Therapeutic compounds

Abstract

To provide tetrahydroisoquinoline compounds that are Nrf2 activators.SOLUTION: The invention provides compounds illustrated by the formula in the figure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 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 processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or disorders associated with inhibition of Nrf2 activation and / or Keap1-Nrf2 protein-protein interaction. [Background technology]

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

[0003] It has been shown that Nrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects, and Nrf2 mRNA was negatively correlated with pack-years. Nrf2 protein levels in COPD subjects were significantly lower than that in control subjects. CSE-induced A549 cell apoptosis was increased in a time- and concentration-dependent manner and was significantly increased by Nrf2 knockdown (Non-Patent Document 1). Therefore, increasing Nrf2 levels in the lungs of COPD patients should result in a reduction of inflammatory processes that lead to harmful structural alterations in the lung and slow disease progression. Nrf2 may also be expected to show positive benefits in other respiratory diseases that exhibit an oxidative stress component, such as acute, chronic, and severe asthma (Non-Patent Document 2), acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome (Non-Patent Document 3), pulmonary fibrosis including pulmonary fibrosis of unknown cause (Non-Patent Document 4), and cystic fibrosis (Non-Patent Document 5) (Non-Patent Document 6).

[0004] The cardioprotective properties of Nrf2 have been demonstrated in models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, and heart failure (NPL 7). The Nrf2 activator bardoxolone methyl recently completed a phase II trial in patients with pulmonary arterial hypertension (PAH), and a phase III trial is underway based on significant improvements in 6-minute walking distance. While bardoxolone covalently reacts with Keap1, compounds that activate Nrf2 via mechanisms other than Keap1 binding should also be expected to be therapeutically useful in PAH, particularly in patients who also have an underlying connective tissue disorder (CTD), such as scleroderma or lupus erythematosus. Oxidative stress is elevated in diseased myocardium, resulting in increased levels of reactive oxygen species that negatively impact cardiac function (NPL 8). Nrf2 activation has been shown to suppress myocardial oxidative stress, cardiac apoptosis, hypertrophy, fibrosis, and dysfunction in a mouse model of pressure overload (Non-Patent Document 9) and protect against cardiac ischemia / reperfusion injury in a rodent model (Non-Patent Document 10). Furthermore, excessive production of oxidants in the cardiovascular system due to impaired antioxidant defense has also been described in metabolic diseases such as obesity, metabolic syndrome, and diabetes, and activation of Nrf2 has also been proposed as a promising therapeutic strategy (Non-Patent Document 11). In addition, the Nrf2 activator sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes (Non-Patent Document 12). Therefore, it is expected that drugs that activate Nrf2 should be useful for several cardiovascular and metabolic diseases, including, but not limited to, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmia, heart failure with reduced ejection fraction, diabetic cardiomyopathy, diabetic nephropathy, metabolic syndrome, obesity, diabetes (type 1 or type 2), and insulin resistance.

[0005] Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality due to the lack of effective therapies. Early brain injury (EBI) and cerebral vasospasm (CVS) are the two most important pathophysiological mechanisms related to brain damage and poor prognosis in patients with SAH (Non-Patent Document 13). Evidence from experimental SAH studies indicates a protective role of the Nrf2 / ARE pathway in EBI and CVS after SAH. Administration of sulforaphane (SFN) to rats after SAH enhances the activity of the Nrf2-ARE pathway, attenuates vasospasm in the basilar artery, and suppresses the release of inflammatory cytokines (Non-Patent Document 14). Intracerebral hemorrhage (ICH) is the primary event in 10-15% of the 15 million strokes that occur worldwide each year. In vitro studies have demonstrated that Nrf2 activators rapidly increase HO-1 expression in astrocytes and reduce their vulnerability to hemoglobin or hemin. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss, and neurological damage (NPL 15). Ischemic stroke induces reactive oxygen species, causing oxidative and inflammatory responses in the ischemic brain. To date, recombinant tissue plasminogen activator is the only available treatment for ischemic stroke. However, this treatment does not prevent oxidative stress and inflammation in the ischemic brain. D3T, a sulfur-containing dithiolethione compound found in cruciferous plants, has been reported to induce antioxidant genes via activation of Nrf2. D3T has been shown to attenuate cerebral infarction and ameliorate neurological damage in stroke-affected animals (NPL 16). Additionally, D3T reduced CNS-infiltrating inflammatory immune cells, including neutrophils and monocytes, in the ischemic brain. Furthermore, D3T-induced suppression of inflammatory cytokine production was observed in wild-type, but not Nrf2-deficient, microglia. Furthermore, the protective effect of D3T on attenuating ischemic cerebral infarction was abolished in Nrf2-deficient stroke animals and stroke animals treated with an HO-1 inhibitor.These results suggest that D3T-mediated suppression of inflammation in the ischemic brain is mediated through the Nrf2 / HO-1 pathway, and therefore targeting the Nrf2 / HO-1 pathway may be a promising therapeutic strategy for ameliorating neuroinflammation in ischemic stroke.

[0006] Nrf2 is thought to play an important role in several hemoglobinopathies, such as beta-thalassemia and sickle cell disease (SCD). SCD is a recessive genetic disorder caused by a single missense mutation resulting in a mutated beta-globin protein, hemoglobin S (HbS). Under low oxygen concentrations, HbS polymerizes, causing deformation of red blood cells, which are prone to rupture and release free heme into the plasma. The resulting oxidative stress and inflammation cause damage in multiple organs. Loss of Keap1 and the resulting constitutive activation of Nrf2 have been shown to improve prognosis in SCD model mice (Non-Patent Document 17; Non-Patent Document 18). Nrf2 activation has been shown to slow the progression of hemolytic anemia and organ failure (Non-Patent Document 19), and loss of Nrf2 function exacerbates the pathophysiology of SCD in transgenic SCD mice (Non-Patent Document 17). Global activation of Nrf2 by the known compound D3T reduces mortality in a heme-induced acute chest syndrome model in transgenic SCD mice (Non-Patent Document 20). Additionally, Nrf2 activators have also been shown to regulate fetal hemoglobin (HbF) expression through direct binding to the gamma-globin promoter and modification of chromatin structure at the beta-globin locus. In sickle cell cells, Nrf2 provides a unique benefit through HbF induction, inhibiting hemoglobin S polymerization and protecting against oxidative stress caused by chronic hemolysis (Non-Patent Document 21). Therefore, the development of small molecule activators of Nrf2 has the potential to ameliorate the clinical severity of other diseases in which increased HbF is beneficial, such as sickle cell disease and beta-thalassemia.

[0007] Nrf2 function is altered in many neurodegenerative disorders, including Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, and Friedreich's ataxia (NPL 22). Nrf2 activation alleviates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases (NPL 23) and in cultures of human cells expressing mutant proteins. Tecfidera (dimethyl fumarate) activates Nrf2 (in addition to other mechanisms) and is approved in the United States for the treatment of relapsing-remitting multiple sclerosis. The Nrf2 activator omaveloxolone (RTA-408), currently in Phase II trials for the treatment of Friedrich's ataxia, a genetic neurodegenerative disorder, met its primary endpoint of change in the modified Friedrich's Ataxia Rating Scale (mFARS) compared with placebo after 48 weeks of treatment. Thus, targeting Nrf2 signaling may offer a therapeutic option to delay the onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

[0008] Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints and is characterized by periods of disease exacerbation and remission. Multiple joints may be affected, resulting in permanent joint destruction and deformity. Nrf2 has been found to be activated in the joints of arthritic mice and RA patients. Nrf2 knockout mice have more severe cartilage damage and additional oxidative damage, and the expression of Nrf2 target genes is enhanced in Nrf2 wild-type but not knockout mice during antibody-induced arthritis (Non-Patent Document 24). Furthermore, in an animal model of rheumatoid arthritis using serum transfer from K / BxN transgenic mice to Nrf2(- / -) mice, Nrf2 deficiency accelerated the incidence of arthritis, and the animals showed widespread disease affecting both the front and rear paws (Non-Patent Document 25).

[0009] Ulcerative colitis (UC) and Crohn's disease (CD) are chronic relapsing-remitting forms of ulcerative colitis (IBD) caused by dysfunction of the intestinal epithelium. Damage to intestinal epithelial cells can disrupt the intestinal epithelial barrier function and promote abnormal immune responses and inflammatory states. Therefore, an intact intestinal epithelium is crucial for a healthy intestine, and cytoprotective agents that can target intestinal epithelial cells would be beneficial for the treatment of UC and CD. CPUY192018, a small molecule inhibitor of Keap1-Nrf2 protein-protein interaction (and therefore an Nrf2 activator), demonstrated cytoprotective effects in experimental models of UC induced by dextran sulfate sodium in both NCM460 cells and mouse colon (Non-Patent Document 26). Furthermore, Nrf2 knockout mice have been shown to exhibit increased susceptibility to colitis-associated colorectal cancer (Non-Patent Document 27).

[0010] Fumaderm, a mixture of three salts of dimethyl fumarate (DMF) and monoethyl fumarate, was approved in Germany in 1994 for the treatment of psoriasis. A potential form of DMF, monomethyl fumarate (MMF), has been shown to increase global and nuclear Nrf2 levels in primary mouse keratinocytes and result in enhanced mRNA expression of several Nrf2-downstream effectors, such as heme oxygenase-1 and peroxiredoxin-6 (Non-Patent Document 28). Other skin disorders, such as radiation-induced dermatitis / skin damage, atopic dermatitis, and wound healing, may benefit from treatment with Nrf2 activators (Non-Patent Document 29).

[0011] Activation of Nrf2 has been shown to have beneficial effects in both liver and kidney diseases. NAFLD (nonalcoholic fatty liver disease) is recognized as the leading cause of chronic liver disease worldwide. NAFLD represents a spectrum of diseases, some of which can progress to cirrhosis and hepatocellular carcinoma (HCC). While all subtypes of NAFLD increase the risk of cardiovascular events and mortality, nonalcoholic steatohepatitis (NASH) is the major diagnostic subtype of NAFLD that predisposes patients to cirrhosis and liver-related complications. There are currently approved pharmacological treatments for NAFLD and NASH. However, knockout of Nrf2 in mice significantly predisposes to NASH stimulated by either a methionine- and choline-deficient (MCD) diet (NPL 30) or a high-fat (HF) diet (NPL 31), and pharmacological activation of Nrf2 has been shown to reverse NASH in mouse models (NPL 32). Other liver diseases, such as toxicity-induced liver disease, viral hepatitis, and cirrhosis, may benefit from treatment with Nrf2 activators. Oxidative stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models of acute kidney injury (AKI) in which Nrf2 is transiently and slightly activated. Genetic or pharmacological enhancement of Nrf2 activity in renal tubules significantly ameliorates AKI-associated damage and prevents the progression of AKI to chronic kidney disease (CKD) by reducing oxidative stress. However, a phase III clinical trial of KEAP1 inhibitors, CDDO-Me or bardoxolone-methyl, for patients with stage 4 CKD and type 2 diabetes mellitus (T2DM) was discontinued due to the occurrence of cardiovascular events. Recent clinical studies have shown accumulating positive effects of KEAP1 inhibitors in moderate stages of CKD, leading to the resumption of phase II trials. Data from an ongoing project demonstrate that Nrf2 activators / KEAP1 inhibitors improve glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns (Non-Patent Document 33). Inflammatory responses and oxidative stress have been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common chronic kidney disease with a relatively poor prognosis and inadequate treatment regimens.CXA-10, which upregulates the Nrf2 pathway, is currently undergoing clinical trials for focal segmental glomerulosclerosis (FIRSTx—Study of Oral CXA-10 in Primary Focal Segmental Glomerulosclerosis (FSGS); Non-Patent Document 34). A phase II study showed that bardoxolone methyl significantly improved renal function in patients with autosomal dominant polycystic kidney disease (ADPKD), CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), or FSGS after 12 weeks of treatment (Non-Patent Document 35). Alport syndrome is the second most common genetic cause of renal failure, caused by a genetic defect in type IV collagen, a component of the glomerular basement membrane. Bardoxolone methyl is currently being studied in these patients because it is thought to affect the underlying pathological processes related to mitochondrial dysfunction, inflammation, and oxidative stress, suggesting that Nrf2 activators may be useful in this disease.

[0012] Oxidative stress plays a crucial role in the initiation and progression of cancer (NPL 36). Due to its importance in maintaining redox cellular homeostasis, Nrf2 is considered a cytoprotective transcription factor and tumor suppressor. At low homeostatic levels, Nrf2 can scavenge ROS, carcinogens, and other DNA-damaging agents, resulting in the inhibition of tumor initiation and metastasis (NPL 37). Evgen is currently evaluating SFX-01 (sulforaphane-cyclodextrin complex) in the treatment and evaluation of metastatic breast cancer (STEM), including ER+ / HER- metastatic breast cancer (NPL 38). Bardoxolone derivatives have been shown to prevent vinyl carbamate-induced lung cancer in A / J mice (NPL 39). Therefore, activators of Nrf2 may have a role in cancer prevention.

[0013] Age-related macular degeneration (AMD) is a major cause of blindness in Western countries, and oxidative stress plays a major role in AMD pathogenesis and progression. Nrf2 activators have been shown to protect cultured cells mimicking the outer layers of the retina from oxidative stress, suggesting their potential to preserve vision in patients with early-stage AMD (Non-Patent Document 40). In addition, Nrf2 activators may also be useful in other ocular conditions, such as Fuchs' endothelial corneal dystrophy and uveitis.

[0014] Therefore, given the role of Nrf2 in multiple indications, there is a continuing need for agents capable of activating Nrf2. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Yamada,BMC Pulmonary Medicine,doi:10.1186 / s12890-016-0189-1 [Non-patent document 2] Sussan,Am J Physiol Lung Cell Mol Physiol,doi:10.1152 / ajplung.00398.2014 [Non-patent document 3] 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 [Non-patent document 4] Kikuchi,Respir Res,doi:10.1186 / 1465-9921-11-31 [Non-patent document 5] Chen,PLoS One,doi:10.1371 / journal.pone.0003367 [Non-patent document 6] Cho,Toxicol Appl Pharmacol,doi:10.1016 / j.taap.2009.07.024

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

[0017] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0018] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0019] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by Nrf2 activation.

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

[0021] In another aspect, the present invention relates to a method for treating a disease or disorder mediated by Nrf2 activation, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

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

[0023] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease, or non-alcoholic steatohepatitis.

[0024] In another aspect, the invention provides the use of a compound, or a pharmaceutically acceptable salt, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0025] In another aspect, the present invention provides a method of treating chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

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

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

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

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

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

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

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

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

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

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

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

[0037] "Cycloalkyl" means a hydrocarbon monocyclic or bicyclic ring containing carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bicyclic rings can be fused or spiro-linked; examples of bicyclic cycloalkyl groups include bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, spiro[2.4]heptane, bicyclo[4.1.0]heptane, and bicyclo[2.2.1]heptane.

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

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

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

[0041] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring atoms, more usually 5 to 10 ring atoms. A heteroaryl group may be, for example, a 5- or 6-membered monocyclic ring, or a 9- or 10-membered bicyclic ring, e.g., a bicyclic structure formed from fused 5- and 6-membered rings or two fused 6-membered rings. Each ring can typically contain up to about four heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, more usually up to two, e.g., one heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring may be basic, such as imidazole or pyridine nitrogens, or essentially non-basic, such as indole or pyrrole nitrogens. Generally, there will be fewer than five basic nitrogen atoms (including amino groups, if any, in the ring substituents) present in a heteroaryl group. Preferably, the term "heteroaryl" or "heteroaromatic" will refer to a five- or six-membered monocyclic heteroaryl ring as defined above.

[0042] 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, and isoquinolyl. quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings is non-aromatic saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur.Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, dorobenzo[d]isoxazolyl, 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazinyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0043] Non-limiting examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0044] Non-limiting examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0045] Illustrative examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl.

[0046] Illustrative examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl.

[0047] Specific non-limiting examples of bicyclic heteroaryl groups containing a 5-membered ring fused to a 5-membered ring include, but are not limited to, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, and 1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl.

[0048] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl encompasses both monovalent and divalent species. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In this particular embodiment, aryl is phenyl or naphthyl, particularly phenyl.

[0049] The term "carboxylic acid mimetic group" generally refers to a surrogate structure or isostere of the carboxylic acid group that maintains the characteristics of the carboxylic acid group necessary for biological activity but modifies the physicochemical properties of the resulting compound, such as acidity or lipophilicity. Such carboxylic acid mimetic groups are known to those skilled in the art of medicinal chemistry. Examples of carboxylic acid mimetic groups include, but are not limited to, tetrazole, 3-trifluoromethyl-1,2,4-triazole, hydroxamic acid, hydroxamic acid ester, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, sulfonylurea, acylurea, thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one, thiadiazol-5(4H)-one, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetramic acid, cyclopentane-1,3-dione, and cyclopentane-1,2-dione.

[0050] The term "optionally substituted" refers to both groups, structures, or molecules that are substituted and those that are not substituted.

[0051] Where an optional substituent is selected from "one or more" groups, this definition is understood to include selecting all of the substituents from one of the specified groups or selecting the substituents from two or more of the specified group.

[0052] The phrase "compounds of the invention" refers to both the compounds disclosed generically and specifically herein.

[0053] Compounds of the Invention In a first aspect, the present invention provides a compound of formula I [ka] (In the formula, R 1 is C 1~4 Alkylene-R 11, heterocyclyl, and 8- to 10-membered bicyclic heteroaryl, wherein the heterocyclyl is selected from C 1~4 Alkyl, -C(O)-R 12 , SO2-R 13 , C 1~3 Alkylene-OR 14 and C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from heteroaryl, which is optionally substituted with one or more substituents independently selected from alkoxy and cyano; and said 8- to 10-membered bicyclic heteroaryl is selected from C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, OH and C 1~3 optionally substituted with one or more substituents independently selected from alkoxy; R 2 is hydrogen, fluoro, chloro and C 1~3 alkyl; R 3 is hydrogen, fluoro, chloro, bromo, C 1~3 Alkoxy, C 1~3 Alkyl, C 1~3 selected from haloalkyl and cyano; R 4 is hydrogen or C 1~4 is alkyl; R 5 is -C(O)-C 1~4 alkyl, —C(O)-heteroaryl or —C(O)-aryl, wherein the heteroaryl and aryl are C 1~4 Alkyl, halo, hydroxy, C 1~3 Alkoxy, CO2R 15 and cyano; or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring; The 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 3~7 optionally spiro-attached to the cycloalkyl group; and The heteroaryl and heterocyclyl rings are 1~4 Alkyl, Halo, OH, C 1~3 Alkoxy, C 1~3 Haloalkyl, Cyano, NR 16 R 17 , C(O)R 18 , S(O)R 19 and SO2R 20 optionally substituted with one or more substituents independently selected from L 1 and L 2 is a bond and -CR 21 R 22 - independently selected from; R 6 and R 7 is hydrogen, C 1~4 Alkyl, and C 3~7 independently selected from cycloalkyl; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; R 8 is CO2R 23 , C(O)NHSO2C 1~3 alkyl, tetrazolyl, 3-trifluoromethyl-1,2,4-triazol-5-yl and carboxylic acid mimetic groups selected from hydroxamic acids, hydroxamic acid esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, sulfonylureas, acylureas, thiazolidinediones, oxazolidinediones, oxadiazol-5(4H)-ones, thiadiazol-5(4H)-ones, oxathiadiazole-2-oxides, oxadiazole-5(4H)-thiones, isoxazoles, tetramic acids, cyclopentane-1,3-dione and cyclopentane-1,2-dione; R 9 is hydrogen, C1~4 Alkyl, hydroxy, C 1~3 selected from alkoxy and halo; R 10 is hydrogen and C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; or L 2 is a bond and R 7 and R 10 together with the atoms to which they are attached form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocyclyl ring; the heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The cycloalkyl ring optionally contains one or two carbon-carbon double bonds, and optionally a C 1~3 bridged by alkylene groups or R 9 optionally a C linking C* to a ring carbon atom 1~3 an alkylene group; and The cycloalkyl and heterocyclyl rings are 1~4 Alkyl, Halo, OH, C 1~3 Alkoxy, C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl and deuterium; R 11 is -C(O)-R 24 , -SO2-R 25 , -NR 26 C(O)-R 27 , -NR 28 SO2-R 29 , heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl groups are selected from C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; and said heterocyclyl group is 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy, oxo, and cyano; R 12 is C 1~4 Alkyl, C 3~7 Cycloalkyl, OR 31 , N.R. 32 R 33 , aryl and heteroaryl, wherein the aryl and heteroaryl are selected from C 1~4 Alkyl, Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; R 13 is C 1~4 Alkyl, C 3~7 Cycloalkyl, heteroaryl, heterocyclyl and NR 34 R 35 wherein the heteroaryl and heterocyclyl are selected from C 1~4 Alkyl, Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; R 17 is hydrogen, C 1~4 Alkyl, C(O)C 1~3 Alkyl and C(O)NR 36 R 37 Selected from; R 18 , R 19 and R 20 is C 1~4 Alkyl, OH, C 1~3 Alkoxy and NR 38 R 39 are independently selected from; R 24 is C 1~4 Alkyl, NR40 R 41 and OR 42 Selected from; R 25 is C 1~4 Alkyl and NR 43 R 44 Selected from; R 27 is C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~3 selected from haloalkyl, heterocyclyl, aryl and heteroaryl, wherein said aryl and heteroaryl are selected from C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 45 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; R 29 is C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~3 haloalkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl are selected from C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 46 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; R 30 is hydroxy, C 1~3 Alkoxy, C 3~7 Cycloalkyl, cyano and NR 47 R 48 Selected from; R 40 is hydrogen and C 1~4 alkyl; R 41 is hydrogen, C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~3selected from alkoxy, aryl and heteroaryl; or R 40 and R 41 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 C 1~4 Alkyl, Halo, OH, C 1~3 Alkoxy, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl and cyano; R 45 and R 46 is 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 is hydrogen, C 1~4 Alkyl and C 3~7 cycloalkyl) or a pharmaceutically acceptable salt thereof.

