о¥ ⁿ l,У Cl (15.2R)-2-((5)-5-chloro-8-((6.7- dihydro-4R-[1,2,3]triazolo[5,1- c] [1,4]oxazin-3-yl)methoxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5- yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 176 (400 MHz, CDC1 ₃ ) δ 15.18 (bs, 1H), 7.29 (d, 1H), 6.93 (d, 1H), 5.96 (dd, 1H), 5.22 (d, 1H), 5.14 (d, 1H), 4.93 (d, 1H), 4.84 (d, 1H), 4.42 (t, 2H), 4.17-3.94 (m, 4H ), 3.94 (m, 1H), 3.45 (d, 1H), 3.14 (dd, 1H), 3.113.02 (m, 2H), 2.76 (m, 1H), 2.60 (m, 1H), 2.45-2.35 (m, 2H), 2.13 (d, 1H), 1.88-1.75 (m, 2H), 1.70-1.50 (m , 3H), 1.35 (m, 1H), 1.13 (s, 3H), 1.03 (m, 1H), 0.70-0.48 (m, 4H). Method 3: 4.20 minutes, 612.3 [M+H] ⁺ 191 NN AND V ⁰ ' ¹ 1 ^F । ^N o on 7 f 7 T U ^N 1 (15,2R)-2-((5)-5-bromo-8-((1-methyl-5(methyl trifluoro)-1H-1,2,3-triazol-4yl)methoxy)-1 -(( 2-oxopyrrolidin1 -yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 63 of example 190 (400 MHz, CDC1 ₃ ) δ 15.21 (bs, 1H), 7.48 (d, 1H), 6.97 (d, 1H), 5.97 (dd, 1H), 5.30 (m, 2H), 4.22 (m, 3H), 4.08-3.92 (m, 2H), 3.84 (m, 1H), 3.70 (m, 1H), 3.21-3.10 (m, 2H), 3.03 (m, 1H), 2.73 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.28 (m, 1H) , 2.16 (m, 1H), 1.98-1.87 (m, 2H), 1.83 (m, 2H), 1.68-1.45 (m, 3H), Method 3: 4.72 minutes, 656.3 [M+H] ⁺ 1.42-1.25 (m, 1H), 1.12 (s, 3H), 1.01 (m, 1H). 192 C NN ^F 7 / ov h 'A Cl (15.2D)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -(oxetan-3-yl)- 1H1,2,3-triazol-4-yl)methoxy)-1-((6oxo-5-azaspiro[2.4]heptan-5- yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 176 (300 MHz, CDC1 ₃ ) δ 15.15 (bs, 1H), 7.30 (d, 1H), 6.97 (d, 1H), 6.94 (t, 1H), 5.96 (dd, 1H), 5.72 (m, 1H), 5.38-5.19 (m, 4H), 5.08 (m, 2H), 4.17-3.81 (m, 3H), 3.42 (d, 1H), 3.19-3.00 (m, 3H), 2.76 (m, 1H), 2.59 (d, 1H), 2.47-2.30 (m, 2H), 2.11 (d, 1H), 1.89-1.73 (m, 2H), 1.711.48 (m, 3H), 1.44-1.20 (m, 1H), 1.12 (s, 3H), 1.02 (m, 1H), 0.70-0.43 (m, 4H). Method 3: 4.72 minutes, 662.4 [M+H] ⁺ 193 F ^f A _F NN y-AjN O^/\ ^F to C ^N o°Y ^OH h'-v Cl (15.27^)-2-((5)-8-((1.5- bis(diforomethyl)-1H-1,2,3-triazol4-yl)methoxy)-5-chloro-1-((2oxopyrrolidin-1-yl)methyl)-1,2,3,4tetrahydroisoquinolin-2-carbonyl )1-methylcyclohexane-1-carboxylic acid 176 (300 MHz, CDC1 ₃ ) δ 7.67 (t, 1H), 7.32 (d, 1H), 7.12 (t, 1H), 6.97 (d, 1H), 5.97 (dd, 1H), 5.41-5.27 (m, 2H), 4.12 (dd, 1H), 4.06-3.76 (m, 2H), 3.46 (d, 1H), 3.19 (dd, 1H), 3.13-3.00 (m, 2H), 2.75 (m, 1H), 2.58 (m, 1H), 2.47-2.33 (m, 2H), 2.11 (d, 1H), 1.90-1.75 (m, 2H), 1.72-1.21 (m, 4H), 1.13 (s, 3H), 1.02 (m, 1H), 0.71-0.45 (m, 4H). Method 10: 2.47 minutes, 656.3 [M+H] ⁺

- 192 045906

197 \NN A'n ογ% ^F A / ^N A o^oh o / ο γ ο'ν' Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -methyl- 1H-1,2,3triazol-4-yl)methoxy)-1 -((6-oxo-5 azaspiro[2.4]heptan-5-yl)methyl)1,2,3, 4-tetrahydroisoquinoline-2carbonyl)cyclohexane-1-carboxylic acid 123 (300 MHz, DMSO-d ₆ ) δ 11.69 (bs, 1H), 7.80-7.31 (m, 2H), 7.14 (d, 1H), 5.77 (m, 1H), 5.28 (s, 2H), 4.16 (s, 3H), 4.06-3.82 (m, 2H), 3.60 (m, 1H), 3.42-3.21 (m, 2H), 2.96 (m, 1H), 2.84 (m, 1H), 2.76-2.56 (m, 2H), 2.34 (m, 1H), 2.26-2.01 (m, 3H), 1.83-1.60 (m, 3H), 1.59-1.32 (m, 2H), 1.31-1.04 (m, 2H), 0.640.34 (m , 4H). Method 13: 2.43 minutes, 606.3 [M+H] ⁺ 198 A% (15.2R)-2-((5)-5-bromo-8-((5- (difluoromethyl)-1 -methyl- 1H-1,2,3triazol-4-yl)methoxy)-1 -((6-oxo-5 azaspiro[2.4]heptan-5-yl)methyl)1,2,3, 4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 190 and 63 of example 123 (400 MHz, DMSO-d ₆ ) δ 15.27 (bs, 1H), 7.48 (d, 1H), 7.07-6.76 (m, 2H), 5.96 (dd, 1H), 5.30 (d, 1H), 5.25 (d, 1H), 4.18 (s, 3H), 4.11 (dd, 1H), 4.00 (m, 1H), 3.87 (m , 1H), 3.44 (d, 1H), 3.15 (dd, 1H), 3.09-2.98 (m, 2H), 2.74 (m, 1H), 2.58 (m, 1H), 2.452.35 (m, 2H), 2.12 (d, 1H), 1.89-1.77 (m, 2H), 1.68-1.47 (m, 3H), 1.421.25 (m, 1H), 1.13 (s, 3H), 1.02 (m, 1H), 0.72-0.42 (m, 4H). Method 3: 4.64 minutes, 664.3 [M+H] ⁺ 199 \ NN Af V / „ o^oh ο ί ο Y ά'Λ ^χ Cl (15.27?)-2-((5)-5-chloro-8-((1-methyl-5(oxetan-3-yl)- 1H-1,2,3-triazol-4yl)methoxy)- 1 -((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 176 (400 MHz, CDC1 ₃ ) δ 15.22 (bs, 1H), 7.31 (d, 1H), 7.10 (d, 1H), 5.94 (dd, 1H), 5.39 (d, 1H), 5.33 (d, 1H), 5.14 (dd, 1H), 5.08 (dd, 1H), 4.83 (t, 1H), 4.76 (t, 1H), 4, 40 (m, 1H), 4.12 (dd, 1H), 4.06-3.95 (m, 4H), 3.88 (m, 1H), 3.36 (d, 1H), 3.20 (dd, 1H), 3.08 (m, 1H), 3.03 (d, 1H), 2.75 (m, 1H), 2.60 (dd, 1H), 2.45-2.34 ( m, 2H), 2.12 (d, 1H), 1.89-1.75 (m, 2H), 1.67-1.47 (m, 3H), 1.42-1.26 (m, 1H), 1.13 (s, 3H), 1.03 (m, 1H), 0.66-0.45 (m, 4H). Method 3: 4.10 minutes, 626.4 [M+H] ⁺ 200 \ NN ^f a,n o ya ^F f ° °y ^ot ¢0 and Cl (15.2R)-2-((5)-5-chloro-8-((5- (difluoromethyl)-1 -methyl-1H-1,2,3triazol-4-yl)methoxy)-1 -((3 oxomorpholino)methyl)-1,2,3,4tetrahydroisoquinoline-2-carbonyl)1 -methylcyclohexane-1 -carboxylic acid 196 (400 MHz, DMSO-d ₆ ) δ 11.77 (bs, 1H), 7.58 (t, 1H), 7.39 (d, 1H), 7.15 (d, 1H), 5.84 ( dd, 1H), 5.42-5.23 (m, 2H), 4.33 (dd, 1H), 4.17 (s, 3H), 4.03-3.88 (m, 2H), 3 .85-3.55 (m, 4H), 3.39 (m, 1H), 2.97 (m, 1H), 2.90-2.76 (m, 3H), 2.70 (m, 1H ), 2.25 (m, 1H), 1.71-1.46 (m, 3H), 1.45-1.17 (m, 4H), 1.10 (s, 3H) Method 3: 4.37 minutes, 610.4 [M+N] ⁺

