Cannabinoid receptor 1 antagonists / inverse agonists and uses thereof

Abstract

Disclosed herein are compounds suitable for use in treating disorders such as diabetic disease, dyslipidemia, cardiovascular disease, inflammatory disease, liver disorder, cancer, or obesity or its comorbidities.Also disclosed are compositions containing one or more of the compounds of the present invention and the use of the compounds of the present invention in treating disorders in subjects.

Description

[Background technology]

[0001] Obesity is associated with an increase in the overall mass of adipose tissue (i.e., body fat), particularly concentrated in the abdominal region. Obesity is an epidemic in the United States. The prevalence of obesity has been gradually increasing over the years among all racial and ethnic groups. Recent data from the Centers for Disease Control and Prevention and the National Center for Health Statistics report that 66% of the adult population is overweight (BMI: 25.0-29.9), 31% is obese (BMI: 30-39.9), and 5% is extremely obese (BMI: >40.0). Among children aged 6-19, 32% are overweight and 17% are obese. This translates to 124 million Americans being medically overweight, and 44 million of these are considered obese. Obesity accounts for more than 300,000 deaths each year and will soon surpass tobacco use as the leading cause of preventable death in the United States. Obesity is a chronic disease that directly contributes to numerous dangerous comorbidities, including type 2 diabetes, cardiometabolic disease, liver damage, cardiovascular disease, inflammatory disease, premature aging, and some types of cancer. Type 2 diabetes, a serious and life-threatening disorder with increasing prevalence in both adult and pediatric populations, is currently the seventh leading cause of death in the United States. Obesity is the greatest risk factor for developing type 2 diabetes, as more than 80% of patients with type 2 diabetes are overweight. Growing clinical evidence indicates that the best way to manage type 2 diabetes is to lose weight. Therefore, there is a continuing need to develop improved drugs to treat or prevent obesity.

[0002] The cannabinoid system, consisting of cannabinoid receptors (CB1 and CB2) and their endogenous ligands (e.g., anandamide, 2-AG), plays an important role in the regulation of food intake and energy metabolism. CB1 receptors are widely expressed in the brain, including the cortex, hippocampus, amygdala, pituitary gland, and hypothalamus. CB1 receptors have also been identified in numerous peripheral organs and tissues, including the thyroid gland, adrenal glands, reproductive organs, adipose tissue, liver, muscle, pancreas, kidney, and gastrointestinal tract. CB2 receptors are located almost exclusively in immune and blood cells (Endocrine Reviews 2006, 27, 73).

[0003] Δ, a plant-derived cannabinoid agonist 9 -Tetrahydrocannabinol (Δ 9 -THC) is the main psychoactive component of marijuana and binds to both CB1 and CB2 receptors. 9 -THC has been widely reported to increase appetite and food intake in humans and animals (hyperphagia). This hyperphagia effect is largely blocked by pre-administration of a selective CB1 receptor blocker (i.e., a CB1 blocker) (e.g., rimonabant (SR141716A, Acomplia®)), indicating that CB1 receptor activation increases Δ 9 -Strongly supports the idea that it mediates the hyperphagic effects of THC (Endocrine Reviews 2006,27,73).

[0004] CB1 receptors are one of the most abundant and widely distributed G protein-coupled receptors in the mammalian brain. It is now known that the appetite suppressant effects of CB1 antagonists can be mediated either by direct action on CB1 receptors in brain regions associated with hunger and satiety (e.g., the hypothalamus, the mesolimbic region) or by direct action on CB1 receptors in peripheral tissues (e.g., adipose tissue, the kidney) [J. Clin Invest 2010, 120:2953; Obesity 2011, 19:1325]. However, CB1 receptors are much more widely distributed in the brain (e.g., the neocortex, hippocampus, thalamus, cerebellum, and pituitary gland), and CB1 antagonists interact with targeted CB1 receptors in the hypothalamus and mesolimbic region to suppress appetite, while also reaching untargeted CB1 receptors that play a small, if any, role in appetite control. Binding to non-targeted receptors can often result in unwanted side effects of CNS drugs (Endocrine Reviews 2006, 27:73). For example, the CB1 blockers rimonabant and taranabant cause psychiatric and neurological side effects, including depressed mood, anxiety, irritability, insomnia, dizziness, headache, seizures, and suicidality.

[0005] These side effects appear to be dose-dependent, with the weight-reducing effects of rimonabant and taranabant being most pronounced at the highest doses (JAMA 2006, 311, 323; Cell Metabolism 2008, 7, 68). The occurrence of therapeutic effects (appetite suppression) and side effects over the same dose range strongly suggests that, because brain-penetrant CB1 blockers do not selectively target CB1 receptors in the brain, both effects are mediated by concurrent antagonism of CB1 receptors in both "targeted" and "non-targeted" brain regions.

[0006] The beneficial effects of the CB1 antagonist rimonabant on body weight, adiposity, and diabetes and cardiometabolic risk factors, such as hypertension, insulin resistance, and blood lipids, cannot be explained solely by weight loss resulting from CNS-mediated appetite suppression (JAMA 2006, 311, 323). Approximately 50% of this benefit likely derives from its interaction with CB1 receptors in peripheral tissues known to play an active role in metabolism, including adipose tissue, liver, muscle, pancreas, kidney, and gastrointestinal tract.

[0007] Studies have identified two splice variants of human CB1R mRNA: hCB1A (Rinaldi-Carmona et al., 1996; Shire et al., 1995) and hCB1B (Ryberg et al., 2005; Xiao et al., 2008). Notably, hCB1B has an internal deletion of 33 amino acids between Leu-21 and Gly-55 at its N-terminus (Gonzalez-Mariscal, Krzysik-Walker, Doyle, et al., 2016). Further studies have demonstrated significant differences in the distribution of these splice variants (hCB1 and hCB1b) in human tissues (Gonzalez-Mariscal, Krzysik-Walker, Doyle, et al., 2016). First, the hCB1B isoform was found to be highly expressed in human liver (where it is the dominant isoform) and pancreatic beta cells, but not in the brain. Second, expression in liver and beta cells was significantly increased in obese individuals (BMI ≥ 30.0) compared with non-obese individuals (BMI ≤ 30.0). Because rimonabant binds to the two receptors (hCB1 and hCB1b) with similar affinity (Gonzalez-Mariscal, Krzysik-Walker, Doyle, et al., 2016), the ability to more selectively target hCB1b may offer an additional advantage over compounds such as rimonabant.

[0008] Thus, there is a continuing need to discover effective and highly selective CB1 receptor blockers that exhibit reduced or no adverse CNS side effects, including mood disorders. In particular, it would be desirable to discover compounds that preferentially target CB1b receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, pancreas, and gastrointestinal tract) while sparing CB1 receptors in the brain. Summary of the Invention

[0009] The present disclosure provides novel pyrazoline compounds and pharmaceutically acceptable salts thereof that are cannabinoid 1 (CB1) receptor antagonists / inverse agonists, pharmaceutical compositions of such compounds, and uses of such compounds for the treatment of disorders mediated by the CB1 receptor.

[0010] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, and OCH; R 2 is C1-C6 alkyl or phenyl optionally substituted with F or CN, and R 3 is phenyl substituted with one or two substituents selected from F, Cl, CF3, CN, OCH3, C2-C6 alkynyl, and C(O)NH2, or a 5- or 6-membered heteroaryl containing one to three nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl; R 4 , R 4 ', R 5 , and R 5 ' are independently H or C1-C6 alkyl, and R 6 and R 7are independently H, OH, or C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1-2 nitrogen atoms and optionally substituted with C1-C6 alkyl; R 8 is H or CH3, provided that: (i) R 1 is not 4-chlorophenyl or 4-methoxyphenyl; (ii) R 2 is phenyl substituted with C1-C6 alkyl or CN; (iii) R 3 is not 4-chlorophenyl, 3-cyanophenyl, or 3-methoxyphenyl; (iv) R 4 and R 5 one of R is C1-C6 alkyl; 6 and R 7 is not H; and (vi) R 8 is CH3; or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound has formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN, or OCH3, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound has formula (IIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN, or OCH3, and R 2a is H or CN, or a pharmaceutically acceptable salt thereof. 2a is H. In other embodiments, R 2a is CN.

[0013] In some embodiments, the compound has formula (IIIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN, or OCH3, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound has formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN, or OCH3, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound has formula (IIB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN, or OCH3, and R 2a is H or CN, or a pharmaceutically acceptable salt thereof. 2a is H. In other embodiments, R 2a is CN.

[0016] In some embodiments, the compound has formula (IIIB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN, or OCH3, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments of any of the aspects described herein (e.g., Formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 1a is F. In some embodiments of any of the aspects described herein (e.g., Formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 1a is Cl. In some embodiments of any of the aspects described herein (e.g., Formulas (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 1a is OCH3.

[0018] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 3 is phenyl substituted with one or two groups selected from F, Cl, CF, CN, OCH, C-C alkynyl, or C(O)NH. For example, R 3 teeth, [ka] is.

[0019] In some embodiments, R 3 teeth, [ka] is.

[0020] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 3 is a 5- or 6-membered heteroaryl containing 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl. For example, R 3 teeth, [ka] is.

[0021] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 4 is H.

[0022] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 4 is C1-C6 alkyl, for example, methyl or isopropyl.

[0023] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 5 is H.

[0024] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 5 is C1-C6 alkyl, for example, methyl or isopropyl.

[0025] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 is H.

[0026] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 is C1-C6 alkyl, for example, R 6 is methyl, ethyl, or isopropyl.

[0027] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 is OH.

[0028] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 7 is H.

[0029] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 7 is C1-C6 alkyl, for example, methyl, ethyl, or isopropyl.

[0030] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 7 is OH.

[0031] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 and R 7 together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocycloalkyl containing 1 to 2 nitrogen atoms and optionally substituted with C1-C6 alkyl, such as [ka] is formed.

[0032] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 8 is H.

[0033] In some embodiments of any of the aspects described herein (e.g., Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 8 is CH3.

[0034] In some embodiments, the compound is selected from any of compounds 1-86, 103-110, 155-172, 175-182 in Table 1, or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents selected from halogen, C1-C6 alkoxy, and CN; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted with halogen or CN; R 3 is phenyl substituted with one or more substituents selected from halogen, C1-C6 alkoxy, CF3, CN, C2-C6 alkynyl, and C(O)NH2, or a 5- or 6-membered heteroaryl containing 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl; R 6 and R 7 are independently H, OH, or C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1-2 nitrogen atoms and optionally substituted with C1-C6 alkyl, and L is [ka] and R 8 is H or C1-C6 alkyl, and R 4 , R 4 ', R 5 , and R 5' is independently H or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, and X is O or NR 9 and R 9 is H or C1-C6 alkyl, and y and z are independently 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the compound has formula (IVA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN, or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the compound has the formula (VA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN, or C1-C6 alkoxy, and R 2a is H, halogen, C1-C6 alkoxy, or CN, or a pharmaceutically acceptable salt thereof. 2a is H. In other embodiments, R 2a is CN.

[0038] In some embodiments, the compound has formula (VIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN, or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the compound has formula (IVB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN, or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the compound has formula (VB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN, or C1-C6 alkoxy, and R 2a is H, halogen, C1-C6 alkoxy, or CN, or a pharmaceutically acceptable salt thereof. 2a is H. In other embodiments, R 2a is CN.

[0041] In some embodiments, the compound has formula (VIB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN, or C1-C6 alkoxy, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments of any of the aspects described herein (e.g., Formulas (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 1a is F.

[0043] In some embodiments of any of the aspects described herein (e.g., Formulas (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R1a is Cl.

[0044] In some embodiments of any of the aspects described herein (e.g., Formulas (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 1a is OCH3.

[0045] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 3 is phenyl substituted with one or two groups selected from halogen, CF, CN, C-C alkoxy, C-C alkynyl, or C(O)NH. For example, R 3 teeth, [ka] is.

[0046] In some embodiments, R 3 teeth, [ka] is.

[0047] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 3 is a 5- or 6-membered heteroaryl containing 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl. For example, R 3 teeth, [ka] is.

[0048] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 4 is H.

[0049] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 4 is C1-C6 alkyl, for example, methyl or isopropyl.

[0050] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 5 is H.

[0051] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 5 is C1-C6 alkyl, for example, methyl or isopropyl.

[0052] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 is H.

[0053] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 is C1-C6 alkyl, for example, R 6 is methyl, ethyl, or isopropyl.

[0054] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R6 is OH.

[0055] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 7 is H.

[0056] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 7 is C1-C6 alkyl, for example, methyl, ethyl, or isopropyl.

[0057] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R7 is OH.

[0058] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 and R 7 together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocycloalkyl containing 1 to 2 nitrogen atoms and optionally substituted with C1-C6 alkyl, such as [ka] is formed.

[0059] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 8 is H.

[0060] In some embodiments of any of the aspects described herein (e.g., Formulas (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 8 is CH3.

[0061] In some embodiments, the compound is selected from compounds 99-102, 111-154, 173-174, 183-250 in Table 1, or any of their pharmaceutically acceptable salts.

[0062] In another aspect, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, and OCH; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted with F or CN, and R 3 is phenyl substituted with one or more substituents selected from F, Cl, CF3, CN, OCH3, C2-C6 alkynyl, and C(O)NH2, or a 5- or 6-membered heteroaryl containing 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl; R 4 , R 4 ', R 5 , and R 5 ' are independently H or C1-C6 alkyl, and R 6 and R 7 are independently H, OH, or C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1-2 nitrogen atoms and optionally substituted with C1-C6 alkyl; R 8 is H or C1-C6 alkyl, and n is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound is selected from any of compounds 87-98 in Table 1, or a pharmaceutically acceptable salt thereof.

[0064] In another aspect, the disclosure provides a pharmaceutical composition comprising any of the compounds described herein (e.g., any of the compounds of Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0065] In another aspect, the disclosure provides a method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described herein (e.g., any of the compounds of Formulae (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1), or a pharmaceutically acceptable salt thereof, wherein the disease is a diabetic disease, a dyslipidemia disease, a cardiovascular disease, an inflammatory disease, a liver disorder, or cancer.

[0066] In some embodiments, the disease is a diabetic disease, eg, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, or insulin resistance.

[0067] In some embodiments, the disorder is a dyslipidemia disorder, for example, undesirable blood lipid levels, low levels of high density lipoprotein, high levels of low density lipoprotein, high levels of triglycerides, or a combination thereof.

[0068] In some embodiments, the disease is a cardiovascular disease, such as atherosclerosis, high blood pressure, stroke, or heart attack.

[0069] In some embodiments, the disease is an inflammatory disease, such as osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, or obesity-related inflammation.

[0070] In some embodiments, the disease is a liver disorder, for example, liver inflammation, liver fibrosis, nonalcoholic steatohepatitis, fatty liver, hepatomegaly, alcoholic liver disease, jaundice, cirrhosis, or hepatitis.

[0071] In some embodiments, the disease is cancer, for example, colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, or hepatocellular carcinoma.

[0072] In another aspect, the disclosure provides a method of treating obesity or a comorbidity of obesity, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described herein (e.g., any of the compounds of Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1), or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the comorbidity of obesity is diabetes, dyslipidemia, metabolic syndrome, dementia, cardiovascular disease, or liver disease.

[0074] In some embodiments, the comorbidities of obesity are hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; osteoarthritis; venous stasis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; atherosclerotic disease; pseudotumor cerebri; accidental death; increased risks associated with surgery; osteoarthritis; high cholesterol; or increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies.

[0075] In another aspect, the disclosure provides a method of regressing adipose tissue deposits in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds described herein (e.g., any of the compounds of Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1), or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments of any of the methods described herein, the method further comprises administering to a patient a second therapeutic agent, such as a PPAR-γ agonist, a biguanide, insulin or an insulin mimetic, a sulfonylurea, an α-glucosidase inhibitor, an HMG-CoA reductase inhibitor, a sequestrant, nicotinyl alcohol, nicotinic acid or a salt thereof, a PPAR-α agonist, a cholesterol absorption inhibitor, an acyl-CoA:cholesterol acyltransferase inhibitor, probucol, a PPAR-α / γ agonist, an ileal bile acid transporter inhibitor, an insulin receptor activator, a dipeptide Tidyl peptidase IV inhibitors, exenatide, pramlintide, FBPase inhibitors, glucagon receptor antagonists, glucagon-like peptide 1, glucagon-like peptide 1 receptor agonists, growth hormone secretagogues, growth hormone secretagogue receptor agonists, growth hormone secretagogue receptor antagonists, melanocortin agonists, melanocortin 4 receptor agonists, beta-3 agonists, serotonin 2C receptor agonists, orexin antagonists, melanin-concentrating hormone 1 antagonists, melanin-concentrating hormone 2 agonists, melanin-concentrating hormone 2 receptor antagonists, melanin-concentrating hormone 1 antagonists, melanin-concentrating hormone 2 receptor antagonists, melanin-concentrating hormone 2 receptor antagonists, melanin-concentrating hormone 1 ... Nin-concentrating hormone 2 antagonists, galanin antagonists, CCK agonists, CCK-A agonists, corticotropin-releasing hormone agonists, NPY5 antagonists, NPY1 antagonists, histamine receptor-3 modulators, histamine receptor-3 blockers, beta-hydroxysteroid dehydrogenase-1 inhibitors, phosphodiesterase inhibitors, phosphodiesterase-3B inhibitors, norepinephrine transport inhibitors, non-selective serotonin / norepinephrine transport inhibitors, ghrelin antagonists, leptin derivatives, bombesin receptor Subtype 3 agonists, ciliary neurotrophic factor or its derivatives, monoamine reuptake inhibitors, uncoupling protein-1 activators, uncoupling protein-2 activators, uncoupling protein-3 activators, thyroid hormone beta agonists, fatty acid synthase inhibitors, diacylglycerol acetyltransferase 2 inhibitors, acetyl-CoA carboxylase-2 inhibitors, glucocorticoid antagonists, acyl-estrogens, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylic acid transporter inhibitors, glucose transporter inhibitors, sodium-glucose cotransporters,The method further comprises administering to the subject a phosphate transporter inhibitor, a serotonin reuptake inhibitor, a thiazolidinedione, metformin, topiramate, an opiate antagonist, a nonselective transport inhibitor, or an MAO inhibitor. In some embodiments, the second therapeutic agent is a glucagon-like peptide 1 receptor agonist (e.g., liraglutide, semaglutide, exenatide, lixisenatide, dulaglutide, or tirzepatide).

[0077] In some embodiments of any of the methods described herein, the subject is a human.

[0078] In another aspect, the disclosure discloses the use of any of the compounds described herein (e.g., any of the compounds of Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in any of the methods disclosed herein.

[0079] In another aspect, the disclosure provides compounds (e.g., any of the compounds of formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1) for use in any of the methods disclosed herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

[0080] [Figure 1] 1 shows a graph showing the weight change in C57BL / 6J mice fed a high-fat diet and administered Compound 9, semaglutide, tirzepatide, a combination of Compound 9 and semaglutide, and a combination of Compound 9 and tirzepatide. [Figure 2] FIG. 1 shows a graph depicting the brain / plasma ratio of orally administered Compound 9 (10 mg / kg) compared to orally administered rimonabant (10 mg / kg) in C57BL / 6J mice as measured by area under the curve from 0 to 24 hours post-dose (AUC0-24) and maximum concentration (Cmax). DETAILED DESCRIPTION OF THE INVENTION

[0081] definition To facilitate understanding of the present invention, a number of terms are defined below. Terms defined herein have meanings commonly understood by one of ordinary skill in the art relevant to the present invention. Terms such as "a," "an," and "the" are not intended to refer solely to a singular entity, but rather encompass the general type for which a specific example may be used for illustration. While terms herein are used to describe particular embodiments of the present invention, their use does not limit the invention except as defined in the claims.

[0082] As used herein, any value stated in a range of values ​​includes both the upper and lower limits, and any value subsumed within the upper and lower limits.