[0054] Specific compounds of the present invention include, for example, compounds of Formula I, or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , R 6 , R7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 17 , R 18 , R 19 , R 20 , R 24 , R 25 , R 27 , R 29 , R 30 , R 40 and R 41 Each of has any of the meanings defined in any of paragraphs (1) to (86) hereinbefore or hereinafter: (1)R 1 is C 1~4 Alkylene-R 11 is; (2)R 1 is CH2-R 2 is; (3)R 1 is CH2CH2-R 11 is; (4)R 1 is CH(Me)-R 11 is; (5)R 1 is C 1~4 Alkyl, -C(O)-R 12 , SO2-R 13 , heteroaryl and C 1~3 Alkylene-OR 14 and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; (6)R 1 is C 1~4 Alkyl, -C(O)-R 12 , SO2-R 13 , heteroaryl and C 1~3 Alkylene-OR 14and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C 1~4 Alkyl and C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl; (7)R 1 are -C(O)-R 12 , SO2-R 13 , heteroaryl and C 1~3 Alkylene-OR 14 and wherein the heteroaryl is piperidinyl or pyrrolidinyl optionally substituted with one or more substituents independently selected from C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; (8)R 1 is -C(O)-R 12 , SO2-R 13 , heteroaryl and C 1~3 Alkylene-OR 14 and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C 1~4 Alkyl or C 3~7 optionally substituted cycloalkyl; (9)R 1 is the following group: [ka] (In the formula, [ka] represents the point of attachment of the group to the remaining oxygen atoms of the compound, and each group is represented by -C(O)-R 12 , SO2-R 13 , heteroaryl and C 1~3 Alkylene-OR 14 and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C 1~4 Alkyl or C 3~7optionally substituted with cycloalkyl; (10)R 1 is C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, OH and C 1~3 is an 8-10 membered bicyclic heteroaryl optionally substituted with one or more substituents independently selected from alkoxy; (11)R 1 is C 1~4 Alkyl, OH and C 3~7 is an 8-membered bicyclic heteroaryl optionally substituted with one or more substituents independently selected from alkoxy; (12)R 1 is C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, OH and C 1~3 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazolyl, or 1,4,5,6-tetrahydrocyclo-penta[d][1,2,3]triazol-5-yl, each optionally substituted with one or more substituents independently selected from alkoxy; (13)R 1 is the following group: [ka] (In the formula, [ka] represents the point of attachment of the group to the remaining oxygen atoms of the compound, and each group is 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy, heterocycloalkyl, and cyano; (14)R 1 is the following group: [ka] (In the formula, [ka] represents the point of attachment of the group to the remaining oxygen atoms of the compound, and each group is 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and cyano; (15)R 1 is the following group: [ka] (In the formula, [ka] represents the point of attachment of the group to the remaining oxygen atoms of the compound, and each group is 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy, heterocycloalkyl, and cyano; (16)R 1 is the following group: [ka] (In the formula, [ka] represents the point of attachment of the group to the remaining oxygen atoms of the compound, and each group is 1~4 Alkyl and C 1~3haloalkyl); (17)R 1 teeth, [ka] (In the formula, [ka] represents the point of attachment of the group to the remaining oxygen atoms of the compound, and the group is C 1~4 Alkyl and C 1~3 haloalkyl); (18)R 1 teeth, [ka] is; (19)R 2 is selected from hydrogen, fluoro and chloro; (20)R 2 is hydrogen or fluoro; (21)R 3 is hydrogen, chloro, bromo, C 1~3 Alkoxy, C 1~3 Alkyl, C 1~3 selected from haloalkyl and cyano; (22)R 3 is selected from hydrogen, chloro, bromo, methoxy, methyl, trifluoromethyl and cyano; (23)R 3 is selected from hydrogen and chloro; (24)R 3 is chloro; (25)R 4 is hydrogen; (26)R 5 is -C(O)-C 1~4 alkyl or -C(O)-aryl, wherein the aryl group is C 1~4 Alkyl, halo, hydroxy, C 1~3 Alkoxy, CO2R 15and cyano; (27)R 4 is hydrogen and R 5 is -C(O)-C 1~4 alkyl or -C(O)-aryl, wherein the aryl group is C 1~4 Alkyl, halo, 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 the aryl group is selected from halo, hydroxy, and COR 15 optionally substituted with one or more substituents selected from; (29)R 4 is hydrogen and R 5 is —C(O)-aryl, the aryl group being selected from fluoro, hydroxy and COR 15 is phenyl optionally substituted with one or more substituents selected from (30)R 4 and R 5 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring; The 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 3~7 optionally spiro-attached to the cycloalkyl group; and The heteroaryl and heterocyclyl rings are 1~4 Alkyl, Halo, OH, C 1~3 Alkoxy, C 1~3 Haloalkyl, Cyano, NR 16 R 17 , C(O)R 18 , S(O)R 19 and SO2R 20 optionally substituted with one or more substituents independently selected from (31)R 4 and R 5 together with the nitrogen atom to which they are attached form a 5-membered heteroaryl or heterocyclyl ring; The heterocyclyl ring contains a —C(O)— moiety attached to a nitrogen atom and is optionally fused to an aryl or heteroaryl ring, or 3~7 optionally spiro-attached to the cycloalkyl group; and The heteroaryl and heterocyclyl rings are optionally selected from the group consisting of C 1~4 Alkyl, Halo, OH, C 1~3 substituted with one or more substituents independently selected from alkoxy and cyano; (32)R 4 and R 5 together with the nitrogen atoms to which they are attached, form C 1~4 Alkyl, Halo, OH, C 1~3 forming a 5-membered heteroaryl ring optionally substituted with one or more substituents independently selected from alkoxy and cyano; (33)R 4 and R 5 together with the nitrogen atoms to which they are attached, form C 1~4 forming a 5-membered heteroaryl ring optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; (34)R 4 and R 5 together with the nitrogen atoms to which they are attached, form C 1~4 forming a pyrazolyl ring optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; (35)R 4 and R 5 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl ring, said heterocyclyl ring containing a —C(O)— moiety attached to the nitrogen atom and optionally fused to an aryl or heteroaryl ring, or C 3~7 and said heterocyclyl ring is optionally spiro-bonded to a cycloalkyl group; and 1~4optionally substituted with one or more substituents independently selected from alkyl, halo, 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, said heterocyclyl ring containing a —C(O)— moiety attached to the nitrogen atom and which is optionally fused to a phenyl or heteroaryl ring or optionally spiro-bonded to a cyclopropyl group; and said heterocyclyl ring is optionally substituted with one or more substituents independently selected from methyl, fluoro, and OH; (37)R 4 and R 5 together with the nitrogen atoms to which they are attached: [ka] (wherein the saturated ring of the heterocyclic moiety is C 3~7 Optionally spiro-bonded to a cycloalkyl group, and said heterocyclic moiety is C 1~4 optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; (38)R 4 and R 5 together with the nitrogen atoms to which they are attached: [ka] wherein the saturated ring of the heterocyclic moiety is optionally spiro-linked to a cyclopropyl group, and said heterocyclic moiety is optionally substituted with one or more substituents independently selected from methyl, fluoro, and OH; (39)R 4 and R 5 together with the nitrogen atom to which they are attached form the following heterocyclic moiety: [ka] wherein the heterocyclic moiety is optionally spiro-linked to the cyclopropyl group and optionally substituted with one or more substituents independently selected from methyl and fluoro; (40)R 4 and R 5 together with the nitrogen atom to which they are attached form the following heterocyclic moiety: [ka] wherein the heterocyclic moiety is optionally spiro-attached to the cyclopropyl group and 1~3 optionally substituted with alkyl, said cyclopropyl and / or C 1~3 The alkyl group is attached to the heterocyclic ring at either the alpha or beta position relative to the carbonyl group; (41)L 1 and L 2 is independently selected from a bond and -CH2-; (42)L 1 is a bond and L 2 is -CH2-; (43)L 1 is CH2-, and L 2 is a bond; (44)L 1 and L 2 are both bonds; (45)R 6 and R 7 is hydrogen and C 1~4 independently selected from alkyl; (46)R 6 and R 7 are independently selected from hydrogen and methyl; (47)R 6 and R 7 together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; (48)R 8 is CO2R 23 , C(O)NHSO2C 1~3selected from alkyl, tetrazolyl and 3-trifluoromethyl-1,2,4-triazol-5-yl; (49)R 8 is CO2R 23 , C(O)NHSO2C 1~3 selected from alkyl and tetrazolyl; (50)R 8 is selected from CO2H, C(O)NHSO2Me and tetrazolyl; (51)R 8 is CO2H; (52)R 9 is hydrogen, C 1~4 Alkyl, C 1~3 selected from alkoxy and halo; (53)R 9 is selected from hydrogen, methyl, methoxy and fluoro; (54)R 9 is C 1~4 Alkyl, C 1~3 selected from alkoxy and halo; (55)R 9 is selected from methyl, methoxy and fluoro; (56)R 9 is hydrogen or C 1~4 is 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 together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; (61)L 2 is a bond and R 7 and R 10 together with the atoms to which they are attached form a 4-, 5-, or 6-membered cycloalkyl or heterocyclyl ring; the heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The cycloalkyl ring optionally contains one or two carbon-carbon double bonds, and optionally a C 1~3 bridged by alkylene groups or R 9 optionally a C linking C* to a ring carbon atom 1~3 an alkylene group; and The heteroalkyl and heterocyclyl rings are optionally selected from the group consisting of C 1~4 Alkyl, Halo, OH, C 1~3 substituted with one or more substituents independently selected from alkoxy and deuterium; (62)L 1 and L 2 are both bonds and R 7 and R 10 together with the atoms to which they are attached form a 4-, 5-, or 6-membered cycloalkyl or heterocyclyl ring; the heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The cycloalkyl ring optionally contains a carbon-carbon double bond and optionally a C 1~3 bridged by alkylene groups or R 9 optionally a C linking C* to a ring carbon atom 1~3 an alkylene group; and The heteroalkyl and heterocyclyl rings are optionally selected from the group consisting of C 1~4 Alkyl, Halo, OH, C 1~3 substituted with one or more substituents independently selected from alkoxy and deuterium; (63)L 2 is a bond and R 7 and R 10 together with the atoms to which they are attached form a 4-, 5-, or 6-membered cycloalkyl ring, said cycloalkyl ring optionally containing a C linking two carbon atoms of the ring. 1~3 bridged by alkylene groups or R 9 optionally a C linking C* to a ring carbon atom 1~3alkylene group, and the cycloalkyl ring is C 1~4 Alkyl, Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy and deuterium; (64)L 2 is a bond and R 7 and R 10 together with the atoms to which they are attached form a cyclohexyl ring, said cyclohexyl ring optionally containing a carbon-carbon double bond and optionally a C linking two carbon atoms of the ring. 1~3 bridged by alkylene groups or R 9 optionally a C linking C* to a ring carbon atom 1~3 alkylene group, and the cyclohexyl ring is C 1~4 optionally substituted with one or more substituents independently selected from alkyl, halo, OH, and deuterium; (65)R 11 is -C(O)-R 24 , -NR 26 C(O)-R 27 and heteroaryl, wherein the heteroaryl is selected from C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; (66)R 11 is -C(O)-R 24 and R 24 is NR 40 R 41 and OR 42 Selected from; (67)R 11 is -NR 26 C(O)-R 27 and R 27 is C 1~4 Alkyl, C 3~7selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the aryl and heteroaryl are C 1~4 Alkyl and C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl; (68)R 11 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 heteroaryl optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; (69)R 11 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , C 1~3 heteroaryl optionally substituted with one or more substituents independently selected from alkoxy, and cyano; (70)R 11 is methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, cyano, oxetanyl, CH2-R 30 and CH2CH2-R 30 is heteroaryl optionally substituted with one or more substituents independently selected from (71)R 11 are C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl or triazolopyridinyl optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl and cyano; (72)R 11 teeth, [ka] and each heteroaryl is selected from C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy, heterocycloalkyl, and cyano; (73)R 11 is oxazolyl, isoxazolyl, or 1,2,3-triazolyl, each of which is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 optionally substituted with one or more substituents independently selected from alkoxy, heterocycloalkyl, and cyano; (74)R 11 is C 1~4 Alkyl, C 1~3 Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 1,2,3-triazolyl optionally substituted with one or more substituents independently selected from alkoxy, heterocycloalkyl, and cyano; (75)R 11 is C 1~4 Alkyl, C 1~3Haloalkyl, C 3~7 Cycloalkyl, C 1~4 Alkylene-R 30 , Halo, OH, C 1~3 heterocyclyl optionally substituted with one or more substituents independently selected from alkoxy, oxo, and cyano; (76)R 11 is C 1~4 Alkyl, C 1~3 heterocyclyl optionally substituted with one or more substituents independently selected from haloalkyl, halo, OH, and oxo; (77)R 11 is C 1~4 Alkyl, C 1~3 dihydroisoxazolyl or dihydropyridinyl optionally substituted with one or more substituents independently selected from haloalkyl, halo, OH, and oxo; (78)R 29 is C 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~3 haloalkyl and heteroaryl, wherein the heteroaryl is selected from C 1~4 Alkyl and C 1~3 optionally substituted with one or more substituents independently selected from haloalkyl; (79)R 29 is methyl, ethyl or cyclopropyl; (80)R 30 is hydroxy, C 1~3 Alkoxy, C 3~7 selected from cycloalkyl and cyano; (81)R 30 is 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 41together with the nitrogen atom to which they are attached form a 5-membered heteroaryl or heterocyclyl ring, said heteroaryl and heterocyclyl rings being C 1~4 Alkyl, Halo, OH, C 1~3 Alkoxy, C 3~7 optionally substituted with one or more substituents independently selected from cycloalkyl and cyano; (85)R 40 and R 41 together with the nitrogen atom to which they are attached form a 5-membered heterocyclyl ring, said heterocyclyl ring being 1~4 optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; (86)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 methyl, fluoro and OH.

[0055] Preferably, R 1 is as defined in any one of the above items (1) to (18). In one embodiment, R 1 is as defined in item (2) above. In another embodiment, R 1 is as defined in the above items (7) to (9). In another embodiment, R 1 is as defined in any one of the above paragraphs (13) to (18). In a further embodiment, R 1 is as defined in the above items (16) to (18).

[0056] Preferably, R 2 is as defined in any one of the above items (19) to (20). 2 is as defined in item (20) above.

[0057] Preferably, R 3is as defined in any one of the above paragraphs (21) to (24). In another embodiment, R 3 is as defined in the above items (23) to (24).

[0058] Preferably, R 4 is as defined in item (25) above.

[0059] Preferably, R 5 is as defined in item (26) above.

[0060] Preferably, R 4 and R 5 is as defined in any one of the above paragraphs (27) to (29). In another embodiment, R 4 and R 5 is as defined in item (29) above. In some embodiments, R 4 and R 5 is as defined in the above items (30) to (40). In another embodiment, R 4 and R 5 is as defined in the above items (37) to (40). In another embodiment, R 4 and R 5 is as defined in item (34) above. In a further embodiment, R 4 and R 5 is as defined in item (40) above.

[0061] Preferably, L 1 and L 2 is as defined in any one of the above paragraphs (41) to (44). In another embodiment, L 1 and L 2 is as defined in item (44) above.

[0062] Preferably, R 6 and R 7is as defined in any one of the above paragraphs (45) to (47). In another embodiment, R 6 and R 7 is as defined in item (46) above.

[0063] Preferably, R 8 is as defined in any one of the above paragraphs (48) to (51). In another embodiment, R 8 is as defined in the above items (50) to (51). In one embodiment, R 8 is as defined in item (51) above.

[0064] Preferably, R 9 is as defined in any one of the above paragraphs (52) to (58). In another embodiment, R 9 is as defined in the above items (57) to (58). In one embodiment, R 9 is as defined in item (58) above.

[0065] Preferably, R 10 is as defined in item (59) above.

[0066] Preferably, R 9 and R 10 is as defined in item (60) above.

[0067] Preferably, L 2 , R 7 and R 10 is as defined in any one of the above paragraphs (61) to (64). In another embodiment, L 2 , R 7 and R 10 is as defined in item (64) above.

[0068] Preferably, R 11is as defined in any one of the above paragraphs (65) to (77). In another embodiment, R 11 is as defined in the above paragraphs (72) to (74). In another embodiment, R 11 is as defined in paragraphs (73) to (74) above. In a further embodiment, R 1 is as defined in paragraph (2) above, and R 11 is as defined in the above items (72) to (74).

[0069] Preferably, R 29 is as defined in the above items (78) to (79). In one embodiment, R 29 is as defined in item (79) above.

[0070] Preferably, R 30 is as defined in the above items (80) to (81). In one embodiment, R 30 is as defined in item (81) above.

[0071] Preferably, R 40 is as defined in item (82) above.

[0072] Preferably, R 41 is as defined in item (83) above.

[0073] Preferably, R 40 and R 41 is as defined in any one of the above paragraphs (84) to (86). In another embodiment, R 40 and R 41 is as defined in item (86) above.

[0074] In a further group of compounds, the compounds have the structural formula IA shown below: [ka] (In the formula, L 1 and L 2 and R 1 ~R 10 is as defined herein before).

[0075] In a further group of compounds, the compounds have the structural formula IA shown above, where R 1 is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); L 1 and L 2 is as defined in any one of the above paragraphs (41) to (44); R 6 and R 7 is as defined in any one of the above paragraphs (45) to (47); R 8 is as defined in any one of the above paragraphs (48) to (51); R 9 is as defined in any one of the above paragraphs (52) to (58); and R 10 is as defined in item (59) above).

[0076] In a further group of compounds, the compounds have structural formula IB shown below: [ka] (In the formula, R 1 ~R 6 , R8 and R 9 is as defined herein before).

[0077] In a further group of compounds, the compounds have the structural formula IB shown above, where R 1is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); R 6 is hydrogen or methyl; R 8 is as defined in any one of the above paragraphs (48) to (51); and R 9 is as defined in any one of the above items (52) to (58).

[0078] In a further group of compounds, the compounds have the structural formula IB shown above, where R 1 is as defined in any one of the above paragraphs (13) to (18); R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); R 6 is hydrogen or methyl; R 8 is as defined in any one of the above paragraphs (50) to (51); and R 9 is as defined in any one of the above items (57) to (58).

[0079] In a further group of compounds, the compounds have the structural formula IC shown below: [ka] (In the formula, R 1 ~R 6 and R 9 is as defined herein before).

[0080] In a further group of compounds, the compounds have the structural formula IC shown above, where R 1 is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); R 6 is hydrogen or methyl; and R 9 is as defined in any one of the above items (57) to (58).

[0081] In a further group of compounds, the compounds have the structural formula ID shown below: [ka] (In the formula, R 1 ~R 3 , R 6 and R 9 is as defined herein before).

[0082] In a further group of compounds, the compounds have the structural formula ID shown above, where R 1 is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 6 is hydrogen or methyl; and R 9 is as defined in any one of the above items (57) to (58).

[0083] In a further group of compounds, the compounds have the structural formula ID shown above, where R 1is as defined in any one of paragraphs (9) and (13) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 6 is hydrogen; and R 9 is as defined in item (58) above).

[0084] In a further group of compounds, the compounds have the structural formula IE shown below: [ka] (In the formula, R 1 ~R 6 , R 8 and R 9 is as defined herein before).