- 193 045906

202 N.N. l ' - N 7- ^λ Г , _N ~JN=N ^F IN NH ° i V 1 Jl JJ Cl 5-(((5)-2-(( 17?, 25)-2-( 1R-tetrazol-5yl)cyclohexane-1 -carbonyl)-5 -chloro8-((5 -(difluoromethyl)-1 -methyl- 1R1,2,3-triazol-4-yl)methoxy)-1,2,3,4tetrahydroisoquinolin-1 -yl)methyl)5-azaspiro[2.4] heptan-6-one 81 (400 MHz, CDC1 ₃ ) δ 7.29-7.22 (m, 1H), 6.96 (t, 1H), 6.93 (d, 1H), 6.04 (m, 1H), 5, 34-5.23 (m, 2H), 4.19 (s, 3H), 4.09 (dd, 1H), 4.03-3.81 (m, 2H), 3.52 (d, 1H) , 3.41 (m, 1H), 3.19-2.86 (m, 4H), 2.81-2.59 (m, 2H), 2.38 (d, 1H), 2.16 (d , 1H), 1.831.33 (m, 7H), 0.74-0.48 (m, 4H). Method 9b: 1.55 minutes, 630.2 [M+H] ⁺ 204 F/ ^S %. A YV ο=/γΑ ^F to / ^N Οχ,ΟΗ o / o 4 ^x SE\'| Cl (15.27?)-2-((5)-5-chloro-8-((5- (difluoromethyl)thiazol-4-yl)methoxy)1 -((b-oxo-5 -azaspiro[2.4]heptan-5 yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 135 (400 MHz, CDC1 ₃ ) δ 8.88 (s, 1H), 7.30 (d, 1H), 7.03 (t, 1H), 6.92 (d, 1H), 5.99 (m, 1H), 5.39-5.22 (m, 2H), 4.12 (m, 1H), 4.05-3.83 (m, 2H), 3.45 (m, 1H), 3.18 (m, 1H), 3.07 (m, 1H), 2.97 (m, 1H), 2.76 (m, 1H), 2.58 (d, 1H), 2.48-2.26 ( m, 2H), 2.12 (m, 1H), 1.92-1.75 (m, 2H), 1.73-1.44 (m, 3H), 1.43-1.19 (m, 1H), 1.13 (s, 3H), 1.02 (m, 1H), 0.73-0.41 (m, 4H). Method 9b: 1.61 minutes, 622.2 [M+H] ⁺ 205 . :T (15.27?)-2-((5)-5-chloro-8-((5methylthiazol-4-yl)methoxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5yl)methyl)- 1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 204 (300 MHz, CDC1 ₃ ) δ 8.58 (s, 1H), 7.30 (d, 1H), 6.94 (d, 1H), 5.97 (dd, 1H), 5.18 (d, 1H), 5.12 (d, 1H), 4.11 (dd, 1H), 4.03-3.76 (m, 2H), 3.39 (d, 1H), 3.18 (dd, 1H ), 3.06 (m, 1H), 2.83 (d, 1H), 2.73 (m, 1H), 2.58 (dd, 1H), 2.52 (s, 3H), 2.41 (m, 1H), 2.35 (d, 1H), 2.12 (d, 1H), 1.92-1.74 (m, 2H), 1.73-1.19 (m, 4H), 1.13 (s, 3H), 1.01 (m, 1H), 0.67-0.40 (m, 4H). Method 14 (up to 50% A): 1.59 minutes, 586.4 [M+H] ⁺ 206 NN to /ο°Υ ^ΟΗ ¢0 and Cl (15.27?)-2-((5)-5-chloro-8-((2-methyl-2R1,2,3-triazol-4-yl)methoxy)-1-((6oxo-5-azaspiro [2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)- 1-methylcyclohexane-1-carboxylic acid 204 (300 MHz, CDC1 ₃ ) δ 7.59 (s, 1H), 7.30 (d, 1H), 6.87 (d, 1H), 6.00 (dd, 1H), 5.18 (d, 1H), 5.11 (d, 1H), 4.224.07 (m, 4H), 4.05-3.77 (m, 2H), 3.52 (d, 1H), 3.16 (dd, 1H ), 3.122.98 (m, 2H), 2.74 (m, 1H), 2.59 (m, 1H), 2.48-2.34 (m, 2H), 2.13 (d, 1H) , 1.92-1.75 (m, 2H), 1.74-1.20 (m, 4H), 1.14 (s, 3H), 1.02 (m, 1H), 0.74-0 .45 (m, 4H). Method 14 (up to 50% A): 1.48 minutes, 570.5 [M+H] ⁺

- 194 045906

209 _L AD, / o °γ° ^Η Α ^Λ<Ϊ ' Cl (1D27?)-2-((15)-5-chloro-8-((6,7dihydro-5R-pyrrolo[2.1 c] [1,2,4]triazol-7-yl)oxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5yl)methyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)1-methylcyclohexane-1-carboxylic acid 135 (400 MHz, MeOD) δ 8.54 (s, 1H), 7.38 (m, 1H), 7.20 (m, 1H), 5.92 (m, 1H), 5.87 (m, 1H ), 4.39 (m, 1H), 4.29-4.19 (m, 1H), 4.15-3.99 (m, 2H), 3.78 (m, 1H), 3.40 ( m, 1H), 3.35-3.23 (m, 1H), 3.17 (dd, 1H), 3.13-3.03 (m, 2H), 2.99 (m, 1H), 2 .94-2.80 (m, 2H), 2.46-2.33 (m, 2H), 2.22 (m, 1H), 1.88-1.16 (m, 9H), 0.99 -0.87 (m, 1H), 0.69-0.51 (m, 4H). Method 9b: 1.24 minutes, 582.3 [M+H] ⁺ 211 Ar A Λο°γ ^ΟΗ '/'-у Cl (15.27?)-2-((X)-5-chloro-8-((1-methyl-2oxo-1,2-dihydropyridin-3 yl)methoxy)-1 -((6-oxo-5azaspiro [2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 135 (400 MHz, CDC1 ₃ ) δ 7.43 (m, 1H), 7.32 (dd, 1H), 7.28 (d, 1H), 6.86 (d, 1H), 6.16 (t, 1H), 6.07 (dd, 1H), 5.12 (d, 1H), 4.94 (d, 1H), 4.16 (dd, 1H), 4.01 (m, 1H), 3, 90 (dd, 1H), 3.61 (d, 1H), 3.58 (s, 3H), 3.28 (dd, 1H), 3.16 (d, 1H), 3.08 (dd, 1H ), 2.75 (m, 1H), 2.61 (d, 1H), 2.48-2.34 (m, 2H), 2.14 (d, 1H), 1.91-1.77 ( m, 2H), 1.761.20 (m, 4H), 1.14 (s, 3H), 1.03 (m, 1H), 0.89-0.44 (m, 4H). Method 9b: 1.53 minutes, 596.3 [M+H] ⁺ 214 °,Ό γ + Λο°γ ^ΟΗ ¢6^ Cl (15.27?)-2-((X)-5-chloro-8-((1-methyl-6oxo-1,6-dihydropyridin-2yl)methoxy)-1 -((6-oxo-5azaspiro[ 2.4]heptan-5-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid 135 (300 MHz, CDC1 ₃ ) δ 7.38-7.26 (m, 2H), 6.80 (d, 1H), 6.68-6.60 (m, 1H), 6.32-6.25 (m, 1H), 6.04 (dd, 1H), 5.04-4.87 (m, 2H), 4.19 (dd, 1H), 4.06-3.76 (m, 2H), 3.60 (s, 3H), 3.43 (d, 1H), 3.16-2.95 (m, 2H), 2.89 (d, 1H), 2.77 (m, 1H), 2 .60 (dd, 1H), 2.48-2.30 (m, 2H), 2.13 (d, 1H), 1.90-1.75 (m, 2H), 1.72-1.22 (m, 4H), 1.14 (s, 3H), 1.04 (m, 1H), 0.72-0.43 (m, 4H). Method 13: 2.19 minutes, 596.3 [M+H] ⁺ 215 „ ο^οη ο / ο Υ ¢6 ν (15.27?)-2-(( 1 $)-5 -chloro-8-(( 1 -methyl1,4,5,6- tetrahydrocyclopenta[(1][1,2,3]triaz ol-5-yl)oxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4- tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid (isomer 1) 135 (300 MHz, CDC1 ₃ ) δ 7.35 (d, 1H), 6.88 (d, 1H), 5.92 (dd, 1H), 5.78 (m, 1H), 4.11 (dd, 1H), 4.04-3.83 (m, 5H), 3.38 (d, 1H), 3.17-2.98 (m, 3H), 2.95-2.54 (m, 6H) , 2.47-2.35 (m, 2H), 2.09 (d, 1H), 1.88-1.75 (m, 2H), 1.71-1.21 (m, 4H), 1 .14 (s, 3H), 1.02 (m, 1H), 0.72-0.51 (m, 4H) Method 9d: 3.11 minutes, 595.9 [M+H] ⁺ 216 Ν' ^Ν ν O==/%L / ο°γ ^ΟΗ uU Cl (15.27?)-2-(( 1 $)-5 -chloro-8-(( 1 -methyl1,4,5,6- tetrahydrocyclopenta[(1][1,2,3]triaz ol-5-yl)oxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)1,2,3,4- tetrahydroisoquinoline-2carbonyl)-1-methylcyclohexane-1 carboxylic acid (isomer 2) 135 (300 MHz, CDC1 ₃ ) δ 7.34 (d, 1H), 6.78 (d, 1H), 5.93 (dd, 1H), 5.67 (dd, 1H), 4.13 (dd, 1H), 4.05 (s, 3H), 4.01-3.88 (m, 2H), 3.30-2.64 (m, 9H), 2.60 (m, 1H), 2.42 (m, 1H), 2.33 (d, 1H), 2.12 (d, 1H), 1.89-1.76 (m, 2H), 1.73-1.21 (m, 4H), 1.14 (s, 3H), 1.02 (m, 1H), 0.68-0.47 (m, 4H). Method 9d: 3.12 minutes, 595.9 [M+H] ⁺