[0083] As used herein, "compounds of the disclosure" and similar terms refer to CB1 antagonists or inverse agonists described herein, including compounds of Formula I and subformulas thereof, and compounds in Table 1, and salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof, whether or not explicitly noted.

[0084] Those of ordinary skill in the art will understand that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., isotopic forms in which one or more atoms are replaced by atoms of a different isotopic type, e.g., hydrogen is replaced by deuterium). Unless otherwise stated, or otherwise clear from context, the depicted structures can be understood to represent any such isomeric or isotopic forms individually or in combination.

[0085] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, e.g., enantiomers and diastereomers, are intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, for example, by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as isomeric mixtures or separated isomeric forms.

[0086] In some embodiments, one or more compounds described herein may exist in different tautomeric forms. Unless explicitly excluded, as is clear from the context, reference to such a compound encompasses all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the accompanying migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and total charge as the referenced form. Examples of moieties having prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms may be in equilibrium or may be sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric forms arise from acetal interconversion.

[0087] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound described herein that is suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts, including inorganic or organic acids. Salts may be prepared in situ during the final isolation and purification of the compounds described herein, or separately, by reacting the free base group with a suitable acid.

[0088] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve a beneficial or desired result, e.g., a clinical result; thus, "therapeutically effective amount" will depend on the context in which it is applied.

[0089] As used herein, and as is well understood in the art, "treating" a condition or "treatment" of various diseases or disorders is an effort to achieve a beneficial or desired result, e.g., a clinical outcome. Beneficial or desired results may include, but are not limited to, alleviation of one or more symptoms or conditions; a reduction in the severity of the disease, disorder, or condition; a stable (i.e., not worsening) state of the disease, disorder, or condition; a delay or slowing of the progression of the disease, disorder, or condition; an improvement or alleviation of the disease, disorder, or condition; and a remission that may be detectable or undetectable (either partial or complete). "Alleviation" of a disease, disorder, or condition means that the severity and / or undesirable clinical symptoms of the disease, disorder, or condition are reduced and / or the time course of progression is delayed or prolonged compared to the severity or time course in the absence of treatment.

[0090] As used herein, the term "subject" may be a human, a non-human primate, or other mammal, such as, but not limited to, a dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In a preferred embodiment, the subject is a human.

[0091] As used herein, the term "pharmaceutical composition" refers to an active compound formulated with one or more pharmaceutically acceptable excipients. In some embodiments, the compounds of the present invention are present in a unit dose suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to an appropriate population. In certain embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those suitable for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, or capsules; and parenteral administration, such as parenteral administration by subcutaneous, intramuscular, or intravenous injection.

[0092] As used herein, the term "pharmaceutically acceptable excipient" refers to any inert ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is biocompatible and suitable for administration to a subject. Exemplary excipients include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes, humectants, emulsifiers, diluents, film-forming or coating agents, flavors, fragrances, glidants, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with the variety of agents and substances useful as excipients.

[0093] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic radical that, when unsubstituted, contains only C and H. A monovalent alkyl group does not include any substituents on the alkyl group. For example, when an alkyl group is attached to a compound, the monovalent alkyl means that it is attached to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, an alkyl group can contain, for example, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C8, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-methylpropyl, and 2,2-dimethylpropyl.

[0094] As used herein, the term "alkynyl" refers to a branched or straight-chain monovalent saturated aliphatic radical containing at least one carbon-carbon triple bond and, when unsubstituted, containing only C and H. A monovalent alkynyl group does not include any substituents on the alkynyl group. For example, when an alkynyl group is attached to a compound, the monovalent alkynyl means that it is attached to the compound and does not include any additional substituents that may be present on the alkynyl group. In some embodiments, an alkynyl group can contain, for example, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C2-C8, C2-C6, C2-C4, or C2-C3). Examples include, but are not limited to, ethynyl and propynyl.

[0095] As used herein, the term "alkylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. A divalent alkylene group does not contain any substituents on the alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene.

[0096] As used herein, the term "heterocycloalkyl" refers to a saturated, non-aromatic, monocyclic ring system having at least one heteroatom (e.g., N, O, or S) as a ring atom, and all other ring atoms are carbon atoms. A heterocyclyl ring can have 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are heteroatoms independently selected from the group consisting of N, O, and S. For example, a heterocycloalkyl group can be a five-membered ring (i.e., a five-membered heterocycle) containing one or more (e.g., 1, 2, 3, or 4) ring atoms that are heteroatoms independently selected from the group consisting of N, O, and S. As another example, a heterocycloalkyl group can be a six-membered ring (i.e., a six-membered heterocycle) containing one or more (e.g., 1, 2, 3, or 4) ring atoms that are heteroatoms independently selected from the group consisting of N, O, and S. Examples of heterocyclic groups include, but are not limited to, pyrrolidine, thiolane, tetrahydrofuran, morpholine, piperidine, and piperazine, 2H-pyran, 4H-pyran, and tetrahydropyran.

[0097] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or fused bicyclic or polycyclic ring system having at least one heteroatom as a ring atom. For example, a heterocyclyl ring can have 5 to 10 ring atoms (e.g., 5, 6, 7, 8, 9, or 10; i.e., a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl), where one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyrrole, pyrazole, isoxazole, imidazole, thiazole, thiophene, furan, diazole, triazole, tetrazole, oxazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3,4-oxatriazole, 1,2,3,4-thiatriazole, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.

[0098] As used herein, the phrase "optionally substituted X" is intended to be equivalent to "X, optionally substituted, said X" (e.g., "alkyl, optionally substituted, said alkyl)." This is not intended to imply that the feature "X" (e.g., alkyl) is itself optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that do not substantially change when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0099] The term "combination therapy" refers to a method of treatment that includes administering at least two therapeutic agents, optionally in one or more pharmaceutical compositions, to a subject as part of a therapeutic regimen. For example, combination therapy can include administration of a single pharmaceutical composition containing at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy can include administration of two or more pharmaceutical compositions, each composition containing one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. The two or more agents can optionally be administered simultaneously (as a single or separate composition) or sequentially (as separate compositions). Therapeutic agents can be administered in effective amounts. Therapeutic agents can be administered in therapeutically effective amounts. In some embodiments, the effective amount of one or more therapeutic agents when used in combination therapy can be lower than the therapeutic amount of the same therapeutic agent when used as a monotherapy, e.g., due to an additive or synergistic effect of the combination of two or more therapeutic agents.

[0100] As used herein, the term "CB1" or "CB1 receptor" refers to cannabinoid receptor type 1. CB1 is a G protein-coupled cannabinoid receptor encoded by the CNR1 gene in humans. Human CB1 receptors are found primarily in the brain and nervous system, as well as in peripheral organs and tissues. At least seven splice variants of the human CNR1 gene have been identified. CB1b is a splice variant of the CB1 receptor.

[0101] As used herein, the term "CB1 b " refers to a splice variant of the human CB1 receptor. CB1 b CB1 is a form of CB1 that is preferentially expressed in beta cells and liver parenchymal cells (e.g., particularly in obese individuals), but is not significantly expressed in the brain. b is described, for example, in Patent Application Publication No. US20060115816. bSelective inhibition of CB1b in disorders related to CB1 may reduce the side effects associated with CB1 inhibition in the brain (e.g., psychiatric and neurological side effects including depressed mood, anxiety, irritability, insomnia, dizziness, headache, seizures, and suicidal ideation).

[0102] Disclosed herein are compounds, pharmaceutical compositions, and uses of the pharmaceutical compositions for the treatment of disorders modulated by the cannabinoid 1 (CB1) receptor in a subject.

[0103] compound The present disclosure provides compounds (e.g., CB1 receptor modulators) that are useful for treating disorders mediated by the CB1 receptor. The compounds generally have the formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, and OCH; R 2 is C1-C6 alkyl or phenyl optionally substituted with F or CN, and R 3 is phenyl substituted with one or two substituents selected from F, Cl, CF3, CN, OCH3, C2-C6 alkynyl, and C(O)NH2, or a 5- or 6-membered heteroaryl containing one to three nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl; R 4 , R 4 ', R 5 , and R 5 ' are independently H or C1-C6 alkyl, and R 6 and R 7 are independently H, OH, or C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1-2 nitrogen atoms, where the heteroaryl is optionally substituted with C1-C6 alkyl; R 8 is H or CH3, provided that: (i) R1 is not 4-chlorophenyl or 4-methoxyphenyl; (ii) R 2 is phenyl substituted with C1-C6 alkyl or CN; (iii) R 3 is not 4-chlorophenyl, 3-cyanophenyl, or 3-methoxyphenyl; (iv) R 4 and R 5 one of R is C1-C6 alkyl; 6 and R 7 is not H; and (vi) R 8 is CH3; at least one of the following is true.

[0104] The compound also generally has the formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents selected from halogen, C1-C6 alkoxy, and CN; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted with halogen or CN; R 3 is phenyl substituted with one or more substituents selected from halogen, C1-C6 alkoxy, CF3, CN, C2-C6 alkynyl, and C(O)NH2, or a 5- or 6-membered heteroaryl containing 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl; R 6 and R 7 are independently H, OH, or C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1-2 nitrogen atoms and optionally substituted with C1-C6 alkyl, and L is [ka] and R 8is H or C1-C6 alkyl, and R 4 , R 4 ', R 5 , and R 5 ' is independently H or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, and X is O or NR 9 and R 9 is H or C1-C6 alkyl, and y and z are independently 1, 2, or 3.

[0105] The compound also generally has the formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more substituents selected from F, Cl, CN, and OCH; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted with F or CN, and R 3 is phenyl substituted with one or more substituents selected from F, Cl, CF3, CN, OCH3, C2-C6 alkynyl, and C(O)NH2, or a 5- or 6-membered heteroaryl containing 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted with C1-C6 alkyl; R 4 , R 4 ', R 5 , and R 5 ' are independently H or C1-C6 alkyl, and R 6 and R 7 are independently H, OH, or C1-C6 alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl containing 1-2 nitrogen atoms and optionally substituted with C1-C6 alkyl; R 8 is H or C1-C6 alkyl, and n is 1, 2, or 3.

[0106] In some embodiments, the disclosure features compounds that are inverse agonists of the CB1 receptor.

[0107] In some embodiments, the disclosure features compounds that are antagonists of the CB1 receptor.

[0108] In some embodiments, the present disclosure features compounds that have increased affinity for the CB1 receptor compared to known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1, the contents of which are incorporated herein by reference in their entireties.

[0109] In some embodiments, the present disclosure features compounds that have increased selectivity for the CB1 receptor compared to known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0110] In some embodiments, the present disclosure features compounds that have both increased affinity and increased selectivity for the CB1 receptor compared to known CB1 modulators, such as rimonabant, taranabant, and the compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0111] In some embodiments, the present disclosure features compounds that exhibit reduced blood-brain barrier penetration compared to known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0112] In some embodiments, the present disclosure provides a method for the treatment of rheumatoid arthritis (Hercules 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 0-24 The compounds are characterized in that they exhibit a brain / plasma ratio in a subject of less than 0.2 (e.g., less than 0.15, less than 0.12, less than 0.1, less than 0.08, less than 0.06, or less than 0.05) as measured by .

[0113] In some embodiments, the present disclosure provides a compound that, when orally administered to mice at a dose of 10 mg / kg, exhibits a maximum concentration (C max The compounds are characterized in that they exhibit a brain / plasma ratio in a subject of less than 0.1 (e.g., less than 0.08, less than 0.06, less than 0.04, less than 0.02, or less than 0.01) as measured by .

[0114] In some embodiments, the present disclosure features compounds that have increased oral bioavailability compared to known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0115] In some embodiments, the present disclosure features compounds that have an improved safety or efficacy profile compared to known CB1 modulators, such as rimonabant, taranabant, and the compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0116] In some embodiments, the disclosure features compounds that result in a reduced risk (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%) of a psychiatric adverse event (e.g., suicidality) in a treated subject compared to subjects treated with known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0117] In some embodiments, the present disclosure features compounds that have an enhanced ability to reduce leptin levels compared to known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0118] In some embodiments, the present disclosure provides compounds that inhibit the CB1 activity of the CB1 receptor, for example, as compared to known CB1 modulators, such as rimonabant, taranabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1. b In some embodiments, the compounds of the present disclosure bind to human CB1b with an affinity that is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or 20-fold greater than the affinity for the human CB1 receptor.

[0119] Representative compounds are shown in Table 1.

[0120] Pharmaceutical Composition The pharmaceutical compositions of the present disclosure contain one or more of the compounds disclosed herein (e.g., one or more of the compounds of formulae (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and in Table 1) as therapeutic compounds. The pharmaceutical compositions contain a therapeutically effective amount of the compound as well as a pharmaceutically acceptable excipient and can be formulated by methods known to those skilled in the art. In some embodiments, pharmaceutical compositions for treating cancer contain one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and in Table 1), and may be formulated and / or administered with or without other therapeutic agents for particular conditions. Examples of such therapeutic agents (second therapeutic agents) are described herein.

[0121] The compounds disclosed herein (e.g., compounds of formulas (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and in Table 1) can be used in the form of a free base or in the form of a salt, and as a solvate. All forms are within the scope of the present disclosure.

[0122] Exemplary routes of administration of a pharmaceutical composition (or compound of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration.

[0123] Oral dosage forms Pharmaceutical compositions of the present invention include those formulated for oral administration ("oral dosage forms"), which may be in the form of, for example, a tablet, capsule, liquid solution or suspension, powder, or liquid or solid crystals containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0124] Pharmaceutical compositions for oral administration may be provided as chewable tablets, hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared using the ingredients described above based on tablets and capsules in a conventional manner, for example, using a mixer, fluidized bed apparatus, or spray-drying apparatus.

[0125] Liquid forms for oral administration into which the compounds and compositions of the present invention may be incorporated include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar vehicles.

[0126] Formulations for parenteral administration The pharmaceutical compositions of the present invention can be administered in pharmaceutically acceptable parenteral formulations (e.g., intravenous, intramuscular, subcutaneous, etc.) as described herein. Pharmaceutical compositions may be administered parenterally in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. For example, to prepare such compositions, the compounds of the present invention can be dissolved or suspended in a parenterally acceptable liquid vehicle. Acceptable vehicles and solvents that can be used include water; water adjusted to a suitable pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer's solution; and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, or n-propyl parahydroxybenzoate. Further information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference in its entirety.

[0127] Parenteral formulations can be any of the following five general types of preparations recognized by the USP-NF as suitable for parenteral administration: (1) "Injection": A liquid preparation that is a drug substance (e.g., a compound of the present invention) or a solution thereof; (2) "Solid formulation for injection": A drug substance (e.g., a compound of the present invention) as a dry solid combined with a sterile vehicle suitable for parenteral administration as an injection; (3) "Emulsified injectable": a liquid preparation of a drug substance (e.g., a compound of the present invention) dissolved or dispersed in a suitable emulsion vehicle; (4) "Injectable suspension": a liquid preparation of a drug substance (e.g., a compound of the present invention) suspended in a suitable liquid medium; and (5) "Solid formulation for injection suspension": A drug substance (e.g., a compound of the present invention) as a dry solid combined with a suitable sterile vehicle for parenteral administration as an injection suspension.

[0128] Exemplary formulations for parenteral administration include solutions of the compound in water, suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, and in oils. Under normal storage and use conditions, these preparations may contain preservatives to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23rd Ed., Adejare, Ed., Academic Press (2020) and The United States Pharmacopeia and National Formulary (USP-NF 2021 Issues 1-3), published in 2021.

[0129] Formulations for parenteral administration may contain, for example, sterile water, saline, polyalkylene glycols (e.g., polyethylene glycol), vegetable oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene / polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions or gels for administration in the form of nasal drops.

[0130] How to use Without wishing to be bound by theory, the present disclosure is based in part on the discovery that the compounds of the present disclosure are peripherally confined (i.e., unable to cross the blood-brain barrier, or have poor ability to cross the blood-brain barrier, or are readily removed from the brain by active transport systems), and therefore produce no or limited CNS effects. Thus, the compounds of the present disclosure may provide improved administration safety, for example, with respect to CNS effects, along with peripherally mediated efficacy in the treatment of disorders regulated by CB1, such as diabetic diseases, dyslipidemia, cardiovascular diseases, inflammatory diseases, liver disorders, cancer, and obesity and its comorbidities.

[0131] Thus, in some embodiments, the present disclosure provides a method of treating a diabetic disease in a subject (e.g., a human) using a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of diabetic diseases include, but are not limited to, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, and insulin resistance. In some embodiments, the diabetic disease is type 1 diabetes. In some embodiments, the diabetic disease is type 2 diabetes. In some embodiments, the diabetic disease is impaired glucose tolerance. In some embodiments, the diabetic disease is type 1 diabetes. In some embodiments, the diabetic disease is inappropriate impaired glucose tolerance. In some embodiments, the diabetic disease is insulin resistance.

[0132] In some embodiments, the present disclosure provides a method of treating a dyslipidemia in a subject (e.g., a human) using a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of dyslipidemia include, but are not limited to, undesirable blood lipid levels, low levels of high density lipoprotein, high levels of low density lipoprotein, high levels of triglycerides, and combinations thereof. In some embodiments, the dyslipidemia is undesirable blood lipid levels. In some embodiments, the dyslipidemia is a low level of high density lipoprotein. In some embodiments, the dyslipidemia is a high level of low density lipoprotein. In some embodiments, the dyslipidemia is an undesirable blood lipid level.

[0133] In some embodiments, the present disclosure provides a method of treating cardiovascular disease in a subject (e.g., a human) with a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of cardiovascular disease include, but are not limited to, atherosclerosis, high blood pressure, stroke, and heart attack. In some embodiments, the cardiovascular disease is atherosclerosis. In some embodiments, the cardiovascular disease is high blood pressure. In some embodiments, the cardiovascular disease is stroke. In some embodiments, the cardiovascular disease is heart attack.

[0134] In some embodiments, the disclosure provides a method of treating an inflammatory disease in a subject (e.g., a human) using a compound of the disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of inflammatory diseases include, but are not limited to, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and obesity-related inflammation. In some embodiments, the inflammatory disease is osteoarthritis. In some embodiments, the inflammatory disease is osteoarthritis. In some embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the inflammatory disease is inflammatory bowel disease. In some embodiments, the disorder is obesity-related inflammation.

[0135] In some embodiments, the present disclosure provides a method of treating liver damage in a subject (e.g., a human) using a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of liver damage include, but are not limited to, liver inflammation, liver fibrosis, non-alcoholic steatohepatitis, fatty liver, hepatomegaly, alcoholic liver disease, jaundice, cirrhosis, and hepatitis. In some embodiments, the liver damage is liver inflammation. In some embodiments, the liver damage is liver fibrosis. In some embodiments, the liver damage is non-alcoholic steatohepatitis. In some embodiments, the liver damage is fatty liver. In some embodiments, the liver damage is hepatomegaly. In some embodiments, the liver damage is alcoholic liver disease. In some embodiments, the liver damage is jaundice. In some embodiments, the liver damage is cirrhosis. In some embodiments, the liver damage is hepatitis.

[0136] In some embodiments, the disclosure provides a method of treating cancer in a subject (e.g., a human) with a compound of the disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of cancer include, but are not limited to, colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, and hepatocellular carcinoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is alveolar rhabdomyosarcoma. In some embodiments, the cancer is hepatocellular carcinoma.