[0085] In a further group of compounds, the compounds have the structural formula IE shown above, where R 1 is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (21) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); R 6 is hydrogen or methyl; R 8 is as defined in any one of the above paragraphs (48) to (51); and R 9 is as defined in any one of the above items (52) to (58).

[0086] In a further group of compounds, the compounds have the structural formula IE shown above, where R 1 is as defined in any one of the above paragraphs (13) to (18); R 2is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); R 6 is hydrogen or methyl; R 8 is as defined in any one of the above paragraphs (50) to (51); and R 9 is as defined in any one of the above items (57) to (58).

[0087] In a further group of compounds, the compounds have the structural formula IF shown below: [ka] (In the formula, R 1 ~R 6 and R 9 is as defined herein before).

[0088] In a further group of compounds, the compounds have the structural formula IF shown above, where R 1 is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 4 and R 5 is as defined in any one of the above paragraphs (37) to (40); R 6 is hydrogen or methyl; and R 9 is as defined in any one of the above items (57) to (58).

[0089] In a further group of compounds, the compounds have the structural formula IG shown below: [ka] (In the formula, R 1 ~R 3 , R 6 and R 9 is as defined herein before).

[0090] In a further group of compounds, the compounds have the structural formula IG shown above, where R 1 is as defined in any one of paragraphs (7) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (21) to (24); R 6 is hydrogen or methyl; and R 9 is as defined in any one of the above items (57) to (58).

[0091] In a further group of compounds, the compounds have the structural formula IG shown above, where R 1 is as defined in any one of paragraphs (9) and (13) to (18) above; R 2 is as defined in item (20) above; R 3 is as defined in any one of the above paragraphs (23) to (24); R 6 is hydrogen; and R 9 is as defined in item (58) above).

[0092] Particular compounds of the invention include any one of the following: (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(2-(5-methylisoxazole-3-carboxamido)ethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(2-(benzo[d]oxazole-2-carboxamido)ethoxy)-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)-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(5-methylisoxazole-3-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(2-methylthiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5,7-dichloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-1-((1-oxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(2-methylthiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-methylisoxazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((2-ethyl-2H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((1S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((1-oxo-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(imidazo[1,2-a]pyridin-7-ylmethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-benzo[d]imidazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-bromo-8-((7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((4-ethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-cyano-1-ethyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((1S)-5-bromo-8-(1-(1-methyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((1S)-5-bromo-8-(1-(1-isopropyl-1H-1,2,3-triazol-4-yl)ethoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-8-((1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-(2,2-difluoroethyl)-1H-imidazol-2-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-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-2-yl)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-2-yl)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-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-cyano-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxy-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-methylthiazol-2-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isothiazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-chloro-8-(isothiazol-3-ylmethoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((1S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-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)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (R)-4-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-4-oxobutanoic acid; 1-(((S)-2-((1R,2S)-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-isopropyl-1,2,4-oxadiazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyrimidin-5-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-(pyridazin-3-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid; 3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydrofuran-2-carboxylic acid; (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-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; 2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4,4-difluorocyclopentane-1-carboxylic acid; (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-oxopyrrolidin-1-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-1-yl)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-1-yl)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-1-yl)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-((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-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (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-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-ethylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (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-carboxylic 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-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-(((R)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2S)-2-((S)-5-chloro-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-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; (1S,2R)-2-((S)-5-chloro-8-((5,5-dimethyl-4,5-dihydroisoxazol-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; (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((2,5-bis(difluoromethyl)-2H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-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-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-3-carboxylic acid; (R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)bicyclo[2.2.2]octane-1-carboxylic acid; (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-carboxy-4,4-d2 acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-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; (1S,2S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; 1-(((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-2-((1R,2S)-2-methyl-2-(2H-tetrazol-5-yl)cyclohexane-1-carbonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((4,4-dimethyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-methyl-4-(trifluoromethyl)isoxazol-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; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-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-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(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-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((1S)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((6,7-difluorobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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; (1S,2S)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-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-((4-(trifluoromethyl)pyrimidin-5-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-1-methyl-2-((S)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((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; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-fluoro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)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-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]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; (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]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][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; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-imidazol-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; (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]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-(((S)-1-(methylsulfonyl)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-5-yl)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]oxazin-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; (1S,2R)-1-methyl-2-((S)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1,5-bis(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-2-methyl-5-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-(((S)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-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]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(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)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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((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; (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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid; 5-(((S)-2-((1R,2S)-2-(1H-tetrazol-5-yl)cyclohexane-1-carbonyl)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)thiazol-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; (1S,2R)-2-((S)-5-chloro-8-((5-methylthiazol-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; (1S,2R)-2-((S)-5-chloro-8-((2-methyl-2H-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; (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic 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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxy-4,5-d2 acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-2-oxo-1,2-dihydropyridin-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; (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-6-oxo-1,6-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; (1S,2R)-2-((1S)-5-chloro-8-((1-methyl-1,4,5,6-tetrahydrocyclopenta[d][1,2,3]triazol-5-yl)oxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-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; (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-fluoro-1-methylcyclohexane-1-carboxylic acid; (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)-1-methylcyclohexane-1-carboxy-4-d acid; (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-1-methylcyclohexane-1-carboxylic acid; (1S,2R,5S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid; (1S,2R,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-5-hydroxy-1-methylcyclohexane-1-carboxylic acid; (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-1-methylcyclohexane-1-carboxylic acid; (2S,3R)-3-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)tetrahydro-2H-pyran-2-carboxylic acid; (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-1-methylcyclohexane-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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-6-hydroxy-1-methylcyclohexane-1-carboxylic acid; (1S,2S,3R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid; and (1S,2S,3S)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-hydroxy-1-methylcyclohexane-1-carboxylic acid; or a pharmaceutically acceptable salt thereof.

[0093] In certain embodiments, the compound of formula I is selected from the following compounds: (1S,2R)-2-((S)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(((S)-1-acetylpyrrolidin-3-yl)oxy)-5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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; (1S,2R)-2-((S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-(((S)-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)oxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-(((S)-1-(5-methylthiazol-2-yl)pyrrolidin-3-yl)oxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-1-((1-oxoisoindolin-2-yl)methyl)-8-((5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (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-((5-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-cyano-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((1-oxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-bromo-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-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)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-isopropyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((3-methylisoxazolo[5,4-b]pyridin-6-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-(benzo[d]isoxazol-3-ylmethoxy)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-((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-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (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-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-3-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-ethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-carboxylic 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-((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-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-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-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-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; (1S,2R)-2-((S)-5-chloro-8-((4-methylisoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-carboxy-4,4-d2 acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2-methoxyethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-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-((4,4-dimethyl-2-oxopyrrolidin-1-yl)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-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-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-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(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-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-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((1S)-5-chloro-8-((7-fluoro-2,7a-dihydrobenzo[d]isoxazol-3-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-cyclopropyl-5-(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-1-methyl-2-((S)-5-methyl-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)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-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]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; (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]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-5H-pyrrolo[2,1-c][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; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)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]triazolo[4,3-a]pyridin-3-yl)methoxy)-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-5-yl)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]oxazin-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; (1S,2R)-1-methyl-2-((S)-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-bromo-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-8-((1,5-bis(difluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((S)-2-methyl-5-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-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]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(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)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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((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; (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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid; (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxy-4,5-d2 acid; (1S,2R)-2-((1S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxo-4-(trifluoromethyl)pyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-fluoro-1-methylcyclohexane-1-carboxylic acid; and (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)-1-methylcyclohexane-1-carboxy-4-d acid; or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the compound of formula I is selected from the following compounds: (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-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-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclopentane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-cyclopropyl-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((4-(difluoromethyl)pyrimidin-5-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; (1S,2R)-2-((S)-5-chloro-1-((2-oxopyrrolidin-1-yl)methyl)-8-((4,5,6,7-tetrahydrobenzo[d]isoxazol-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-carboxy-4,4-d2 acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(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-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-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-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; (1S,2R)-2-((S)-5-chloro-1-((3-oxomorpholino)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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)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-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((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; (1S,6R)-6-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohex-3-ene-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1R,3S,4R,6S)-4-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-methylbicyclo[4.1.0]heptane-3-carboxylic acid; (1S,2R,4S,5R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxy-4,5-d2 acid; (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-fluoro-1-methylcyclohexane-1-carboxylic acid; and (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)-1-methylcyclohexane-1-carboxy-4-d acid; or a pharmaceutically acceptable salt thereof.

[0095] In certain embodiments, the compound of formula I is selected from the following compounds: (1S,2R)-2-((S)-5-chloro-8-((1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-1-(((R)-4-methyl-2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (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-carboxylic acid; (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-carboxy-4,4-d2 acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-8-((4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((2-oxopyrrolidin-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methoxy)-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; (1S,2R)-2-((S)-5-chloro-8-((5-(difluoromethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-7-fluoro-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylic acid; and (1S,2R,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)-1-methylcyclohexane-1-carboxy-4-d acid; or a pharmaceutically acceptable salt thereof.

[0096] The various functional groups and substituents comprising the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More typically, the molecular weight of the compound will be less than 750, for example, less than 700 or less than 650.

[0097] Suitable or preferred features of any compound of the present invention may also be suitable features of any other embodiment.

[0098] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid). In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., calcium salts or magnesium salts), ammonium salts, or salts with organic bases that produce physiologically acceptable cations (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine).

[0099] Compounds with the same molecular formula but different properties, bonding order, or spatial arrangement of atoms are called "isomers." Isomers with different spatial arrangement of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, pairs of enantiomers can exist. Enantiomers can be described by the absolute configuration of their asymmetric center, as expressed by the Cahn-Prelog R- and S-sequencing rules, or by the direction in which the molecule rotates the plane of polarized light, as dextro- or levo-dominate (i.e., (+) or (-) dominance, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0100] The compounds of the present invention typically have one or more asymmetric centers; therefore, such compounds can be produced as individual (R) or (S) isomers, or as mixtures thereof. Unless otherwise specified, the description or naming of a specific compound in the specification and claims is intended to encompass both individual enantiomers, diastereoisomers, and mixtures thereof (racemic or otherwise). Methods for determining stereochemistry and separating stereoisomers (e.g., by synthesis from optically active starting materials or by separating racemates) are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomer centers (E and Z isomers). It should be understood that the present invention encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that have Nrf2 activation activity.

[0101] The present invention also includes compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D), 3 H(T) and any isotopic form thereof; C is 12 C. 13 C. 14 C may be any isotope; O may be 16 O. 18 It may be any isotope such as O.

[0102] It should also be understood that certain compounds of the present invention can exist in unsolvated as well as solvated forms, such as hydrated forms, etc. It should be understood that the present invention encompasses all such solvated forms that possess Nrf2 activation activity.

[0103] It is to be understood that certain compounds of the present invention may have polymorphic forms, and that the present invention encompasses all such forms that possess Nrf2 activating activity.

[0104] The compounds of the present invention can exist in several different tautomeric forms, and references to the compounds of the present invention encompass all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, even if only one is specifically described or presented, all other forms are encompassed by the compounds of the present invention. Tautomeric forms include, for example, keto, enol, and enolate forms, which are in the form of the following exemplary tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro. [ka]

[0105] The compounds of the present invention containing an amine functionality may form N-oxides. When referring to compounds of Formula I containing an amine functionality herein, N-oxides are also included. In some compounds containing an amine functionality, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides include N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 147-148. More specifically, N-oxides can be generated by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane, according to the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514).

[0106] The compounds of the present invention can be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. A prodrug can be formed when the compounds of the present invention have a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxy or hydroxy groups of the compounds of the present invention, and in vivo cleavable amide derivatives that can be formed at the carboxy or amino groups of the compounds of the present invention.

[0107] Therefore, when the compound represented by formula I defined above can be obtained by organic synthesis or by cleaving its prodrug in the human or animal body, these compounds are included in the present invention. Therefore, in addition to the compound represented by formula I produced by organic synthesis means, the present invention also includes this type of compound produced by metabolism of a precursor compound in the human or animal body. That is, the compound represented by formula I may be a compound produced by synthesis or a compound produced by metabolism.

[0108] Suitable pharmaceutically acceptable prodrugs of compounds of Formula I are those that, based on sound medical judgment, are suitable for administration to the human or animal body, do not exhibit undesirable pharmacological activity, and are not excessively toxic.

[0109] Various forms of prodrugs are described, for example, in the following documents: a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0110] Suitable pharmaceutically acceptable prodrugs of the compounds of formula I having a carboxy group are, for example, in vivo cleavable esters thereof. The in vivo cleavable esters of the compounds of formula I having a carboxy group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable carboxy esters include C 1~6 Alkyl (methyl, ethyl, tert-butyl, etc.) esters, C 1~6 Alkoxymethyl esters (e.g., methoxymethyl esters), C 1~6Alkanoyloxymethyl esters (pivaloyloxymethyl esters, 3-phthalidyl esters, etc.), C 3~8 Cycloalkylcarbonyloxy-C 1~6 Alkyl esters (cyclopentylcarbonyloxymethyl ester, 1-cyclohexylcarbonyloxyethyl ester, etc.), 2-oxo-1,3-dioxolenylmethyl esters (5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, etc.) and C 1~6 Alkoxycarbonyloxy-C 1~6 Examples include alkyl esters (such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester).

[0111] Suitable pharmaceutically acceptable prodrugs of the compound of formula I having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compound of formula I having a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the original hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for generating a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for generating a hydroxy group include C 1~10 Alkanoyl groups (acetyl, benzoyl, phenylacetyl, substituted benzoyl, substituted phenylacetyl groups, etc.), C 1~10 Alkoxycarbonyl group (ethoxycarbonyl group, N,N-(C 1~6 ) 2-carbamoyl group, 2-dialkylaminoacetyl group, 2-carboxyacetyl group, etc. Examples of the substituent on the ring of the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4Suitable pharmaceutically acceptable ether-forming groups for generating a hydroxy group include α-acyloxyalkyl groups (acetoxymethyl, pivaloyloxymethyl, etc.).

[0112] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxy group are, for example, in vivo cleavable amides thereof, e.g., amines (e.g., ammonia), C 1~4 Alkylamines (methylamine, etc.), (C 1~4 Alkyl) 2 amines (dimethylamine, N-ethyl-N-methylamine, diethylamine, etc.), C 1~4 Alkoxy C 2~4 Alkylamines (e.g., 2-methoxyethylamine), phenyl C 1~4 These include amides formed with alkylamines (such as benzylamine) and amino acids (such as glycine) or their esters.

[0113] Suitable pharmaceutically acceptable prodrugs of the compounds of formula I having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C acetyl, benzoyl, phenylacetyl, substituted benzoyl, substituted phenylacetyl, etc. 1~10 Examples of the amide formed with the alkanoyl group include: aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 alkyl)piperazin-1-ylmethyl.

[0114] The in vivo effects of the compounds of Formula I may be exerted in part by one or more metabolic products produced in the human or animal body following administration of the compounds of Formula I. As noted above, the in vivo effects of the compounds of Formula I may also be exerted through metabolism of a precursor compound (prodrug).

[0115] It should also be understood that other groups may be covalently attached to the compounds of Formula I at any suitable position, such as solubilizing moieties (e.g., PEG polymers), moieties that allow them to be attached to solid supports (e.g., biotin-containing moieties, etc.), targeting ligands (e.g., antibodies or antibody fragments), etc.

[0116] synthesis When referring to the synthetic methods described below and those used to prepare starting materials, it should be understood that all reaction conditions presented (including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures) can be selected by one skilled in the art.

[0117] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0118] Necessary starting materials can be obtained by standard organic chemistry procedures. The preparation of such starting materials is illustrated in the accompanying Examples, along with representative process variations that follow. Alternative starting materials necessary can be obtained by analogous procedures to those exemplified, within the ordinary skill of an organic chemist.

[0119] It will be understood that during the synthesis of the compounds of the invention, or of certain starting materials in the processes defined below, it may be desirable to protect certain substituents to prevent undesired reactions. Those skilled in the chemical arts will understand the circumstances under which such protection is necessary and how such protecting groups can be put in place and subsequently removed.

[0120] For examples of protecting groups, see any of the many general texts on the subject, such as "Protective groups in Organic Synthesis (3rd Ed), John Wiley & Sons, NY (1999)", T. Greene & P. Wuts. Removal of the protecting group can be carried out by any convenient method described in the literature or known to those skilled in the chemical arts that is suitable for removing the protecting group in question. Such methods are selected so that removal of the protecting group has minimal adverse effects on other groups in the molecule.

[0121] Thus, in some of the reactants mentioned herein, if the reactant contains groups such as, for example, amino, carboxy, hydroxy groups, it may be desirable to protect this group.

[0122] For example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, such as an alkanoyl group (such as an acetyl group), an alkoxycarbonyl group (such as a methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl group), an arylmethoxycarbonyl group (such as a benzyloxycarbonyl group), or an aroyl group (such as a benzoyl group). The deprotection conditions for the above-mentioned protecting groups will necessarily vary with the protecting group chosen. Thus, for example, an acyl group (such as an alkanoyl group, an alkoxycarbonyl group, an aroyl group, etc.) can be removed by hydrolysis with a suitable base, such as, for example, an alkali metal hydroxide (such as, for example, lithium hydroxide, sodium hydroxide). Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, etc., and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid (for example, BF3·OEt2).A suitable other protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine (for example, dimethylaminopropylamine) or hydrazine.

[0123] Those skilled in the art will recognize that the compounds of the present invention can be prepared in various ways by known methods. Compounds of Formula I can be prepared by the methods described below, or by the methods shown in the experimental section, or by similar methods. The routes described herein are merely illustrative of some methods that can be used to synthesize compounds of Formula I, and those skilled in the art will understand that the order of reaction steps is not limited to the order described. It will also be understood that the assignment of nucleophiles and electrophiles is not limited to that described herein, and that in some cases it may be appropriate to reverse the assignment. Various approaches to chemical synthesis strategies are described in "Organic Synthesis: The Disconnection Approach", 2nd edition, S. Warren and P. Wyatt (2008).

[0124] General Method A [ka] In a typical synthetic procedure, the phthalimide, when used as a protecting group, is removed using a typical reagent (e.g., hydrazine), and the amine is converted to the desired substituted NR 4 R 5 The third step involves the introduction of the required ether via either conventional methods such as alkylation with an alkyl halide or activated alcohol, e.g., mesylate, triflate, or a Mitsunobu reaction using reagents such as DBAD or DEAD and an appropriate phosphine. The Boc protecting group is then removed, typically by treatment with HCl. L 1 C(R 6 )(R 7 )L 2 C(R 8 )(R 9 )R 10The group can be introduced from an appropriately substituted and protected bis-acid derivative; ideally, one of the acid groups is activated for reaction with the amine of the tetrahydroisoquinoline (THIQ) scaffold, and the other acid group is suitably protected, for example, as a benzyl or dimethoxybenzyl ester, or by ring-opening of an appropriate cyclic anhydride, or by reaction with an acid chloride. A typical amide coupling reagent such as HATU is used to effect acid activation. In the final step, the protecting group is removed from the carboxylic acid by an appropriate methodology, such as hydrolysis, hydrogenolysis, a strong acid such as HCl or TFA, or a Lewis acid such as BBr3.

[0125] General Method B [ka] In a further exemplary procedure, the order of steps may be changed compared to General Method A. The first two steps are carried out as described in General Method A. Then, in the third step, the Boc protecting group (CO2 t Bu) is typically removed by treatment with HCl. 1 C(R 6 )(R 7 )L 2 C(R 8 )(R 9 )R 10 The protecting group is introduced in the fourth step as described in general method A, followed by the required ether, either via conventional methods such as alkylation with an alkyl halide or activated alcohol, e.g., mesylate, triflate, or via Mitsunobu reaction using reagents such as DBAD or DEAD and an appropriate phosphine. In the final step, the protecting group is removed from the carboxylic acid by appropriate methodology such as hydrolysis, hydrogenolysis, strong acids such as HCl or TFA, or Lewis acids such as BBr.

[0126] General Method C [ka] In further exemplary procedures, the order of steps may be changed compared to general methods A and B. The required ether is introduced in the first step via further conventional methods as described above in general methods A and B. The phthalimide protecting group is removed in the second step, and the amine is converted to the desired substituted NR 4 R 5 The Boc protecting group is then removed, followed by the addition of L 1 C(R 6 )(R 7 )L 2 C(R 8 )(R 9 )R 10 A group can be introduced in the fifth step. The final step involves removal of the carboxylic acid protecting group as described in the general method above.