Biological tests

Fluorescence Polarization (FP) Interaction Analysis of Kelch-Like Protein KEAPI

Inhibition of NRF2 Kelch domain interaction was determined using a fluorescence polarization (FP) assay in a black 384-well microplate. Compounds were tested on the Biomek FX robot starting at a starting concentration of 10 µM with serial dilutions of 1:3 to obtain a 12-point dose-response curve. Each well contained 2 nM FITC-labeled NRF2 peptide (FITC-LDEETGEFL-NH2) and 25 nM human KEAP1 enzyme (N-terminal, residues 321-609)

- 195 045906 in a final volume of 20 μl of assay buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 5 mM MgCl ₂ , 0.005% Tween-20, 0.005% BSA, 0.5% DMSO) in the presence different concentrations of the test compound. Unlabeled peptide (LDEETGEFL-NH2) at a concentration of 50 μM (negative control) and 0.5% DMSO (positive control) was used to determine the measurement range.

After incubation at room temperature for 1 h, fluorescence polarization (excitation at 470 nm/emission at 530 nm) was measured using an Envision plate reader. IC ₅₀ values were determined by fitting the data to a four-parameter logistic fitting model using XLfit or XE Runner within ActivityBase. The detection limit in the analysis was set such that compounds with concentrations below 10 nM were not detected. The IC ₅₀ values for the example compounds are shown in Table 1. 4.

Table 4

Example connection no. 1C ₅₀ (nM) Example connection no. 1C ₅₀ (nM) Example connection no. 1C ₅₀ (nM) 1 12 76 6.7 151 ND 2 12 77 7.8 152 7.2 3 5.6 78 7.8 153 9.0 4 9.0 79 6.7 154 9.3 5 6.1 80 4.8 155 16 6 5.6 81 14 156 5.1 7 6.2 82 7.7 157 5.9 8 8.2 83 7.8 158 6.3 9 7.7 84 6.1 159 6.7 10 15 85 9.9 160 5.0 eleven 5.1 86 5.0 161 7.9 12 5.8 87 150 162 6.3

- 196 045906

13 8.5 88 AND 163 5.3 14 3.7 89 8.2 164 6.0 15 5.1 90 9.1 165 8.4 16 8.1 91 6.1 166 7.5 17 9.7 92 15 167 16 18 10 93 7.2 168 8.5 19 9.7 94 7.7 169 62 20 5.4 95 8.0 170 6.6 21 4.7 96 18 171 6.4 22 4.7 97 17 172 6.0 23 10 98 10 173 6.5 24 9.1 99 9.7 174 AND 25 15 100 5.1 175 14 26 14 101 1900 176 6.2 27 8.3 102 4.8 177 5.3 28 14 103 6.7 178 6.4 29 16 104 5.5 179 5.3 thirty 9.2 105 7.1 180 7.6 31 4.5 106 5.1 181 5.1 32 6.0 107 6.6 182 5.1 33 5.1 108 5.9 183 5.4 34 5.0 109 9.7 184 2.9 35 9.9 BUT 6.3 185 6.2 36 AND 111 6.1 186 5.6 37 13 112 9.4 187 6.0 38 9.3 113 10 188 4.9 39 8.3 114 7.4 189 5.0 40 9.0 115 9.7 190 5.6 41 5.2 116 73 191 5.2 42 7.9 117 8.2 192 8.5 43 10 118 8.4 193 7.7 44 4.2 119 8.1 194 7.9 45 4.9 120 6.2 195 13 46 37 121 6.3 196 5.6

- 197 045906

47 68 122 9.7 197 5.1 48 8.0 123 5.8 198 5.2 49 AND 124 8.4 199 5.3 50 7.7 125 9.2 200 5.1 51 10 126 5.6 201 3.3 52 13 127 7.0 202 9.8 53 6.2 128 8.7 203 6.2 54 3.6 129 5.5 204 6.9 55 5.6 130 6.7 205 5.5 56 4.2 131 12 206 6.6 57 6.6 132 5.1 207 5.1 58 8.0 133 ND 208 580 59 AND 134 8.2 209 8.4 60 96 135 5.3 210 5.9 61 5.6 136 22 211 6.8 62 14 137 6.3 212 5.7 63 9.1 138 7.9 213 5.2 64 6.3 139 5.7 214 5.2 65 AND 140 4.5 215 71 66 5.7 141 7.0 216 6.4 67 8.5 142 5.0 217 9.8 68 8.4 143 5.2 218 6.8 69 6.9 144 3.6 219 5.3 70 5.9 145 6.4 220 7.0 71 6.5 146 5.7 223 5.0 72 4.8 147 5.1 224 5.8 73 16 148 6.6 225 6.5 74 6.8 149 28 226 5.0 75 6.5 150 5.0

ND=He defined

Analysis of NQO1 mRNA in Beas2B cells

Activation of NRF2-mediated NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) gene expression was measured using the following assay procedure:

BEAS-2B cells (ATCC CRL-9609) were seeded into 96-well clear-well plates at 20,000 cells/well in 75 μl of cell culture medium and incubated overnight (37°C, 5% CO ₂ ). On day 2, 25 µl of compound or controls were added to the cells and left for 24 hours. On day 3, the medium was aspirated from the plate and the Cells-to-CT™ 1-Step TaqMan® Kit was used to perform expression analysis directly on cultured cells without RNA extraction (Ambion A25603) in accordance with the manufacturer's instructions.

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. Samples were 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) using human beta-actin as an internal control. cDNA was amplified using an NQO1-specific primer using a 1-step RT-PCR master mix (Ambion Cells-to-CT™ 1-Step TaqMan® Kit A25603). Primer/probe sets used for cDNA amplification were obtained from TaqMan Gene Expression Assays (Applied Biosystems). The relative quantitation comparative CT technique (AAST) was used to calculate the relative mRNA level of the NQO1 target gene as described in

- 198 045906 Applied Biosystems Chemistry Guide. Data expressed as increases in target gene mRNA compared to vehicle control (0.1% DMSO) and EC50 values were determined by fitting the data to a four-parameter logistic model fitting using XLfit or XE Runner within ActivityBase. The EC50 values for the example compounds are shown in Table 1. 5.