[0137] In some embodiments, the present disclosure provides a method of treating obesity or a comorbidity thereof in a subject (e.g., a human) using a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof. Examples of comorbidities of obesity include, but are not limited to, hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; osteoarthritis; venous stasis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; atherosclerotic disease; pseudotumor cerebri; accidental death; increased risks associated with surgery; osteoarthritis; high cholesterol; or an increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies. In some embodiments, the comorbidity of obesity is hypertension. In some embodiments, the comorbidity of obesity is gallbladder disease. In some embodiments, the comorbidity of obesity is gastrointestinal disorders. In some embodiments, the comorbidity of obesity is menstrual irregularities. In some embodiments, the comorbidity of obesity is osteoarthritis. In some embodiments, the comorbidity is venous stasis ulcers. In some embodiments, the comorbidity of obesity is pulmonary hypoventilation syndrome. In some embodiments, the comorbidity of obesity is sleep apnea. In some embodiments, the comorbidity of obesity is snoring. In some embodiments, the comorbidity of obesity is coronary artery disease. In some embodiments, the comorbidity of obesity is atherosclerotic disease. In some embodiments, the comorbidity of obesity is pseudotumor cerebri. In some embodiments, the comorbidity of obesity is accident proneness. In some embodiments, the comorbidity of obesity is increased risk associated with surgery. In some embodiments, the comorbidity of obesity is osteoarthritis. In some embodiments, the comorbidity of obesity is high cholesterol, hi some embodiments, the comorbidity of obesity is an increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies.

[0138] The dosage of the compounds of the present disclosure depends on factors including the route of administration, the disease being treated, and the physical characteristics of the subject, such as age, weight, and health. Typically, the amount of a compound disclosed herein (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), (III), or Table 1) contained in a single dose will be an amount that effectively treats the disease without inducing significant toxicity. Pharmaceutical compositions of the disclosure containing one or more of the compounds disclosed herein (e.g., one or more of the compounds of formulae (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and in Table 1) can be administered to a subject in need thereof, one or more times daily or as medically necessary.

[0139] Combination therapy In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, is administered with a second therapeutic agent, e.g., a therapeutic agent suitable for treating any of the disorders described herein.

[0140] Examples of suitable second therapeutic agents for administration with a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, include, but are not limited to, PPAR-γ agonists (e.g., a glitazone, e.g., troglitazone, pioglitazone, englitazone, MCC-555, and rosiglitazone), biguanides (e.g., metformin, benzodiazepines, benzocaine, benzodiazepines ... amine and phenformin), insulin or insulin mimetics, sulfonylureas (e.g., tolbutamide or glipizide), α-glucosidase inhibitors (e.g., acarbose), HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, or rivastatin), sequestrants (e.g., cholestyramine, colestipol, or dialkylaminoalkyl derivatives of cross-linked dextran), nicotinyl alcohol, nicotinic acid or its salts, PPAR-α agonists (e.g., phenformin, nofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate, and bezafibrate), cholesterol absorption inhibitors, acyl-CoA:cholesterol acyltransferase inhibitors, probucol, PPAR-α / γ agonists, ileal bile acid transporter inhibitors, insulin receptor activators, dipeptidyl peptidase IV inhibitors, exenatide, pramlintide, FBPase inhibitors, glucagon receptor antagonists, glucagon-like peptide 1, glucagon-like peptide 1 receptor agonists (e.g., liraglutide, sema glutide, exenatide, lixisenatide, dulaglutide, and tirzepatide), growth hormone secretagogues, growth hormone secretagogue receptor agonists, growth hormone secretagogue receptor antagonists, melanocortin agonists, melanocortin 4 receptor agonists, beta-3 agonists, serotonin 2C receptor agonists, orexin antagonists, melanin-concentrating hormone 1 antagonists, melanin-concentrating hormone 2 agonists, melanin-concentrating hormone 2 antagonists, galanin antagonists, CCK agonists, CCK-A agonists,corticotropin-releasing hormone agonists, NPY5 antagonists, NPY1 antagonists, histamine receptor-3 modulators, histamine receptor-3 blockers, beta-hydroxysteroid dehydrogenase-1 inhibitors, phosphodiesterase inhibitors, phosphodiesterase-3B inhibitors, norepinephrine transport inhibitors, non-selective serotonin / norepinephrine transport inhibitors (e.g., sibutramine, phentermine, or fenfluramine), ghrelin antagonists, leptin derivatives, bombesin receptor subtype 3 agonists, ciliary neurotrophic factor or its derivatives (e.g., Axokine), monoamine reuptake inhibitors, uncoupling protein-1 activators, uncoupling protein-2 activators agents, uncoupling protein-3 activators, thyroid hormone beta agonists, fatty acid synthase inhibitors, diacylglycerol acetyltransferase 2 inhibitors, acetyl-CoA carboxylase-2 inhibitors, glucocorticoid antagonists, acyl-estrogens, lipase inhibitors (e.g., orlistat), fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, sodium-glucose cotransporters, phosphate transporter inhibitors, serotonin reuptake inhibitors, thiazolidinediones, metformin, topiramate, opiate antagonists (e.g., naltrexone), nonselective transport inhibitors (e.g., amfebutamone), or MAO inhibitors (e.g., moclobemide, brofaromine, BW A616U, Ro 41-1049, RS-2232, SR 95191, harmaline, harmane, amiflamine, BW 1370U87, FLA 688, FLA 788; bifemelane, clorgyline, LY 51641, MDL 72394, 5-(4-benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one, 5-(4-arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazole, lazabemide, Ro 16-6491, alumoxatone, XB308, RS-1636, RS-1653, NW-1015, SL 340026, L-selegiline, rasagiline, pargyline, AGN 1135, MDL 72974, MDL 72145, MDL 72638, LY 54761, MD 780236, MD 240931,Bifemelane, toloxatone, cimoxatone, iproniazid, phenelzine, nialamide, phenylhydrazine, 1-phenylcyclopropylamine, isocarboxazid, or tranylcypromine.

[0141] In some embodiments, a compound of the disclosure (e.g., a compound of formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with a glucagon-like peptide 1 analogue. In some embodiments, a compound of the disclosure (e.g., a compound of formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with semaglutide.

[0142] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, is administered with a gastric inhibitory polypeptide analog. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, is administered with tirzepatide.

[0143] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with a glucagon-like peptide 1 analog. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), or (IIIB), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with liraglutide.

[0144] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, is administered with a glucagon-like peptide 1 analog. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, is administered with exenatide.

[0145] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with a glucagon-like peptide 1 analog. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with lixisenatide.

[0146] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with a glucagon-like peptide 1 analog. In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), or (III), or a compound in Table 1), or a pharmaceutically acceptable salt thereof, is administered with dulaglutide. [Example]

[0147] Example 1: Synthesis of intermediates Synthesis of (S)-2-aminopropane-1-sulfonamide (I1) Synthesis of (S)-2-(((benzyloxy)carbonyl)amino)propyl methanesulfonate (I1.1): [ka] Methanesulfonyl chloride (1.92 mL, 24.8 mmol, 1.04 equiv.) in dichloromethane (48 mL) was added over 30 min to a solution of (S)-(1-hydroxypropan-2-yl)benzylcarbamate (5.0 g, 23.9 mmol, 11.0) and triethylamine (3.7 mL, 26.3 mmol, 1.1 equiv.) in dichloromethane (96 mL) at 0 °C. After stirring for 16 h at room temperature, the reaction mixture was washed with saturated aqueous sodium bicarbonate (80 mL) and brine (80 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the expected product as a white solid (6.85 g, 23.8 mmol, 99% yield). LC-MS (ESI+): 288.1 (M+H + ).

[0148] Synthesis of (S)-S-(2-(((benzyloxy)carbonyl)amino)propyl) ethanethioate (I1.2): [ka] Potassium thioacetate (13.6 g, 119.2 mmol, 5.0 equiv.) was added to a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)propyl methanesulfonate (6.85 g, 23.8 mmol, 11.1) in dimethylformamide (120 mL). After stirring at room temperature for 18 h, the solvent was partially removed under reduced pressure, diluted with ethyl acetate (100 mL), and washed with water (80 mL). The combined organic phases were washed with brine (60 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a dark oil, which was purified by flash chromatography on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give a brownish solid (6.3 g, 23.7 mmol, 99% yield). LC-MS (ESI+): 268.1 (M+H) + ).

[0149] Synthesis of (S)-benzyl(1-(chlorosulfonyl)propan-2-yl)carbamate (I1.3): [ka] A solution of 50% hydrogen peroxide (13.5 mL, 0.63 mL / mmol) in acetic acid (49 mL) was added dropwise to a solution of (S)-S-(2-(((benzyloxy)carbonyl)amino)propyl) ethanethioate (5.73 g, 21.4 mmol, I1.2) in acetic acid (36 mL). After stirring at room temperature for 18 hours, palladium on activated carbon was added to quench excess hydrogen peroxide, and the resulting mixture was filtered through a pad of Celite. The filtrate was concentrated to dryness under reduced pressure.

[0150] The resulting brown oil was poured into dichloromethane (120 mL) and triphosgene (8.9 g, 30.0 mmol, 1.4 equiv.) was added, followed by dimethylformamide (3.0 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the residue was purified on silica gel eluting with dichloromethane / methanol mixtures (0 / 100 to 10 / 90, v / v) to give a beige solid (5.43 g, 18.7 mmol, 87% yield). LC-MS (ESI+): 292.0 (M+H + ).

[0151] Synthesis of (S)-benzyl(1-sulfamoylpropan-2-yl)carbamate (I1.4): [ka] Ammonia gas was bubbled through a stirred solution of (S)-(1-(chlorosulfonyl)propan-2-yl)benzylcarbamate (5.4 g, 18.5 mmol, I1.3) in dichloromethane (185 mL) at room temperature for 15 minutes. Once stirring was complete, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting off-white solid was used in the next step without further purification (5.0 g, 18.4 mmol, 99% yield). LC-MS (ESI+): 273.2 (M+H + ).

[0152] Synthesis of (S)-2-aminopropane-1-sulfonamide (I1): [ka] A solution of (S)-(1-sulfamoylpropan-2-yl)benzylcarbamate (5.3 g, 19.5 mmol, I1.4) in ethanol (195 mL) containing 10% palladium on carbon powder (Pd / C, 10 wt%) (2.0 g, 0.1 equiv.) was first degassed under reduced pressure and then saturated with hydrogen gas, which was repeated three times. After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered through a Celite pad and concentrated under reduced pressure to give the expected compound as a brownish-white solid (2.65 g, 98% yield). LC-MS (ESI+): 139.0 (M+H+ ).

[0153] Synthesis of N-(bis-methylsulfanyl-methylene)-3-trifluoromethyl-benzenesulfonamide (I2) [ka] To a solution of 3-(trifluoromethyl)benzenesulfonamide (5.0 g, 22.2 mmol, 12.0 ml) and carbon disulfide (2.18 mL, 36.4 mmol, 1.6 equiv) in dimethylformamide (74 mL) cooled in an ice bath was added a solution of potassium hydroxide (2.94 g, 52.4 mmol, 2.4 equiv) in water (11 mL) dropwise, maintaining the internal temperature below 10° C. After stirring at 0° C. for 1 h, iodomethane (3.2 mL, 51.5 mmol, 2.3 equiv) was added dropwise, maintaining the internal temperature below 10° C. After stirring at room temperature for up to 2 h, water (35 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the expected product as a pale yellow solid without further purification (5.75 g, 17.5 mmol, 79% yield). LC-MS (ESI+): 330.0 (M+H + ).

[0154] Synthesis of dimethyl ((2-chlorophenyl)sulfonyl)carbonimidodithioate (I3) [ka] To a solution of 2-chlorobenzenesulfonamide (4.7 g, 24.5 mmol, 1 equiv.) and carbon disulfide (2.4 mL, 40.2 mmol, 1.6 equiv.) in dimethylformamide (87 mL) cooled in an ice bath was added a solution of potassium hydroxide (3.2 g, 57.8 mmol, 2.4 equiv.) in water (13 mL) dropwise, while maintaining the internal temperature below 10 °C. After stirring at 0 °C for 1 h, iodomethane (3.5 mL, 56.9 mmol, 2.3 equiv.) was added dropwise, while maintaining the internal temperature below 10 °C. After warming to room temperature for 2 h, water (35 mL) was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product as a pale yellow solid, which was used without further purification (6.0 g, 20.3 mmol, 83% yield). LC-MS (ESI+): 295.9 (M+H + ).

[0155] Synthesis of dimethyl ((2-ethynylphenyl)sulfonyl)carbonimidodithioate (I4) Synthesis of 2-bromobenzenesulfonamide (I4.1): [ka] Ammonia gas was bubbled through a solution of 2-bromobenzenesulfonyl chloride (5.0 g, 19.6 mmol, 1.0 equiv) in tetrahydrofuran (100 mL) for 10 minutes. Upon completion, the reaction mixture was filtered through a silica pad, washed with ethyl acetate, and concentrated under reduced pressure to give a beige solid that was used directly without further purification (4.4 g, 18.8 mmol, 95%). LC-MS (ESI+): 236.0 (M+H + ).

[0156] Synthesis of 2-((trimethylsilyl)ethynyl)benzenesulfonamide (I4.2) [ka] Bis(triphenylphosphine)palladium chloride (0.65 g, 0.93 mmol, 0.05 equiv.) and (trimethylsilyl)acetylene (3.3 mL, 23.3 mmol, 1.25 equiv.) were added to a solution of 2-bromobenzenesulfonamide (4.4 g, 18.6 mmol, 14.1 mL) and copper(I) iodide (0.18 g, 0.93 mmol, 0.05 equiv.) in degassed triethylamine (78 mL). The resulting mixture was refluxed at 90 °C for 18 h. Upon completion, the reaction mixture was filtered through a Celite pad, washed with ethyl acetate, concentrated, and purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v) to give the expected compound as a beige solid (1.8 g, 7.1 mmol, 38% yield). LC-MS (ESI+): 254.0 (M+H + ).

[0157] Synthesis of dimethyl ((2-ethynylphenyl)sulfonyl)carbonimidodithioate (I4) [ka] 2-((trimethylsilyl)ethynyl)benzenesulfonamide (1.28 g, 5.05 mmol, I4.2) and carbon disulfide (0.5 mL, 8.3 mmol, 1.6 equiv.) were dissolved in dimethylformamide (9 mL), and the mixture was cooled in an ice bath. A solution of potassium hydroxide (0.67 g, 11.9 mmol, 2.4 equiv.) in water (3 mL) was then added dropwise, maintaining the internal temperature below 10 °C. The resulting mixture was stirred at 0 °C for 1 h. After that time, iodomethane (0.73 mL, 11.7 mmol, 2.3 equiv.) was added dropwise, maintaining the internal temperature below 10 °C, and the resulting mixture was stirred to room temperature for 2 h. Once the starting material was consumed, water (15 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected compound as a yellowish solid (0.47 g, 1.6 mmol, 32% yield). LC-MS (ESI+): 286.0 (M+H + ).

[0158] Synthesis of dimethyl ((3-ethynylphenyl)sulfonyl)carbonimidodithioate (I5) Synthesis of 3-((trimethylsilyl)ethynyl)benzenesulfonamide (I5.1): [ka] Bis(triphenylphosphine)palladium chloride (0.65 g, 0.93 mmol, 0.05 equiv.) and (trimethylsilyl)acetylene (3.3 mL, 23.3 mmol, 1.25 equiv.) were added to a solution of 3-bromobenzenesulfonamide (4.4 g, 18.6 mmol, 1.0 equiv.) and copper(I) iodide (0.18 g, 0.93 mmol, 0.05 equiv.) in degassed triethylamine (78 mL). After stirring at 90 °C for 18 h, the reaction mixture was filtered through a pad of Celite, washed with ethyl acetate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v) to give the expected compound as a beige solid (4.45 g, 17.6 mmol, 94% yield). LC-MS (ESI+): 254.0 (M+H + ).

[0159] Synthesis of dimethyl ((3-ethynylphenyl)sulfonyl)carbonimidodithioate (I5) [ka] To 3-((trimethylsilyl)ethynyl)benzenesulfonamide (4.45 g, 17.6 mmol, 15.1) and carbon disulfide (1.7 mL, 28.8 mmol, 1.6 equiv.) in dimethylformamide (30 mL) cooled in an ice bath was added a solution of potassium hydroxide (2.3 g, 41.4 mmol, 2.4 equiv.) in water (10 mL) dropwise, maintaining the internal temperature below 10 °C. After stirring at 0 °C for 1 h, iodomethane (2.5 mL, 40.7 mmol, 2.3 equiv.) was added dropwise, maintaining the internal temperature below 10 °C. After warming to room temperature over 2 h, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected compound as a yellowish solid (2.65 g, 9.29 mmol, 53% yield). LC-MS (ESI+): 286.0 (M+H + ).

[0160] Synthesis of methyl ((2,4-difluorophenyl)sulfonyl)carbamate (I6) [ka] To a solution of I6.0 (0.9 g, 4.66 mmol, CAS number: 13656-60-5) in acetonitrile (15 mL) was added triethylamine (1.62 mL, 11.65 mmol, 2.5 equiv.) and methyl carbonochloridate (577.40 μL, 7.45 mmol, 1.6 equiv.) at 0 °C. The resulting mixture was allowed to warm slightly to room temperature and stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and concentrated under reduced pressure. The residue was redissolved in water (5 mL) and adjusted to pH = 3 with aqueous HCl (1 N). The suspension was filtered, and the filter cake was dried under high vacuum to give I6 as a white solid (0.3 g, 1.19 mmol, 26%). 1 H NMR: 400 MHz, DMSO-d6δ ppm 3.73 (s, 3H), 6.93-7.13 (m, 2H), 7.92 (br s, 1H), 8.11 (td, J=8.47, 6.05 Hz, 1H).

[0161] I7: Synthesis of methyl ((3,5-difluorophenyl)sulfonyl)carbamate (I7) [ka] To a solution of I7.0 (5 g, 25.88 mmol, 1 equiv) in acetonitrile (50 mL) was added triethylamine (9.01 mL, 64.71 mmol, 2.5 equiv) and methyl carbonochloridate (3.21 mL, 41.41 mmol, 1.6 equiv) at 0 °C. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (25 mL) and concentrated under reduced pressure. The residue was redissolved in water (5 mL) and adjusted to pH = 3 with aqueous HCl (1 N). The suspension was filtered, and the filter cake was dried under high vacuum to give I7 as a white solid (2 g, 7.56 mmol, 29%). LCMS (ESI+): m / z 239.1 (M+H) + .1 H NMR: 400 MHz, DMSO-d6δ ppm 3.60 (s, 3H), 7.58 (br d, J=4.77 Hz, 2H), 7.73 (br t, J=9.29 Hz, 1H).

[0162] Synthesis of (R)-2-aminopropane-1-sulfonamide (I8) Synthesis of (R)-(1-hydroxypropan-2-yl)benzylcarbamate (I8.1) [ka] To a solution of D-alaninol (2.0 g, 26.6 mmol, 18.0 eq.) and potassium carbonate (7.4 g, 53.5 mmol, 2.01 eq.) in tetrahydrofuran / water (50 mL, 1:1) was added benzyl chloroformate (4.2 mL, 29.3 mmol, 1.1 eq.) at 0° C. After stirring at room temperature for 1 h, the reaction mixture was extracted with ethyl acetate (75 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a white solid, which was used in the next step without further purification (5.5 g, 26.3 mmol, 98% yield). LC-MS (ESI+): 210.1 (M+H + ).

[0163] Synthesis of (R)-2-(((benzyloxy)carbonyl)amino)propyl methanesulfonate (I8.2) [ka] Methanesulfonyl chloride (2.12 mL, 27.3 mmol, 1.04 equiv.) in dichloromethane (52 mL) was added to a solution of (R)-(1-hydroxypropan-2-yl)benzylcarbamate (5.5 g, 26.3 mmol, 18.1) and triethylamine (4.03 mL, 28.9 mmol, 1.1 equiv.) in dichloromethane (104 mL) at 0 °C. After stirring in an ice bath for 30 min, the mixture was stirred at room temperature for an additional 30 min. After stirring was complete, the reaction mixture was subsequently washed with saturated aqueous sodium bicarbonate (80 mL) and brine (80 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the expected product as a white solid (7.5 g, 26.2 mmol, 99% yield). LC-MS (ESI+): 288.1 (M+H + ).