[0127] R 3 The THIQ scaffold where is bromo can be constructed according to the route outlined in Scheme 1. [ka]

[0128] R 8 Compounds where R is —COOH can be prepared by commonly known methods via reaction of an appropriate nitrile with an azide, as shown in Scheme 2. 8 The tetrazole group may be converted to other groups such as tetrazole as defined by [ka]

[0129] R 3 Variants at the R 3 is bromo derived from chemical reactions well known in the art as shown in Schemes 3 and 4. 3 Compounds of the invention where R is H or Cl can be prepared from intermediates 3is Br according to the method outlined in Scheme 3. [ka]

[0130] As shown in Scheme 4, bromo R 3 Conversion of the substituent to a suitable boronate or boronic acid allows for the preparation of fluoro and trifluoro derivatives. Bromo can be converted to an alkyl group via reaction with a suitable alkyl boronate using a suitable palladium catalyst; for example, the alkyl is methyl, a suitable boronate is 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, and a suitable palladium catalyst is Pd(dppf)Cl. 3 Compounds where is cyano can be prepared from the bromo derivative by treatment with a palladium catalyst such as Pd(PPh3)4 and a cyanating agent such as Zn(CN)2. [ka]

[0131] -NR 4 R 5 Compounds of the invention in which represents an indolinone can be prepared according to Scheme 5 by sequential reduction of the corresponding phthalimide with sodium borohydride followed by triethylsilane. [ka]

[0132] Group-NR 4 R 5 Compounds of the invention, wherein —NR represents a pyrrolidinone, can be prepared by removal of the phthalimide group with hydrazine, followed by conversion of the resulting primary amine to a pyrrolidinone by reaction with an appropriate lactone or ω-haloester, or to an indolinone, according to the route outlined in Scheme 6. 4 R 5 can be prepared from intermediates which exhibit a phthalimide group. [ka]

[0133] R 2 Compounds of the invention in which R is a halo substituent can be converted to R by treatment with a suitable halogenating agent, such as N-chlorosuccinimide, as shown in Scheme 7. 2 can be prepared from intermediates or embodiments of the present invention where is hydrogen. [ka]

[0134] Pharmaceutical Composition The compounds of the invention will usually, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Thus, according to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0135] The pharmaceutical compositions of the present invention may be prepared and packaged in bulk form, or a safe and effective amount of the compound of the present invention may be extracted and subsequently administered to a patient with a powder, syrup, or the like. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage form, with each physically discrete unit containing a safe and effective amount of the compound of the present invention. When prepared in unit dosage form, the pharmaceutical compositions of the present invention typically contain 1 mg to 1000 mg.

[0136] The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and wafers), topical use (e.g., as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels), transdermal administration such as via a transdermal patch, administration by inhalation (e.g., as dry powders, aerosols, suspensions, and solutions), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0137] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or solvent that is involved in providing form or consistency to a pharmaceutical composition. Each excipient should be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would substantially reduce the effectiveness of the compound of the present invention when administered to a patient and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. In addition, each excipient should be of sufficiently high purity to render it pharmaceutically acceptable.

[0138] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected.In addition, suitable pharmaceutically acceptable excipients can be selected for the specific function they can perform in the composition.For example, some pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of a uniform dosage form.Some pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of a suitable dosage form.Some pharmaceutically acceptable excipients can be selected for their ability to facilitate the transport or delivery of the compound of the present invention when administered from one organ or part of the body of a patient to another organ or part of the body.Some pharmaceutically acceptable excipients can be selected for their ability to improve patient compliance.

[0139] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavors, flavor masking agents, colorants, anti-caking agents, hemectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will understand that certain pharmaceutically acceptable excipients may serve more than one function and may serve different functions depending on the amount of excipient present in the formulation and the other ingredients present in the formulation.

[0140] Those skilled in the art possess the knowledge and skill to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the present invention. In addition, there are several sources of information available to those skilled in the art that describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0141] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0142] When combined with one or more excipients to produce a single dosage form, the amount of active ingredient will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg) of active agent, compounded with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98 percent by weight of the total composition.

[0143] The dose of a compound of formula I to be used for therapeutic or prophylactic purposes will, of course, vary according to principles of medicine, depending on the nature and severity of the animal's or patient's condition, its age and sex, and the route of administration.

[0144] Generally, when the compounds of the present invention are used for therapeutic or prophylactic purposes, a daily dose ranging from, for example, 0.1 mg / kg body weight to 75 mg / kg body weight, if divided doses are necessary, will be administered. Generally, lower dosages will be administered when parenteral routes are employed. Thus, for example, when administered intravenously or intraperitoneally, the dose will generally be in the range of, for example, 0.1 mg / kg body weight to 30 mg / kg body weight. Similarly, when administered by inhalation, the dose will be in the range of, for example, 0.05 mg / kg body weight to 25 mg / kg body weight. Oral administration, particularly in tablet form, may also be preferred. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of a compound of the present invention.

[0145] Route of administration The compounds of the invention or pharmaceutical compositions containing the active compounds can be administered to a subject by any conventional route of administration, either systemically / peripherally or locally (ie, to the desired site of action).

[0146] Routes of administration include, but are not limited to, oral administration (e.g., by ingestion); buccal administration; sublingual administration; transdermal administration (e.g., by patch, plaster, etc.); transmucosal administration (e.g., by patch, plaster, etc.); nasal administration (e.g., by nasal spray); ocular administration (e.g., by eye drops); pulmonary administration (e.g., by aerosol, e.g., orally or nasally, e.g., by inhalation or insufflation therapy). administration by intravenous, intra-arterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid, and intrasternal administration; by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0147] In a preferred embodiment, the compounds of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, are administered orally or via inhalation.

[0148] Therapeutic Uses and Applications The compounds of the present invention are activators of Nrf2. As a result, they are potentially useful therapeutic agents for the treatment of diseases or conditions mediated by Nrf2 activation.

[0149] Thus, in one aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0150] In another aspect, the present invention relates to a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[0151] In another aspect, the invention relates to the use of a compound of the invention as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated by Nrf2 activation.

[0152] In another aspect, the present invention relates to a method for treating a disease or disorder mediated by Nrf2 activation, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0153] Examples of specific diseases or conditions that the compounds of formula (I) and their pharmaceutically acceptable salts may be used to treat include any one of the following: chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown cause, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, hypersensitivity reactions, and the like. The present invention relates to a cancer or inflammatory bowel disorder, including, but not limited to, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy, or uveitis.

[0154] In particular, the compounds of the present invention (including pharmaceutically acceptable salts) may be used in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0155] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, and the like. Provided is a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of fatty liver disease, non-alcoholic steatohepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy, or uveitis.

[0156] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease, or non-alcoholic steatohepatitis.

[0157] In another aspect, the present invention relates to a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, and the like. and 200 mg of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of alcoholic fatty liver disease, non-alcoholic steatohepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy, or uveitis.

[0158] In another aspect, the invention provides the use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0159] In another aspect, the present invention provides a method for treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease and uveitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy, or uveitis, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0160] In another aspect, the present invention provides a method of treating chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0161] In another aspect, the present invention provides a method for activating Nrf2 in vitro, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0162] In another aspect, the present invention provides a method for activating Nrf2 in vivo, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof.

[0163] In another aspect, the present invention provides a method for activating Nrf2 in vitro and / or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0164] Combination Therapy The compounds of the invention can be administered alone, as monotherapy, or in combination with one or more additional therapeutic agents, the choice of which will, of course, depend on the disease or condition to be treated and its severity.

[0165] It is common to use combination therapies to treat specific medical conditions.

[0166] According to a particular aspect of the present invention, there is provided a combination suitable for use in the treatment of a disease or condition associated with Nrf2 activation, comprising a compound of the present invention as defined herein before, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0167] According to aspects of the present invention, the present invention is directed to treating chronic obstructive pulmonary disease, acute, chronic and severe asthma, acute lung injury / acute respiratory distress syndrome with or without multiple organ dysfunction syndrome, pulmonary fibrosis including pulmonary fibrosis of unknown etiology, cystic fibrosis, diabetes, atherosclerosis, hypertension, heart failure, myocardial infarction and repair, cardiac tissue repair, cardiac arrhythmias, cardiac hypertrophy, heart failure with preserved ejection fraction, diabetic cardiomyopathy, obesity, metabolic syndrome, diabetes, insulin resistance, pulmonary arterial hypertension, subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, beta-thalassemia, sickle cell disease, rheumatoid arthritis, irritable bowel disorder, ulcerative colitis, Crohn's disease, psoriasis, radiation-induced dermatitis, atopic dermatitis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, There is provided a combination suitable for use in the prophylaxis or treatment of hepatitis, toxicity-induced liver disease, viral hepatitis and cirrhosis, chronic kidney disease, diabetic nephropathy, autosomal dominant polycystic kidney disease, CKD associated with type 1 diabetes mellitus (T1D), IgA nephropathy (IgAN), Alport syndrome, focal segmental glomerulosclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, multiple sclerosis, Friedreich's ataxia, lung cancer, breast cancer, colon cancer, age-related macular degeneration (AMD), Fuchs' endothelial corneal dystrophy or uveitis, which combination comprises a compound of the invention as defined herein before, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0168] In a further aspect of the invention, there is provided a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more further therapeutic agents.

[0169] When the term "combination" is used herein, it should be understood to mean simultaneous administration, staggered administration, or sequential administration. In one embodiment of the present invention, "combination" refers to simultaneous administration. In another embodiment of the present invention, "combination" refers to staggered administration. In a further embodiment of the present invention, "combination" refers to sequential administration. When sequential or staggered administration is performed, the delay in administration of the second component should be such that the beneficial effect of the combination is not lost.

[0170] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a combination of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more further therapeutic agents, together with a pharmaceutically acceptable diluent or carrier.

[0171] The one or more additional therapeutic agents may further comprise a compound of the invention. Thus, in one embodiment, a pharmaceutical composition is provided comprising two compounds of the invention, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0172] According to certain aspects of the invention, combinations are provided which are suitable for use in the treatment of allergic, inflammatory or autoimmune diseases (e.g., asthma or COPD); cardiovascular or metabolic diseases (e.g., diabetes); neurodegenerative diseases; chronic kidney or liver disease; sickle cell disease; pulmonary arterial hypertension; cancer prevention or treatment; or for use in aiding transplantation.

[0173] In certain aspects of the invention, combinations are provided which are suitable for use in the prevention or treatment of chronic obstructive pulmonary disease, asthma, pulmonary arterial hypertension, diabetes, chronic kidney disease, Friedreich's ataxia, sickle cell disease or non-alcoholic steatohepatitis.

[0174] Examples of other therapeutic agents that may be used as part of a combination therapy with the compounds of the invention (e.g., as one of two or more active agents as part of a dual or triple combination) include, but are not limited to, the following: (i) beta2-adrenergic receptor agonists (which may be racemic or single enantiomers) including salmeterol, salbutamol, formoterol, salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline, vilanterol, olodaterol and salts thereof; (ii) anticholinergics that act as antagonists at muscarinic receptors, including ipratropium (e.g., as the bromide sold under the name Atrovent, CAS 22254-24-6), oxitropium and tiotropium (e.g., as the bromide sold under the name Spiriva, CAS 136310-93-5), revatropate, LAS-34273, aclidinium, glycopyrronium, umeclidinium and salts thereof; (iii) corticosteroid anti-inflammatory agents, examples of which include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, fluticasone furoate, beclomethasone esters (e.g., 17-propionate ester or 17,21-dipropionate ester), budesonide, flunisolide, mometasone esters (e.g., mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541, and ST-126; (iv) anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, JAK inhibitors, Pi3K inhibitors, inhibitors of leukotriene synthesis (e.g., montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g., adenosine 2a agonists), cytokine antagonists (e.g., chemokine antagonists, CCR3 antagonists, etc.) or inhibitors of cytokine synthesis, or 5-lipoxygenase inhibitors; (v) vasodilators and antiproliferative agents (e.g., prostanoids and PDE5 inhibitors), including epoprostenol (Floran), treprostinil (Remodulin), iloprost (Ventavis), treprostinil (Tyvaso), bosentan (Tracleer), ambrisentan (Retailis), sildenafil (Revatio), and tadalafil (Adcirca); (vi) antidiabetic drugs, including insulin, biguanides (e.g., metformin), sulfonylureas (e.g., glimepiride), meglitinides (e.g., repaglinide), thiazolidinediones (e.g., pioglitazone), dipeptidyl peptidase IV inhibitors (e.g., sitagliptin), incretin mimetics / GLP-1 analogs (e.g., liraglutide, exenatide, dulaglutide), sodium glucose cotransporter-2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, and empagliflozin), and α-glucosidase inhibitors (e.g., acarbose); (vii) hydroxyurea and other drugs used to treat sickle cell disease, such as L-glutamine, NCX1443, GBT440 (voxelotor), pan-selectin antagonists (GMI-1070, rivipancel), humanized anti-P-selectin antibodies (SelG1, clinalizumab), P-selectin aptamers, sebparin, regadenoson, ticagrelor, N-acetyl-cysteine (NAC), phosphodiesterase 9 inhibitors (e.g., PF-04447943, IMR-687, BAY 73-6691, BAY 41-2271); and (viii) ASK1 inhibitors such as selonsertib, FXR agonists such as obeticholic acid, ACC inhibitors such as GS-9674, Px-102, GS-0976, and PPARα / δ agonists such as elafibranor.

[0175] The above-referenced combinations may conveniently be presented for use in the form of pharmaceutical formulations and therefore pharmaceutical formulations comprising a combination as defined above in association with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.

[0176] Such combination / conjunction treatment may be achieved by way of the simultaneous, sequential or different administration of the individual components of the treatment, hi one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.

[0177] Such combination therapy utilizes the compounds of the present invention in dosage ranges described herein and other pharmaceutically active agents, such as in approved dosage ranges and / or dosages described in the relevant published references. [Example]

[0178] General steps: The following examples illustrate procedures for preparing compounds of the present invention. Starting materials are prepared according to procedures known in the art or exemplified herein, or are commercially available. Commercially available reagents were used without further purification. If no reaction temperature is specified, reactions were carried out at room temperature (usually 18-27°C).

[0179] The compounds described in this invention are 1 When characterized by H NMR spectroscopy, spectra were recorded on a 500 MHz Bruker, 400 MHz Bruker, 250 MHz Bruker, 300 MHz JEOL, or 400 MHz JEOL instrument. If temperature was not included, the spectrum was recorded at ambient temperature. Chemical shift values are expressed in parts per million (ppm). When NMR spectra are complex due to the presence of interconverting isomers, approximate partial integrations of the signals are reported, or only characterization of the major isomer is reported. The following abbreviations are used for NMR signal multiplicity: s = singlet, b = broad, t = triplet, q = quartet, m = multiplet, d = doublet.

[0180] Analytical LCMS When the compounds described in this invention are characterized by LCMS data, retention times and molecular weights are determined using the methods listed in the table below. When the compounds of this invention appear as slowly interconverting stereoisomers, multiple retention times are reported.

[0181] [Table 1]

[0182] [Table 2]

[0183] [Table 3]

[0184] [Table 4]

[0185] Preparative HPLC Preparative HPLC was performed using various preparative systems with variable wavelength UV detection or a Mass Directed AutoPrep (MDAP) system as listed in the table below. Collection was triggered by UV, MS, or a combination of the two. UV detection was at selected wavelengths, typically 210 nm, 230 nm, or 280 nm. Mass spectra were recorded on a mass spectrometer using alternating scan positive and negative electrospray ionization.

[0186] [Table 5]

[0187] [Table 6]

[0188] Preparative Chiral SFC Preparative chiral SFC was performed using one of the methods outlined below.

[0189] Method 1: Waters Thar Prep100 Preparative SFC System (2767 Liquid Handler with P200, CO2 Pump, 2545 Modifier Pump, 2998 UV / VIS Detector, Stack Injection Module). Column: Diacel Chiralpak IA / IB / IC YMC Amylose / Cellulose C (5 μm, 20-21.2 × 250 mm) maintained at 40 °C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF with modifier selected from Me2NH, formic acid as specified. Gradient / isotropic solvent as specified.

[0190] Method 2: Waters Thar Prep100 Preparative SFC System (2767 Liquid Handler with P200, CO2 Pump, 2545 Modifier Pump, 2998 UV / VIS Detector, Stack Injection Module). Column: Phenomenex Lux Cellulose-4 (5 μm, 20-21.2 x 250 mm) maintained at 40 °C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF with modifier selected from Me2NH, formic acid as specified. Gradient / isotropic solvent as specified.

[0191] Method 3: Waters Thar Prep100 preparative SFC system (2767 liquid handler with P200, CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, stack injection module). Column: YMC Amylose-C / Amylose-SA / Cellulose-C / Cellulose-SB / Cellulose-SC (5 μm, 20 × 250 mm), maintained at 40 °C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF with formic acid. Gradient / isotropic as specified.

[0192] Method 3a: Waters Thar Prep100 Preparative SFC System (2767 Liquid Handler with P200, CO2 Pump, 2545 Modifier Pump, 2998 UV / VIS Detector, Stack Injection Module). Column: YMC Amylose-C / Amylose-SA / Cellulose-C / Cellulose-SB / Cellulose-SC (5 μm, 20 × 250 mm), maintained at 40 °C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF with Me2NH. Gradient / isotropic as specified.

[0193] Method 4: Waters Thar Prep100 Preparative SFC System (2767 Liquid Handler with P200, CO2 Pump, 2545 Modifier Pump, 2998 UV / VIS Detector, Stack Injection Module). Column: Phenomenex Lux Cellulose-3 (5 μm, 20-21.2 x 250 mm) maintained at 40 °C. Conditions: Supercritical fluid CO2 and eluent selected from MeOH, EtOH, IPA, MeCN, EtOAc, THF with modifier selected from Me2NH, formic acid as specified. Gradient / isotropic solvent as specified.

[0194] [Table 7]

[0195] [Table 8]

[0196] Synthesis of intermediates Intermediate 1: 2-(1,3-dioxoisoindolin-2-yl)acetyl chloride [ka] 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) was added thionyl chloride (1039 mL, 14.24 mol) at room temperature. The mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The reaction mixture was concentrated in vacuo to give the title compound (605 g, 99%), which was used without further purification. 1 H NMR(300MHz,CDCl3)δ 7.96-7.87(m,2H),7.85-7.74(m,2H),4.81(d,2H).

[0197] Intermediate 2: 2-(1,3-dioxoisoindolin-2-yl)-N-(3-methoxyphenethyl)acetamide [ka] 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) was added a solution of Intermediate 1 (232 g, 1.04 mol) in DCM (1.2 L) at 5 °C. The reaction mixture was stirred at room temperature for 18 h, followed by the addition of hydrochloric acid (2 M; 2.4 L) and stirring the mixture for 1 h. The mixture was filtered, and the precipitate was washed with water and then dried in vacuo. The residue was dissolved in DCM (10.0 L), washed with saturated aqueous NaHCO3, the organics were dried over MgSO4, 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 organics were dried over MgSO4, filtered, and concentrated in vacuo to give a further portion of a white solid (61.4 g). The isolated solids were combined to give the title compound (328 g, 82%) as a white solid which was used without further purification. LCMS (Method 7): 1.68 min, 339.1 [M+H] + .

[0198] Intermediate 3: N-(2-bromo-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide [ka] To a stirred solution of Intermediate 2 (328 g, 970 mmol) in DMF (3.2 L) was added NBS (173 g, 970 mmol) in small portions over 0.5 h. The reaction mixture was heated at 40° C., then cooled to room temperature and allowed to stand at room temperature for 18 h. 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, and the separated aqueous phase and combined organics were concentrated in vacuo to give the title compound (314 g, 76%), which was used without further purification. 1 H NMR(300MHz,CDCl3)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).

[0199] Intermediate 4: 2-((5-bromo-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a suspension of intermediate 3 (312 g, 748 mmol) in MeCN (5.0 L) was added phosphorus pentoxide (630 g, 4.44 mol). The reaction mixture was heated at 60° C. for 4 hours, cooled to room temperature, and allowed to stand at room temperature for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to a volume of 500 mL. The filtered solid was dissolved in water (4.0 L) and combined with the organic layer. The combined mixture was heated at 40° C. for 1 hour, cooled to room temperature, and saturated aqueous NaHCO3 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] + .