Table 5

Example connection no. EC ₅₀ (nM) Example connection no. EC ₅₀ (nM) Example connection no. EC ₅₀ (nM) 1 850 76 2.5 151 16 2 150 77 6.7 152 10 3 120 78 57 153 7.0 4 13 79 1.2 154 18 5 2.5 80 110 155 4.8 6 78 81 260 156 0.29 7 48 82 1.3 157 4.9 8 48 83 35 158 1.2 9 24 84 36 159 0.22

- 199 045906

10 140* 85 34 160 0.72 eleven 3.5 86 8.3 161 AND 12 8.6 87 300 162 2.4 13 530 88 78 163 0.78 14 2.9 89 5.1 164 2.6 15 850 90 8.1 165 AND 16 2.0 91 0.21 166 40 17 110 92 180 167 280 18 73 93 15 168 85 19 130 94 7.8 169 140 20 20 95 3.7 170 ο,ιι 21 7.9 96 210 171 19 22 15 97 750 172 1.1 23 33 98 330 173 35 24 41 99 520 174 6.6 25 150 100 3.4 175 35 26 58 101 710 176 2.8 27 18 102 ι,ο 177 2.2 28 93 103 67 178 13 29 100 104 27 179 4.1 thirty 17 105 24 180 1.1 31 8.5 106 2.9 181 0.69 32 75 107 0.35 182 0.83 33 22 108 1.5 183 5.8 34 z, z 109 7.4 184 5.6 35 7.5 110 1.3 185 56 36 130 111 2.5 186 4.7 37 44 112 280 187 43 38 17 113 240 188 7.9 39 45 114 16 189 0.27 40 94 115 4.2 190 8.6 41 1.5 116 1900 191 2.1 42 18 117 37 192 3.8 43 18 118 59 193 1.8

- 200 045906

44 10 119 18 194 12 45 110 120 1.2 195 6.8 46 60 121 AND 196 0.97 47 76 122 86 197 0.51 48 4.4 123 0.26 198 0.24 49 19 124 6.8 199 0.34 50 2.0 125 thirty 200 1.2 51 110.0 126 32 201 0.33 52 140.0 127 2.6 202 79 53 1.4 128 1.9 203 0.4 54 7.2 129 0.95 204 13 55 73 130 21 205 19 56 4.8 131 200 206 34 57 2.7 132 5.7 207 0.89 58 68 133 20 208 3300 59 21 134 2.2 209 290 60 2.8 135 0.91 210 0.24 61 63 136 1700 211 43 62 120 137 6.7 212 1.9 63 84 138 0.8 213 2.2 64 23 139 140 214 41 65 97 140 150 215 550 66 27 141 35 216 110 67 4.8 142 0.21 217 43 68 32 143 0.05 218 0.98 69 140 144 0.022 219 0.18 70 55 145 4.9 220 15 71 78 146 0.23 223 15 72 2.8 147 0.29 224 42 73 130 148 22 225 110 74 22 149 73 226 14 75 8.3 150 0.97

* in case of one test > 500 nM

PK/PD analysis method

Male Wistar Han rats (Charles River labs) were dosed orally or intravenously with the test compound at a specified concentration. The intravenous dose was administered by slow bolus injection into the tail vein. The oral composition was administered into the stomach through a gastric tube. The actual administration time was recorded.

From the tail vein, 2 x 0.25 ml blood samples were collected at certain time points into tubes containing K ₂ EDTA. The collected blood samples were then either centrifuged to obtain blood plasma or transferred into 1.5 ml PCR RNAlater tubes containing 650 μl RNAlater.

Immediately after collection, blood samples were placed on natural ice. As soon as possible, 0.25 ml of blood samples were centrifuged in K2EDTA (+4°C, 1500 g, 10 min) and the resulting blood plasma was stored in appropriately labeled polypropylene tubes in a freezer at -80°C to determine pharmacokinetic parameters in plasma blood. An additional 0.25 ml of blood samples in 1.5 ml PCR RNAlater tubes containing 650 μl of RNAlater were stored in the refrigerator at 4°C until blood pharmacodynamic parameters were determined.

After the last sampling, each animal was killed by an overdose of anesthetic via a maximally rapid intravenous injection of pentobarbitone Na and death was confirmed by displacement.

- 201 045906 cervical vertebrae.

The lungs were removed from each animal and divided into 4 equal parts immediately after extraction. The first two parts of the lung (labeled left and right) were placed in a 5 ml tube of RNAlater tissue protect containing 5 ml of RNAlater stabilizing reagent and stored at 4°C to stabilize the RNA (PD analysis). The two remaining parts (labeled left and right) were weighed and quickly frozen by immersion in liquid nitrogen in polypropylene tubes (RC analysis).

The liver was also taken from each animal. Six illustrative parts (of similar size to those of the lung parts) were selected from different areas (no more than 0.5 cm thick). Four parts (no more than 0.5 cm thick) were placed in two different (two parts per tube) 5 ml RNAlater tissue protect tubes containing 5 ml of RNAlater stabilizing reagent (tissue sections were completely immersed in the RNA later solution) and stored at 4°C (PD analysis). The two remaining portions were weighed and quickly frozen by immersion in liquid nitrogen in separate polypropylene tubes (maximum 0.5 g per tube, RC analysis).

In some studies, the heart, spleen and brain were also collected from each animal. Such tissues were cut into four pieces of equal size, and two pieces were placed in a separate 5 ml RNA later tissue protect tube containing 5 ml of RNAlater stabilizing reagent and stored at 4°C. The remaining two parts were weighed and placed separately in polypropylene tubes and quickly frozen by immersion in liquid nitrogen.

Test tubes containing the RNA stabilizing reagent were stored at approx. +4°C in order to ensure the penetration of the stabilizing reagent for RNA into the thickness of the tissue. Quick frozen sections were stored in a freezer at −80°C.

Samples for PK studies were quantified using a protein precipitation-based method and LC-MS/MS analysis. Before analysis, thawed tissue samples were weighed and homogenized followed by the addition of HPLC grade water using an Omni-Prep Bead Ruptor (Omni Inc., Kennesaw, GA, USA) at 4°C. Plasma and tissue homogenate samples were subjected to extraction using protein precipitation with acetonitrile acidified with 0.1% formic acid containing internal standard(s). The samples were mixed and centrifuged at 4000 rpm, 4°C for 30 min to remove precipitated proteins and the supernatant was suitably diluted with HPLC grade water in a 96-well plate. Exemplary aliquots of blood plasma and tissue homogenates were analyzed for test compound by LC-MS/MS using Waters Xevo TQ-S (Waters Xevo, Elstree, UK) against calibration curves generated to a matrix-compatible standard and quality control standards. Standards were prepared by aliquoting known concentrations of control blood plasma and tissue homogenates containing the test compound and extracting as described for experimental samples.

Real-time RNA and PNR extraction for NQO1 gene expression analysis in in-vivo PD studies was performed as described below.

Total RNA was isolated using the RNeasy plus mini RNA isolation kit (Qiagen) or Mouse RiboPure ^TM -Blood RNA Isolation Kit (ThermoFisher Scientific) according to the manufacturer's instructions and quantified using an Agilent RNA 6000 Nano instrument. Real-time PCR was performed using a C-1000 thermal cycler (BioRad) using rat beta-actin as an internal control. DNA was amplified using an NQO1/Nqo1-specific primer using Universal Master Mix (Applied Biosystems). Primer/probe sets used for cDNA amplification were obtained from TaqMan Gene Expression Assays (Applied Biosystems). The comparative CT (ΔΔCT) relative quantification method was used to calculate the relative mRNA level of the NQO1 target gene as described in the Applied Biosystems Chemistry Guide. Data were expressed as the increase in target gene mRNA compared to vehicle control treated according to each tissue type.