[0164] Synthesis of (R)-S-(2-(((benzyloxy)carbonyl)amino)propyl) ethanethioate (I8.3) [ka] Potassium thioacetate (14.9 g, 130 mmol, 5.0 equiv.) was added to a stirred solution of (R)-2-(((benzyloxy)carbonyl)amino)propyl methanesulfonate (7.5 g, 26.0 mmol, 18.2 ml) in dimethylformamide (120 mL). After stirring at room temperature for 18 h, the solvent was partially removed under reduced pressure, diluted with ethyl acetate (70 mL), and extracted with water (60 mL). The organic phase was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a dark oil, which was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give a brownish oil (6.74 g, 25.2 mmol, 96% yield). LC-MS (ESI+): 268.1 (M+H) + ).

[0165] Synthesis of (R)-(1-(chlorosulfonyl)propan-2-yl)benzylcarbamate (I8.4) [ka] A solution of 50% hydrogen peroxide (15 mL, 0.63 mL / mmol) in acetic acid (55 mL) was added dropwise to a solution of (R)-S-(2-(((benzyloxy)carbonyl)amino)propyl) ethanethioate (6.74 g, 25.2 mmol, 18.3 l) in acetic acid (40 mL). After stirring at room temperature for 18 hours, palladium on activated carbon was added to quench excess hydrogen peroxide, and the resulting mixture was filtered through a pad of Celite. The filtrate was concentrated to dryness under reduced pressure. The brown oil was poured into dichloromethane (120 mL) and triphosgene (10.4 g, 35.3 mmol, 1.4 equiv.) was added, followed by dimethylformamide (3.5 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with a dichloromethane / methanol mixture (0 / 100 to 10 / 90, v / v) to give a beige solid (5.9 g, 20.3 mmol, 80% yield). LC-MS (ESI+): 292.0 (M+H + ).

[0166] Synthesis of (R)-(1-sulfamoylpropan-2-yl)benzylcarbamate (I8.5) [ka] Ammonia gas was bubbled through a stirred solution of (R)-(1-(chlorosulfonyl)propan-2-yl)benzylcarbamate (5.9 g, 20.2 mmol, 18.4 ml) in dichloromethane (200 mL) at room temperature for 15 minutes. Once stirring was complete, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting off-white solid was used in the next step without further purification (5.48 g, 20.1 mmol, 99% yield). LC-MS (ESI+): 273.0 (M+H + ).

[0167] Synthesis of (R)-2-aminopropane-1-sulfonamide (I8) [ka] To a solution of (R)-(1-sulfamoylpropan-2-yl)benzylcarbamate (5.48 g, 20.2 mmol, I8.5) in ethanol (200 mL) was added 10% palladium on carbon (Pd / C, 10 wt%) (2.0 g, 0.1 equivalents). The mixture was degassed under reduced pressure and then saturated with hydrogen, which was repeated three times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Upon completion of stirring, the mixture was filtered through a Celite pad and concentrated under reduced pressure to give the expected compound as a brown solid (2.7 g, 19.6 mmol, 97% yield). LC-MS (ESI+): 139.0 (M+H + ).

[0168] Synthesis of dimethyl ((4-ethynylphenyl)sulfonyl)carbonimidodithioate (I9) Synthesis of ((trimethylsilyl)ethynyl)benzenesulfonamide (I9.1) [ka] Bis(triphenylphosphine)palladium chloride (0.45 g, 0.63 mmol, 0.05 equiv.) and (trimethylsilyl)acetylene (2.26 mL, 15.9 mmol, 1.25 equiv.) were added to a solution of 4-bromobenzenesulfonamide (3.0 g, 12.7 mmol, 19.0 mL) and copper(I) iodide (0.12 g, 0.63 mmol, 0.05 equiv.) in triethylamine (48 mL). After stirring at 90 °C for 18 h, the reaction mixture was filtered through a pad of Celite, washed with ethyl acetate, and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v) to give a beige solid (2.8 g, 11.1 mmol, 87% yield). LC-MS (ESI+): 254.1 (M+H) + ).

[0169] Synthesis of dimethyl ((4-ethynylphenyl)sulfonyl)carbonimidodithioate (I9) [ka] To 4-((trimethylsilyl)ethynyl)benzenesulfonamide (0.8 g, 3.16 mmol, I9.1) and carbon disulfide (0.31 mL, 5.18 mmol, 1.6 equiv) dissolved in DMF (4.5 mL) in an ice bath was added a solution of potassium hydroxide (0.42 g, 7.4 mmol, 2.4 equiv) in water (1.5 mL) dropwise, maintaining the internal temperature below 10 °C. After stirring at 0 °C for 1 h, iodomethane (0.46 mL, 7.3 mmol, 2.3 equiv) was added dropwise, maintaining the internal temperature below 10 °C. After stirring to room temperature for 2 h, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as an orange solid (0.39 g, 1.37 mmol, 43% yield). LC-MS (ESI+): 286.0 (M+H + ).

[0170] Synthesis of (S)-2-amino-3-methylbutane-1-sulfonamide (I10) Synthesis of (S)-2-(1-hydroxy-3-methylbutan-2-yl)isoindoline-1,3-dione (I10.1) [ka] (S)-Valinol (5.00 g, 48.4 mmol, 1 equiv.) and phthalic anhydride (7.54 g, 50.9 mmol, 1.05 equiv.) were condensed by stirring in a sealed capped flask at 140 °C for 18 hours. Upon completion of stirring, the reaction mixture was diluted with ethyl acetate (75 mL) and then washed sequentially with saturated aqueous sodium bicarbonate (60 mL), water (50 mL), 10% aqueous citric acid (50 mL), and brine (50 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give an oily crude product, which was purified by silica column chromatography eluting with heptane / ethyl acetate mixtures to give (S)-2-(1-hydroxy-3-methylbutan-2-yl)isoindoline-1,3-dione as a yellowish oil (10.2 g, 43.8 mmol, 90% yield). LC-MS (ESI+): 234.112 (M+H + ).

[0171] Synthesis of (S)-S-(2-(1,3-dioxoisoindolin-2-yl)-3-methylbutyl) ethanethioate (I10.2) [ka] To a solution of diethyl azodicarboxylate (40%, 2.15 mL, 4.71 mmol, 2.2 equiv.) and triphenylphosphine (1.24 g, 4.71 mmol, 2.2 equiv.) in toluene and THF (10 mL) was added (S)-2-(1-hydroxy-3-methylbutan-2-yl)isoindoline-1,3-dione (0.5 g, 2.14 mmol, 110.1) and thioacetic acid (0.34 mL, 4.71 mmol, 2.2 equiv.) dissolved in THF (10 mL) sequentially at room temperature. After stirring at room temperature for 18 hours, the mixture was diluted with ethyl acetate (60 mL) and washed with aqueous sodium carbonate (1 M, 50 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50, v / v) to give (S)-S-(2-(1,3-dioxoisoindolin-2-yl)-3-methylbutyl)ethanethioate (I10.2) as a yellow oil (0.51 g, 1.75 mmol, 82% yield). LC-MS (ESI+): 292.1 (M+H + ).

[0172] Synthesis of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonic acid (I10.3) [ka] A mixture of hydrogen peroxide and acetic acid (1:2, v / v) (9.30 mL) was added to a solution of (S)-S-(2-(1,3-dioxoisoindolin-2-yl)-3-methylbutyl)ethanethiolate (1.03 g, 3.53 mmol, 110.2 ml) in acetic acid (3 mL). After stirring at room temperature for 18 h, palladium on activated carbon was added to quench the excess hydrogen peroxide. The resulting mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The oily residue was co-evaporated with toluene (2 x 10 mL) and concentrated to dryness to give a brown oil, which was used in the next step without further purification (0.99 g, 3.33 mmol, 94% yield). LC-MS (ESI+): 298.074 (M+H + ).

[0173] Synthesis of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonyl chloride (I10.4): [ka] (S)-2-(1,3-Dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonic acid (0.94 g, 3.17 mmol, I10.3) in thionyl chloride (3 mL) was refluxed at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated and co-evaporated with toluene three times to give a brown crude product, which was purified by flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50) to give (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonyl chloride (I10.4) as a thick yellowish oil (0.55 g, 1.75 mmol, 55% yield). LC-MS (ESI+): 316.040 (M+H + ).

[0174] Synthesis of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonamide (I10.5) [ka] Ammonia gas was bubbled through a stirred solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonyl chloride (0.51 g, 1.62 mmol, 110.4 ml) in dichloromethane (15 mL) at room temperature until no more precipitate formed. Once stirring was complete, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting white solid was used in the next step without further purification (0.45 g, 1.52 mmol, 94% yield). LC-MS (ESI+): 297.090 (M+H + ).

[0175] Synthesis of (S)-2-amino-3-methylbutane-1-sulfonamide (I10) [ka] Hydrazine hydrate (0.32 mL, 4.55 mmol, 3 equiv.) was added to a solution of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonamide (0.45 g, 1.52 mmol, I10.5) in ethanol (8.5 mL). After stirring at reflux for 5 h, the reaction mixture was filtered and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure to give (S)-2-amino-3-methylbutane-1-sulfonamide (I10.6) as a white solid, which was used directly without further purification (0.25 g, 1.51 mmol, 99% yield). LC-MS (ESI+): 167.100 (M+H + ).

[0176] Synthesis of dimethyl ((1-methyl-1H-imidazol-4-yl)sulfonyl)carbonimidodithioate (I11) [ka] To 1-methyl-1H-imidazole-4-sulfonamide (0.47 g, 2.9 mmol, 1 equiv.) and carbon disulfide (0.29 mL, 4.8 mmol, 1.6 equiv.) dissolved in DMF (10 mL) cooled in an ice bath was added a solution of potassium hydroxide (0.39 g, 6.9 mmol, 2.4 equiv.) in water (2 mL) dropwise, while maintaining the internal temperature below 10° C. After stirring at 0° C. for 1 hour, iodomethane (0.42 mL, 6.8 mmol, 2.3 equiv.) was added dropwise, while maintaining the internal temperature below 10° C. After stirring to room temperature for 1 hour, the reaction was diluted with water (15 mL) and extracted with ethyl acetate (30 mL × 2). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as a white solid (65 mg, 0.25 mmol, 8% yield). LC-MS (ESI+): 265.9 (M+H + ).

[0177] Synthesis of dimethyl ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (I12): Synthesis of 4-(benzylthio)-1H-1,2,3-triazole (I12.1) [ka] To a solution of sodium 1H-1,2,3-triazole-4-thiolate (5.0 g, 40.61 mmol, 1.0 equiv.) in ethanol (50 mL) was added benzyl bromide (4.83 mL, 40.6 mmol, 1.0 equiv.) dropwise over 5 min at 0 °C. After warming to room temperature and stirring for 1 h, the solvent was removed under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with brine (40 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the expected compound as a white solid (7.7 g, 40.31 mmol, 99%). LC-MS (ESI+): 192.1 (M+H + ).

[0178] Synthesis of intermediate 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazoles (I12.2-I12.4) [ka] To a solution of 4-(benzylthio)-1H-1,2,3-triazole (7.7 g, 40.2 mmol, 12.1%) in dimethylformamide (80 mL) containing potassium carbonate (14.0 g, 100.6 mmol, 2.5 equiv.) was added 2-iodopropane (8.05 mL, 80.5 mmol, 2.0 equiv.) dropwise at 0 °C. After warming to room temperature and stirring for an additional 18 h, the solvent was partially removed. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 50 mL). The organic phases were collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give an oil, which was purified by flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v) to give the corresponding triazole regioisomer as a colorless oil.

[0179] 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole (I12.2): 5.36 g, 57%. LC-MS (ESI+): 234.1 (M+H + ). 1H NMR (400 MHz, DMSO-d6, 25℃): δ = 7.65 (s, 1H), 7.19-7.29 (m, 5H), 4.69-4.81 (m, 1H), 4.16 (s, 2H), 1.43 ppm (d, J = 6.7 Hz, 6H).

[0180] 5-(benzylthio)-1-isopropyl-1H-1,2,3-triazole (I12.3): 1.04 g, 11%. LC-MS (ESI+): 234.1 (M+H + ). 1H NMR (400 MHz, DMSO-d6, 25℃): δ = 7.76 (s, 1H), 7.21-7.30 (m, 3H), 7.17 (dd, J = 7.7, 1.4 Hz, 2H), 4.59 (spt, J = 6.7 Hz, 1H), 4.10 (s, 2H), 1.28 ppm (d, J = 6.8 Hz, 6H).

[0181] 4-(benzylthio)-1-isopropyl-1H-1,2,3-triazole (I12.4): 1.95 g, 21%. LC-MS (ESI+): 234.1 (M+H + ). 1H NMR (400 MHz, DMSO-d6, 25℃): δ = 8.07 (s, 1H), 7.18-7.28 (m, 5H), 4.75 (spt, J = 6.7 Hz, 1H), 4.09-4.12 (m, 2H), 1.43 ppm (d, J = 6.8 Hz, 6H).

[0182] Synthesis of 2-isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride (I12.5) [ka] To a solution of 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole (5.36 g, 23.0 mmol, 112.5 mL) in a mixture of AcOH / HO (46 / 23 mL) was added N-chlorosuccinimide (12.3 g, 91.9 mmol, 4.0 equiv.) at 0 °C. After stirring at room temperature for 18 h, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (75 mL). The organic phase was then washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with an ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) to give the expected sulfonyl chloride as a colorless oil (4.1 g, 19.6 mmol, 85%). LC-MS (ESI+): 210.0 (M+H + ).

[0183] Synthesis of 2-isopropyl-2H-1,2,3-triazole-4-sulfonamide (I12.6) [ka] Ammonia gas was bubbled through a solution of 2-isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride (4.70 g, 22.4 mmol, 112.5 ml) in dichloromethane (100 mL) at room temperature for 10 minutes. Upon completion, the solvent was removed under reduced pressure, and the resulting slurry was triturated with ethyl acetate. The precipitate was removed by filtration through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the sulfonamide as a yellow oil, which was used in the next step without further purification (4.2 g, 22.1 mmol, 98% yield). LC-MS (ESI+): 191.1 (M+H + ).

[0184] Synthesis of dimethyl ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (I12): [ka] To 2-isopropyl-2H-1,2,3-triazole-4-sulfonamide (4.2 g, 22.1 mmol, 112.6 mL) and carbon disulfide (2.2 mL, 36.2 mmol, 1.6 equiv.) in dimethylformamide (36 mL) cooled in an ice bath was added a solution of potassium hydroxide (2.9 g, 52.1 mmol, 2.4 equiv.) in water (12 mL) dropwise, while maintaining the internal temperature below 10°C. After stirring at 0°C for 1 hour, iodomethane (3.2 mL, 51.2 mmol, 2.3 equiv.) was added dropwise, while maintaining the internal temperature below 10°C. After stirring to room temperature for 2 hours, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using an ethyl acetate / heptane mixture (0 / 100 to 30 / 70, v / v) to give the expected compound as a white solid (2.9 g, 9.86 mmol, 45% yield). LC-MS (ESI+): 295.0 (M+H + ).

[0185] Synthesis of dimethyl ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (I13) [ka] Synthesis of I13.1, I13.2, and I13.3: To a solution of 4-(benzylthio)-1H-1,2,3-triazole (7.75 g, 40.5 mmol, 113.0 eq) in dimethylformamide (80 mL) containing potassium carbonate (12.3 g, 89.1 mmol, 2.2 equiv.) at 0 °C, 2-iodomethane (5.04 mL, 81.0 mmol, 2.0 equiv.) was added dropwise to the mixture at 0 °C. After stirring at room temperature for 18 h, the solvent was partially removed. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 50 mL). The organic phases were collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give an oil, which was purified by flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v) to give the corresponding triazole regioisomer as a colorless oil.

[0186] 4-(benzylthio)-2-methyl-2H-1,2,3-triazole (I13.1): 3.02 g, 36%. 1 H NMR (400 MHz, DMSO-d6, 25°C): δ = 7.67 (s, 1H), 7.2-7.3 (m, 5H), 4.18 (s, 2H), 4.10 (s, 3H) ppm. LC-MS (ESI+): 206.1 (M+H + ). HPLC RT: 1.529 min (Method: TACC21-6).

[0187] 5-(benzylthio)-1-methyl-1H-1,2,3-triazole (I13.2): 1.04 g, 11%. 1 H NMR (400 MHz, DMSO-d6, 25℃): δ = 7.70 (s, 1H), 7.2-7.3 (m, 3H), 7.1-7.2 (m, 2H), 4.09 (s, 2H), 3.73 (s, 3H) ppm. LC-MS (ESI + ): 206.1 (M+H+). HPLC RT: 1.334 min (Method: TACC21-6).

[0188] 4-(benzylthio)-1-methyl-1H-1,2,3-triazole (I13.3): 1.95 g, 21%. 1 H NMR (400 MHz, DMSO-d6, 25℃): δ = 8.01 (s, 1H), 7.2-7.3 (m, 5H), 4.11 (s, 2H), 3.99 (s, 3H) ppm. LC-MS (ESI+): 206.1 (M+H + ). HPLC RT: 1.250 min (Method: TACC21-6).

[0189] Synthesis of 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (I13.4) [ka] To a solution of 4-(benzylthio)-2-methyl-2H-1,2,3-triazole (3.0 g, 14.7 mmol, 113.1) in a mixture of acetic acid (46 mL) and water (23 mL) was added N-chlorosuccinimide (7.8 g, 58.8 mmol, 4.0 equiv.) at 0 °C. After stirring at room temperature for 18 h, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (75 mL). The organic phase was then washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the expected sulfonyl chloride as a colorless oil, which was used without further purification (2.5 g, 13.8 mmol, 95%). LC-MS (ESI+): 182.1 (M+H + ).

[0190] Synthesis of 2-methyl-2H-1,2,3-triazole-4-sulfonamide (I13.5) [ka] Ammonia gas was bubbled through a solution of 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (2.56 g, 14.1 mmol, 113.4 ml) in dichloromethane (100 mL) at room temperature for 10 minutes. Upon completion, the solvent was removed under reduced pressure and the resulting slurry was triturated with ethyl acetate. The precipitate was removed by filtration through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the sulfonamide as a yellow oil, which was used in the next step without further purification (2.2 g, 13.6 mmol, 97% yield). LC-MS (ESI+): 163.0 (M+H + ).

[0191] Dimethyl ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (I13) [ka] To 2-methyl-2H-1,2,3-triazole-4-sulfonamide (2.2 g, 13.7 mmol, 113.5 mL) and carbon disulfide (1.35 mL, 22.4 mmol, 1.6 equiv.) in dimethylformamide (21 mL) cooled in an ice bath was added a solution of potassium hydroxide (1.8 g, 32.3 mmol, 2.4 equiv.) in water (7 mL) dropwise, maintaining the internal temperature below 10° C. After stirring at 0° C. for 1 hour, iodomethane (2.0 mL, 31.8 mmol, 2.3 equiv.) was added dropwise, maintaining the internal temperature below 10° C. After stirring to room temperature for 2 hours, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using an ethyl acetate / heptane mixture (0 / 100 to 30 / 70, v / v) to give the expected compound as a yellowish viscous oil (1.17 g, 4.4 mmol, 32% yield). LC-MS (ESI+): 267.0 (M+H + ).

[0192] Synthesis of the intermediate dimethyl ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-carbonimidodithioate (I14) Synthesis of (E)-3-(4-chlorophenyl)-N'-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (I14.1) [ka] To a solution of 5-(benzylthio)-1-isopropyl-1H-1,2,3-triazole (1.04 g, 4.5 mmol, 112.3 eq.) in acetic acid (8 mL) and water (4 mL) was added N-chlorosuccinimide (2.4 g, 17.8 mmol, 4.0 equiv.) at 0 °C. After stirring at room temperature for 18 h, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v) to give the expected sulfonyl chloride as a white solid (0.62 g, 2.9 mmol, 67%). LC-MS (ESI+): 210.0 (M+H + ).