[0200] Intermediate 5: (S)-5-Bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde [ka] A solution of benzeneruthenium(II) chloride dimer (3.78 g, 7.6 mmol, CAS: 37366-09-9) and (1S,2S)-(+)-Np-tosyl-1,2-diphenylethylenediamine (6.78 g, 18.5 mmol, CAS: 167316-27-0) in MeCN (300 mL) under argon was stirred at room temperature for 1 hour. To this was added MeCN (2.1 L) and DCM (300 mL), followed by Intermediate 4 (205 g, 457 mmol) and MeCN (1.4 L). To the reaction mixture was added a solution of formic acid and triethylamine (1:1; 760 mL), and the reaction mixture was stirred at room temperature under argon for 72 hours. The reaction mixture was diluted with water (2.0 L) and the pH was adjusted to 8.0 by adding NaHCO3. The mixture was diluted with DCM (3.0 L), and the organics were washed with water, dried over MgSO4, and filtered. The organics were passed through a silica plug, eluting with 66% EtOAc in DCM, and the combined organics were concentrated in vacuo to give the title compound (215 g, 99%), which was used without further purification. LCMS (Method 4): 0.91 min, 431.1 [M+H] + .

[0201] Intermediate 6: (S)-2-((5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a suspension of Intermediate 5 (215 g, 451 mmol) in THF (1.5 L) was added HCl (2 M aqueous solution; 2.14 L, 4.33 mol) and the mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 was added slowly to adjust the pH to 8. The mixture was extracted with DCM (2 x 2.0 mL) and the combined organics were dried over MgSO4 and filtered. The solution was concentrated in vacuo and the residue was recrystallized twice from MeCN (1.0 L + 250 mL). The resulting precipitate was filtered and dried in vacuo to give the title compound (113 g, 59%), which was used without further purification. LCMS (Method 7a): 2.30 min, 401.1 [M+H] + . 1 H NMR(300MHz,CDCl3)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,0H),3.43-3.32(m,1H),3.06(qd,1H),2.56-2.82(m,2H).

[0202] Intermediate 7: (S)-2-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a solution of Intermediate 6 (141 g, 351 mmol) in DCM (2.5 L) was added boron tribromide (1 M in DCM; 1.34 L, 1.44 mol) dropwise over 1 h at 0 °C, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was cooled to 0 °C, and MeOH (150 mL) was added slowly, and the mixture was stirred for 1.5 h. The resulting precipitate was isolated by filtration, washed with DCM, and dried in vacuo at 50 °C to give the title compound (Intermediate 7-HBr) (129 g, 71%). Hydrochloric acid (2 M aqueous solution; 3.0 L) was added to the combined organics, and the mixture was stirred for 1 h. 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 separated, adjusted to pH 8 by addition of Na2CO3, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (3.67 g, 2%) which was used without further purification. LCMS (Method 9a): 1.87 min, 389.1 [M+H] + .

[0203] Intermediate 8: (S)-tert-butyl 5-bromo-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] 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 h. The final portion of di-tert-butyl dicarbonate (3.37 g, 15.45 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and the mixture was extracted with DCM. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (145 g, assumed quantitative), which was used without further purification. LCMS (Method 9a): 2.54 min, 487.1 [MH] - .

[0204] Intermediate 9: (S)-2-((8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a solution of intermediate 6 (250 mg, 0.62 mmol) in THF (6 mL) and EtOH (6 mL) was added Pd / C (10%; 25 mg). The mixture was stirred under an atmosphere of hydrogen at room temperature and atmospheric pressure for 48 h. An additional portion of Pd / C (10%; 10 mg) was added, and the mixture was stirred under an atmosphere of hydrogen for 72 h. The mixture was then filtered through a pad of Celite® and washed with EtOH (10 mL) and MeOH (10 mL). The filtrate was concentrated in vacuo. Purification by flash column chromatography (19% EtOAc in DCM and 1% 7M NH3 in MeOH to 16% EtOAc in DCM and 4% 7M NH3 in MeOH) gave the title compound (153 mg, 76%). LCMS (Method 4): 0.76 min, 323.23 [M+H] + .

[0205] Intermediate 10: (S)-2-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a solution of intermediate 9 (200 mg, 0.62 mmol) in DCM (2 mL) was added boron tribromide (1 M in DCM; 3.1 mL, 3.1 mmol) under argon at −10° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 0° C. and MeOH (1 mL) was added. The mixture was warmed to room temperature, concentrated in vacuo, and the residue was stirred in saturated aqueous NaHCO (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 organics were washed with brine (10 mL), dried over NaSO, and concentrated in vacuo to give the title compound (130 mg, 68%), which was used without further purification. LCMS (Method 4): 0.66 min, 309.19 [M+H] + .

[0206] Intermediate 11: (S)-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] 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 h. Saturated aqueous NaHCO3 (150 mL) was added and the mixture was stirred for 15 min. The layers were separated and the organic layer was washed with water (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was diluted with a 1:1 mixture of IPA and heptane (50 mL) and the mixture was stirred for 1 h. The solid was filtered and washed with pentane (50 mL) to give the title compound (3.8 g, 85%), which was used without further purification. LCMS (Method 4): 0.82 min, 407.4 [MH] - .

[0207] Intermediate 12: (S)-tert-butyl 5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] 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 h and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with water (×2), brine, dried over MgSO4, 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%), which was used without further purification. LCMS (Method 9a): 2.57 min, 441.2 [MH] - .

[0208] 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; 24424-99-5). The reaction mixture was stirred at room temperature for 66 hours. An additional portion of di-tert-butyl dicarbonate (3.56 g, 16.31 mmol) was added and the mixture was stirred for 2 hours, after which additional di-tert-butyl dicarbonate (1.6 g, 7.33 mmol) was added and the mixture was stirred for an additional hour. The reaction mixture was washed with water, and the organics were separated, dried (MgSO), and filtered. The organics were concentrated in vacuo (to approximately 500 mL) and the mixture was allowed to stand at room temperature for 18 hours. The precipitate was isolated by filtration, washed with Et2O, and dried in vacuo (50 °C) to give the title compound (43.3 g, 72%). LCMS (Method 9a): 2.33 min, 441.1 [MH] - . 1H NMR (300 MHz, CDCl) d 7.91-7.85 (m, 2H), 7.74 (dq, 2H), 7.23-7.18 (m, 1H), 6.80-6.76 (m, 1H), 5.49-5.78 (1H), 4.08 (dd, 1H), 3.83-4.00 (1H), 3.22-3.54 (1H), 2.87-3.04 (1H), 2.61-2.84 (1H), 1.20 (s, 4H), 1.03 (d, 5H). The organics were concentrated in vacuo and combined with the crude material from the following experiment (Method 3) for further purification.

[0209] Method 3: To a suspension of intermediate 55-HCl (49.3 g, 130 mmol) in DCM (1.0 L) was added DIPEA (57.36 mL, 329 mmol) followed by di-tert-butyl dicarbonate (22.49 g, 103.05 mmol; CAS: 24424-99-5). The reaction mixture was allowed to stir at room temperature for 66 hours. An additional portion of di-tert-butyl dicarbonate (0.46 g, 2.12 mmol) was added and the mixture was stirred for 2 hours, after which additional di-tert-butyl dicarbonate (0.5 g, 2.29 mmol) was added and the mixture was stirred for an additional hour. The reaction mixture was washed with water, and the organics were separated, dried (MgSO), and filtered. The organics were concentrated in vacuo (to approximately 500 mL), and the mixture was allowed to stand at room temperature for 18 hours. The precipitate was isolated by filtration, washed with Et2O, and dried in vacuo (50 °C) to give the title compound (26.95 g, 46%). LCMS (Method 9a): 2.38 min, 441.1 [MH] - The organics were concentrated in vacuo and combined with the concentrated organics from Method 2 for further purification by flash column chromatography (silica; 40% EtOAc in heptane) to give a further batch of the title compound (32.4 g, 72.7 mmol). LCMS (Method 9): 2.56 min, 441.1 [MH].

[0210] Intermediate 13: tert-butyl (1S)-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] To a stirred suspension of intermediate 11 (400 mg, 0.98 mmol) in MeOH (8 mL) was added NaBH (148 mg, 3.9 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 72 h, then quenched with saturated aqueous NH Cl (ca. 15 mL) and acidified by the addition of 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 [MH] + .

[0211] Intermediate 14: (S)-2-((8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindolin-1-one [ka] 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 h and then concentrated in vacuo. The residue was partitioned between DCM (2 mL) and saturated aqueous NaHCO (5 mL). The layers were separated and the aqueous layer was washed with DCM (10 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (30 mg, 84%), which was used without further purification. 1 H NMR(400MHz,CDCl3)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),4.5 2(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).

[0212] Intermediate 15: (1S)-5-bromo-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] To a stirred solution of Intermediate 8 (4.58 g, 9.4 mmol) in anhydrous THF (130 mL) cooled in an ice / salt water bath under a nitrogen atmosphere was added NaBH (0.53 g, 14.1 mmol) and MeOH (15 mL). The solution was warmed to room temperature and stirred for 30 min. A second portion of NaBH (0.53 g, 14.1 mmol) was added and stirring continued for 45 min. An additional portion of NaBH (0.36 g, 9.4 mmol) was added and the mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with water, acidified to pH 3-4 with 10% citric acid, and extracted with EtOAc. The combined organics were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo to give the title compound (4.4 g, 97%), which was used without further purification. LCMS (Method 2): 1.46 min, 511.2 / 513.2 [M+Na] + .

[0213] Intermediate 16: (S)-2-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindolin-1-one [ka] To a stirred solution of Intermediate 15 (4.44 g, 9.07 mmol) in TFA (50 mL, 652 mmol) was added triethylsilane (2.5 mL, 15.65 mmol). The mixture was stirred at room temperature for 90 min and then diluted with DCM (200 mL). Saturated aqueous NaHCO3 was carefully added, followed by ammonia (30-33 wt% aqueous solution; 100 mL). The aqueous layer was extracted with DCM, and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. MeCN (40 mL) and DCM (10 mL) were added to the residue, and the resulting suspension was sonicated for 5 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] + .

[0214] Intermediate 17: (1S)-5-chloro-8-hydroxy-1-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] To a stirred solution of Intermediate 12 (2.18 g, 4.92 mmol) in anhydrous THF (72 mL) was added NaBH (0.28 g, 7.38 mmol) followed by anhydrous MeOH (8 mL) under argon at 0 °C. The mixture was stirred at 0 °C for 5 min, warmed to room temperature, and stirred for 75 min. An additional portion of NaBH (0.28 g, 7.38 mmol) was added, and the mixture was stirred at room temperature for an additional 2 h. Additional NaBH (0.19 g, 4.92 mmol) was added, and the mixture was stirred at room temperature for an additional 19 h. The mixture was quenched with saturated aqueous NaHCO (120 mL) and subsequently acidified to pH 5 with 10% aqueous citric acid (220 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (2.18 g, assumed quantitative) which was used without further purification. LCMS (Method 2): 1.44 min, 467.2 / 469.2 [M+Na] + .

[0215] Intermediate 18: (S)-2-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindolin-1-one [ka] To a stirred solution of Intermediate 17 (1.98 g, 4.45 mmol) in TFA (33.6 mL, 436.2 mmol) under argon, triethylsilane (1.07 mL, 6.68 mmol) was added, and the resulting solution was stirred at room temperature for 2 h. The mixture was diluted with DCM (300 mL), and saturated aqueous NaHCO3 (440 mL) was carefully added and stirred until the pH reached 8–9. The aqueous layer was further extracted with DCM (2 × 300 mL), and the combined organics were dried over Na2SO4, 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 (×3), and dried in vacuo at 40 °C. Purification by flash column chromatography (Puriflash 40 g, 0–5% MeOH in DCM) afforded the title compound (420 mg, 35%). LCMS (method 1): 0.79 min, m / z 329.1[M+H] + .

[0216] Intermediate 19: (S)-1-(aminomethyl)-5-bromo-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] 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 h, forming a colorless precipitate. The mixture was cooled to room temperature, and the precipitated solid was removed by filtration, washing the solid with EtOH (20 mL). The filtrate was concentrated in vacuo to give the title compound (3.24 g, assumed quantitative), which was used without further purification. LCMS (Method 2): 1.01 min, 357.1 [M+H] + .

[0217] Intermediate 20: (S)-5-bromo-8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] A stirred solution of methyl 4-bromobutanoate (1.52 g, 8.4 mmol; CAS: 4897-84-1), Intermediate 19 (3.24 g, 7 mmol), and triethylamine (1.47 mL, 10.55 mmol) in toluene (70 mL) was heated at reflux for 18 h. A second portion of methyl 4-bromobutanoate (250 mg, 1.38 mmol) was added, and the mixture was heated at reflux for an additional 5 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with 10% aqueous citric acid, water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (100 g silica column, Biotage SNAP, 0–100% EtOAc in DCM, followed by 0–100% MeOH in DCM) afforded the title compound (1.41 g, 47%). LCMS (method 2): 1.48 min, 447.2 (M+Na) + .

[0218] Intermediate 21: (S)-1-((5-bromo-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one [ka] A stirred solution of intermediate 20 (826 mg, 1.94 mmol) in DCM (60 mL) was treated with TFA (3 mL, 39.2 mmol), and the resulting solution was stirred at room temperature for 2 h. The mixture was diluted with DCM (50 mL) and water (50 mL) and basified to pH 8 by the addition of saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (593 mg, 94%), which was used without further purification. LCMS (Method 2): 0.74 min, both Br isotopes 325.1 [M+H] + .

[0219] Intermediate 22: (S)-1-(aminomethyl)-5-chloro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] Method 1: To a solution of intermediate 12 (2.35 g, 5.31 mmol) in EtOH (50 mL) was added hydrazine hydrate (1.29 mL, 26.5 mmol) and the mixture was heated at reflux for 24 h. The reaction 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 silica column Puriflash HC / Biotage SNAP, 0-30% EtOAc in MeOH) afforded the title compound (1.49 g, 90%). LCMS (Method 2): 1.01 min, 313.0 [M+H] + .

[0220] Method 2: To a stirred suspension of Intermediate 12 (40.0 g, 90.3 mmol) in EtOH (150 mL) was added hydrazine monohydrate (16.9 mL, 226 mmol, CAS: 7803-57-8), and the resulting mixture was heated to 75 °C and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with additional IMS, and filtered. The filter cake was washed with cold EtOH, and the combined filtrate was concentrated in vacuo to approximately 400 mL. The solution was allowed to stand for 18 h, then filtered to remove the precipitate, which was washed with cold EtOH. The filtrate was concentrated in vacuo, and to the residue was added EtOAc (100 mL) and MeCN (100 mL). The suspension was filtered and concentrated in vacuo to give the title compound (24.5 g, 82% yield).

[0221] Intermediate 23: (S)-5-chloro-8-hydroxy-1-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] 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). After the reaction was heated at reflux for 24 h, an additional portion of methyl 4-bromobutanoate (1.24 g, 6.86 mmol) in toluene (1 mL) and triethylamine (1.1 mL, 7.93 mmol) was added, and the reaction was heated at reflux for an additional 6.5 h. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc, washed sequentially with brine (20 mL), water (20 mL), dried over MgSO, and concentrated in vacuo. Purification by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (200 g silica column Puriflash HC / Biotage SNAP, 0-100% EtOAc in cyclohexane) gave the title compound (1.29 g, 64%). LCMS (Method 2): 1.43 min, 403 [M+Na] + .

[0222] Intermediate 24: (S)-1-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)pyrrolidin-2-one [ka] To a stirred mixture of Intermediate 23 (203 mg, 0.530 mmol) in anhydrous DCM (8 mL) was added TFA (0.82 mL, 10.66 mmol) dropwise under argon, and the resulting solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (5 mL) and adjusted to pH 8-9 by the addition of saturated aqueous NaHCO3 (ca. 8 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (173 mg, assumed quantitative), which was used without further purification. LCMS (Method 2): 0.75 min, 281.1 [M+H] + .

[0223] Intermediate 25: (1R,2S)-2-((benzyloxy)carbonyl)cyclohexane-1-carboxylic acid [ka] To a suspension of cis-1,2-cyclohexanedicarboxylic anhydride (10 g, 65.0 mmol, CAS: 13149-00-3) and quinidine (23 g, 71.4 mmol) in toluene (200 mL) was added dropwise over 30 min at −10° C. under argon. The reaction mixture was then stored in a refrigerator at 0° C. for 5 days. After warming to room temperature, the mixture was diluted with EtOAc (150 mL) and toluene (150 mL). The solution was washed with aqueous HCl (1 M; 2×200 mL) followed by brine (200 mL). The organic layer was dried over NaSO and concentrated in vacuo to approximately 350 mL, and a solution of (R)-alpha-methylbenzylamine (7.86 g, 65 mmol) in toluene (75 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes, then seeded with small crystals of the pure ammonium salt (prepared by taking a small aliquot of the solution and concentrating it to dryness) and stirred for an additional 18 hours. The solid was then collected by filtration, washed with toluene (50 mL), and dried in vacuo. The solid was then partitioned between EtOAc (250 mL) and 1M aqueous HCl (200 mL). The EtOAc layer was collected, washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (10 g, 58%, >99% ee). Chiral HPLC (Chiralpak IA 4.6 × 250 mm, 90:10 hep / IPA + 0.1% TFA, flow rate 1 mL / min); Rt = 6.2 min. LCMS (Method 4): 0.51 min, 236.3 [M+H] + . 1 H NMR(400MHz,CDCl3)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),1.85-1.75(m,2H),1.61-1.35(m,4H).

[0224] Intermediate 26: (1S,2R)-2-(chlorocarbonyl)cyclohexane-1-carboxylate benzyl [ka] To a solution of intermediate 25 (0.50 g, 1.90 mmol) in DCM (5 mL) was added oxalyl chloride (0.82 mL, 9.53 mmol). The reaction mixture was stirred at room temperature for 3 h, after which the reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene (2×20 mL) in vacuo to give the title compound (0.57 g, 100%), which was used without further purification. 1 H NMR(400MHz,CDCl3)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,m),1.60-1.37(m,4H).

[0225] Intermediate 27: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclohexane-carboxylic acid; (1R)-1-phenylethanamine [ka] A solution of (2,4-dimethoxyphenyl)methanol (32.7 g, 195 mmol, CAS: 7314-44-5) in toluene (50 mL) was added dropwise over 1 h to a suspension of cis-1,2-cyclohexanedicarboxylic 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. The solution was then transferred to a refrigerator and allowed to stand 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 and filtered. A portion of the filtrate (approximately 2 mL) was concentrated in vacuo, and ether (2 mL) was added to the residue, followed by (1R)-1-phenylethanamine (1 drop; CAS 3886-69-9). The resulting solid was collected by trituration. (1R)-1-phenylethanamine (8.4 mL, 64.9 mmol) was added to the remaining filtrate with stirring. The solid recovered from the previous trituration was added to this solution, and the mixture was left 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. 1 H NMR (300 MHz, MeOD) δ 7.42-7.20 (m, 6H), 6.49-6.44 (m, 2H), 5.11-4.90 (m, 2H), 4.32 (q, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.76-2.65 (m, 2H), 2.13-1.33 (m, 11H). The above reaction was repeated with 10 g of cis-1,2-cyclohexanedicarboxylic anhydride to give 20.6 g of the title compound (68%).

[0226] Intermediate 28: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclohexane-1-carboxylic acid [ka] Intermediate 27 (16.4 g, 36.98 mmol) was partitioned between citric acid (10% aqueous solution; 80 mL) and EtOAc (400 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (11.5 g, 99%), which was used without further purification. 1 H NMR(300MHz,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),1.75-1.71(m,2H),1.47-1.41(m,4H).

[0227] Intermediate 29: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclohexane-1-carboxylic acid [ka] To a stirred solution of Intermediate 28 (11.5 g, 35.68 mmol) in anhydrous THF (92 mL) was added LDA (2 M / heptane / ethylbenzene in THF; 44.6 mL, 89.19 mmol) dropwise over 2 h at −25 °C under argon. The mixture was stirred at −25 °C for 30 min, followed by the dropwise addition of iodomethane (6.66 mL, 107.03 mmol), and the reaction was stirred at −25 °C for 1 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with 10% aqueous citric acid, the aqueous layer was further extracted with EtOAc, and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (eluting with 2–5% MeOH in DCM) afforded the title compound (2.1 g, 13%). 1 H NMR(400MHz,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).