Claims (33)

1. Compound of formula IA: FORMULA OF THE INVENTION 'R ⁴ O .R ⁹ P ¹ ° - 202 045906 where R ¹ is selected from C1-4alkylene-k ¹¹ , 5-6 membered heterocyclyl and 8-10 membered bicyclic heteroaryl; wherein said 5-6-membered heterocyclyl is optionally substituted with one or more substituents independently selected from C1-4alkyl, -C(O)-R ¹² , SO2-R ¹³ , _C1-3 alkylene-OI ¹⁴ and 5-6-membered heteroaryl, which is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _3-7 cycloalkyl, halogen, OH, C _{1-3 alkoxy} and cyano; and wherein said 8-10 membered bicyclic heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _3-7 cycloalkyl, halogen, OH and C _{1-3 alkoxy} ; R ² is selected from hydrogen, fluorine, chlorine and C ₁ - ₃ alkyl; R ³ is selected from hydrogen, fluorine, chlorine, bromine, C ₁ - ₃ alkoxy, C ₁ - ₃ alkyl, C ₁ - ₃ haloalkyl and cyano; ^R4 and ^R5 , taken together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring, wherein: said heterocyclyl ring contains one or more -C(O)- moieties attached to a nitrogen atom and is optionally fused to a phenyl or 5-6 membered heteroaryl ring or optionally attached via a spiro bond to a C _3-7 cycloalkyl group; and said heteroaryl and heterocyclyl rings are optionally substituted with one or _{more substituents} independently selected from C _1-4 alkyl, halogen, OH, C _1-3 alkoxy, C _1-3 haloalkyl, cyano, NR ¹⁶ R ¹⁷ , C(O)R ¹⁸ , S(O)R ¹⁹ and SO2R ²⁰ ; L ¹ and L ² are independently selected from the relationship and -CR ²¹ R ²² -; R ⁶ and R ⁷ are independently selected from hydrogen, C _1-4 alkyl and C _3-7 cycloalkyl; or R ⁶ and R ⁷ taken together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered cycloalkyl ring; R ⁸ is selected from CO2R ²³ , C(O)H^O ₂ C _1-3 -alkyl, tetrazolyl, 3-trifluoromethyl-1,2,4-triazol-5-yl and a carboxylic acid mimetic group selected from hydroxamic acids, esters of hydroxamic acids, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfonylureas, acylureas, thiazolidinedione, oxazolidinedione, oxadiazol-5(4R)-one, thiadiazol-5(4R)-one, oxathiadiazol-2 -oxide, oxadiazole-5(4R)-thione, isoxazole, tetramic acid, cyclopentane-1,3-diones and cyclopentane-1,2-diones; R ⁹ is selected from hydrogen, C _1-4 alkyl, hydroxy, C _1-3 alkoxy and halogen; R ¹⁰ is selected from hydrogen and C _1-4 alkyl; or R ⁹ and R ¹⁰ taken together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered cycloalkyl ring; or L ² represents a bond, and R ⁷ and R ¹⁰ taken together with the atoms to which they are attached form a 4-, 5-, 6- or 7-membered cycloalkyl or heterocyclyl ring, wherein said heterocyclyl ring contains 1 or 2 heteroatom independently selected from nitrogen, oxygen and sulfur; said cycloalkyl ring optionally contains 1 or 2 carbon-carbon double bonds and is optionally bridged by _a C ₁ - 3 alkylene group connecting two carbon atoms of the ring, or R ⁹ is optionally a C ₁ - ₃ alkylene group connecting C* to ring carbon atom; and said cycloalkyl and heterocyclyl rings are optionally substituted with one _or more substituents independently selected from C _1-4 alkyl, halogen, OH, C _1-3 alkoxy, C _1-3 haloalkyl and deuterium _; R ¹¹ is selected from -C(O)-R ²⁴ , -SO2-R ²⁵ , -NR ²⁶ C (O)-R ²⁷ , -NR ²⁸ SO2-R ²⁹ , 5-6 membered heterocyclyl, phenyl, 5-6 -membered monocyclic heteroaryl and 8-9 membered bicyclic heteroaryl; wherein said phenyl and 5-6-membered monocyclic heteroaryl and 8-9-membered bicyclic heteroaryl groups are optionally substituted with one or more substituents independently selected from C1-4alkyl, _{C1-3haloalkyl , C3-7cycloalkyl} , _{C1- 4} alkylene-R ³⁰ , halogen, OH, C1-3 alkoxy, 5-6 membered heterocyclyl and cyano; and said 5-6 membered heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-3haloalkyl, C3-7cycloalkyl, C1-4alkylene- ^K30 , halogen, OH, _C1-3alkoxy , oxo and cyano ; R ¹² is selected from C1-4alkyl, C3-7cycloalkyl, OR ³¹ , NR ³² R ³³ , phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from C1-4 alkyl, halogen, OH, C ₁ - ₃ alkoxy and cyano; R ¹³ is selected from C1-4 alkyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl and NR ³⁴ R ³⁵ , wherein said 5-6 membered heteroaryl and 5-6 membered heterocyclyl are optionally substituted with one or several substituents independently selected from C1-4 alkyl, halogen, OH, _C1-3 alkoxy and cyano; R ¹⁷ is selected from hydrogen, C _1-4 alkyl, C (O) C ₁ - ₃ alkyl and C (O)NR ³⁶ R ³⁷ ; R ¹⁸ , R ¹⁹ and _R ²⁰ are independently selected from C _1-4 alkyl, OH, C _1-3 alkoxy and NR38R ³⁹ ; R ²⁴ is selected from C _1-4 alkyl, NR ⁴⁰ R ⁴¹ and OR ⁴² ; - 203 045906 R ²⁵ is selected from C _1-4 alkyl and NR43R ⁴⁴ ; R ²⁷ is selected from C _1-4 alkyl, C _3-7 cycloalkyl, _C1-3 haloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl and 8-9 membered bicyclic heteroaryl, wherein said phenyl , the 5-6 membered monocyclic heteroaryl and the 8-9 membered bicyclic heteroaryl are optionally substituted with one or more substituents independently selected from _C1-4 alkyl, C^haloalkyl, _C3-7 cycloalkyl, _C1-4 alkylene^ ⁴⁵ , halogen, OH, C^alkoxy and cyano; R ²⁹ is selected from C _1-4 alkyl, C _3-7 cycloalkyl, C _1-3 haloalkyl, phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl are optionally substituted with one or more substituents, regardless selected from C _1-4 alkyl, C ^ haloalkyl, C _3-7 cycloalkyl, C ^ alkylene R ⁴⁶ , halogen, OH, C ^ alkoxy and cyano; R ³⁰ is selected from hydroxy, C^alkoxy, C _3-7 cycloalkyl, cyano and NR ⁴⁷ R ⁴⁸ ; R ⁴⁰ is selected from hydrogen and C _1-4 alkyl; R ⁴¹ is selected from hydrogen, C^alkyl, _C3-7 cycloalkyl, C^alkoxy, phenyl and 5-6 membered heteroaryl; or R ⁴⁰ and R ⁴¹ , taken together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heteroaryl or heterocyclyl ring, said heteroaryl and heterocyclyl rings being optionally substituted by one or more substituents independently selected from C _{1- 4} alkyl, halogen, OH, C^alkoxy, C _3-7 cycloalkyl and cyano; R ⁴⁵ and R ⁴⁶ are independently selected from hydroxy, C^alkoxy and C _3-7 cycloalkyl; And R ¹⁴ , R ¹⁵ , R ¹⁶ , R ²¹ , R 22 , R ²³ , R ²⁶ , R ²⁸ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , ^{R 38 ,} R ³⁹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁷ and R ⁴⁸ are independently selected from hydrogen, C _1-4 alkyl and C _3-7 cycloalkyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein L ² represents a bond and R ⁷ and R ¹⁰ taken together with the atoms to which they are attached form a 4-, 5- or 6-membered cycloalkyl ring. 3. A compound according to claim 1, wherein said compound is characterized by the structural formula IB shown below: R ⁵ R ³ (IB), where R1-R ⁶ , R ⁸ and R ⁹ are as defined in claim 1, and the cyclohexyl ring is optionally substituted with one or more substituents independently selected from C1-4 alkyl, halogen, OH, C^ alkoxy and deuterium, and the cyclohexyl ring is optionally bridged by a C-alkylene group connecting two ring carbons, or ^R9 is optionally a C-alkylene group connecting C* to a ring carbon. 4. A compound according to any one of claims 1 to 3, where R ⁸ represents CO2R ²³ and R ²³ represents hydrogen. 5. A compound according to any one of claims 1-4, where R ⁹ represents hydrogen or C _1-4 alkyl. 6. A compound according to any one of claims 1 to 5, where R ⁹ represents hydrogen or methyl. 7. A compound according to any one of claims 1 to 6, where R ¹ represents C _1-4 alkylene-K ¹¹ . 8. The compound according to claim 7, where R ¹ represents CH2-R ¹¹ . 9. A compound according to any one of claims 1 to 9, where R ¹¹ is selected from -C(O)-R ²⁴ , -NR ²⁶ C (O)-R ²⁷ , 5-6-membered heterocyclyl, phenyl, 5-6- membered monocyclic heteroaryl and 8-9 membered bicyclic heteroaryl, wherein said phenyl, 5-6 membered monocyclic heteroaryl and 8-9 membered bicyclic heteroaryl groups are optionally substituted with one or more substituents independently selected from C-alkyl, C-haloalkyl , C3-7cycloalkyl, C1-4alkylene-I ³⁰ , halogen, OH, C^alkoxy, 5-6-membered heterocyclyl and cyano; and said 5-6 membered heterocyclyl group is optionally substituted with one or more substituents independently selected from C1-4 alkyl, C^haloalkyl, _C3-7 cycloalkyl, _C1-4 alkylene^ ³⁰ , halogen, OH, C^alkoxy, oxo and cyano. 10. A compound according to any one of claims 1 to 8, where R ¹¹ represents a 5-6 membered monocyclic heteroaryl or an 8-9 membered bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from C^alkyl, C^haloalkyl , C _3-7 cycloalkyl, C _1-4 alkylene^ ³⁰ , halogen, OH, C^alkoxy, heterocyclyl and cyano. - 204 045906 11. A compound according to any one of claims 1 to 8, where R ¹¹ represents a 5-6 membered monocyclic heteroaryl or an 8-9 membered bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from methyl, ethyl, isopropyl, difluoromethyl , trifluoromethyl, chlorine, fluorine, cyclopropyl, methoxy, cyano, oxetanyl, CH2-R ³⁰ and C2H4-R ³⁰ . 12. A compound according to any one of claims 1 to 8, where R ¹¹ represents pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl, each of which is optionally substituted with one or more substituents independently selected from C1-4 alkyl, _{C1-3 haloalkyl} , _C3-7 cycloalkyl, _C1-4 ^alkyleneA0 , halogen, OH, Ci-uI.ikokcu, 5-6 membered heterocyclyl and cyano. 13. A compound according to any one of claims 1 to 8, where R ¹¹ represents heteroaryl selected from: wherein each heteroaryl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, C _{1 -} 3 haloalkyl, C _3-7 cycloalkyl, C _1-4 alkylene ^{A 0} , halogen, OH, ('dikoxy, 5-6 -membered heterocyclyl and cyano. 14. The connection according to any one of claims 1-6, where R ¹ is selected from: - 205 045906 where .· .· / / represents the point of attachment to the oxygen atom of the rest of the compound and where each heteroaryl group is optionally substituted by one or more substituents independently selected from C _1-4 alkyl, C ₁ - ₃ haloalkyl, C _3-7 cycloalkyl, C _1-4 alkylene^ ³⁰ , halogen, OH, Ci-uL'ikokcu, 5-6-membered heterocyclyl and cyano. 15. A compound according to any one of claims 1 to 6, where R ¹ represents a 5-6 membered heterocyclyl, optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , 5- 6-membered heteroaryl and C^alkylene-OR ¹⁴ , wherein said 5-6-membered heteroaryl is optionally substituted with one or more substituents independently selected from C1-4alkyl _{, C3-7cycloalkyl} , halogen, OH, _C1-3alkoxy and cyano. 