[0193] Synthesis of 1-isopropyl-1H-1,2,3-triazole-5-sulfonamide (I14.2) [ka] Ammonia gas was bubbled through a solution of 1-isopropyl-1H-1,2,3-triazole-5-sulfonyl chloride (0.62 g, 2.97 mmol, 114.1) in dichloromethane (30 mL) at room temperature for 10 minutes. Upon completion, the solvent was removed under reduced pressure and the resulting slurry was triturated with ethyl acetate. The precipitate was removed by filtration through a pad of Celite, and the filtrate was concentrated under reduced pressure to give the sulfonamide as a yellow oil, which was used in the next step without further purification (0.55 g, 2.89 mmol, 97% yield). LC-MS (ESI+): 191.0 (M+H + ).

[0194] Synthesis of dimethyl ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)carbonimidodithioate (I14) [ka] To 1-isopropyl-1H-1,2,3-triazole-5-sulfonamide (0.55 g, 2.9 mmol, 114.2%) and carbon disulfide (0.28 mL, 4.7 mmol, 1.6 equiv.) in dimethylformamide (6 mL) cooled in an ice bath was added a solution of potassium hydroxide (0.4 g, 6.8 mmol, 2.4 equiv.) in water (2 mL) dropwise, while maintaining the internal temperature below 10°C. After stirring at 0°C for 1 hour, iodomethane (0.42 mL, 6.7 mmol, 2.3 equiv.) was added dropwise, while maintaining the internal temperature below 10°C. After stirring to room temperature for 2 hours, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using an ethyl acetate / heptane mixture (0 / 100 to 30 / 70, v / v) to give the expected compound as a colorless oil (0.29 g, 0.97 mmol, 34% yield). LC-MS (ESI+): 295.0 (M+H + ).

[0195] Synthesis of methyl ((1-methyl-1H-pyrazol-4-yl)sulfonyl)carbamate (I15) [ka] To a solution of I15.0 (300 mg, 1.86 mmol, 1 equiv) in acetonitrile (3 mL) was added triethylamine (647.65 μL, 4.65 mmol, 2.5 equiv) and methyl carbonochloridate (230.67 μL, 2.98 mmol, 1.6 equiv) at 0° C. After stirring at room temperature for 12 h, the reaction mixture was quenched with water (5 mL) and concentrated under reduced pressure to give a residue. The residue was redissolved in water (5 mL). The mixture was adjusted to pH=3 with aqueous HCl (1N) and filtered. The filter cake was dried under high vacuum to give I15 (300 mg) as a white solid, which was used in the next step without further purification. LCMS (ESI+): m / z 219.9 (M+H) + .

[0196] Synthesis of 3-amino-2-methylpropane-1-sulfonamide (I16) Synthesis of benzyl (3-hydroxy-2-methylpropyl)carbamate (16.1) [ka] To a solution of 3-amino-2-methyl-propan-1-ol (3.67 g, 41.2 mmol, 1.0 equiv.) and potassium carbonate (11.4 g, 82.3 mmol, 2.0 equiv.) in tetrahydrofuran / water (1:1) (136 mL) was added benzyl chloroformate (6.4 mL, 45.3 mmol, 1.1 equiv.) at 0 °C. After stirring at room temperature for 1 h, the solvent was partially removed under reduced pressure. The mixture was extracted with ethyl acetate (60 mL), separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane (0 / 100 to 100 / 0, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as a colorless oil (0.6 g, 6% yield). LC-MS (ESI+): 224.1 (M+H) + ).

[0197] Synthesis of 3-(((benzyloxy)carbonyl)amino)-2-methylpropyl methanesulfonate (I16.2) [ka] To a mixture of benzyl (3-hydroxy-2-methylpropyl)carbamate (0.562 g, 2.517 mmol, 116.1) and triethylamine (0.39 mL, 2.77 mmol, 1.1 equiv.) in dichloromethane (8 mL) was added methanesulfonyl chloride (0.2 mL, 2.6 mmol, 1.05 equiv.) at 0 °C. After stirring at room temperature for 1 h, the reaction was diluted with dichloromethane (25 mL) and washed with ammonium chloride (20 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the expected product as a colorless oil (0.73 g, 97% yield). LC-MS (ESI+): 302.7 (M+H + ).

[0198] Synthesis of S-(3-(((benzyloxy)carbonyl)amino)-2-methylpropyl) ethanethioate (I16.3) [ka] Potassium thioacetate (1.4 g, 12.2 mmol, 5.0 equiv.) was added to a solution of 3-(((benzyloxy)carbonyl)amino)-2-methylpropyl methanesulfonate (0.73 g, 2.4 mmol, I16.2) in dimethylformamide (9 mL). After stirring at room temperature for 18 h, the reaction mixture was diluted with ethyl acetate (45 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica eluting with an ethyl acetate / heptane mixture (0 / 100 to 70 / 30, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as a yellow oil (0.49 g, 71% yield). LC-MS (ESI+): 281.9 (M+H + ).

[0199] Synthesis of benzyl (2-methyl-3-sulfamoylpropyl)carbamate (I16.4) [ka] To a solution of N-chlorosuccinimide (0.93 g, 7.0 mmol, 4.0 equiv.) in acetonitrile (29 mL) containing 2 M hydrochloric acid solution (1.02 mL, 2.04 mmol, 1.2 equiv.), S-(3-(((benzyloxy)carbonyl)amino)-2-methylpropyl)ethanethiolate (0.49 g, 1.7 mmol, 116.3) in acetonitrile (29 mL) was added dropwise at 0 °C. After stirring at room temperature for 1 h, 25% ammonia in water (29 mL) was added. After stirring at room temperature for 2 h, the solvent was partially removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with an ethyl acetate / heptane mixture (0 / 100 to 70 / 30, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as a white solid (0.45 g, 90% yield). LC-MS (ESI+): 286.9 (M+H + ).

[0200] Synthesis of 3-amino-2-methylpropane-1-sulfonamide (I16) [ka] To a solution of benzyl (2-methyl-3-sulfamoylpropyl)carbamate (0.5 g, 1.7 mmol, I16.4) in ethanol (17 mL) was added 10 wt% palladium on carbon (0.2 g, 0.17 mmol, 0.1 equiv.). The reaction mixture was degassed under reduced pressure and saturated with hydrogen (this was repeated three times). After stirring under a hydrogen atmosphere at room temperature for 4 hours, the suspension was filtered through a Celite pad and concentrated under reduced pressure to give the expected amine as a brown solid (0.185 g, 70% yield). LC-MS (ESI+): 153.0 (M+H + ).

[0201] Synthesis of 4-aminobutane-2-sulfonamide (I17) Synthesis of 3-(benzyloxy)butanenitrile (I17.1) [ka] To potassium tert-butoxide (0.04 g, 0.335 mmol, 0.01 equiv.) under a nitrogen atmosphere were added benzyl alcohol (3.62 g, 33.45 mmol, 1.0 equiv.) and but-3-enenitrile (2.74 mL, 33.45 mmol, 1.0 equiv.). After stirring at room temperature for 16 h, the mixture was neutralized, subjected to aqueous workup, dried, filtered, and concentrated. The residue was purified on silica gel using an ethyl acetate / heptane mixture (0 / 100 to 40 / 60, v / v) to give the expected product as a colorless oil (3.56 g, 20.3 mmol, 61% yield). LC-MS (ESI+): 176.2 (M+H) + ).

[0202] Synthesis of the intermediate 3-(benzyloxy)butan-1-amine (I17.2) [ka] A solution of 3-(benzyloxy)butanenitrile (3.24 g, 18.5 mmol, 117.1) containing platinum(IV) oxide (0.21 g, 0.92 mmol, 0.05 equiv.) in ethanol (185 mL) was degassed under reduced pressure and saturated with hydrogen (this was repeated three times). After stirring under a hydrogen atmosphere at room temperature for 72 h, the suspension was filtered through a Celite pad and concentrated under reduced pressure to give the expected amine as a colorless oil (3.3 g, 22.1 mmol, quantitative yield). LC-MS (ESI+): 180.3 (M+H + ).

[0203] Synthesis of 2-(3-(benzyloxy)butyl)isoindoline-1,3-dione (I17.3) [ka] Phthalic anhydride (3.3 g, 22.1 mmol, 1.1 equiv.) and 3-(benzyloxy)butan-1-amine (3.6 g, 20.1 mmol, 117.2 eq.) were dissolved in acetic acid. After stirring at reflux for 16 h, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 20 / 80, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected product as a colorless oil (3.05 g, 9.8 mmol, 49% yield). LC-MS (ESI+): 309.9 (M+H) + ).

[0204] Synthesis of 2-(3-hydroxybutyl)isoindoline-1,3-dione (I17.4) [ka] A solution of 2-(3-(benzyloxy)butyl)isoindoline-1,3-dione (3.05 g, 9.8 mmol, 117.3 ml) containing palladium on carbon (10 wt%) (1.0 g, 0.98 mmol, 0.1 equiv.) in ethanol (100 mL) was degassed under reduced pressure and then saturated with hydrogen, which was repeated three times. After stirring at room temperature for 4 hours, the suspension was filtered through a pad of Celite and concentrated under reduced pressure to give the expected alcohol as a brown solid (2.1 g, 9.7 mmol, quantitative yield). LC-MS (ESI+): 219.9 (M+H + ).

[0205] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butan-2-yl methanesulfonate (I17.5) [ka] To a mixture of 2-(3-hydroxybutyl)isoindoline-1,3-dione (2.1 g, 9.7 mmol, 117.4 ml) and triethylamine (1.48 mL, 10.6 mmol, 1.1 equiv.) in dichloromethane (32 mL) was added methanesulfonyl chloride (0.79 mL, 10.2 mmol, 1.05 equiv.) at 0 °C. After stirring at room temperature for 1 h, the mixture was diluted with dichloromethane (20 mL) and extracted with ammonium chloride (30 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash column chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected compound as a colorless oil (1.3 g, 4.37 mmol, 45% yield). LC-MS (ESI+): 297.9 (M+H) + ).

[0206] Synthesis of S-(4-(1,3-dioxoisoindolin-2-yl)butan-2-yl) ethanethiolate (I17.6) [ka] Potassium thioacetate (2.5 g, 21.9 mmol, 5.0 equiv.) was added to a solution of 4-(1,3-dioxoisoindolin-2-yl)butan-2-yl methanesulfonate (1.3 g, 4.37 mmol, I17.5) in dimethylformamide (15 mL). After stirring at room temperature for 18 h, the solvent was partially removed under reduced pressure. The residue was diluted with ethyl acetate (40 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 70 / 30, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as a yellow oil (0.94 g, 3.4 mmol, 77% yield). LC-MS (ESI+): 277.9 (M+H + ).

[0207] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonic acid (I17.7) [ka] To a solution of S-(4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)ethanethiolate (0.94 g, 3.4 mmol, I17.6) in acetic acid (4 mL) was added a mixture of hydrogen peroxide (30% w / w in water) (4 mL) in acetic acid (8 mL). After stirring at room temperature for 16 h, palladium on carbon (10% wt, 50% wet) was added to quench excess hydrogen peroxide. The resulting suspension was filtered through a pad of Celite and concentrated under reduced pressure. The residue was co-evaporated with toluene (x3) and concentrated to dryness under reduced pressure to give a brown solid which was used in the next step without further purification (0.82 g, 2.9 mmol, 85% yield). LC-MS (ESI+): 283.8 (M+H + ).

[0208] Synthesis of (1,3-dioxoisoindolin-2-yl)butane-2-sulfonyl chloride (I17.8) [ka] A solution of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonic acid (0.82 g, 2.9 mmol, I 17.7) in thionyl chloride (10 mL) was refluxed at 80 °C for 16 h. Upon completion, the solvent was removed under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected compound as a colorless oil (0.38 g, 1.25 mmol, 43% yield). LC-MS (ESI+): 301.8 (M+H + ).

[0209] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonamide (I17.9) [ka] Ammonia was bubbled through a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonyl chloride (0.38 g, 1.25 mmol, I 17.8) in tetrahydrofuran (5 mL) for 10 min. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the expected sulfonamide as a white solid (0.35 g, 1.24 mmol, quantitative yield). LC-MS (ESI+): 282.9 (M+H + ).

[0210] Synthesis of 4-aminobutane-2-sulfonamide (I17) [ka] To a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonamide (0.35 g, 1.24 mmol, 117.9 ml) in ethanol (5 mL) was added 50-60% hydrazine hydrate (0.15 mL, 2.48 mmol, 2.0 equiv). After stirring at 80 °C for 1.5 h, the reaction was allowed to cool and diluted with cold ethanol (10 mL). The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a white solid that was used in the next step without further purification (0.19 g, 1.25 mmol, quantitative yield). LC-MS (ESI+): 153.0 (M+H + ).

[0211] Synthesis of 4-aminobutane-1-sulfonamide (I18) Synthesis of S-(4-(1,3-dioxoisoindolin-2-yl)butyl)ethanethioate (I18.1) [ka] Potassium thioacetate (12.1 g, 106.3 mmol, 3.0 equiv.) was added to a stirred solution of N-(4-bromobutyl)phthalimide (10 g, 35.4 mmol, 1.0 equiv.) in tetrahydrofuran (350 mL). After stirring at 85 °C for 5 h, the solvent was removed under reduced pressure. The resulting slurry was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 30 / 70, v / v) to give the expected product as a pale pink solid (7.3 g, 26.3 mmol, 74% yield). LC-MS (ESI+): 278.0 (M+H) + ).

[0212] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonic acid (I18.2) [ka] A mixture of hydrogen peroxide (30% w / w in water) (23 mL) and acetic acid (46 mL) was added to a solution of S-(4-(1,3-dioxoisoindolin-2-yl)butyl)ethanethioic acid (7.3 g, 26.3 mmol, 1.0 equiv.) in acetic acid (23 mL). After stirring at room temperature for 16 h, palladium on carbon (10 wt%) was added to quench excess hydrogen peroxide. The resulting mixture was filtered through a pad of Celite and concentrated under reduced pressure. The oily residue was co-evaporated with toluene (×2) and then concentrated to dryness under reduced pressure to give a beige solid, which was used in the next step without further purification (7.1 g, 25.1 mmol, 96% yield). LC-MS (ESI+): 284.0 (M+H + ).

[0213] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonyl chloride (I18.3) [ka] To a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonic acid (7.18 g, 25.3 mmol, 118.2 ml) in thionyl chloride (25 mL) was added dimethylformamide (1 mL). After stirring at 80 °C for 16 h, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (60 mL) and washed with saturated sodium bicarbonate solution (45 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with an ethyl acetate / heptane mixture (0 / 100 to 40 / 60, v / v) to give the expected sulfonyl chloride as a beige solid (5.22 g, 17.3 mmol, 68% yield). LC-MS (ESI+): 302.1 (M+H + ).

[0214] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonamide (I18.4) [ka] Ammonia gas was bubbled into a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonyl chloride (5.22 g, 17.3 mmol, 118.3 ml) in tetrahydrofuran (100 mL) for 10-15 minutes. Upon completion, the reaction mixture was filtered through a pad of Celite, washed with additional tetrahydrofuran (35 mL), and concentrated under reduced pressure to give a beige solid, which was used in the next step without further purification (4.80 g, 17.0 mmol, 98% yield). LC-MS (ESI+): 283.0 (M+H + ).

[0215] Synthesis of 4-aminobutane-1-sulfonamide (I18) [ka] 4-(1,3-Dioxoisoindolin-2-yl)butane-1-sulfonamide (4.80 g, 17.0 mmol, 118.4%) and 50-60% hydrazine hydrate (6.3 mL, 102 mmol, 6.0 equiv.) were refluxed in ethanol (170 mL). After stirring at 80 °C for 18 h, the reaction mixture was allowed to cool and diluted with cold ethanol (50 mL). The filtrate was concentrated under reduced pressure to give the expected compound as a white solid, which was used in the next step without further purification (2.2 g, 14.5 mmol, 85% yield). LC-MS (ESI+): 153.1 (M+H) + ).

[0216] Synthesis of the intermediate 3-(4-chlorophenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole (I19) [ka] Synthesis of intermediate (I19.1) A mixture of I19.0 (15 g, 76.27 mmol, 1 equiv.), dimethylamine hydrochloride (24.88 g, 305.08 mmol, 4 equiv.), acetic acid (1.96 mL, 34.32 mmol, 0.45 equiv.), and formaldehyde (5.25 mL, 190.67 mmol, 2.5 equiv.) was stirred at 80 °C for 18 h. After stirring at 120 °C for 2 h in a microwave reactor, the mixture was cooled to room temperature, quenched with saturated NH4Cl (aqueous, 100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give I19.1 (10 g, 43.13 mmol, 56%) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI+): m / z 209.1 (M+H)+. 1H NMR:400 MHz, CDCl3δ ppm 1.05 (d, J=6.79 Hz, 6H), 2.95 (quin, J=6.91 Hz, 1H), 5.38 (s, 11H), 5.66 (d, J=1.31 Hz, 1H), 7.34 (d, J=8.58 Hz, 2H), 7.59 - 7.70 (m, 2H).

[0217] Synthesis of intermediate I19 To a solution of I19.1 (3 g, 14.38 mmol, 1 equiv.) in ethanol (30 mL) was added hydrazine monohydrate (3.49 mL, 71.88 mmol, 5 equiv.) at room temperature. After stirring at 80 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ethanol (20 mL) and filtered to give I19 (1 g, 4.04 mmol, 28%) as a white solid. LCMS (ESI+): m / z 223.1 (M+H)+. 1 H NMR:400 MHz, DMSO-d6δ ppm 0.66 (d, J=6.79 Hz, 3H), 0.92 (d, J=6.91 Hz, 3H), 1.96 (td, J=6.85, 3.58 Hz, 1H), 3.35 - 3.41 (m, 2H), 3.42 - 3.49 (m, 1H), 7.37 - 7.45 (m, 2H), 7.60 - 7.66 (m, 2H).

[0218] Example 2: Synthesis of compounds Synthesis of (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((S)-1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 1) and (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-(1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 2) [ka] To a solution of (S)-2-aminopropane-1-sulfonamide (105 mg, 0.76 mmol, 1.5 equiv., I1) and triethylamine (0.22 mL, 1.52 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (250 mg, 0.51 mmol, 1.0, CAS number: 1148142-85-1). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (25 mL) and washed with aqueous HCl (2 N, 20 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica flash chromatography eluting with an ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) to give a colorless oil (a mixture of both diastereoisomers). To separate the diastereomers, a second chromatography run was performed using a gentle gradient of an acetic acid / heptane mixture (0 / 100 to 70 / 30, v / v) to obtain both fractions separately.

[0219] Compound 1: (26.1 mg, 0.044 mmol, 9% yield, 97% purity, 94% de, OR: -35.4). 1 H NMR (DMSO-d6, 400 MHz) δ 7.98 (br s, 1H), 7.8-7.9 (m, 2H), 7.72 (d, J=8.6 Hz, 2H), 7.5-7.6 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 6.93 (br s, 2H), 5.10 (dd, J=4.4, 11.2 Hz, 1H), 4.53 (t, J=11.2 Hz, 1H), 4.40 (br s, 1H), 4.13 (br dd, J=3.9, 11.0 Hz, 1H), 3.4 (m, 1H), 3.22 (dd, J=6.3, 14.1 Hz, 1H), 1.28 (d, J=6.7 Hz, 3H). LC-MS (ESI+): 594.0 (M+H + ).