[0228] Intermediate 30: (1R,2S)-2-[(2,4-dimethoxyphenyl)methoxycarbonyl]cyclopentane-carboxylic acid; (1R)-1-phenylethanamine [ka] To a stirred suspension of (3aR,6aS)-4,5,6,6a-tetrahydro-3aH-cyclopenta[c]furan-1,3-dione (10 g, 71.36 mmol, CAS: 35878-28-5) and (S)-(6-methoxy-4-quinolyl)-[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol (25.46 g, 78.49 mmol, CAS: 56-54-2) in toluene (150 mL) was added (2,4-dimethoxyphenyl)methanol (37.82 mL, 214.07 mmol) in toluene (50 mL) dropwise over 1 h at −5° C. The solution was then transferred to a refrigerator and allowed to stand for 5 days. The solution was washed with 1 M aqueous HCl (400 mL) and brine (100 mL). The organic layer was dried over MgSO4 and filtered. A portion of the filtrate (approximately 2 mL) was concentrated in vacuo, and ether (2 mL) was added to the residue, followed by (1R)-1-phenylethanamine (1 drop; CAS 3886-69-9). The resulting solid was collected by trituration. Next, (1R)-1-phenylethanamine (9.2 mL, 71.36 mmol) was added to the bulk of the filtrate with stirring. The solid recovered from the previous trituration was added to this solution, and the mixture was left 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. 1 H NMR(300MHz,DMSO-d6)δ 7.37-7.10(m,6H),6.53-6.45(m,2H),5.02-4.77(m,2H),4.81-4.59(m,2 H),4.04-3.97(m,1H),3.73(d,6H),2.94-2.70(m,2H),1.85-1.19(m,9H).

[0229] Intermediate 31: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)cyclopentane-1-carboxylic acid [ka] 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. 1 H NMR(300MHz,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).

[0230] Intermediate 32: (1R,2S)-2-(((2,4-dimethoxybenzyl)oxy)carbonyl)-2-methylcyclopentane-1-carboxylic acid [ka] To a stirred solution of Intermediate 31 (13.2 g, 42.8 mmol) in anhydrous THF (120 mL) was added LDA (2 M / heptane / ethylbenzene in THF; 53.5 mL, 107 mmol) dropwise over 45 min under argon at −25° C. The mixture was stirred at −25° C. for 30 min, and iodomethane (2.67 mL, 42.81 mmol) was added dropwise. The reaction was stirred for 30 min and then quenched with saturated aqueous NH4Cl. EtOAc was added, and the aqueous layer was extracted with EtOAc. The combined organics were washed with 10% citric acid solution, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (2–5% MeOH in DCM) afforded the title compound (1.9 g, 14%). 1H NMR(300MHz,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).

[0231] Intermediate 33: (1S,2R)-1-methylcyclohexane-1,2-dicarboxylate 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-(2,4-dimethoxybenzyl) [ka] To a stirred solution of crude intermediate 29 (13.5 g, 40.0 mmol) in DMF (72 mL) was added HATU (19.8 g, 52.0 mmol; CAS: 148893-10-1) at room temperature under argon, and the reaction mixture was stirred for 5 minutes. DIPEA (7.67 mL, 44.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3.5 hours. The reaction was diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo. Purification on a Teledyne ISCO CombiFlash® Rf+ (330 g silica column Puriflash HC, 0-75% EtOAc in cyclohexane) afforded the title compound (14.4 g, 79%). LCMS (Method 16): 1.59 min, 477.3 [M+Na] + . 1 H NMR(400MHz,CDCl3)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).

[0232] Intermediate 34: (1S,2R)-1-methylcyclopentane-1,2-dicarboxylate 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-(2,4-dimethoxybenzyl) [ka] 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 room temperature under argon 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 organics were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g silica column Puriflash HC, 0-50% EtOAc in cyclohexane) to give the title compound (771 mg, 38%). LCMS (Method 16): 1.49 min, 463.3 [M+Na] + . 1 H NMR(400MHz,CDCl3)δ:8.71(dd,1H),8.40(dd,1H),7.42(dd,1H),7.27-7.24(m,1H),6.42(d,2 H),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).

[0233] Intermediate 35: (S)-tert-butyl 5-chloro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] 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 heated under reflux for 30 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Brine was added to this, and the mixture was extracted with DCM. The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g silica column Puriflash HC, 5-80% EtOAc in cyclohexane) to give the title compound (2.89 g, 82%). LCMS (Method 17): 1.66 min, 407.1[M+H] + The above reaction was repeated with 24.0 g of intermediate 22 to give 24.8 g (79%).

[0234] Intermediate 36: (S)-5-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-5-azaspiro[2.4]heptan-6-one hydrochloride [ka] A solution of intermediate 35 (2.35 g, 5.78 mmol) in HCl (4 M in dioxane; 29 mL, 116 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene (×2) to give the title compound (1.98 g, assumed quantitative), which was used without further purification. LCMS (Method 17): 0.79 min, 307.1 [M+H] + .

[0235] Intermediate 37: 2,4-dimethoxybenzyl (1S,2R)-2-((S)-5-chloro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1-methylcyclohexane-1-carboxylate [ka] 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 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., forming a precipitate. 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] + .

[0236] Intermediate 38: (R)-4-iodo-3-methylbutanoate ethyl ester [ka] To a stirred solution of (R)-4-methyldihydrofuran-2(3H)-one (13.4 g, 134 mmol, CAS: 65284-00-6) in EtOH (250 mL) was added trimethylsilyl iodide (38.1 mL, 268 mmol) dropwise at −20° C. The solution was stirred at −20° C. for 30 minutes. Triethyl orthoformate (22.3 mL, 134 mmol) was then added and the reaction was stirred at reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash column chromatography (silica, 5% EtOAc in heptane) to afford the title compound (24.3 g, 71%). 1 H NMR(300MHz,CDCl3)δ:4.15(q,2H),3.32-3.23(m,2H),2.46(dd,1H),2.24(dd,1H),2.07-1.99(m,1H),1.30-1.25(t,3H),1.06(d,3H).

[0237] Intermediate 39: (1R,6S)-6-(methoxycarbonyl)-6-methylcyclohex-3-ene-1-carboxylic acid [ka] To a stirred solution of (1R,6S)-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, lithium diisopropylamide solution (1.0 M in THF / hexanes; 143 mL, 143 mmol) was added dropwise, and the resulting solution was stirred at −25 °C for 30 min. To this, iodomethane (10.65 mL, 171.0 mmol) was added dropwise, and the solution was allowed to warm slowly to room temperature over 4 h. The mixture was quenched with saturated aqueous NH4Cl (200 mL) and subsequently partitioned between EtOAc (200 mL) and 10% aqueous citric acid (200 mL). The aqueous layer was further extracted with EtOAc (2 x 200 mL) and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (11.4 g, quantitative). 1 H NMR(400MHz,CDCl3)δ 5.67-5.59(m,2H),3.71(s,3H),3.02-2.98(m,1H),2.78-2.72(m,1H), 2.61-2.55(m,1H),2.48-2.36(m,1H),2.09-2.01(m,1H),1.26(s,3H).

[0238] Intermediate 40: (1S,2R)-1-methylcyclohex-4-ene-1,2-dicarboxylic acid 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)1-methyl [ka] To a stirred solution of intermediate 39 (2.15 g, 10.9 mmol) in DMF (50 mL) was added HATU (4.54 g, 11.9 mmol; CAS: 148893-10-1) under argon at room temperature, and the reaction mixture was stirred at room temperature for 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 and extracted with EtOAc, and the combined organics were washed with water, brine, dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (80 g silica column Puriflash HC / Biotage SNAP, 0-10% MeOH in DCM) to give the title compound (2.30 mg, 67%). LCMS (Method 16): 1.29 min, 339.0 [M+Na] + .

[0239] Intermediate 41: (E)-1-Fluoro-2-methoxy-4-(2-nitrovinyl)benzene [ka] A solution of 4-fluoro-3-methoxybenzaldehyde (57 g, 370 mmol; CAS: 128495-46-5), ammonium acetate (14.25 g, 185 mmol), and nitromethane (100.14 mL, 1850 mmol) in acetic acid (150 mL) was heated at 100 °C for 5 h. The reaction mixture was cooled to room temperature overnight. The resulting solid was collected by filtration, washed with diethyl ether, and the solid was dried in vacuo. The solid was suspended in DCM (1 L) and washed with water. The organic layer was filtered to remove the precipitate, dried (NaSO), filtered, and concentrated in vacuo to give the title compound (42 g, 200 mmol, 54%). The precipitate was dissolved in 2-MeTHF, and the organic layer was washed with water, brine, dried (NaSO), and evaporated to give additional product as a yellow solid (11 g, 55.2 mmol, 15% yield). The acetic acid mother liquor was evaporated and diluted with IMS. The resulting solid was collected by filtration and washed with IMS to give another batch of product (1.5 g). These batches were combined to give the title compound (54.5 g, 74%), which was used without further purification. 1 H NMR (300MHz; CDCl3)δ:7.95(d,1H),7.52(d,1H),7.16-7.08(m,3H),3.95(s,3H).

[0240] Intermediate 42: 2-(4-fluoro-3-methoxyphenyl)ethan-1-amine [ka] 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) pre-cooled in an ice-salt bath. The mixture was stirred for 15 minutes until all gas evolution subsided. A solution of Intermediate 41 (22 g, 111.6 mmol) in 2-methyltetrahydrofuran (660 mL) was added dropwise, ensuring that the temperature remained <20°C. The cooling bath was removed, and the mixture was heated under reflux for 5 minutes, then cooled in an ice-salt bath. IPA (57 mL) was added dropwise, followed by sodium hydroxide (2 M, 39 mL). 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 ca. 98:1 (ca. 1.5 L) followed by 10% MeOH in DCM (ca. 1.5 L). The filtrate was concentrated in vacuo to give the title compound (18.8 g, 99%), which was used without further purification. 1 H NMR(400MHz,CDCl3)7.02-6.97(m,1H),6.80(dd,1H),6.74-6.68(m,1H),3.89-3.88(s,3H),2.96(t,2H),2.71(t,2H),1.24-1.18(m,2H).

[0241] Intermediate 43: 2-(1,3-dioxoisoindolin-2-yl)-N-(4-fluoro-3-methoxyphenethyl)acetamide [ka] To a solution of intermediate 42 (49.3 g, 291 mmol) and DIPEA (101.5 mL, 583 mmol) in DCM (250 mL) cooled in an ice-salt bath under nitrogen was added dropwise a solution of intermediate 1 (65.2 g, 291 mmol) in DCM (1.25 L). The mixture was stirred over 2 h while warming from 0 °C to room temperature. The resulting precipitate was isolated by filtration and washed thoroughly with DCM. The solid was dried in vacuo to give the title compound (83 g, 80%), which was used without further purification. 1H NMR(400MHz,CDCl3)d 7.89-7.86(m,2H),7.77-7.74(m,2H),6.90(dd,1H),6.78(dd,1H),6.66(d dd,1H),5.75(s,1H),4.29(s,2H),3.88(s,3H),3.52(q,2H),2.79(t,2H).

[0242] Intermediate 44: N-(2-chloro-4-fluoro-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide [ka] 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 at 50 °C for 1 h, then cooled and concentrated in vacuo. Water (ca. 2 L) was added to the resulting residue and the resulting precipitate was stirred for 1 h. The solid was isolated by filtration, washed with water, EtO, air-dried, and evaporated in vacuo to give the title compound (85.8 g, 94%), which was used without further purification. LCMS (Method 15): 1.43 min, 391.3 [M+H] + .

[0243] Intermediate 45: 2-((5-chloro-7-fluoro-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] A solution of intermediate 44 (5 g, 12.79 mmol) in nitromethane (200 mL) was stirred at 108 °C under nitrogen and poured into a suspension of phosphorus pentoxide (10.9 g, 76.77 mmol) in nitromethane, also at 108 °C, and the resulting mixture was stirred at 108 °C for 1 h. The mixture was cooled to room temperature, and the solvent was decanted into a flask and concentrated in vacuo. The combined residue was diluted with approximately 500 mL of water, and the resulting mixture was heated at 40 °C for 30 min. The mixture was cooled and neutralized portionwise with solid sodium carbonate, followed by extraction with DCM (3 × 200 mL). The combined extracts were washed with brine, dried (MgSO), and concentrated in vacuo. The residue was suspended in diethyl ether, and EtOAc was added. The resulting precipitate was isolated by filtration and dried in vacuo to give the title compound (4.1 g, 86%), which was used without further purification. LCMS (Method 15): 1.64 min, 373.2[M+H] + .

[0244] Intermediate 46: 2-((5-chloro-7-fluoro-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] A stirred suspension of Intermediate 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 while 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 organics were washed with brine, dried (MgSO), and concentrated in vacuo. The residue was triturated in EtOAc to give the title compound (16.8 g, 43% yield). The mother liquor was concentrated in vacuo, and the residue was triturated in a mixture of EtO and EtOAc to give additional title compound (12.3 g, 30%), which was used without further purification. Combined total yield (29.1 g, 73%). LCMS (Method 15): 1.60 min, 374.2[M+H] + .

[0245] Intermediate 47: 2-((5-chloro-7-fluoro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione hydrobromide [ka] 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 boron tribromide in DCM (1 M; 131 mL, 131 mmol) dropwise over 1.5 hours. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction was quenched by dropwise addition to ice-water (130 mL) 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 give the title compound (8.6 g, 60%), which was used without further purification. LCMS (Method 2): 0.96 min, 361.0 [M+H] + .

[0246] Intermediate 48: (S)-tert-butyl 5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-7-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] To a suspension of intermediate 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 under argon for 1 h. The reaction mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with DCM, and the combined organics were washed with brine, dried (NaSO), 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 silica column Puriflash HC, 0-10% EtOAc in DCM) to give a further 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) / CO2, 100 ml / min, 120 bar, 40 °C) gave the title compound (first-eluting enantiomer; 0.99 g, 47%). The absolute stereochemistry was confirmed by small molecule X-ray crystallography of the carboxylic acid final compound arising from enantiomer 2. LCMS (Method 15): 1.41 min, 483.1 [M+Na] + . 1 H NMR(400MHz;DMSO-d6)δ 7.95-7.80(m,4H),7.42-7.37(m,1H),5.60-5.45(m,1H),4.19-3.75(m,3H), 3.45-3.35(m,1H),2.83-2.79(m,1H),2.63-2.53(m,1H),1.03-0.95(m,9H).

[0247] Intermediate 49: (S)-1-(aminomethyl)-5-chloro-7-fluoro-8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] 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 h. The reaction mixture was cooled to room temperature, diluted with cold MeCN, filtered, and the filtrate concentrated in vacuo. The residue was dissolved in IMS (5 mL) and stirred at room temperature for 18 h. The solution was filtered, the solid washed with cold IMS, and the filtrate concentrated in vacuo to give the title compound (700 mg, 96% yield), which was used without further purification. LCMS (Method 15): 1.34 min, 331.2 [M+H] + .

[0248] Intermediate 50: (S)-tert-butyl 5-chloro-7-fluoro-8-hydroxy-1-((6-oxo-5-azaspiro[2.4]heptan-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] A 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 heated under reflux for 18 h. An additional portion of methyl 2-(1-(bromomethyl)cyclopropyl)acetate (156 mg, 0.75 mmol) and triethylamine (0.16 mL, 1.14 mmol) was added and the mixture was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned with brine, diluted, extracted with DCM and the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (40 g silica column Puriflash HC, 0-100% EtOAc in cyclohexane) to give the title compound (426 mg, 66%). LCMS (Method 2): 1.64 min, 447.1 [M+Na] + .

[0249] Intermediate 51: N-(2-chloro-5-methoxyphenethyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide [ka] To a stirred solution of Intermediate 2 (870 g, 2.573 mol) in DMF (13.0 L), divided among four flasks, was added N-chlorosuccinimide (361 g, 2.701 mol; 128-09-6), divided equally between each reaction. The reaction mixture was heated to 80 °C for 2 h, cooled to room temperature, and combined in two batches. Each batch was concentrated in vacuo to approximately 1 L. The mixture was allowed to stand for 18 h, and the resulting precipitate was collected by filtration. The organics were each diluted with DCM (2.5 L) and washed with water (2 L). The organics were concentrated in vacuo, and the resulting slurry was combined with the previously isolated solid and filtered (both batches were processed separately). The solid was washed with EtO and concentrated in vacuo to give two batches of the title compound (435.5 g and 419.2 g, 79%), which were used without further purification. LCMS (Method 9a): 2.02 min, 373.4 [M+H] + . 1 H NMR(300MHz,CDCl3)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(d d,1H),5.78(s,1H),4.29(d,2H),3.75-3.80(m,3H),3.56(q,2H),2.94(d,2H).

[0250] Intermediate 52: 2-((5-chloro-8-methoxy-3,4-dihydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a suspension of intermediate 51 (419 g, 965 mmol) in MeCN (7.5 L) divided among three flasks was added phosphorus pentoxide (813 g, 5.73 mol; CAS: 1314-56-3). The mixture was heated to 60° C. for 20 hours. The organic phase (approximately 1.5 L) was decanted from the precipitate and concentrated in vacuo. Water (2.5 L) was added to the remaining solid. The acetonitrile concentrate was washed into this solution with water (500 mL), and the mixture was heated to 40° C. for 1 hour. The resulting solution was cooled to room temperature and divided into two flasks. Saturated aqueous sodium carbonate solution was added to these with stirring until the pH reached near pH 9. The precipitated solid was collected by filtration and washed with water (500 mL). The combined mixture was dried in vacuo at 40° C. to give the title compound (353 g, 93%), which was used without further purification. LCMS (Method 9a): 2.42 min, 355.0 [M+H] + .

[0251] Intermediate 53: (S)-5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carbaldehyde [ka] A solution of benzeneruthenium(II) chloride dimer (4.67 g, 9.35 mmol; CAS: 37366-09-9) and (1S,2S)-(+)-Np-tosyl-1,2-diphenylethylenediamine (8.38 g, 22.88 mmol; CAS: 167316-27-0) in MeCN (300 mL) under argon was 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). To each mixture was added MeCN (520 mL) and DCM (150 mL). To each flask was added Intermediate 52 (201 mg, 565 mmol), 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 divided into two portions and added to two reaction flasks. The mixtures were stirred under argon at room temperature for 3 days. To each was added water (1 L), followed by solid sodium bicarbonate until the mixture reached a pH of 8-9. DCM (1.5 L) was added to each reaction, and the aqueous layers were separated. The organics were further washed with water and combined. The organic phase was filtered and passed through a plug of silica, eluting with a 2:1 mixture of EtOAc in DCM (approximately 4 L). The organics were concentrated in vacuo to give the title compound (192.3 g, ca. 76%; mixture with Intermediate 54), which was used without further purification. LCMS (Method 9a): 2.28 min, 385.4 [M+H] + .

[0252] Intermediate 54: (S)-2-((5-chloro-8-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] 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 heated at reflux for 18 h. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution was added slowly until a pH of 8–9 was reached. The mixture was extracted with DCM (5 L), and the combined organics were dried over MgSO, filtered, and concentrated in vacuo. Recrystallization from acetonitrile gave a solid that 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].

[0253] Intermediate 55: (S)-2-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione [ka] To a solution of Intermediate 54 (95.5 g, 268 mmol) in DCM (2 L) was added boron tribromide (1 M in DCM; 1.02 L, 1.02 mol; 10294-33-4) dropwise over 1 h at 0 °C. The reaction mixture was warmed to room temperature and stirred for 48 h. The reaction was cooled to 0 °C and quenched with MeOH (200 mL). The mixture was allowed to stand for 2 h, and the precipitate was isolated by filtration. The precipitate was washed with DCM and dried in vacuo (50 °C) to give (S)-2-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)-isoindoline-1,3-dione hydrobromide (57.3 g, 51%). To a stirred solution of the DCM filtrate, aqueous hydrochloric acid (2 M; 2 L) was added, and the mixture was stirred for 1 h. The precipitate was isolated by filtration and dried in vacuo (50 °C) to give (S)-2-((5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)isoindoline-1,3-dione as a mixture of hydrobromide and hydrochloride salts (49.3 g, ca. 45%). The acidic aqueous phase was separated, adjusted to pH 8-9 by addition of solid sodium bicarbonate, and extracted with DCM. The organics were dried (MgSO), filtered, and concentrated in vacuo to give the title compound (2.53 g, 2%). 2-[[(1S)-5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]isoindoline-1,3-dione hydrobromide LCMS (Method 10): 0.99 min, 343.0 [M+H] + 2-[[(1S)-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-[[(1S)-5-chloro-8-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]isoindoline-1,3-dione: LCMS (Method 9a): 1.93 min, 343.3 [M+H] + .

[0254] Intermediate 56: (S)-tert-butyl 5-chloro-1-((1,3-dioxoisoindolin-2-yl)methyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka] 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 h, 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-CO2 t Bu] + . 1 H NMR(300MHz,CDCl3)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).

[0255] Intermediate 57: (S)-1-(aminomethyl)-5-chloro-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl [ka] 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 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOH. The filtrate was concentrated in vacuo, and the residue was triturated with EtO. The mixture was filtered, and the filter cake was washed with EtO. The filtrate was concentrated in vacuo to give the title compound (4.5 g, 99%), which was used without further purification. LCMS (Method 9): 0.95 min, 327.1 [M+H] + .