16. A compound according to any one of claims 1 to 6, where R ¹ represents piperidinyl or pyrrolidinyl, each of which is optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , 5- 6-membered heteroaryl and C1-3alkylene-OR ¹⁴ , wherein said 5-6membered heteroaryl is optionally substituted with one or more substituents independently selected from C1-4alkyl, _C3-7 cycloalkyl _{, halogen, OH, C1-3 alkoxy} and cyano . 17. The compound according to claim 16, where R ¹ represents pyrrolidinyl, optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , 5-6-membered heteroaryl and C1-Zalculene- OR ¹⁴ , wherein said 5-6-membered heteroaryl is optionally substituted with _C1-4 alkyl or C _3-7 cycloalkyl. 18. A compound according to any one of claims 1 to 6, where R ¹ is selected from one of the following groups: where jvw represents the point of attachment of the group to the oxygen atom of the rest of the compound and where each group is optionally substituted with one or more substituents independently selected from -C(O)-R ¹² , SO2-R ¹³ , 5-6 membered heteroaryl and C1-alculene -OR ¹⁴ , wherein said 5-6 membered heteroaryl is optionally substituted with C1-4 alkyl or C _3-7 cycloalkyl. 19. A compound according to any one of claims 1 to 18, where R ² represents hydrogen or fluorine. - 206 045906 20. A compound according to any one of claims 1 to 19, where R ³ represents hydrogen or chlorine. 21. A compound according to any one of claims 1 to 20, where R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl or heterocyclyl ring, wherein said heterocyclyl contains a -C(O) fragment - attached to a nitrogen atom, and is optionally fused to a phenyl or 5-6 membered heteroaryl ring or optionally attached via a spiro bond to a C _3-7 cycloalkyl group, and wherein said heteroaryl and heterocyclyl are optionally substituted with one or more independently selected substituents from C _1-4 alkyl, halogen, OH, k^alkoxy and cyano. 22. The compound according to claim 21, where R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5-membered heteroaryl ring, optionally substituted by one or more substituents independently selected from C _1-4 alkyl, halogen and he. 23. A compound according to claim 22, wherein the 5-membered heteroaryl ring is pyrazolyl. 24. The compound according to claim 21, where R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl ring, wherein said heterocyclyl contains a fragment -C(O)- attached to a nitrogen atom, and is optionally fused to a phenyl ring or optionally attached via a spiro bond to a C _3-7 cycloalkyl group, and wherein said heterocyclyl is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen and OH. 25. A compound according to any one of claims 1 to 20, wherein R ⁴ and R ⁵ , taken together with the nitrogen atom to which they are attached, form a heterocyclic moiety selected from one of the following: wherein the saturated ring of the heterocyclic moiety is optionally attached via a spiro bond to a C _3-7 cycloalkyl group and wherein said heterocyclic moiety is optionally substituted with one or more substituents independently selected from C _1-4 alkyl, halogen and OH. 26. A compound according to claim 1, which is selected from any of the following: (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazol-3-carboxamido)ethoxy)1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(2-(benzo[d]oxazol-2-carboxamido)ethoxy)-1-((1,3-dioxoisoindolin-2-yl)methyl)1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-8-(((S)-1 -acetylpyrrolidin-3 -yl)oxy)-1 -((1,3-dioxoisoindolin-2-yl)methyl)- 1,2,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((S)-1-(5-methylisoxazol-3-carbonyl)pyrrolidin- 3 -yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-5 -bromo-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-((k)-1 -(thiazol-5-carbonyl )pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-((k)-1 -(thiazol-5-carbonyl)pyrrolidin-3 yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-((k)-1 -(2-methylthiazol-5-carbonyl)pyrrolidine -3 -yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d][1,2,3 ]mriazol-5yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(( 1 -methyl- 1H-1,2,3-triazol-4 -yl)methoxy)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-(( 1 -methyl-1 H-benzo^]imidazol-5-yl )methoxy)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(((S)-1-acetyln-pyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl) methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((1,3-dioxoisoindolin-2-yl) methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-8-(((S)-1 -acetylpyrrolidin-3-yl)oxy)-5,7-dichloro-1 -((1,3-dioxoisoindolin-2yl )methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-5 -chloro-1 -((1,3-dioxoisoindolin-2-yl)methyl)-8-((k)-1 -(thiazol-5-carbonyl )pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; - 207 045906 (1 S,2R)-2-((S)-1-(( 1 -oxoisoindolin-2-yl)ven)-8-((^)-1 -(thiazol-5-carbonyl)pyrrolidin- 3 yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (u,2K)-2-((b)-8-([1,2,4|triaz>olo[4,3-a|pyridin-3-ylmstoxy)-5-bromo-1-((1- oxoisoindolin-2-yl)venger)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^,2K)-2-((b)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)mstoxy)-1-((1-oxoisoindolin-2-yl) mstil)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (u,2K)-2-((b)-8-((1-mestil-1H-bsn>oSh|[1,2,3|triazol-5-yl)mstoxy)-1-((1-oxo '^>>oindolin-2-yl)ventil)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylicacid; (1 S,2R)-2-((S)-8-(((S)-1 -acetylpyrrolidin-3 -yl)oxy)-5-bromo-1 -((1 -oxoisoindolin-2-yl)venger )1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(2-mstilthiazol-5-carbonyl)pyrrolidin-3-yl)oxy)-1-((1 -oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-5 -bromo-8-((D)-1 -(5-methylthiazol-2-yl)pyrrolidin-3 -yl)oxy)-1-(( 1 -oxoisoindolin2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-mstilpyridazin-3-yl)pyrrolidin-3-yl)oxy)-1-((1 -oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1 S,2R)-2-((S)-5-bromo-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1 -((1-oxoisoindoline -2-yl)methyl) 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,2,4-oxadiazol-3-yl)meΊΌxi)-1-((1-oxoisoindoline-2- yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-mesthyl-1H-imidazol-4-yl)mstoxy)-1-((1-oxoisoindolin-2-yl)venge) 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-mstilisoxazol-3-yl)mstoxy)-1-((1-oxoisoindolin-2-yl)mstyl)1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((2-ethyl-2H-1,2,3-triazol-4-yl)mstoxy)-1-((1-oxoisoindolin- 2-yl)venstyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (u,2K)-2-((^)-5-bromo-8-((5-mstilthiazol-2-yl)mstoxy)-1-((1-oxo-1,3,3a,4,5, 6-hsxahydro-2Nisoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-Ίriazol-5-yl)methoxy)-1-((1-oxoisoindolin- 2-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^,2K)-2-((b)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^^)-2-(^)-5-bromo-8-((1-(cyclopropylmstil)-1H-1,2,3-triazol-4-yl)mstoxy)-1-((1-oxoisoindoline2- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(imidazo[1,2-a]pyridin-7-ylmstoxy)-1-((1-oxoisoindolin-2-yl)venger)1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-venzo[d]imidazol-5-yl)mstoxy)-1-((1-oxoisoindolin-2yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1-((1-oxoisoindolin- 2-yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^^)-2-(^)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)mstoxy)-1-((1-oxoisoindolin-2yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-((1-oxoisoindolin-2- yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (u,2K)-2-((b)-5-bromo-8-((7-mstoxy-1-methyl-1H-benz>oSh|[1,2,3|tria'^>> ol-5- yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-te1rahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-venstil-1H-bsnzo[d][1,2,3]triazol-5-yl) mstoxy)-1-( (1-oxoisoindolin2-yl)venstyl)-1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-mestil-1H-1,2,4-Ίriazol-3-yl)mstoxy)-1-((1-oxoisoindolin- 2-yl)venstyl)1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-imidazol-2-yl)mstoxy)-1-((1-oxoisoindolin-2-yl)mstyl) 1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (^^)-2-(^)-5-bromo-8-((5-(difluoromstyl)-1-mestil-1H-1,2,3-triazol-4-yl)mstoxy)-1-(( 1-oxoisoindolin-2-yl)ven)-1,2,3,4-ts1rahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((4-ethyl-4H-1,2,4-triazol-3-yl)mstoxy)-1-((1-oxoisoindolin- 2-yl)venstyl)1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-cyano-1-ethyl-1H-imidazol-4-yl)mstoxy)-1-((1-oxoisoindolin-2- yl)ven)-1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)ven)-8-((5,6,7,8-tstrahydro-[1,2 ,4]triazolo[4,3a|pyridin-3-yl)mstoxy)-1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; (^^)-2-((^)-5-bromo-8-(1-(1-mestil-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindoline -2-yl)venstyl)1,2,3,4-tstrahydroisoquinoline-2-carbonyl)cyclohxane-1-carboxylic acid; - 208 045906 (1S,2R)-2-((1S)-5-bromo-8-(1-(1-isopropyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-( (1-oxoisoindolin-2yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-5-chloro-8-((1-methyl-1H-benzoI|[1.2.3|triazol-5-yl)methoxy)-1-((1-oxoisoindoline -2yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-8-([1.2.4|triaz>olo[4.3-а|pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindoline-2- yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-8-((1-(2,2,2-trifluoroethyl)-1H- imidazol-2yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-(2,2-difluoroethyl)-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin- 2yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-5-chloro-8-((5-(di((((()tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-((1-oxoisoindolin-2-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1- ((1-oxoisoindolin-2-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-ethyl-1H-pyrazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl) 1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin- 2yl)methyl)-1.2.3.4-tetrahydro'^> ₍ oquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin- 2yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-fluoro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin- 2yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methyl-1-((1-oxoisoindolin- 2yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-5-cyano-8-((1-isopropyl-1H-1.2.3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2yl) methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxy-1-((1-oxoisoindolin- 2yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-8-((1-isopropyl-1H-1.2.3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl) 5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazol-5-carbonyl)pyrrolidine3 -yl)oxy)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([1,2,4]Ίriazolo[4,3-a]pyridin-3-ylmeΊΌxi)-5-bromo-1-((2-oxopyrrolidine- 1-yl)methyl)1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2 ,3,4tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-5-bromo-8-((5-isopropyl-1.2.4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl) -1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-8-(oenzol|isoxazol-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4tetrahydroisoquinoline-2 -carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-8-(oenzoI|isothiazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4tetrahydroisoquinoline-2 -carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-2-ylmethoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methylisothiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1.2.3.4- tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-5-chloro-8-(isothiazol-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4tetrahydroisoquinoline-2-carbonyl )cyclohexane-1-carboxylic acid; (^.2C)-2-((b)-8-(oenzol|isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4tetrahydroisoquinoline-2 -carbonyl)cyclohexane-1-carboxylic acid; (^.2K)-2-((^)-5-bromo-8-((1-opropyl-1H-1.2.3-triazol-4-yl)methoxy)-1-((3-methyl- 2-oxopyrrolidin1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1-(((R)- 4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1-((6-oxo- 5-azaspiro[2.4]heptan5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1-(((S)- 4-methyl-2-oxopyrrolidin-1 -yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridin-3-ylmethoxy)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; - 209 045906 (i.2C)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-ethyl-1H-1.2.3-triazol-4-yl) methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (C)-4-((b)-8-(benzoI|isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-3.4-dihydroisoquinoline-2(1H) -yl)-3-methyl-4-oxobutanoic acid; 1-(((b)-2-((1C^)-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-8-(oenzol|isoxazol-3-ylmethoxy)5-chloro-1 ,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one; (i.2C)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl) methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((4-methyl-1Hpyrazol-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrimidin-5-ylmethoxy)-1,2,3,4- tetrahydroisoquinoline-2-caroonyl)cyclohexane-1-caroonic acid; (i.2C)-2-((b)-5-chloro-8-((5-(di(((()tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid; (1R,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid; (^.2C)-2-((b)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1.2.3.4-tetrahydroisoquinoline-2- carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2- oxopyrrolidin1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-( (2-oxopyrrolidin-1yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- ((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-(imidazo[1,2-a]pyrimidin-2-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1.2 .3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-(isoxazolo[5,4-b]pyridin-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1.2 .3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([l,2,4]Ίriazolo[4,3-a]pyridin-3-ylmeΊΌxi)-5-chloro-1-((2-oxopyrrolidine- 1-yl)methyl)1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1yl) methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; 3-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-((2- oxopyrrolidin1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid; 3-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-((2- oxopyrrolidin1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)tetrahydro(|)uranium-2-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-indazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl) 1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methoxy)-1-((2- oxopyrrolidin1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (i.2C)-2-((b)-8-(oenzol|isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4tetrahydroisoquinoline-2 -carbonyl)-1-methylcyclohexane-1-carboxylic acid; 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin1- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluorocyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((2- oxopyrrolidin1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin- 1yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1R,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-fluorocyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin- 1yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2- oxopyrrolidin-1yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1- ((2oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 - 210 045906 carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( (R)-4-methyl2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1carboxylic acid; (^.2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1carboxylic acid; (^.2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-(((K)-4-methyl2-oxopyrrolidin-1 -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)-1-(( (R)-3-methyl2-oxopyrrolidin-1-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)-1-(( (R)-3-methyl2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1 carboxylic acid; (^.2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-(((b)-3-methyl2-oxopyrrolidin-1 -yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1 carboxylic acid; (^.2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-(((b)-3-methyl2-oxopyrrolidin-1 -yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid; (^.2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)- 1-(((b)-4-methyl2-oxopyrrolidin-1 -yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1 carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( 2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroquinoline-2-carbonyl)-1-ethylcyclohexane-1-carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( 2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroquinoline-2-carbonyl)-1-ethylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- ((2-oxopyrrolidinyl^ethyl^D3-tetrahydroisoquinoline^-carbonylGGmethylcyclopengan-Gcarboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- ((2-oxopyrrolidin1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( 2oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( 2oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( 6-oxo-5azaspiro|2.4|heptan-5-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((4.5-dimethylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1.2.3.4- tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((4-chloro-5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl) 1 .2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((4-methylisoxazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4 tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S.2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1.2.3-triazol-4-yl)methoxy)-1-(( 2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(2-methoxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 1-((2-oxopyrrolidin-1 -yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 2-oxopyrrolidin1 -yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1 S.2R)-2-((S)-5 -chloro-1-((^)-3 -methyl-2-oxopyrrolidin-1-yl)methyl)-8-(( 1 -methyl-5 - (trifluoromethyl)1H-1.2.3-triazol-4-yl)methoxy)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1 S.2R)-2-((S)-5 -chloro-1-((A)-3 -methyl-2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 -methyl-5 ( trifluoromethyl)-1H-1.2.3-triazol-4-yl)methoxy)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid; (1S.2R)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5( trifluoromethyl)-1H-1.2.3-triazol-4-yl)methoxy)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1 - 211 045906 methylcyclohexane-1-carboxylic acid; (1 S,2S)-2-((S)-5-chloro-1 -((^)-4-methyl-2-oxopyrrolidin-1 -yl)methyl)-8-(( 1 -methyl-5 - (trifluoromethyl)1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^^)-2-(^)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^^)-2-(^)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-yl)methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl )methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)methoxy)-1-((6-oxo-5azaspiro[ 2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxαzol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (^^)-2-(^)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzoSchisoxazol-3yl)methoxy)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (^^)-2-(^)-8-((2,5-bis(difluoromethyl)-2H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6 -oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; 2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5azaspiro [2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3carboxylic acid; ^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2oxopyrrolidin- 1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.2]octane-1carboxylic acid; (^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic-4,4D2 acid; (^^)-2-(^)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^^)-2-(^)-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)-1methylcyclohexane-1-carboxylic acid ; (^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)- 1-((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic 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-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid; (^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro- 1-((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methoxy)-1-((6-oxo- 5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(( ^)-4-methyl2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid; (^^)-2-(^)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; 1-((^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2-((III^)- 2-methyl-2-(2Htetrazol-5-yl)cyclohexan-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triαzol-4-yl)methoxy)-1- ((4,4-dimethyl2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methyl-4-(trifluoromethyl)isoxazol-3-yl)methoxy)-1-((6-oxo-5 - 212 045906 azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^,2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-(2,2,2-tri(|)thorethyl)-1H-1 ,2,3-triazol-4-yl)methoxy)-1((2-oxopyrrolidin-1 -yl)methyl)-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid ; (^^)-2-(^)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo- 5-azaspiro[2.4]heptan5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)-5-methylisoxazol-3-yl)methoxy)-1-((6-oxo-5azaspiro[2.4] heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^,2K)-2-((b)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo- 5-azaspiro|2.4|heptan5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (^,2K)-2-((b)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((K)- 4-methyl-2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- (((R)-4methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1-(( (R)-4-methyl-2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((1S)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[d]isoxazol-3-yl)methoxy)-1-((2oxopyrrolidine-1- yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1 carboxylic acid; (^.2K)-2-((b)-5-chloro-8-((6.7-di(((torbenzoI|isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1yl)methyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)1,2, 3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1- yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1- yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (^^)-2-(^)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (^^)-2-(^)-5-chloro-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-methylcyclohexane1-carboxylic acid; (^^)-2-(^)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4(trifluoromethyl)pyrimidin-5- yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1methylcyclohexane-1-carboxylic acid; (^^)-2-(^)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid; (^^)-2-(^)-5-chloro-8-((1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-1-methyl-2-((S)-5-methyl-8-((1-methyl-5-(Ίrifluoromethyl)-1H-1,2,3-Ίryazol-4-yl)methoxy )-1-((2oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (^^)-2-(^)-5-chloro-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5- azaspiro[2.4]heptan5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (^^)-2-(^)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-с][1,4]oxazine-3 -yl)methoxy)-1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-Ίriazol-3-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; - 213 045906 (A.2K)-2-((b)-5-(|)tor-8-((1-methyl-5-(tri(|)tormethyl)-1H-1.2.3-triazol-4 -yl)methoxy)-1-((2-oxopyrrolidin-1 -yl)methyl)-1,2,3D-tetrahydroisoquinoline^-carbonylN-methylcyclohexane-1-carboxylic acid; (A.2K)-2-((b)-5-chloro-8-((4.5-dimethyl-4H-1.2.4-triaz,ol-3-yl)methoxy)-1-((6-oxo- 5-az,aspiro|2.4|heptan5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (A.2K)-2-((b)-5-chloro-1-((6-oxo-5-az,aspiro|2.4|heptan-5-yl)ven)-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-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-с][1,2,3]triazol-3-yl) methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6, 7-tetrahydro-[1,2,3]riazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-с][1,2,4]Ίriazol-3-yl) methoxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisocho:nolin-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (A.2K)-2-((b)-5-chloro-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro|2.4| heptan-5yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((5,6,7, 8-tetrahydro-[1,2,4]riazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (A.2K)-2-((b)-5-chloro-8-(((b)-1-(methylsul(|)onyl)pyrrolidin-3-yl)oxy)-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)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4] heptan-5yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine -3-yl)methoxy)-1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid ; (1S,2R)-1-methyl-2-((S)-8-((1-methyl-5-(Ίriforomethyl)-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- ((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-5-(Ίriforomethyl)-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- ((2-oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (A2K)-2-((b)-5-chloro-8-((5-(di(|)tormethyl)-1-(oxetan-3-yl)-1H-1.2.3-triazol-4-yl )methoxy)-1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid; (A.2K)-2-((b)-8-((1.5-bis(di(|)tormethyl)-1H-1.2.3-triaz>ol-4-yl)methoxy)-5-chloro-1 -((6-oxo-5-a'^>>aspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylicacid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- (((R)-2-methyl-5oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-Ίriazol-4-yl)methoxy)-1- (((S)-2-methyl-5oxopyrrolidin-1-yl)methyl)-1.2.3.4-tetrahydroquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]riazolo [1,5-a]pyridin3-yl)methoxy)-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)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy )-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((3-oxomorpholino)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1 - 214 045906 carboxylic acid; 5-((^)-2-((N^)-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl1H -1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one; (N^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro- 1-((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid; (N^)-2-(^)-5-chloro-8-((5-(difluoromethyl)thiazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5yl )methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methylthiazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptane-5- yl)methyl)1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (N^)-2-(^)-5-chloro-8-((2-methyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5- azaspiro[2.4]heptan5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (N^^^)-4-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptan-3 carboxylic acid; (1S,3S,4R,6R)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy )-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3carboxylic acid ; (1S,2R)-2-((1S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl) oxy)-1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (N^^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic-4,5D2 acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methoxy)-1-((6-oxo- 5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (NH)-2-((NH)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (2-oxo-4(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1carboxylic acid; (N^)-2-(^)-5-chloro-8-((1-methyl-6-oxo-1,b-dihydropyridin-2-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; (N2)-2-((A)-5-chloro-8-((1-methyl-1,4,5,6-tetrahydrocyclopenta[1,2,3]triazol-5-yl)oxy)-1 -((6oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic acid; (N^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluoro-1-methylcyclohexane1-carboxylic acid; (N^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoro-1-methylcyclohexane1-carboxylic acid; (N^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane1-carboxylic-4D acid; (N^^)-2-0R)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(( 6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane1-carboxylic acid; (N^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane1-carboxylic acid; (N^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane1-carboxylic acid; (N^^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-( (6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-hydroxy-1-methylcyclohexane1-carboxylic acid; (2S,3R)-3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1- ((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-2carboxylic acid; (1R,2R,6S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane - 215 045906 1-carboxylic acid; (1R,2R,6R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane1-carboxylic acid; (1S,2S,3R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triαzol-4-yl)methoxy)- 1-((6-oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane1-carboxylic acid and (^^ ^)-2-(^)-5-chloro-8-((5-(difluoromethyl)-1-methyl-III-1,2,3-triazol-4-yl)methoxy)-1-((6- oxo-5azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane1-carboxylic acid; or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 28. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 29. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 30. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 31. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 in therapy for the treatment of diseases or disorders mediated by activation of Nrf2. 32. Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 in the treatment of chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury/acute respiratory distress syndrome with with or without concomitant multiple organ failure syndrome, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and recovery from it, cardiac remodeling, types of cardiac - 216 045906 arrhythmia, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes mellitus, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta thalassemia, sickle cell anemia, rheumatoid arthritis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxin-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease (CKD), 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 hereditary ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' corneal endothelial dystrophy or uveitis. 33. A method of treating a disease or disorder selected from chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury/acute respiratory distress syndrome with or without associated multiple organ dysfunction syndrome, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and recovery from it, cardiac remodeling, types of cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, 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 syndrome, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis-induced toxins of liver disease, viral hepatitis and cirrhosis, chronic kidney disease (CKD), diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgAnephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease , Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's hereditary ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy and uveitis, wherein said the method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.