[0220] Compound 2: (46.7 mg, 0.08 mol, 16% yield, 99% purity, 99% ee, OR: +116.8). 1 H NMR (DMSO-d6, 400 MHz) δ 7.96 (br d, J=8.3 Hz, 1H), 7.8-7.9 (m, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.5-7.6 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 6.95 (s, 2H), 5.09 (dd, J=4.3, 11.2 Hz, 1H), 4.58 (t, J=11.3 Hz, 1H), 4.3-4.5 (m, 1H), 4.08 (br dd, J=4.2, 11.2 Hz, 1H), 3.44 (dd, J=6.3, 14.1 Hz, 1H), 3.24 (dd, J=6.1, 14.1 Hz, 1H), 1.26 (d, J=6.7 Hz, 3H). LC-MS (ESI+): 594.0 (M+H + ).

[0221] (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((R)-1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 3) and (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((R)-1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 4) [ka] To a solution of (R)-2-aminopropane-1-sulfonamide (126 mg, 0.91 mmol, 1.5 equiv.) and triethylamine (0.26 mL, 1.83 mmol, 3.0 equiv.) in dichloromethane (3 mL) was added (E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (300 mg, 0.61 mmol, 1.0 equiv.). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 80 / 20, v / v) to give a colorless oil, which was further subjected to SFC separation to give the following two different diastereomers:

[0222] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0223] Compound 3: (32.0 mg, 0.05 mmol, 9% yield, 99% purity, 99% ee, OR: -79.1). 11H NMR (DMSO-d6, 400 MHz) δ 7.96 (broad d, J = 1.1 Hz, 1H), 7.8 - 7.9 (m, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.5 - 7.6 (m, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 6.96 (broad s, 2H), 5.09 (dd, J = 4.3, 11.2 Hz, 1H), 4.58 (t, J = 11.2 Hz, 1H), 4.41 (broad s, 1H), 4.09 (broad dd, J = 4.1, 11.1 Hz, 1H), 3.44 (dd, J = 6.3, 14.1 Hz, 1H), 3.25 (dd, J = 6.1, 14.1 Hz, 1H), 1.26 (d, J = 6.7 Hz, 3H). LC-MS (ESI+): 596.1 (M + H + ).

[0224] Compound 4: (28.1 mg, 0.05 mol, 8% yield, 99% purity, 99% ee, OR: +48.4). 1 1H NMR (DMSO-d6, 400 MHz) δ 7.98 (broad d, J = 7.8 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.33 (s, 2H), 7.2 - 7.3 (m, 3H), 6.93 (s, 2H), 5.10 (dd, J = 4.2, 11.1 Hz, 1H), 4.53 (t, J = 11.2 Hz, 1H), 4.40 (broad d, J = 4.0 Hz, 1H), 4.13 (broad dd, J = 3.5, 11.0 Hz, 1H), 3.37 (broad d, J = 6.3 Hz, 1H), 3.2 (m, 1H), 1.28 (d, J = 6.6 Hz, 3H). LC-MS (ESI+): 596.0 (M + H + ).

[0225] (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 5), (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 6), (R Synthesis of (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 7) and (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 8) [ka] To a stirred solution of 1-aminopropane-2-sulfonamide hydrochloride (0.18 g, 1.02 mmol, 1.5 equiv.) and triethylamine (0.28 mL, 2.05 mmol, 3.0 equiv.) in dichloromethane (3.5 mL) was added (E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.34 g, 0.68 mmol, 1.0). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with ammonium chloride (15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 60 / 40, v / v) to give a colorless oil as a mixture, which was further subjected to SFC separation to give four isomers.

[0226] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 2.5 mL / min CO2 (60%) / MeOH + 0.1% diethylamine, 35 °C, and 100 bar BPR. The DAD detector acquisition frequency was set at 220 nm. Absolute stereochemistry was not determined. Diastereomers with negative OR were arbitrarily assigned as S isomers.

[0227] Compound 5: (16.1 mg, 0.03 mmol, 4% yield, 99% purity, 99% ee, OR: -63.0). 1 H NMR (CDCl3, 400 MHz) δ 7.85 (br d, J=8.3 Hz, 2H), 7.66 (br s, 1H), 7.53 (br d, J=8.3 Hz, 2H), 7.39 (br d, J=8.3 Hz, 2H), 7.3-7.4 (m, 3H), 7.25 (s, 2H), 7.12 (br d, J=7.0 Hz, 2H), 4.95 (br s, 2H), 4.70 (br dd, J=4.4, 10.2 Hz, 1H), 4.53 (br t, J=11.2 Hz, 1H), 3.9-4.1 (m, 3H), 3.51 (br s, 1H), 1.46 (br d, J=6.2 Hz, 3H). LC-MS (ESI+): 594.1 (M+H + ).

[0228] Compound 6: (27.0 mg, 0.045 mmol, 7% yield, 99% purity, 99% ee, OR: -97.8). 1H NMR (DMSO-d6, 400 MHz) δ 8.13 (br s, 1H), 7.7-7.9 (m, 4H), 7.4-7.6 (m, 4H), 7.2-7.4 (m, 5H), 6.99 (br s, 2H), 5.11 (br d, J=7.1 Hz, 1H), 4.55 (br t, J=11.0 Hz, 1H), 4.13 (br d, J=7.2 Hz, 1H), 3.70 (br d, J=12.5 Hz, 1H), 3.56 (br d, J=6.4 Hz, 1H), 2.8-3.0 (m, 1H), 1.17 (br d, J=6.5 Hz, 3H). LC-MS (ESI+): 594.0 (M+H + ).

[0229] Compound 7: (52.1 mg, 0.09 mmol, 13% yield, 98% purity, 99% ee, OR: +111.1). 1 H NMR (DMSO-d6, 400 MHz) δ 8.1-8.2 (m, 1H), 7.83 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 6.98 (s, 2H), 5.11 (dd, J=4.3, 11.2 Hz, 1H), 4.58 (t, J=11.2 Hz, 1H), 4.08 (dd, J=4.2, 11.1 Hz, 1H), 3.7 (m, 1H), 3.57 (td, J=6.8, 13.9 Hz, 1H), 3.2-3.3 (m, 1H), 1.18 (d, J=7.0 Hz, 3H). LC-MS (ESI+): 594.0 (M+H + ).

[0230] Compound 8: (55.2 mg, 0.093 mmol, 14% yield, 99% purity, 99% ee, OR: +102.2). 1H NMR (DMSO-d6, 400 MHz) δ 8.07 (br s, 1H), 7.7-7.8 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.5 (m, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.2-7.3 (m, 2H), 7.2 (m, 3H), 6.92 (s, 2H), 5.04 (dd, J=4.4, 11.2 Hz, 1H), 4.48 (t, J=11.1 Hz, 1H), 4.07 (br dd, J=4.2, 11.0 Hz, 1H), 3.63 (br d, J=13.3 Hz, 1H), 3.4-3.5 (m, 1H), 3.2 (m, 1H), 1.10 (d, J=6.9 Hz, 3H). LC-MS (ESI+): 594.0 (M+H + ).

[0231] Synthesis of (S,E)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 9) and (R,E)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 10) [ka] To a stirred solution of 2-aminoethane-1-sulfonamide hydrochloride (84 mg, 0.53 mmol, 1.1 equiv.) and triethylamine (0.2 mL, 1.42 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.25 g, 0.47 mmol, 9.0, CAS number: 2561196-52-7) at room temperature. After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with HCl (2 N, 15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC separation conditions.

[0232] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Cellulose-4) 100 mm long x 4.6 mm i.d., 3 μm particle size, in isocratic mode at 2.5 mL / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0233] Compound 9: (54.1 mg, 0.09 mmol, 19% yield, 98% purity, 99% ee). 11H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.25 (ddd, J = 11.6, 6.7, 4.1 Hz, 3H), 7.02 (s, 2H), 5.09 (dd, J = 11.0, 4.1 Hz, 1H), 4.54 (t, J = 11.1 Hz, 1H), 4.05 (dd, J = 11.0, 4.2 Hz, 1H), 3.73 (t, J = 6.6 Hz, 2H), 3.35 - 3.20 (m, 2H). LC-MS (ESI+): 614.0 (M+H + )。

[0234] Compound 10: (57.8 mg, 0.09 mmol, 20% yield, 99% purity, 99% ee). 1 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.25 (ddd, J = 11.4, 6.7, 4.1 Hz, 3H), 7.02 (s, 2H), 5.10 (dd, J = 11.1, 4.3 Hz, 1H), 4.54 (t, J = 11.1 Hz, 1H), 4.05 (dd, J = 10.9, 4.1 Hz, 1H), 3.73 (t, J = 6.7 Hz, 2H), 3.30 - 3.23 (m, 2H). LC-MS (ESI+): 614.0 (M+H + )。

[0235] Synthesis of (S,E)-3-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 11) and (R,E)-3-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 12) Synthesis of Compound 11.1: [ka] To a solution of 3-(4-chlorophenyl)-N-((4-fluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (0.9 g, 1.96 mmol, 11.0 g, CAS number: 656827-60-0) in toluene (6 mL) was added phosphorus pentachloride (0.45 g, 2.16 mmol, 1.1 equiv.) at room temperature. After stirring at 120° C. for 4 hours, the solvent was partially removed under reduced pressure, quenched with water (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a brown foam (0.73 g, 1.54 mmol, 78% yield). LC-MS (ESI+): 476.040 (M+H + ).

[0236] Synthesis of Compounds 11 and 12 [ka] To a stirred solution of 2-aminoethane-1-sulfonamide hydrochloride (0.1 g, 0.63 mmol, 1.5 equiv.) and triethylamine (0.2 mL, 1.4 mmol, 3.0 equiv.) in dichloromethane (4 mL) was added (E)-3-(4-chlorophenyl)-N-((4-fluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.2 g, 0.42 mmol, 11.1). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous ammonium chloride (15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50, v / v) to give a colorless oil as a racemic mixture, which was further subjected to SFC separation conditions.

[0237] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 2.5 mL / min CO2 (60%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0238] Compound 11: (21.4 mg, 0.04 mmol, 9% yield, 99% purity, 99% ee, OR: -114.8). 11H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 5.1, 8.8 Hz, 2H), 7.65 (br s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.3 (m, 3H), 7.2 (m, 2H), 7.1 (m, 4H), 5.37 (br s, 2H), 4.67 (dd, J = 5.3, 11.3 Hz, 1H), 4.53 (t, J = 11.5 Hz, 1H), 4.18 (q, J = 5.9 Hz, 2H), 4.05 (dd, J = 5.4, 11.5 Hz, 1H), 3.54 (br t, J = 5.8 Hz, 2H). LC-MS (ESI+): 564.0 (M+H + ).

[0239] Compound 12: (19.8 mg, 0.035 mmol, 8% yield, 97% purity, 99% ee, OR: +85.1). 1 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 5.1, 8.8 Hz, 2H), 7.62 (br s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.4 (m, 3H), 7.3 (m, 2H), 7.1 (m, 4H), 5.14 (br s, 2H), 4.70 (dd, J = 5.3, 11.3 Hz, 1H), 4.55 (t, J = 11.4 Hz, 1H), 4.20 (q, J = 5.8 Hz, 2H), 4.07 (dd, J = 5.3, 11.5 Hz, 1H), 3.54 (br t, J = 5.8 Hz, 2H). LC-MS (ESI+): 564.1 (M+H + ).

[0240] (S,E)-3-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 13), (S,E)-3-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 14), (R Synthesis of (R,E)-3-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 15) and (R,E)-3-(4-chlorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 16) [ka] To a stirred solution of 1-aminopropane-2-sulfonamide hydrochloride (0.21 g, 1.3 mmol, 1.5 equiv.) and triethylamine (0.33 mL, 2.4 mmol, 3.0 equiv.) in dichloromethane (4 mL) was added (E)-3-(4-chlorophenyl)-N-((4-fluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.38 g, 0.8 mmol, 11.1). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous ammonium chloride (15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 60 / 40, v / v) to give a colorless oil as a racemic mixture, which was further subjected to SFC separation conditions.

[0241] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 2.5 mL / min CO2 (60%) / MeOH + 0.1% diethylamine, 35 °C, and 100 bar BPR. The DAD detector acquisition frequency was set at 220 nm. Absolute stereochemistry was not determined. Diastereomers with negative OR were arbitrarily assigned as S isomers.

[0242] Compound 13: (14.3 mg, 0.025 mmol, 3% yield, 97% purity, 99% ee, OR: -99.2). 1 H NMR (400 MHz, CDCl3) δ 7.9 (m, 2H), 7.62 (br t, J=6.0 Hz, 1H), 7.55 (m, 2H), 7.3 (m, 3H), 7.2 (m, 2H), 7.1 (m, 4H), 4.95 (br s, 2H), 4.68 (dd, J=5.4, 11.4 Hz, 1H), 4.5 (m, 1H), 4.1 (m, 3H), 3.5 (m, 1H), 1.47 (d, J=7.1 Hz, 3H). LC-MS (ESI+): 578.1 (M+H + ).

[0243] Compound 14: (12.5 mg, 0.022 mmol, 3% yield, 96% purity, 99% ee, OR: -120.8). 1 H NMR (400 MHz, CDCl3) δ 7.9 (m, 2H), 7.62 (br t, J=6.0 Hz, 1H), 7.55 (m, 2H), 7.3 (m, 3H), 7.2 (m, 2H), 7.1 (m, 4H), 4.94 (br s, 2H), 4.69 (dd, J=5.4, 11.4 Hz, 1H), 4.54 (t, J=11.5 Hz, 1H), 3.9-4.1 (m, 3H), 3.5 (m, 1H), 1.46 (d, J=7.0 Hz, 3H). LC-MS (ESI+): 578.1 (M+H+ ).

[0244] Compound 15: (7.7 mg, 0.013 mmol, 2% yield, 99% purity, 99% ee, OR: +87.05). 1 H NMR (400 MHz, CDC l3 ) δ 7.95 (m, 2H), 7.62 (br t, J=6.0 Hz, 1H), 7.55 (m, 2H), 7.35 (m, 3H), 7.25 (m, 2H), 7.1 (m, 4H), 4.92 (br s, 2H), 4.69 (dd, J=5.3, 11.4 Hz, 1H), 4.55 (m, 1H), 3.9-4.1 (m, 3H), 3.51 (dt, J=4.0, 7.2 Hz, 1H), 1.47 (d, J=7.0 Hz, 3H). LC-MS (ESI+): 578.1 (M+H + ).

[0245] Compound 16: (9.7 mg, 0.017 mmol, 2% yield, 99% purity, 99% ee, OR: +77.4). 1 H NMR (400 MHz, CDCl3) δ 7.95 (m, 2H), 7.61 (br t, J=6.0 Hz, 1H), 7.55 (m, 2H), 7.35 (m, 3H), 7.25 (m, 2H), 7.15 (m, 4H), 4.88 (br s, 2H), 4.69 (dd, J=5.4, 11.4 Hz, 1H), 4.54 (t, J=11.5 Hz, 1H), 3.9-4.2 (m, 3H), 3.51 (dt, J=4.1, 7.2 Hz, 1H), 1.47 (d, J=7.1 Hz, 3H,). LC-MS (ESI+): 578.1 (M+H + ).

[0246] (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 17), (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 18), (R Synthesis of (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 19) and (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 20) [ka] To a stirred solution of 1-aminopropane-2-sulfonamide hydrochloride (0.114 g, 0.65 mmol, 1.5 equiv.) and triethylamine (0.18 mL, 1.3 mmol, 3.0 equiv.) in dichloromethane (3 mL) was added (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.23 g, 0.43 mmol, 9.0) at room temperature. After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous ammonium chloride (15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 60 / 40, v / v) to give a colorless oil as a racemic mixture, which was further subjected to SFC separation conditions.

[0247] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 2.5 mL / min CO2 (60%) / MeOH + 0.1% diethylamine, 35 °C, and 100 bar BPR. The DAD detector acquisition frequency was set at 220 nm. Absolute stereochemistry was not determined. Diastereomers with negative OR were arbitrarily assigned as S isomers.

[0248] Compound 17: (22.1 mg, 0.035 mmol, 8% yield, 95% purity, 99% ee, OR: -96.0). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 2H), 7.63-7.73 (m, 3H), 7.54 (d, J = 8.6 Hz, 2H), 7.28-7.35 (m, 3H), 7.23-7.27 (m, 2H), 7.09-7.15 (m, 2H), 4.92 (br s, 2H), 4.69 (dd, J = 11.4, 5.4 Hz, 1H), 4.54 (t, J = 11.5 Hz, 1H), 3.93-4.14 (m, 3H), 3.46-3.57 (m, 1H), 1.47 ppm (d, J = 7.0 Hz, 3H). LC-MS (ESI+): 628.1127 (M+H + ).

[0249] Compound 18: (14.3 mg, 0.022 mmol, 5% yield, 99% purity, 99% ee, OR: -90.7). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 7.63-7.73 (m, 3H), 7.51-7.58 (m, 2H), 7.27-7.36 (m, 3H), 7.23-7.27 (m, 2H), 7.12 (dd, J = 7.9, 1.3 Hz, 2H), 4.88 (br s, 2H), 4.70 (dd, J = 11.3, 5.4 Hz, 1H), 4.52 (t, J = 11.5 Hz, 1H), 4.04-4.13 (m, 2H), 3.93-4.03 (m, 1H), 3.45-3.56 (m, 1H), 1.47 ppm (d, J = 7.0 Hz, 3H). LC-MS (ESI+): 628.0 (M+H + ).

[0250] Compound 19: (25.8 mg, 0.04 mmol, 10% yield, 99% purity, 99% ee, OR: +81.8). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 7.68 (br d, J = 8.3 Hz, 3H), 7.54 (d, J = 8.7 Hz, 2H), 7.27-7.35 (m, 3H), 7.23-7.27 (m, 2H), 7.09-7.14 (m, 2H), 4.98 (br s, 2H), 4.70 (dd, J = 11.4, 5.5 Hz, 1H), 4.52 (t, J = 11.5 Hz, 1H), 4.04-4.13 (m, 2H), 3.92-4.02 (m, 1H), 3.46-3.55 (m, 1H), 1.46 ppm (d, J = 7.0 Hz, 3H). LC-MS (ESI+): 628.0 (M+H + ).

[0251] Compound 20: (17.7 mg, 0.03 mmol, 7% yield, 99% purity, 99% ee, OR: +102.7). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.1 Hz, 2H), 7.68 (d, J=8.2 Hz, 3H), 7.6 (m, 2H), 7.4 (m, 4H), 7.3 (m, 1H), 7.2 (m, 2H), 4.85 (br s, 2H), 4.70 (dd, J=5.3, 11.3 Hz, 1H), 4.54 (t, J=11.5 Hz, 1H), 3.9-4.1 (m, 3H), 3.5 (m, 1H), 1.48 (d, J=7.0 Hz, 3H). LC-MS (ESI+): 628.0 (M+H + ).

[0252] Synthesis of (S)-3-(4-chlorophenyl)-N'-((4-ethynylphenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 21) and (R)-3-(4-chlorophenyl)-N'-((4-ethynylphenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 22) Synthesis of Compound 22.1: [ka] Dimethyl ((4-ethynylphenyl)sulfonyl)carbonimidodithioate (0.43 g, 1.5 mmol, 1 equiv.) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.39 g, 1.5 mmol, 21.0 g, CAS number: 59074-26-9) were mixed in pyridine (7.5 mL). After stirring at 120 °C for 18 h, the reaction mixture was concentrated to dryness and the crude product was purified by column chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 30 / 70) to give the expected product as a yellowish oil (0.35 g, 0.71 mmol, 47% yield). LC-MS (ESI+): 494.1 (M+H + ).

[0253] Synthesis of compounds 21 and 22 [ka] 2-Aminoethane-1-sulfonamide hydrochloride (230 mg, 1.44 mmol, 2 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((4-ethynylphenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (355 mg, 0.72 mmol, 21.1 mL) and triethylamine (0.3 mL, 2.16 mmol, 3 equiv.) in methanol (3.6 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the crude product was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40). The desired fractions were collected and re-purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give a colorless oil, which was further subjected to SFC purification to separate the two enantiomers.