[0256] R 1 Method A: 3-(chloromethyl)-5-methylisothiazole [ka] To a stirred solution of (5-methylisothiazol-3-yl)methanol (203 mg, 1.57 mmol, CAS: 1803598-19-7) in chloroform (2 mL), thionyl chloride (0.23 mL, 3.14 mmol) was added dropwise under argon, and the resulting solution was stirred at room temperature for 75 minutes. The reaction mixture was concentrated in vacuo to give 3-(chloromethyl)-5-methylisothiazole (224 mg, 97%), which was used without further purification. 1 H NMR(400MHz;DMSO-d6)δ 7.21(d,1H),4.76(s,2H),2.56(d,3H).

[0257] R 1 Method B: 4-(chloromethyl)-5-(difluoromethyl)-1-methyl-1H-1,2,3-triazole [ka] Step 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) was added. The resulting solution was heated at 80 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water and adjusted to pH 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with EtOAc (2 × 100 mL), and the combined organics were washed with brine, dried (MgSO ), and concentrated in vacuo to give ethyl 5-(difluoromethyl)-1-methyl-triazole-4-carboxylate (7.3 g, 79%), which was used without further purification. LCMS (Method 16): 1.20 min, 206.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.51(t,1H),4.47(q,2H),4.29-4.28(m,3H),1.45(t,3H).

[0258] Step 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 an argon atmosphere. To this, lithium aluminum hydride (1 M in THF; 17.6 mL, 17.6 mmol) was added dropwise, and the reaction mixture was stirred from 0 °C to room temperature for 1 hour. Additional lithium aluminum hydride (1 M in THF; 3 mL, 3 mmol) was added, and the mixture was stirred for 30 minutes. The mixture was cooled in ice water, and 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-1H-1,2,3-triazol-4-yl)methanol (5.7 g, 100%). LCMS (Method 15): 0.68 min, 164.1[M+H] + . 1 H NMR(400MHz;DMSO-d6,)δ 7.45(t,1H),5.42(t,1H),4.62(d,2H),4.13(s,3H).

[0259] Step 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 to this was added thionyl chloride (5.5 mL, 75.5 mmol) dropwise under nitrogen. The reaction mixture was stirred from 0 °C to room temperature for 2 hours 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, quantitative), which was used without further purification. LCMS (Method 2) 0.90 min, 181.9 [M+H] + .

[0260] R 1 Method C: 4-(chloromethyl)-5-(methoxymethyl)-1-methyl-1H-1,2,3-triazole hydrochloride [ka] R 1 Step 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) was added dry triethylamine (2.51 mL, 18 mmol) dropwise over 5 minutes at 0° C. under argon. The mixture was stirred for 10 minutes, followed by stirring 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 dissolved 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 Na2SO4, filtered, and concentrated in vacuo. Purification by flash silica chromatography (50 g silica, 25-60% EtOAc in heptane) gave methyl 2-diazo-4-methoxy-3-oxobutanoate (0.96 g, 91%). 1 H NMR(300MHz,CDCl3)δ:4.53(s,2H),3.84(s,3H),3.47(s,3H).

[0261] R 1Step b. Methylamine (2 M 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) was added under argon. 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 organics were washed with saturated sodium bicarbonate, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (20 g silica, 40 to 100% EtOAc in heptane) to give methyl 5-(methoxymethyl)-1-methyl-1H-1,2,3-triazole-4-carboxylate (218 mg, 40%). 1 H NMR(300MHz, CDCl3)δ:4.90(s,2H),4.12(s,3H),3.96(s,3H),3.38(s,3H).

[0262] R 1 Step c. To a stirred solution of the above intermediate (218 mg, 1.18 mmol) in THF (1.5 mL) and EtOH (6 mL) under argon, sodium borohydride (134 mg, 3.54 mmol) was added 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 h. The mixture was cooled and hydrolyzed with 10% citric acid, followed by removal of volatiles in vacuo. The residue was diluted with water and extracted with 2:1 IPA / chloroform. The combined organic layers were washed with 1:1 brine / saturated sodium bicarbonate, followed by brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (5-(methoxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)methanol (89 mg, 51%). 1 H NMR(300MHz; CDCl3)δ:4.73(s,2H),4.56(s,2H),4.02(s,3H),3.35(s,3H).

[0263] R 1Step 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 h. The reaction mixture was concentrated in vacuo to give 4-(chloromethyl)-5-(methoxymethyl)-1-methyl-1H-1,2,3-triazole hydrochloride (420 mg, 84%), which was used without further purification. 1 H NMR(300MHz,CDCl3)δ:4.74(s,2H),4.58(s,2H),4.07(s,3H),3.39(s,3H).

[0264] R 1 Method D: 3-(chloromethyl)-5-methyl-4-(trifluoromethyl)isoxazole [ka] R 1 Step 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), N-iodosuccinimide (956 mg, 4.25 mmol) was added, and the reaction mixture was stirred at room temperature for 72 h. Water was added, and the mixture was extracted with EtOAc. The combined organics were washed with water, saturated aqueous NaHCO, water, and NaSO, dried over MgSO, filtered, and concentrated in vacuo. The residue was triturated with IPA to give 4-iodo-3-(methoxymethyl)-5-methylisoxazole (542 mg, 57%). 1 H NMR(300MHz,CDCl3)δ:3.99(s,3H),2.56(s,3H).

[0265] R 1Step b. Copper(I) 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 at 85 °C under microwave irradiation for 1 h. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of ammonium chloride, and the aqueous phase was extracted with EtOAc. The combined organics were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash silica chromatography (80% DCM in heptane) to give methyl 5-methyl-4-(trifluoromethyl)isoxazole-3-carboxylate (240 mg, 55%). 1 H NMR(300MHz,CDCl3)δ:4.01(s,3H),2.64(s,3H). 19 F-NMR(283MHz,CDCl3)δ:-56.72(s,3F).

[0266] R 1 Steps c and d. The title compound is reacted with R 1 Prepared from the above intermediate using Method B and used without further purification. 1 H NMR(300MHz,CDCl3)δ:5.49(dd,2H),2.61(q,3H).

[0267] R 1 Method E: 3-(chloromethyl)-4-(difluoromethyl)-5-methylisoxazole hydrochloride [ka] R 1 Step a. Methyl 4-iodo-5-methylisoxazole-3-carboxylate (700 mg, 2.62 mmol, Example 154, R 1Step a): To a stirred solution of potassium vinyltrifluoroborate (1.053 g, 7.86 mmol, CAS: 13682-77-4) and triethylamine (1.1 mL, 7.86 mmol), DCM and [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex (214 mg, 0.26 mmol) were added, and the reaction mixture was heated at 90 °C for 16 h, cooled to room temperature, and concentrated in vacuo. The residue was partitioned between water and DCM, and the aqueous phase was extracted with DCM. The combined organics were washed with brine, dried over MgSO, 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%). 1 H NMR(300MHz,CDCl3)δ 6.80(dd,1H),5.52-5.44(m,2H),3.98(s,3H),2.55(s,3H).

[0268] R 1 Step b. To a solution of the above intermediate (321 mg, 1.92 mmol) in THF (27 mL), osmium tetroxide (49 mg, 0.19 mmol, CAS: 20816-12-0) was added at room temperature, and the reaction mixture was stirred for 5 minutes. To this, sodium periodate (10% on silica, 12.5 g, 5.84 mmol) was added, 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-5-methylisoxazole-3-carboxylate (286 mg, 79%). 1 H NMR(300MHz,CDCl3)δ:10.32(s,1H),4.06(s,3H),2.78(s,3H).

[0269] R 1Step c. 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), bis(2-methoxyethyl)aminosulfur trifluoride solution (50% in THF; 1.44 mL, 3.38 mmol, CAS: 202289-38-1) was added, and the reaction mixture was stirred at room temperature for 16 hours. DCM was added, and the organics were washed with a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with DCM, and the combined organics were washed with brine, dried over MgSO4, 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%). 1 H NMR(300MHz,CDCl3)δ:7.09(t,1H),4.07-3.95(m,3H),2.70-2.60(m,3H).

[0270] R 1 Steps d-e. The title compound (283 mg) was added to R 1 Prepared from the above intermediate using Method B and used without further purification. 1 H NMR(300MHz,CDCl3)δ 6.89-6.53(m,1H),4.81-4.61(m,2H),2.54-2.52(m,3H).

[0271] Intermediates in Table 1 are listed in Table 1 for use in the synthesis of the referenced examples. 1 Prepared according to the same method as Methods A-E.

[0272] [Table 9]

[0273] (R)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl methanesulfonate [ka] Step a. A mixture of 3-chloro-5-methyl-pyridazine (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 h. The mixture was diluted with aqueous NaHCO / brine (1:1; 50 mL) and extracted with ethyl acetate (5 × 50 mL), DCM (50 mL), and IPA / DCM (1:10; 8 × 50 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf200 (12 g silica column Puriflash HC, eluting with 0-10% MeOH in DCM) to give (R)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl methanesulfonate (123 mg, 43%). 1 H NMR(400MHz,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),2.20-2.12(m,2H).

[0274] Step 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), followed by the dropwise addition of methanesulfonyl chloride (0.06 mL, 0.810 mmol). The mixture was stirred at 0° C. for 5 minutes, then at room temperature for 1.75 hours. The mixture was diluted with water (10 mL) and extracted with DCM (5×10 mL). The combined organics were dried over NaSO, filtered, and concentrated in vacuo to give (R)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl methanesulfonate (154 mg, 88%), which was used without further purification. 1H NMR(400MHz,CDCl3)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).

[0275] 5-(chloromethyl)-3-methyl-3H-imidazo[4,5-b]pyridine [ka] Step a. To a stirred solution of 3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg, 1.23 mmol, CAS: 019108-05-4) in MeOH (5 mL) was added sulfuric acid (0.5 mL, 8.9 mmol), and the reaction mixture was stirred at reflux for 16 h. A solution of NaHCO 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 mg, assumed quantitative), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.84(s,1H),8.2(bs,1H),7.97(d,1H),3.95(s,3H).

[0276] Step 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 (3 × 10 mL) and DCM (2 × 10 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo to give methyl 3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (305 mg, assumed quantitative; 2:1 mixture with regioisomeric methyl 1-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate). LCMS (Method 2): 0.77 and 0.78 min, 192.1 [M+H]. + .

[0277] Step c. To the above intermediate (305 mg, 1.6 mmol; 2:1 mixture with methyl 1-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate) in tetrahydrofuran (10 mL) was added LiAlH (0.8 mL, 1.6 mmol, 2 M in THF) at 0 °C. The mixture was stirred at 0 °C for 30 min, then diluted with EtOAc and quenched with a few drops of saturated aqueous NH Cl. The mixture was stirred at room temperature for 10 min, and the organics were dried over Na SO , filtered, and concentrated in vacuo. Purification by flash column chromatography (40 g column, 0-100% 10% 2 M methanol in ammonia (2 M; 10%) in DCM) gave (3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)methanol (60 mg, 23%), which was used without further purification. LCMS (Method 2) 0.17 min, 164.1[M+H] + .

[0278] Step d. To a stirred solution of the above intermediate (60 mg, 0.37 mmol) in chloroform (1 mL) was added thionyl chloride (0.54 mL, 0.74 mmol) dropwise under argon, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (3 x 5 mL) to give the title compound (67 mg, assumed quantitative), which was used without further purification. LCMS (Method 2) 0.93 min, 182.1 [M+H] + .

[0279] 5-(chloromethyl)-4-(difluoromethyl)pyrimidine [ka] Step 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 with aqueous HCl (6 M) to pH 4. 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), filtered, and concentrated to give the product (105 mg). The filtrate was further extracted with n-butanol, dried (MgSO), filtered, and concentrated to give additional product (219 mg). Both batches gave 4-(difluoromethyl)pyrimidine-5-carboxylic acid (0.50 g, 58%). LCMS (Method 10c): 0.50 min, 174.9[M+H] + .

[0280] Step b. To a stirred solution of the above intermediate (219 mg, 1.26 mmol) in THF (11 mL) was added 4-methylmorpholine (0.19 mL, 1.76 mmol) and isobutyl chloroformate (0.22 mL, 1.70 mmol) dropwise under argon at −5° C. The reaction mixture was stirred at −5° C. for 1.5 hours and at room temperature for 1.5 hours. The mixture was cooled to −5° C., and to it was added dropwise a solution of sodium borohydride (71 mg, 1.89 mmol) in water (0.5 mL), and the reaction mixture was stirred for 45 minutes. The reaction mixture was diluted with water and extracted with DCM, and the combined organics were washed with brine, dried (NaSO), 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] + .

[0281] Step c. To a solution of the above intermediate (11 mg, 0.070 mmol) in 1,4-dioxane (0.15 mL) was added phosphorus oxychloride (0.07 mL, 0.70 mmol) and the reaction was stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organics were dried (NaSO), filtered, and concentrated in vacuo to give 5-(chloromethyl)-4-(difluoromethyl)pyrimidine (31 mg, assumed quantitative), which was used without further purification. 1 H NMR(300MHz,CD3OH)δ 9.21(s,1H),9.05(s,1H),6.90(t,1H),4.89(s,2H).

[0282] 3-(Chloromethyl)-5,5-dimethyl-4,5-dihydroisoxazole [ka] Step a. In an autoclave, a solution of 2-methylprop-1-ene (15% wt in THF; 2.0 g, 35.6 mmol; CAS: 115-11-7), ethyl 2-nitroacetate (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 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 automated reverse-phase column chromatography on an 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%). 1 H NMR(300MHz,CDCl3)δ 4.37-4.34(m,2H),2.95(s,2H),1.47(s,6H),1.38(t,3H).

[0283] Step b. To a stirred suspension of sodium borohydride (100 mg, 1.02 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 warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated in vacuo, diluted with water, and acidified to pH 6 using acetic acid. The aqueous phase was extracted with EtOAc, and the combined organics were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (5,5-dimethyl-4,5-dihydroisoxazol-3-yl)methanol (100 mg, 53%). 1 H NMR(300MHz,CDCl3)δ 4.41(s,2H),2.76-2.79(m,3H),1.45(s,6H).

[0284] Step 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 was allowed to warm to room temperature and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and co-evaporated multiple times with toluene to give the title compound (72 mg, 48%), which was used in the next step without further purification. 1 H NMR(300MHz,CDCl3)δ 4.29(s,2H),2.84(s,2H),1.42(s,6H).

[0285] 4-(chloromethyl)-1,5-dimethyl-1H-1,2,3-triazole [ka] Step a. To a stirred solution of 1,5-dimethyltriazole-4-carboxylic acid (5.0 g, 35.4 mmol; CAS: 329064-07-5) in EtOH (21 mL, 354 mmol), sulfuric acid (1.89 mL, 35.4 mmol) was added 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, followed by cooling to room temperature. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (10 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted with EtOAc. The organics were separated, dried (MgSO), and concentrated in vacuo to give ethyl 1,5-dimethyl-1H-1,2,3-triazole-4-carboxylate (4.66 g, 78%). 1 H NMR(300MHz,CDCl3)δ 4.46-4.39(q,2H),4.00(s,3H),2.58(s,3H),1.44-1.39(t,3H).

[0286] Step b. To a stirred solution of the above intermediate (4.66 g, 27.6 mmol) in THF (41 mL) was added dropwise lithium aluminum hydride solution (1 M in THF; 27.56 mL, 27.56 mmol) under an argon atmosphere at 0 °C, and the reaction mixture was stirred from 0 °C to room temperature for 1 h. The mixture was cooled in ice water, and 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 min. 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%). 1 H NMR(300MHz,CDCl3)δ 7.33(s,1H),4.64(s,2H),3.90(s,3H),2.30(s,3H).

[0287] Step c. To a stirred solution of the above intermediate (3.35 g, 26.4 mmol) in DCM (40 mL) cooled in ice water was added thionyl chloride (3.84 mL, 52.7 mmol) dropwise under nitrogen. The reaction mixture was stirred from 0 °C to room temperature for 1 h 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 min, 146.2 [M+H] + .

[0288] 3-(chloromethyl)-7-fluorobenzo[d]isoxazole [ka] Step a. To a stirred solution of methyl 2-(2,3-difluorophenyl)acetate (1.67 g, 8.97 mmol, CAS: 1036273-31-0) in diethyl ether (18 mL), a solution of isopentyl nitrite (2.65 mL, 19.7 mmol) in diethyl ether (10 mL) was added, followed by sodium methoxide (0.78 g, 14.35 mmol) in methanol (11.7 mL), and the mixture was stirred at room temperature for 18 hours. Water was added, and the mixture was acidified using hydrochloric acid (1 M aqueous solution). The mixture was extracted with diethyl ether (×3), and the combined organics were dried over sodium sulfate NaSO and concentrated in vacuo. The residue was purified by flash column chromatography on a Teledyne ISCO CombiFlash® Rf+ (120 g silica column Puriflash HC, 0 to 50% EtOAc in cyclohexane) to give methyl (E)-2-(2,3-difluorophenyl)-2-(hydroxyimino)acetate (1.05 g, 54%). 1 H NMR(400MHz, CDCl3)δ:9.08(br.s,1H),7.31-7.04(m,2H),3.90(s,3H).

[0289] Step 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 was extracted with EtOAc. The combined organics were washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo to give methyl 7-fluorobenzo[d]isoxazole-3-carboxylate (683 mg, 79%). LCMS (Method 2): 1.17 min, 194.0 [MH] - . 1 H NMR(400MHz, CDCl3)δ:7.92(dd,1H),7.43-7.33(m,2H),4.11(s,3H).

[0290] Steps c to d. The title compound (502 mg) was added to R 1 Prepared from the above intermediate using Method B and used without further purification. 1 H NMR(400MHz, CDCl3)δ:7.64-7.62(m,1H),7.34-7.30(m,2H),4.92(s,2H).

[0291] 3-(chloromethyl)-6,7-difluorobenzo[d]isoxazole [ka] The title compound (894 mg) was prepared from methyl 2-(2,3,4-trifluorophenyl)acetate (CAS: 1443340-20-2) using a method similar to that for 3-(chloromethyl)-7-fluorobenzo[d]isoxazole (Example 164). 1 H NMR(400MHz,CDCl3)δ:7.57(ddd,1H),7.28-7.21(m,1H),4.89(s,2H).

[0292] 3-(Chloromethyl)-4,5,6,7-tetrahydrotriazolo[1,5-a]pyridine [ka] Step a. To a stirred solution of methyl 2-(pyridin-2-yl)acetate (5.0 g, 33.1 mmol, CAS: 1658-42-0) in MeCN (83 mL) was added 4-acetamidobenzenesulfonyl azide (7.95 g, 33.1 mmol, CAS: 2158-14-7) and the reaction mixture was cooled to 0 °C under argon. To this was added DBU (3.97 mL, 33.1 mmol) dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. To this was added saturated ammonium chloride solution and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on an Interchim 4125 (120 g silica column Puriflash HP, 0-15% EtOAc in DCM) gave methyl [1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (5.48 g, 89%). 1 H NMR(400MHz,CDCl3)δ 8.86-8.83(m,1H),8.31-8.28(m,1H),7.56(ddd,1H),7.19-7.15(m,1H),4.06(s,3H).

[0293] Step 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 backfilled with hydrogen (×3). The reaction mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 3 hours. The mixture was filtered through Celite® and concentrated in vacuo to give methyl 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (1.98 g, 99%). 1 H NMR(400MHz, CDCl3)δ:4.41(t,2H),3.94(s,3H),3.11(t,2H),2.13-2.06(m,2H),1.98-1.91(m,2H).

[0294] Step 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 minutes. The reaction was stirred under argon at room temperature for 20 hours. The reaction mixture was cooled to 0°C and diluted with 10% citric acid (33 mL), followed by extraction with DCM. The combined organics were washed with water and concentrated in vacuo. The crude product was purified by flash column chromatography on an Interchim Puriflash® 4100 (80 g silica column Puriflash HP, 0 to 30% EtOAc in DCM) to give (4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)methanol (620 mg, 35%). 1 H NMR(400MHz,CDCl3)δ 4.76(s,2H),4.38(t,2H),2.92-2.88(m,3H),2.17-2.10(m,2H),2.05-1.95(m,2H).

[0295] Step d. Thionyl chloride (0.59 mL, 8.1 mmol) was added to Int 170-C (620 mg, 4.1 mmol). Chloroform (6.5 mL) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene (×2), and concentrated in vacuo to give the title compound (702 mg, assumed quantitative), which was used without further purification. LCMS (Method 2): 0.90 min, 171.9 [M+H] + .