[0254] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0255] Compound 21: (63.6 mg, 0.11 mmol, 16% yield, 99% purity, 99% ee, OR: -85.6). 11H NMR (DMSO-d6, 400 MHz) δ 8.18 (br s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 7.03 (s, 2H), 5.09 (dd, J=4.3, 11.2 Hz, 1H), 4.53 (t, J=11.2 Hz, 1H), 4.39 (s, 1H), 4.08 (br dd, J=4.3, 11.1 Hz, 1H), 3.7 - 3.8 (m, 2H), 3.3 (m, 2H). LC-MS (ESI+): 570.0 (M+H + ).

[0256] Compound 22: (56.0 mg, 0.1 mmol, 14% yield, 99% purity, 99% ee, OR: +120.1). 1H NMR (DMSO-d6, 400 MHz) δ 8.1 - 8.2 (m, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 7.02 (s, 2H), 5.09 (dd, J=4.4, 11.2 Hz, 1H), 4.53 (t, J=11.2 Hz, 1H), 4.39 (s, 1H), 4.08 (br dd, J=4.3, 11.2 Hz, 1H), 3.73 (q, J=6.2 Hz, 2H), 3.2 - 3.3 (m, 2H). LC-MS (ESI+): 570.0 (M+H + ).

[0257] Synthesis of (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((R)-1-sulfamoylpropan-2-yl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 23) and (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((R)-1-sulfamoylpropan-2-yl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 24) [ka] To a solution of (R)-2-aminopropane-1-sulfonamide (120 mg, 0.86 mmol, 1.5 equiv.) and triethylamine (0.24 mL, 1.7 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (300 mg, 0.57 mmol, 9.0). After stirring at room temperature for 18 h, the reaction was concentrated under reduced pressure and the crude product was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40, v / v) to give a colorless oil, which was further subjected to SFC separation to give the following two different isomers:

[0258] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0259] Compound 23: (30.0 mg, 0.05 mol, 8% yield, 99% purity, 99% ee, OR: -71.4). 11H NMR (DMSO-d6, 400 MHz) δ 8.03 (broad d, J = 8.2 Hz, 3H), 7.86 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 6.96 (broad s, 2H), 5.10 (dd, J = 4.2, 11.2 Hz, 1H), 4.59 (broad t, J = 11.2 Hz, 1H), 4.39 (broad s, 1H), 4.08 (broad dd, J = 4.1, 11.1 Hz, 1H), 3.45 (dd, J = 6.3, 14.1 Hz, 1H), 3.2 - 3.3 (m, 1H), 1.25 (d, J = 6.7 Hz, 3H). LC-MS (ESI+): 628.0 (M+H + )。

[0260] Compound 24: (16.4 mg, 0.026 mmol, 4% yield, 99% purity, 99% ee, OR: +53.2). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.03 (broad d, J = 8.2 Hz, 3H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 6.93 (s, 2H), 5.11 (dd, J = 4.2, 11.2 Hz, 1H), 4.54 (t, J = 11.1 Hz, 1H), 4.40 (broad d, J = 6.0 Hz, 1H), 4.11 (broad dd, J = 4.4, 11.0 Hz, 1H), 3.4 (m, 1H), 3.21 (broad dd, J = 6.2, 14.1 Hz, 1H), 1.27 (broad d, J = 6.7 Hz, 3H). LC-MS (ESI+): 628.0 (M+H + )。

[0261] Synthesis of (S,E)-3-(4-chlorophenyl)-4-phenyl-N-((S)-1-sulfamoylpropan-2-yl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 25) and (R,E)-3-(4-chlorophenyl)-4-phenyl-N-((S)-1-sulfamoylpropan-2-yl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 26) [ka] To a solution of (S)-2-aminopropane-1-sulfonamide (100 mg, 0.71 mmol, 1.5 equiv.) and triethylamine (0.2 mL, 1.42 mmol, 3.0 equiv.) in dichloromethane (2.5 mL) was added (Z)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (250 mg, 0.47 mmol, 9.0). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40, v / v) to give a colorless oil, which was further subjected to SFC purification to separate the two diastereoisomers.

[0262] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0263] Compound 25: (13.2 mg, 0.02 mol, 4% yield, 99% purity, 99% de, OR: +202.1).1 ¹H NMR (DMSO-d6, 400 MHz) δ 8.0 - 8.1 (m, 3H), 7.86 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 6.96 (s, 2H), 5.10 (dd, J = 4.2, 11.1 Hz, 1H), 4.59 (t, J = 11.2 Hz, 1H), 4.39 (br d, J = 5.1 Hz, 1H), 4.08 (br dd, J = 4.1, 11.1 Hz, 1H), 3.45 (dd, J = 6.3, 14.1 Hz, 1H), 3.24 (dd, J = 6.1, 14.0 Hz, 1H), 1.25 (d, J = 6.7 Hz, 3H). LC-MS (ESI+): 628.0 (M+H + )。

[0264] Compound 26: (16.1 mg, 0.026 mmol, 5% yield, 92% purity, 99% de, OR: -63.4). 1 ¹H NMR (DMSO-d6, 400 MHz) δ 8.03 (br d, J = 8.2 Hz, 3H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.32 (br d, J = 7.2 Hz, 2H), 7.2 - 7.3 (m, 3H), 6.94 (s, 2H), 5.11 (dd, J = 4.1, 11.2 Hz, 1H), 4.54 (t, J = 11.1 Hz, 1H), 4.39 (br s, 1H), 4.11 (br dd, J = 3.9, 10.9 Hz, 1H), 3.4 (m, 1H), 3.2 - 3.3 (m, 1H), 1.27 (d, J = 6.7 Hz, 3H). LC-MS (ESI+): 628.1 (M+H + )。

[0265] Synthesis of (S)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 27) and (R)-3-(4-chlorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 28) Synthesis of Compound 27.1 [ka] N-(bis-methylsulfanyl-methylene)-3-trifluoromethyl-benzenesulfonamide (0.54 g, 1.63 mmol, I2) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.42 g, 1.63 mmol, 1 equiv.) in pyridine (5 mL) were refluxed (120 °C) for 18 h. Upon completion, the reaction mixture was concentrated to dryness and the crude product was purified by column chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 30 / 70, v / v) to give the expected product as a yellow foam (0.6 g, 1.12 mmol, 69% yield). LC-MS (ESI+): 538.1 (M+H) + ).

[0266] Synthesis of compounds 27 and 28 [ka] 2-Aminoethane-1-sulfonamide hydrochloride (90 mg, 0.56 mmol, 1.2 equiv.) was added to a stirred solution of N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylsulfanyl-methylene}-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.46 mmol, 27.1) and triethylamine (0.2 mL, 1.4 mmol, 3 equiv.) in methanol (4 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40, v / v) to give a colorless oil, which was further subjected to SFC purification to separate the two enantiomers.

[0267] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0268] Compound 27: (65.0 mg, 0.10 mmol, 23% yield, 99% purity, 99% ee, OR: -109.5). 11H NMR (DMSO-d6, 400 MHz) δ 8.16 (br s, 1H), 8.08 (br d, J = 7.9 Hz, 1H), 7.97 (s, 1H), 7.85 (br d, J = 7.8 Hz, 1H), 7.60 - 7.72 (m, 3H), 7.38 (d, J = 8.6 Hz, 2H), 7.23 - 7.30 (m, 2H), 7.13 - 7.22 (m, 3H), 6.94 (s, 2H), 5.04 (dd, J = 11.2, 4.3 Hz, 1H), 4.48 (t, J = 11.2 Hz, 1H), 4.00 (dd, J = 11.0, 4.3 Hz, 1H), 3.66 (br d, J = 3.5 Hz, 2H), 3.17 - 3.21 ppm (m, 2H). LC-MS (ESI+): 614.0 (M+H + )。

[0269] Compound 28: (66.3 mg, 0.11 mmol, 23% yield, 99% purity, 99% ee, OR: +86.7). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (br s, 1H), 8.15 (br d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.92 (br d, J = 7.8 Hz, 1H), 7.67 - 7.78 (m, 3H), 7.45 (d, J = 8.6 Hz, 2H), 7.30 - 7.36 (m, 2H), 7.20 - 7.29 (m, 3H), 7.00 (br s, 2H), 5.10 (dd, J = 11.1, 4.3 Hz, 1H), 4.54 (t, J = 11.2 Hz, 1H), 4.07 (dd, J = 11.0, 4.3 Hz, 1H), 3.72 (br s, 2H), 3.23 - 3.28 ppm (m, 2H). LC-MS (ESI+): 614.0 (M+H + )。

[0270] Synthesis of (S)-3-(4-chlorophenyl)-N'-((2-chlorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 29) and (R)-3-(4-chlorophenyl)-N'-((2-chlorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 30) Synthesis of 29.1 [ka] N-(bis-methylsulfanyl-methylene)-2-chloro-benzenesulfonamide (0.5 g, 1.69 mmol, I3) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.42 g, 1.63 mmol, 21.0) in pyridine (6 mL) were refluxed (120 °C) for 18 h. Upon completion, the reaction mixture was concentrated to dryness and the residue was purified by column chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 40 / 60, v / v) to give the desired product as a yellow foam (0.58 g, 1.15 mmol, 71% yield). LC-MS (ESI+): 504.0 (M+H + ).

[0271] Synthesis of compounds 29 and 30 [ka] 2-Aminoethane-1-sulfonamide hydrochloride (368 mg, 2.29 mmol, 2 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((2-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (578 mg, 1.15 mmol, 29.1) and triethylamine (0.5 mL, 3.4 mmol, 3 equiv.) in methanol (4 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure, and the residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 80 / 20, v / v) to give a colorless oil, which was further subjected to SFC purification to separate the two enantiomers.

[0272] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0273] Compound 29: (61.7 mg, 0.11 mmol, 9% yield, 99% purity, 99% ee, OR: -90.0). 1 H NMR (DMSO-d6, 400 MHz) δ 8.16 (br t, J=5.1 Hz, 1H), 8.02 (dd, J=1.5, 7.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.5-7.6 (m, 2H), 7.4-7.5 (m, 3H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 7.02 (s, 2H), 5.09 (dd, J=4.3, 11.2 Hz, 1H), 4.54 (t, J=11.2 Hz, 1H), 4.0-4.1 (m, 1H), 3.77 (q, J=6.3 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 580.2 (M+H + ).

[0274] Compound 30: (59.4 mg, 0.10 mmol, 9% yield, 99% purity, 99% ee, OR: +100.6). 1 H NMR (DMSO-d6, 400 MHz) δ 8.16 (br t, J=5.3 Hz, 1H), 8.02 (dd, J=1.3, 7.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.5-7.6 (m, 2H), 7.4-7.5 (m, 3H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 7.02 (s, 2H), 5.09 (dd, J=4.3, 11.2 Hz, 1H), 4.53 (t, J=11.2 Hz, 1H), 4.0-4.1 (m, 1H), 3.77 (q, J=6.4 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 580.2 (M+H + ).

[0275] Synthesis of (S)-3-(4-chlorophenyl)-N'-((3-chlorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 31) and (S)-3-(4-chlorophenyl)-N'-((3-chlorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 32) [ka] 2-Aminoethane-1-sulfonamide hydrochloride (0.2 g, 1.2 mmol, 1.2 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((3-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (0.51 g, 1.011 mmol, CAS number: 656827-47-3) and triethylamine (0.42 mL, 3.03 mmol, 3 equiv.) in methanol (5 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 80 / 20) to give a colorless oil, which was further subjected to SFC purification and resolved into two enantiomers as white solids.

[0276] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0277] Compound 31: (72.3 mg, 0.12 mmol, 12% yield, 99% purity, 99% ee, OR: -99.1). 11H NMR (DMSO-d6, 400 MHz) δ 8.19 (broad t, J = 5.3 Hz, 1H), 7.76 - 7.81 (multiplet, 2H), 7.71 (doublet, J = 8.6 Hz, 2H), 7.58 - 7.62 (multiplet, 1H), 7.49 - 7.55 (multiplet, 1H), 7.45 (doublet, J = 8.6 Hz, 2H), 7.30 - 7.37 (multiplet, 2H), 7.20 - 7.28 (multiplet, 3H), 7.01 (singlet, 2H), 5.09 (doublet of doublets, J = 11.2, 4.4 Hz, 1H), 4.53 (triplet, J = 11.2 Hz, 1H), 3.99 - 4.10 (multiplet, 1H), 3.69 - 3.80 (multiplet, 2H), 3.27 (broad singlet, 2H) ppm. LC-MS (ESI+): 580.04 (M+H + )。

[0278] Compound 32: (80.4 mg, 0.14 mmol, 14% yield, 99% purity, 99% ee, OR: +111.9). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.19 (broad t, J = 5.2 Hz, 1H), 7.77 - 7.82 (multiplet, 2H), 7.71 (doublet, J = 8.6 Hz, 2H), 7.57 - 7.62 (multiplet, 1H), 7.49 - 7.55 (multiplet, 1H), 7.45 (doublet, J = 8.6 Hz, 2H), 7.30 - 7.36 (multiplet, 2H), 7.20 - 7.29 (multiplet, 3H), 7.01 (singlet, 2H), 5.09 (doublet of doublets, J = 11.1, 4.2 Hz, 1H), 4.53 (triplet, J = 11.2 Hz, 1H), 4.06 (doublet of doublets, J = 11.4, 4.6 Hz, 1H), 3.74 (quartet, J = 6.1 Hz, 2H), 3.27 (broad singlet, 2H) ppm. LC-MS (ESI+): 580.04 (M+H + )。

[0279] Synthesis of (S)-3-(4-chlorophenyl)-N'-((2-ethynylphenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 33) and (R)-3-(4-chlorophenyl)-N'-((2-ethynylphenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 34) Synthesis of 33.1 [ka] Dimethyl ((2-ethynylphenyl)sulfonyl)carbonimidodithioate (0.47 g, 1.63 mmol, I4) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.42 g, 1.63 mmol, 21.0) in pyridine (3 mL) were heated at 120 °C for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50) to give the desired product as a yellow solid (0.24 g, 0.49 mmol, 30% yield). LC-MS (ESI+): 494.0 (M+H + ).

[0280] Synthesis of compounds 33 and 34 [ka] 2-Aminoethane-1-sulfonamide hydrochloride (0.31 g, 1.95 mmol, 4 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((2-ethynylphenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (0.24 g, 0.5 mmol, 33.1) and triethylamine (0.4 mL, 2.9 mmol, 6 equiv.) in methanol (5 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the residue was chromatographed on silica eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give a colorless oil, which was further subjected to SFC purification and resolved into two enantiomers as white solids.

[0281] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0282] Compound 33: (52.2 mg, 0.09 mmol, 19% yield, 95% purity, 99% ee, OR: -61.9). 11H NMR (DMSO-d6, 400 MHz) δ 8.06 (broad singlet, 1H), 7.91 - 7.96 (multiplet, 1H), 7.73 (doublet, J = 8.7 Hz, 2H), 7.58 - 7.63 (multiplet, 1H), 7.47 - 7.54 (multiplet, 2H), 7.45 (doublet, J = 8.7 Hz, 2H), 7.30 - 7.36 (multiplet, 2H), 7.21 - 7.28 (multiplet, 3H), 7.02 (broad singlet, 2H), 5.07 (broad doublet of doublets, J = 11.2, 4.5 Hz, 1H), 4.53 (broad triplet, J = 11.3 Hz, 1H), 4.47 (singlet, 1H), 4.01 - 4.08 (multiplet, 1H), 3.81 (broad singlet, 2H), 3.28 - 3.30 (multiplet, 2H) ppm. LC-MS (ESI+): 570.9 (M+H + )。

[0283] Compound 34: (56.6 mg, 0.10 mmol, 20% yield, 96% purity, 99% ee, OR: +89.9). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.06 (broad singlet, 1H), 7.91 - 7.96 (multiplet, 1H), 7.73 (doublet, J = 8.7 Hz, 2H), 7.58 - 7.64 (multiplet, 1H), 7.47 - 7.55 (multiplet, 2H), 7.45 (doublet, J = 8.7 Hz, 2H), 7.30 - 7.35 (multiplet, 2H), 7.22 - 7.28 (multiplet, 3H), 7.02 (broad singlet, 2H), 5.07 (broad doublet of doublets, J = 11.3, 4.4 Hz, 1H), 4.53 (broad triplet, J = 11.3 Hz, 1H), 4.47 (singlet, 1H), 4.05 (broad doublet of doublets, J = 11.1, 4.3 Hz, 1H), 3.81 (broad singlet, 2H), 3.28 - 3.30 (multiplet, 2H) ppm. LC-MS (ESI+): 570.9 (M+H + )。

[0284] Synthesis of (S)-3-(4-chlorophenyl)-N'-((3-ethynylphenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 35) and (R)-3-(4-chlorophenyl)-N'-((3-ethynylphenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 36) Synthesis of 35.1 [ka] Dimethyl ((3-ethynylphenyl)sulfonyl)carbonimidodithioate (2.65 g, 9.28 mmol, I5) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (2.4 g, 9.28 mmol, 21.0) in pyridine (18 mL) were heated at 120 °C for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50) to give the desired product as a yellow solid (1.94 g, 3.94 mmol, 42% yield). LC-MS (ESI+): 494.0 (M+H + ).

[0285] Synthesis of compounds 35 and 36 [ka] 2-Aminoethane-1-sulfonamide hydrochloride (0.37 g, 2.3 mmol, 4 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((3-ethynylphenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (0.28 g, 0.6 mmol, 1 equiv.) and triethylamine (0.48 mL, 3.4 mmol, 6 equiv.) in methanol (5 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the residue was chromatographed on silica eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give a colorless oil, which was further subjected to SFC purification and resolved into two enantiomers as white solids.

[0286] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0287] Compound 35: (38.2 mg, 0.07 mmol, 12% yield, 97% purity, 99% ee, OR: -98.8). 11H NMR (DMSO-d6, 400 MHz) δ 7.97-8.44 (m, 1H), 7.78-7.89 (m, 2H), 7.66-7.74 (m, J = 8.4 Hz, 2H), 7.57-7.64 (m, 1H), 7.48-7.54 (m, 1H), 7.44 (br d, J = 8.6 Hz, 2H), 7.30-7.36 (m, 2H), 7.20-7.28 (m, 3H), 7.01 (br s, 2H), 5.08 (br dd, J = 11.2, 4.1 Hz, 1H), 4.52 (br t, J = 11.1 Hz, 1H), 4.32 (s, 1H), 4.05 (br dd, J = 11.0, 4.1 Hz, 1H), 3.74 (br t, J = 6.5 Hz, 2H), 3.27 (br d, J = 7.3 Hz, 2H) ppm. LC-MS (ESI+): 570.9 (M+H + )。

[0288] Compound 36: (17.1 mg, 0.03 mmol, 5% yield, 97% purity, 99% ee, OR: +68.0). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.17 (br s, 1H), 7.79-7.90 (m, 2H), 7.70 (br d, J = 8.4 Hz, 2H), 7.62 (br d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.30-7.37 (m, 2H), 7.20-7.28 (m, 3H), 7.01 (br s, 2H), 5.08 (br dd, J = 11.3, 4.1 Hz, 1H), 4.52 (br t, J = 11.2 Hz, 1H), 4.32 (s, 1H), 4.05 (br dd, J = 11.3, 3.9 Hz, 1H), 3.74 (br t, J = 6.5 Hz, 2H), 3.26 ppm (br s, 2H). LC-MS (ESI+): 570.9 (M+H + )。

[0289] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((2,4-difluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 37) and (R,Z)-3-(4-chlorophenyl)-N'-((2,4-difluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 38) [ka] Synthesis of 37.1 To a solution of I6 (580 mg, 2.26 mmol, 1 equiv) in toluene (10 mL) was added methyl N-(2,4-difluorophenyl)sulfonylcarbamate (567.52 mg, 2.26 mmol, 21.0) at room temperature. After stirring at 110 °C for 10 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was triturated with methyl tert-butyl ether (15 mL) to give 37.1 (900 mg, 1.89 mmol, 84%) as a white solid. LCMS (ESI+): m / z 475.9 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 3.67 (dd, J=11.27, 4.83 Hz, 1H), 4.27 (t, J=11.38 Hz, 1H), 4.98 (dd, J=11.44, 4.77 Hz, 1H), 7.15-7.37 (m, 6H), 7.43 (d, J=8.70 Hz, 2H), 7.52-7.64 (m, 1H), 7.85 (d, J=8.58 Hz, 2H), 8.02 (td, J=8.64, 6.44 Hz, 1H), 11.83-12.19 (m, 1H).