[0296] 5-(Bromomethyl)-4-(trifluoromethyl)pyrimidine [ka] Step 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) was added 4-methylmorpholine (1.65 mL, 15.0 mmol, CAS: 109-02-4) followed by isobutyl chloroformate (1.86 mL, 14.32 mmol, CAS: 543-27-1) dropwise under argon at −5° C. The reaction mixture was stirred at −5° C. for 1.5 hours, then at room temperature for 1.5 hours. The mixture was cooled to −5° C., and to it was added 4-methylmorpholine (0.43 mL, 3.90 mmol) and isobutyl chloroformate (0.42 mL, 3.25 mmol). The reaction mixture was stirred at −5° C. for 30 minutes, then at room temperature for 45 minutes, and then cooled to −5° C. again. To this was added a solution of sodium borohydride (738 mg, 19.5 mmol) in water (6 mL) 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 organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on an Interchim Puriflash® 4100 (120 g silica column HP, 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] + .

[0297] Step 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° C. under argon. To this was added a solution of carbon tetrabromide (622 mg, 1.88 mmol) in DCM (2 mL) 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 (40 g silica column Puriflash HP, 0 to 30% EtOAc in DCM) to give the title compound (273 mg, 60%). 1H NMR(400MHz,CDCl3)δ:9.29(1H,s),9.06(1H,s),4.60(2H,s).

[0298] 3-(Bromomethyl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine [ka] Step 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) was added lithium aluminum hydride (1 M in THF; 0.15 mL, 0.15 mmol) dropwise at 0° C. under argon, and the resulting mixture was stirred for 1 hour. The reaction mixture was treated dropwise with water (7 μL), 3 M NaOH (7 μL), and water (14 μL). The resulting mixture was stirred for 1 hour. The reaction mixture was diluted with THF and filtered through a pad of Celite®. The 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-3-yl)methanol (22 mg, 88%), which was used without further purification. LCMS (Method 2): 0.18 min, 156.0 [M+H] + .

[0299] Step b. To a solution of the above intermediate (120 mg, 0.73 mmol) in DCM (4.8 mL) under argon at 0° C. was added triphenylphosphine (206 mg, 0.79 mmol), followed by the dropwise addition of a solution of carbon tetrabromide (261 mg, 0.79 mmol) in DCM (3.2 mL). The reaction mixture was allowed to warm to room temperature over 1 h and then stirred at room temperature for 16 h. Additional triphenylphosphine (96 mg, 0.37 mmol) was added, followed by the dropwise addition of a solution of carbon tetrabromide (122 mg, 0.37 mmol) in DCM (3.2 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. Purification by flash column chromatography on an Interchim Puriflash® 4100 (40 g silica column InterChim HP, 0-30% EtOAc in DCM) afforded the title compound (89 mg, 55%). 1 H NMR(400MHz,CDCl3)δ 4.93(s,2H),4.55(s,2H),4.44(t,2H),4.11(t,2H).

[0300] Methanesulfonic acid (5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazol-4-yl)methyl ester [ka] Step 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) at 0 °C under argon, 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 h and then cooled to room temperature. The reaction mixture was poured into saturated aqueous NaHCO3, diluted with water, and extracted into DCM. The combined organics were washed with saturated aqueous NaHCO3, water, and the layers were separated using a phase separation cartridge. The combined organics 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] +

[0301] Step b. To a stirred solution of the above intermediate (2.0 g, 9.0 mmol) in MeCN (75 mL) was added DBU (3.38 mL, 22.6 mmol) at −20° C., followed by the 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 allowed to warm to room temperature and stirred for 72 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHSO4. The aqueous layer was extracted with EtOAc, and the combined organics were washed with saturated aqueous NaHSO4 (×2), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on Interchim® 4100 (80 g silica column Puriflash HC, 0 to 50% EtOAc in cyclohexane) gave ethyl 5-(difluoromethyl)-1-(oxetan-3-yl)-1H-1,2,3-triazole-4-carboxylate (1.52 g, 68%). LCMS (Method 17): 1.10 min, 248.1 [M+H] +

[0302] Step c. To a solution of the above intermediate (1.3 g, 5.3 mmol) in THF (18 mL) was added lithium aluminum hydride (2 M in THF; 2.6 mL, 5.3 mmol) dropwise at -5°C, and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted into DCM (2 x 100 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give the title compound (882 mg, 82%), which was used without further purification. LCMS (Method 16): 0.60 min, 206.1 [M+H] +

[0303] Step 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 was cooled to 0 °C and methanesulfonyl chloride (0.15 mL, 1.9 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was partitioned between distilled water (50 mL) and DCM (3 × 50 mL). The organic layer was separated, dried over NaSO, 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)-1H-1,2,3-triazole). 1 H NMR(400MHz,CDCl3)δ 6.89-7.15(t,1H),5.73-5.80(m,1H),5.28-5.31(m,2H),5.05-5.09(m,2H),4.77-4.78(m,2H),3.15(s,1.5H).

[0304] 4-(chloromethyl)-1,5-bis(difluoromethyl)-1H-1,2,3-triazole [ka] Step 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 h, followed by room temperature for 18 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (75 g silica, 30–40% EtOAc in heptane) to give ethyl 5-(difluoromethyl)-1-(2,2-dimethylpropanoyloxymethyl)triazole-4-carboxylate (1.15 g, 48%). 1 H NMR(300MHz,CDCl3)δ:7.53(t,1H),6.45(s,2H),4.49(q,2H),1.45(t,3H),1.20(s,9H).

[0305] Step 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 h. The reaction mixture was concentrated in vacuo and then azeotroped with toluene. It was partitioned between hydrochloric acid (2 M) and EtOAc. The combined organics were washed with water, dried (Na SO ), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g silica column, 60 to 100% EtOAc in heptane) to give methyl 5-(difluoromethyl)-1H-triazole-4-carboxylate (345 mg, 59%). The combined fractions were purified again by flash column chromatography (10 g silica column, 20 to 100% EtOAc in heptane) to give another batch (145 mg, 19%). LCMS (Method 10b): 0.48 min, 175.9[MH] - .

[0306] Step c. A mixture of methyl 5-(difluoromethyl)-1H-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 and then cooled to room temperature. The mixture was poured into water and extracted with ethyl acetate. The organics were washed with water, brine, dried (NaSO), filtered, and the filtrate was concentrated in vacuo to give methyl 1,5-bis(difluoromethyl)triazole-4-carboxylate (417 mg, quantitative) as a 7:3 mixture with ethyl 1,4-bis(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate. 1 H NMR(300MHz; CDCl3,298 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).

[0307] Step d. To a stirred solution of sodium borohydride (106 mg, 2.8 mmol) in EtOH (13 mL) under nitrogen, lithium chloride (0.5 M in THF; 4.59 mL, 2.3 mmol) and the above intermediate (417 mg, 1.84 mmol) were added. The reaction mixture was heated at 60 °C for 5 h, followed by stirring at room temperature for 18 h. The reaction mixture was diluted with water, and the crude product was extracted into IPA / chloroform (2:1). The combined organics were washed with brine, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g silica column, 40–60% EtOAc in heptane) to afford [2,5-bis(difluoromethyl)triazol-4-yl]methanol (158 mg, 42%) and the desired compound [1,5-bis(difluoromethyl)triazol-4-yl]methanol (47 mg, 11%). 1 H NMR(300MHz,CDCl3)δ:7.63(t,1H),7.19(t,1H),4.98(s,2H),1.96(br s,OH).

[0308] Step e. 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 room temperature for 21 hours. The reaction mixture was concentrated in vacuo to give the title compound (76 mg, 89%), which was used without further purification. 1 H NMR(300MHz, CDCl3)δ:7.64(t,1H),7.11(t,1H),4.81(s,2H).

[0309] 4-(chloromethyl)-1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazole [ka] Step 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 L-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) over 20 minutes, and the reaction mixture was vigorously stirred overnight at room temperature. 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 an Interchim® 4100 (80 g silica column InterChim HP, 0 to 50% EtOAc in isohexane) gave 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole (2.23 g, 95%). 1 H NMR(400MHz,CDCl3)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).

[0310] Step b. To a solution of the above intermediate (200 mg, 0.67 mmol) in THF (2.6 mL) was added n-butyllithium (2.5 M in hexanes; 0.32 mL, 0.8 mmol) dropwise at −78° C. under argon. The mixture was stirred at −78° C. for 1.25 h, then warmed to −60° C. and stirred for 15 min, then cooled back 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 h, then warmed to room temperature and stirred for an additional 1 h. The reaction mixture was cooled to 0° C. and quenched by the dropwise addition of saturated NH4Cl. The reaction mixture was diluted with EtOAc and extracted into EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on an Interchim Puriflash® 4100 (40 g silica column Puriflash InterChim HP, 0 to 50% EtOAc in cyclohexane) gave 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-5-yl)oxetan-3-ol (116 mg, 44%). 1 H NMR(400MHz,CDCl3)δ 5.06(d,2H),4.94(dd,2H),4.85(s,2H),4.41-4.39(m,1H),3.81(s,2H),0.89(s,9H),0.23(s,9H),0.11(s,6H).

[0311] Step c. To a solution of the above intermediate (94 mg, 0.250 mmol) in THF (3.8 mL) under argon was added sodium hydride (25 mg, 0.63 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, followed by the addition of carbon disulfide (0.13 mL, 0.63 mmol), and the reaction mixture was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for 1 hour. Saturated aqueous NH4Cl was added, the mixture was diluted with EtOAc, and the layers were separated. The organics were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on an Interchim Puriflash® 4100 (12 g silica column InterChim HP, 0 to 50% EtOAc in cyclohexane) gave O-(3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-5-yl)oxetan-3-yl)S-methyl carbonodithioate (92 mg, 89%). 1 H NMR(400MHz,CDCl3)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).

[0312] Step 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 to 120 °C in a sealed vial and stirred for 4 h. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography on an Interchim Puriflash® 4100 (25 g silica column Puriflash InterChim, 0 to 30% EtOAc in cyclohexane) gave 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(oxetan-3-yl)-1H-1,2,3-triazole (55 mg, 76%). LCMS (Method 15): 1.51 min, 284.2 [M+H] + .

[0313] Step e. To a solution of the above intermediate (50 mg, 0.18 mmol) in THF (2 mL) under argon, triethylamine trihydrofluoride (0.14 mL, 0.88 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with EtOAc and water, and the crude product w...

Claims

1. The following formula 【Chemical 1】 (In the formula, R is hydrogen or —C(O)OtBu(Boc); R １ is C １～４ Alkylene-R １１ , heterocyclyl, and 8- to 10-membered bicyclic heteroaryl, wherein said heterocyclyl is selected from C １～４ Alkyl, —C(O)—R １２ , S.O. ２ -R １３ , C １～３ Alkylene-OR １４ , and C １～４ Alkyl, C ３～７ Cycloalkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and heteroaryl optionally substituted with one or more substituents independently selected from cyano; and said 8- to 10-membered bicyclic heteroaryl is １～４ Alkyl, C ３～７ Cycloalkyl, halo, OH, and C １～３ optionally substituted with one or more substituents independently selected from alkoxy; R ２ is hydrogen, fluoro, chloro, and C １～３ alkyl; R ３ is hydrogen, fluoro, chloro, bromo, C １～３ Alkoxy, C １～３ Alkyl, C １～３ haloalkyl, and cyano; R ４ and R ５ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring; The 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 ３～７ optionally spiro-bonded to the cycloalkyl group; and The heteroaryl and heterocyclyl rings are １～４ Alkyl, halo, OH, C １～３ Alkoxy, C １～３ Haloalkyl, cyano, NR １６ R １７ , C(O)R １８ , S(O)R １９ , and SO ２ R ２０ optionally substituted with one or more substituents independently selected from R １１ is -NR ２６ C(O)-R ２７ , heterocyclyl, and heteroaryl, wherein the heteroaryl group is selected from C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; and said heterocyclyl group is １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, oxo, and cyano; R １２ is C １～４ Alkyl, C ３～７ Cycloalkyl, OR ３１ , N.R. ３２ R ３３ , aryl, and heteroaryl, wherein the aryl and heteroaryl are selected from C １～４ Alkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; R １３ is C １～４ Alkyl, C ３～７ Cycloalkyl, heteroaryl, heterocyclyl, and NR ３４ R ３５ wherein said heteroaryl and heterocyclyl are selected from C １～４ Alkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; R １７ is hydrogen, C １～４ Alkyl, C(O)C １～３ Alkyl, and C(O)NR ３６ R ３７ Selected from: R １８ , R １９ , and R ２０ is C １～４ Alkyl, OH, C １～３ Alkoxy and NR ３８ R ３９ are independently selected from R ２７ is heteroaryl optionally substituted with C 1-4 alkyl; R ３０ is hydroxy, C １～３ Alkoxy, C ３～７ Cycloalkyl, cyano, and NR ４７ R ４８ is selected from: R １４ , R １６ , R ２６ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ３９ , R ４７ , and R ４８ is hydrogen, C １～４ Alkyl, and C ３～７ cycloalkyl) or a salt thereof.

2. R １ But C １～４ Alkylene-R １１ and optionally R １ But CH ２ -R １１ 2. The compound according to claim 1, or a salt thereof,

3. R １１ but, (A) C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ heteroaryl optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; (B) Methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, chloro, fluoro, cyclopropyl, methoxy, cyano, oxetanyl, CH ２ -R ３０ , and C ２ H ４ -R ３０ or heteroaryl optionally substituted with one or more substituents independently selected from: (C) Each is C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, benzotriazolyl, benzisoxazolyl, isoxazolopyridinyl, imidazopyridinyl, or triazolopyridinyl optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; or (D) 【Chemistry 2】 is a heteroaryl selected from Each heteroaryl is C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; The compound or salt thereof according to claim 1 or 2.

4. R １ but, (A)-C(O)-R １２ , S.O. ２ -R １３ , heteroaryl, and C １～３ Alkylene-OR １４ and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C １～４ Alkyl, C ３～７ Cycloalkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; (B) each is —C(O)—R １２ , S.O. ２ -R １３ , heteroaryl, and C １～３ Alkylene-OR １４ and wherein the heteroaryl is piperidinyl or pyrrolidinyl optionally substituted with one or more substituents independently selected from １～４ Alkyl, C ３～７ Cycloalkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; (C)-C(O)-R １２ , S.O. ２ -R １３ , heteroaryl, and C １～３ Alkylene-OR １４ and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from １～４ Alkyl or C ３～７ optionally substituted with cycloalkyl; or (D) the following group: 【Chemistry 3】 (In the formula, 【Chemistry 4】 represents the point of attachment of the group to the remaining oxygen atoms of the compound, and each group is —C(O)—R １２ , S.O. ２ -R １３ , heteroaryl, and C １～３ Alkylene-OR １４ and wherein said heteroaryl is optionally substituted with one or more substituents independently selected from C １～４ Alkyl or C ３～７ optionally substituted with cycloalkyl; The compound or salt thereof according to claim 1.

5. R ２ The compound or salt thereof according to any one of claims 1 to 4, wherein is hydrogen or fluoro.

6. R ３ The compound or salt thereof according to any one of claims 1 to 5, wherein is hydrogen or chloro.

7. R ４ and R ５ However, together with the nitrogen atoms to which they are bonded, (A) forming a 5-membered heteroaryl or heterocyclyl ring, said heterocyclyl containing a —C(O)— moiety bonded to a nitrogen atom and optionally fused to an aryl or heteroaryl ring, or ３～７ and wherein said heteroaryl and heterocyclyl are optionally spiro-bonded to a cycloalkyl group, and １～４ Alkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; (B) C １～４ forming a 5-membered heteroaryl ring optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; (C)C １～４ forming a pyrazolyl ring optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; (D) forming a 5- or 6-membered heterocyclyl ring, said heterocyclyl containing a —C(O)— moiety bonded to a nitrogen atom and optionally fused to an aryl ring, or ３～７ optionally spiro-bonded to a cycloalkyl group; and said heterocyclyl is １～４ optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; or (E) Below: 【Chemistry 5】 wherein the saturated ring of the heterocyclic moiety is C ３～７ Optionally spiro-bonded to a cycloalkyl group, and said heterocyclic moiety is C １～４ optionally substituted with one or more substituents independently selected from alkyl, halo, and OH; The compound or salt thereof according to any one of claims 1 to 6. 【Request 8】 【Chemical 6】 2. The compound according to claim 1, or a salt thereof,

9. 【Chemical 7】 2. The compound of claim 1, wherein:

10. 【Chemical 8】 2. The compound according to claim 1, or a salt thereof,

11. 【Chemical 9】 2. The compound of claim 1, wherein:

12. [Catalog 10] 2. The compound according to claim 1, or a salt thereof,

13. 【Catalog 11】 2. The compound of claim 1, wherein:

14. The compound of formula IA is prepared by using the compound of claim 1 or a salt thereof. 【Chemistry 12】 (IA) (In the formula, R １ is C １～４ Alkylene-R １１ , heterocyclyl, and 8- to 10-membered bicyclic heteroaryl, wherein said heterocyclyl is selected from C １～４ Alkyl, —C(O)—R １２ , S.O. ２ -R １３ , C １～３ Alkylene-OR １４ , and C １～４ Alkyl, C ３～７ Cycloalkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and heteroaryl optionally substituted with one or more substituents independently selected from cyano; and said 8- to 10-membered bicyclic heteroaryl is １～４ Alkyl, C ３～７ Cycloalkyl, halo, OH, and C １～３ optionally substituted with one or more substituents independently selected from alkoxy; R ２ is hydrogen, fluoro, chloro, and C １～３ alkyl; R ３ is hydrogen, fluoro, chloro, bromo, C １～３ Alkoxy, C １～３ Alkyl, C １～３ haloalkyl, and cyano; R ４ and R ５ together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heteroaryl or heterocyclyl ring; The 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 ３～７ optionally spiro-bonded to the cycloalkyl group; and The heteroaryl and heterocyclyl rings are １～４ Alkyl, halo, OH, C １～３ Alkoxy, C １～３ Haloalkyl, cyano, NR １６ R １７ , C(O)R １８ , S(O)R １９ , and SO ２ R ２０ optionally substituted with one or more substituents independently selected from L １ and L ２ is a bond and -CR ２１ R ２２ - independently selected from; R ６ and R ７ is hydrogen, C １～４ Alkyl, and C ３～７ independently selected from cycloalkyl; or R ６ and R ７ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; R ８ is CO ２ R ２３ and tetrazolyl; R ９ is hydrogen, C １～４ Alkyl, hydroxy, C １～３ alkoxy, and halo; R １０ is hydrogen and C １～４ alkyl; or R ９ and R １０ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; or L ２ is a bond, and R ７ and R １０ together with the atoms to which they are attached form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocyclyl ring; the heterocyclyl ring contains 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The cycloalkyl ring optionally contains one or two carbon-carbon double bonds, and optionally a C １～３ bridged by alkylene groups or R ９ optionally a C linking C* to a ring carbon atom １～３ an alkylene group; and The cycloalkyl and heterocyclyl rings are １～４ Alkyl, halo, OH, C １～３ Alkoxy, C １～３ optionally substituted with one or more substituents independently selected from haloalkyl, and deuterium; R １１ is -NR ２６ C(O)-R ２７ , heterocyclyl, and heteroaryl, wherein the heteroaryl group is selected from C １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, heterocyclyl, and cyano; and said heterocyclyl group is １～４ Alkyl, C １～３ Haloalkyl, C ３～７ Cycloalkyl, C １～４ Alkylene-R ３０ , Halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, oxo, and cyano; R １２ is C １～４ Alkyl, C ３～７ Cycloalkyl, OR ３１ , N.R. ３２ R ３３ , aryl, and heteroaryl, wherein the aryl and heteroaryl are selected from C １～４ Alkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; R １３ is C １～４ Alkyl, C ３～７ Cycloalkyl, heteroaryl, heterocyclyl, and NR ３４ R ３５ wherein said heteroaryl and heterocyclyl are selected from C １～４ Alkyl, halo, OH, C １～３ optionally substituted with one or more substituents independently selected from alkoxy, and cyano; R １７ is hydrogen, C １～４ Alkyl, C(O)C １～３ Alkyl, and C(O)NR ３６ R ３７ Selected from: R １８ , R １９ , and R ２０ is C １～４ Alkyl, OH, C １～３ Alkoxy and NR ３８ R ３９ are independently selected from R ２７ is heteroaryl optionally substituted with C 1-4 alkyl; R ３０ is hydroxy, C １～３ Alkoxy, C ３～７ Cycloalkyl, cyano, and NR ４７ R ４８ is selected from: R １４ , R １６ , R ２１ , R ２２ , R ２３ , R ２６ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ３９ , R ４７ , and R ４８ is hydrogen, C １～４ Alkyl, and C ３～７ cycloalkyl) or a pharmaceutically acceptable salt thereof.

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