[0290] Synthesis of 37.2 To a solution of 37.1 (500 mg, 1.05 mmol, 1 equiv.) in toluene (5 mL) was added N,N-diisopropylethylamine (274.51 μL, 1.58 mmol, 1.5 equiv.) and phosphorus oxychloride (126.93 μL, 1.37 mmol, 1.3 equiv.) at room temperature. After stirring at 85° C. for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with methyl tert-butyl ether (10 mL) to give 37.2 (400 mg, 809.16 μmol, 77%) as a yellow solid. The solid was used directly in the next step without further purification.

[0291] Synthesis of compounds 37 and 38 To a solution of 37.2 (390 mg, 788.93 μmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (319.32 mg, 3.16 mmol, 439.24 μL, 4 equiv.) and 2-aminoethanesulfonamide (146.93 mg, 1.18 mmol, 1.5 equiv.) at room temperature. After stirring at room temperature for 12 h, the reaction mixture was concentrated under reduced pressure to give a solid, which was triturated with methyl tert-butyl ether (10 mL) to give the racemic compound (380 mg, 652.87 μmol, 83%) as a white solid. The racemic compound was separated by SFC to give compound 37 (22 mg, 35.15 μmol, 5%) and compound 38 (29 mg, 49.82 μmol, 8%) as a white solid.

[0292] SFC method: Column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); Mobile phase A: CO2; Mobile phase B: IPA (0.1% IPAm, v / v); B%: 55%; Run time: 10 min

[0293] Compound 37: 11H NMR (400 MHz, DMSO-d6) δ ppm 3.22 - 3.27 (m, 2H), 3.71 (q, J = 6.32 Hz, 2H), 4.06 (dd, J = 11.00, 4.40 Hz, 1H), 4.54 (t, J = 11.19 Hz, 1H), 5.11 (dd, J = 11.31, 4.34 Hz, 1H), 7.01 (s, 2H), 7.15 (td, J = 8.44, 2.32 Hz, 1H), 7.21 - 7.28 (m, 3H), 7.30 - 7.37 (m, 3H), 7.46 (d, J = 8.56 Hz, 2H), 7.71 - 7.76 (m, 2H), 7.84 - 7.91 (m, 1H), 8.23 (br t, J = 5.50 Hz, 1H). LCMS (ESI+): m / z 582.0 (M + H) + . OR: -118.40

[0294] Compound 38: 1 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22 - 3.28 (m, 2H), 3.71 (q, J = 6.40 Hz, 2H), 4.06 (dd, J = 11.07, 4.34 Hz, 1H), 4.54 (t, J = 11.19 Hz, 1H), 5.11 (dd, J = 11.19, 4.46 Hz, 1H), 6.96 - 7.04 (m, 2H), 7.15 (td, J = 8.50, 2.08 Hz, 1H), 7.21 - 7.28 (m, 3H), 7.30 - 7.39 (m, 3H), 7.43 - 7.49 (m, 2H), 7.71 - 7.77 (m, 2H), 7.83 - 7.92 (m, 1H), 8.23 (br t, J = 5.20 Hz, 1H). LCMS (ESI+): m / z 582.0 (M + H) + . OR: 116.0.

[0295] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((3,5-difluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 39) and (S,Z)-3-(4-chlorophenyl)-N'-((3,5-difluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 40) [ka] Synthesis of 39.1 To a solution of 21.0 (1 g, 3.90 mmol, 1 equiv.) in toluene (10 mL) was added methyl N-(3,5-difluorophenyl)sulfonylcarbamate (978.49 mg, 3.90 mmol, I7) at room temperature. After stirring at 110° C. for 10 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a solid, which was triturated with methyl tert-butyl ether (15 mL) to give 39.1 (690 mg, 1.30 mmol, 34%) as a white solid. LCMS (ESI+): m / z 475.9 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 3.70 (dd, J=11.27, 4.95 Hz, 1H), 4.30 (t, J=11.32 Hz, 1H), 4.99 (dd, J=11.44, 4.77 Hz, 1H), 7.12-7.34 (m, 7H), 7.44 (d, J=8.70 Hz, 2H), 7.67 (br d, J=5.36 Hz, 2H), 7.73-7.83 (m, 2H), 11.43-12.04 (m, 1H).

[0296] Synthesis of 39.2 To a solution of 39.1 (500 mg, 1.05 mmol, 1 equiv.) in toluene (5 mL) was added N,N-diisopropylethylamine (274.51 μL, 1.58 mmol, 1.5 equiv.) and phosphorus oxychloride (126.93 μL, 1.37 mmol, 1.3 equiv.) at room temperature. After stirring at 85° C. for 16 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The solid was triturated with methyl tert-butyl ether (10 mL) to give 39.2 (400 mg, 809.16 μmol, 77%) as a yellow solid. LCMS (ESI+): m / z 493.9 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 4.03 (dd, J=12.59, 5.26 Hz, 1H), 4.68 (t, J=11.80 Hz, 1H), 5.28 (dd, J=10.94, 5.07 Hz, 1H), 7.24-7.36 (m, 6H), 7.47 (d, J=8.56 Hz, 2H), 7.63 (t, J=4.22 Hz, 2H), 7.71 (d, J=8.56 Hz, 2H).

[0297] Synthesis of compounds 39 and 40 To a solution of 39.2 (300 mg, 606.87 μmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (84.47 μL, 606.87 μmol, 1 equiv.) and 2-aminoethanesulfonamide (113.03 mg, 910.31 μmol, 1.5 equiv.) at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure to give a solid, which was triturated with methyl tert-butyl ether (10 mL) to give the racemic compound (220 mg, 321.28 μmol, 53%) as a white solid. LCMS (ESI+): m / z 581.9 (M+H) + The enantiomers were separated by SFC to give compound 39 (35 mg, 60.13 μmol, 18%) and compound 40 (54 mg, 92.78 μmol, 27%) as white solids.

[0298] SFC method: Cartridge: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); Mobile phase A: CO2; Mobile phase B: IPA (0.1% IPAm, v / v); B%: 55%; Execution time: 10 min

[0299] Compound 39: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.23-3.29 (m, 2H), 3.71 (br s, 2H), 4.06 (dd, J=11.13, 4.40 Hz, 1H), 4.54 (t, J=11.19 Hz, 1H), 5.11 (dd, J=11.13, 4.40 Hz, 1H), 7.00 (s, 2H), 7.21-7.28 (m, 3H), 7.30-7.36 (m, 2H), 7.41-7.51 (m, 5H), 7.72 (d, J=8.68 Hz, 2H), 8.25 (br d, J=1.22 Hz, 1H). LCMS (ESI+): m / z 582.0 (M+H) + .OR:124.60.

[0300] Compound 40: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.23-3.29 (m, 2H), 3.72 (br t, J=6.72 Hz, 2H), 4.06 (dd, J=11.07, 4.34 Hz, 1H), 4.53 (t, J=11.13 Hz, 1H), 5.10 (dd, J=11.19, 4.34 Hz, 1H), 7.01 (br s, 2H), 7.21-7.28 (m, 3H), 7.30-7.35 (m, 2H), 7.43-7.50 (m, 5H), 7.71 (d, J=8.56 Hz, 2H), 8.10-8.38 (m, 1H). LCMS (ESI+): m / z 582.10 (M+H) + . OR: 118.00.

[0301] Synthesis of (S,Z)-4-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((2-sulfamoylethyl)amino)methylene)sulfamoyl)benzamide (Compound 41) and (R,Z)-4-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((2-sulfamoylethyl)amino)methylene)sulfamoyl)benzamide (Compound 42) [ka] Synthesis of 41.1 To a solution of 41.0 (1 g, 3.48 mmol, 1 equiv.) in toluene (20 mL) was added 21.0 (891.5 mg, 3.48 mmol, 1 equiv.) at room temperature. After stirring at 110° C. for 10 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (10 mL) to give 41.1 (1.5 g, 2.93 mmol, 84%) as a white solid. LCMS (ESI+): m / z 511.9 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 1.34 (t, J=7.09 Hz, 3H), 3.67 (dd, J=11.31, 4.83 Hz, 1H), 4.27 (t, J=11.37 Hz, 1H), 4.33-4.43 (m, 2H), 4.98 (dd, J=11.43, 4.83 Hz, 1H), 7.15-7.27 (m, 4H), 7.27-7.35 (m, 2H), 7.41-7.48 (m, 2H), 7.81 (d, J=8.56 Hz, 2H), 8.11-8.23 (m, 4H).

[0302] Synthesis of 41.2 To a solution of 41.1 (1.5 g, 2.93 mmol, 1 equiv.) in toluene (10 mL) was added N,N-diisopropylethylamine (765.45 μL, 4.40 mmol, 1.5 equiv.) and phosphorus oxychloride (853.95 μL, 3.80 mmol, 1.3 equiv.) at room temperature. After stirring at 85° C. for 16 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The solid was triturated with ethanol (10 mL) to give 41.2 (1 g, 1.89 mmol, 64%) as a white solid, which was used in the next step without further purification. LCMS (ESI+): m / z 529.9 (M+H) + .

[0303] Synthesis of 41.3 To a solution of 41.2 (1 g, 1.89 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (1.31 mL, 9.45 mmol, 5 equiv.) and 2-aminoethane-1-sulfonamide (351.1 mg, 2.84 mmol, 1.5 equiv.) at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give 41.3 (800 mg, 1.16 mmol, 62%) as a white solid. LCMS (ESI+): m / z 618.0 (M+H) + .

[0304] Synthesis of 41.4 To a solution of ethyl 41.3 (800 mg, 1.29 mmol, 1 equiv.) in tetrahydrofuran (40 mL) and HO (10 mL) was added LiOH·HO (108.64 mg, 2.59 mmol, 2 equiv.) at room temperature. After stirring at room temperature for 7 h, the reaction mixture was concentrated under reduced pressure. The residue was redissolved in water (5 mL) and adjusted to pH = 2 with aqueous HCl (1 N). The mixture solution was extracted with ethyl acetate (5 mL), and the combined organic phases were concentrated under reduced pressure to give 41.4 (500 mg), which was used in the next step without further purification. LCMS (ESI+): m / z 589.0 (M+H) + .

[0305] Synthesis of compounds 41 and 42 To a solution of 41.4 (500 mg, 847.36 μmol, 1 equiv.) in dichloromethane (5 mL) was added 2-methylpropyl carbonochloridate (127.30 mg, 932.09 μmol, 122.41 μL, 1.1 equiv.) and 4-methylmorpholine (257.12 mg, 2.54 mmol, 279.48 μL, 3 equiv.) at 0° C. After stirring at room temperature for 1 h, NH3 / THF (6 M) was added. After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL), washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate / petroleum ether = 1 / 3) to give the racemic compound (80 mg, 108.64 μmol, 13%) as a white solid. LCMS (ESI+): m / z 589.9 (M+H) +. 1 H NMR: 400 MHz, DMSO-d6δ ppm 3.16-3.22 (m, 2H), 3.54 (d, J=6.68 Hz, 2H), 3.59-3.72 (m, 2H), 3.94-4.11 (m, 1H), 4.41-4.58 (m, 1H), 5.07 (dd, J=11.03, 4.23 Hz, 1H), 7.20-7.28 (m, 3H), 7.29-7.36 (m, 2H), 7.40-7.51 (m, 3H), 7.72 (d, J=8.70 Hz, 2H), 7.85-7.96 (m, 4H), 8.08 (s, 1H), 8.28-8.39 (m, 1H).

[0306] The racemate (80 mg, 135.80 μmol, 1 equiv.) was further purified by preparative HPLC and separated by SFC to give compound 41 (6.5 mg, 11.03 μmol, 8%) and compound 42 (6.8 mg, 11.54 μmol, 8.5%) as white solids.

[0307] HPLC separation method: Machine: Gilson 281 Separation HPLC; Mobile phase: A: TFA / H2O=0.075%v / v; B: CAN; C18-1 150*30mm*5μm; flow rate: 25mL / min; wavelength: 220 and 254nm; Time B% 0.0 30 8.0 75 8.1 75 8.2 100 11.2 100 11.3 30 12.5 30

[0308] SFC method: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase A: CO2; mobile phase B: [0.1%NH3H2Oのエタノール]; B%: 50%; execution time: 12 minutes.

[0309] Compound 41: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.25-3.31 (m, 2H), 3.67-3.83 (m, 2H), 4.11 (br dd, J=11.19, 4.19 Hz, 1H), 4.55 (t, J=11.13 Hz, 1H), 5.10 (dd, J=11.19, 4.19 Hz, 1H), 7.03 (s, 2H), 7.20-7.29 (m, 3H), 7.30-7.39 (m, 2H), 7.46 (d, J=8.50 Hz, 2H), 7.53 (br s, 1H), 7.72 (d, J=8.50 Hz, 2H), 7.85-7.92 (m, 2H), 7.93-7.99 (m, 2H), 8.09 (br s, 1H), 8.14-8.23 (m, 1H). LCMS (ESI+): m / z 589.0 (M+H) + .

[0310] Compound 42: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (br s, 2H), 3.74 (br t, J=6.00 Hz, 2H), 4.09 (br dd, J=10.51, 2.88 Hz, 1H), 4.53 (br t, J=11.38 Hz, 1H), 5.09 (br dd, J=10.82, 3.56 Hz, 1H), 5.25-9.53 (m, 1H), 6.91-7.16 (m, 2H), 7.19-7.28 (m, 3H), 7.29-7.37 (m, 2H), 7.41-7.53 (m, 3H), 7.70 (br d, J=8.25 Hz, 2H), 7.85-7.91 (m, 2H), 7.92-7.98 (m, 2H), 8.09 (br s, 1H). LCMS (ESI+): m / z 589.0 (M+H) + .

[0311] Synthesis of (S,E)-3-(4-fluorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 43) and (S,E)-3-(4-fluorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 44) [ka] Synthesis of 43.2 A solution of 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.8 g, 3.3 mmol, 43.0, CAS number: 69433-60-9) and methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.04 g, 3.7 mmol, 43.1, CAS number: 1042414-31-2) in toluene (30 mL) was stirred at 120 °C for 16 h. Upon completion of stirring, the solvent was removed under reduced pressure and the resulting slurry was chromatographed on silica gel eluting with heptane / ethyl acetate mixtures (100 / 0 to 50 / 50, v / v) to give the title product as a brown foam (1.47 g, 2.9 mmol, 91% yield). LC-MS (ESI+): 492.0 (M+H + ).

[0312] Synthesis of 43.3 To a solution of 3-(4-fluorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamide (1.47 g, 3.0 mmol, 43.2 ml) in toluene (6 ml) at room temperature, phosphorus pentachloride (685 mg, 3.29 mmol, 1.1 equiv.) was added at room temperature. After stirring at 120° C. for 4 hours, the solvent was removed under reduced pressure. The residue was filtered and purified by silica gel flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50, v / v) to give the expected compound as a white solid (0.7 g, 1.4 mmol, 46% yield). LC-MS (ESI+): 510.00 (M+H + ).

[0313] Synthesis of compounds 43 and 44 To a solution of 2-aminoethane-1-sulfonamide hydrochloride (0.09 g, 0.56 mmol, 1.1 equiv.) and triethylamine (0.2 mL, 1.43 mmol, 3 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-fluorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.25 g, 0.5 mmol, 43.3) at room temperature. After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous HCl (2 N, 15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to give the following two enantiomers:

[0314] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0315] Compound 43: (33.7 mg, 0.06 mmol, 12% yield, 98% purity, 99% ee). 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (br s, 1H), 8.0-8.1 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 7.7-7.8 (m, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.03 (s, 2H), 5.10 (dd, J=4.2, 11.1 Hz, 1H), 4.53 (s, 1H), 4.06 (br dd, J=4.2, 11.1 Hz, 1H), 3.73 (br d, J=6.3 Hz, 2H), 3.3-3.3 (m, 2H). LC-MS (ESI+): 598.2 (M+H + ).

[0316] Compound 44: (28.4 mg, 0.05 mmol, 10% yield, 99% purity, 99% ee). 1 H NMR (DMSO-d6, 400 MHz) δ 8.1-8.3 (s, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.8-7.9 (d, J=8.3 Hz, 2H), 7.7-7.8 (m, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.03 (s, 2H), 5.1 (m, 1H), 4.53 (s, 1H), 4.0-4.2 (m, 1H), 3.73 (br d, J=6.3 Hz, 2H), 3.3-3.3 (m, 2H). LC-MS (ESI+): 598.3 (M+H + ).

[0317] Synthesis of (S,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (45) and (R,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (46) [ka] Synthesis of 45.1 To a solution of N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (5.86 g, 12.8 mmol, CAS number: 656827-57-5) in toluene (32 mL) was added phosphorus pentachloride (2.9 g, 13.9 mmol, 1.1 equiv.) at room temperature. After stirring at 120° C. for 4 hours, the solvent was removed under reduced pressure. The residue was washed with diethyl ether (50 mL). The remaining solid was filtered and evaporated under reduced pressure to give the expected compound as a pale white solid, which was used in the next step without further purification (1.45 g, 3.05 mmol, 24% yield). LC-MS (ESI+): 476.040 (M+H + ).

[0318] Synthesis of compounds 45 and 46 To a solution of 2-aminoethane-1-sulfonamide hydrochloride (0.13 g, 0.81 mmol, 1.5 equiv.) and triethylamine (0.37 mL, 2.7 mmol, 5 equiv.) in dichloromethane (3 mL) was added (Z)-N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.25 g, 0.53 mmol, 45.1) at room temperature. After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous HCl (2 N, 15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to give the following two enantiomers:

[0319] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0320] Compound 45: (21.4 mg, 0.04 mmol, 7% yield, 99% purity, 99% ee, OR: -70.5). 1 H NMR (DMSO-d6, 400 MHz) δ 8.1-8.2 (s, 1H), 7.7-7.9 (m, 4H), 7.53 (d, J=8.6 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.03 (s, 2H), 5.10 (dd, J=4.4, 11.1 Hz, 1H), 4.52 (t, J=11.2 Hz, 1H), 4.07 (dd, J=4.1, 11.1 Hz, 1H), 3.7-3.8 (m, 2H), S 3.2-3.3 (m, 2H). LC-MS (ESI+): 564.0 (M+H + ).

[0321] Compound 46: (19.8 mg, 0.035 mmol, 7% yield, 99% purity, 99% ee, OR: +19.8). 1 H NMR (DMSO-d6, 400 MHz) δ 8.16 (br s, 1H), 7.7-7.9 (m, 4H), 7.53 (d, J=8.6 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.03 (s, 2H), 5.10 (dd, J=4.3, 11.2 Hz, 1H), 4.52 (s, 1H), 4.07 (dd, J=4.4, 11.1 Hz, 1H), 3.73 (br d, J=5.9 Hz, 2H), S 3.2-3.3 (m, 2H). LC-MS (ESI+): 564.0 (M+H + ).

[0322] (S,E)-3-(4-fluorophenyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (compound 47), (S,E)-3-(4-fluorophenyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (48), (R Synthesis of (R,E)-3-(4-fluorophenyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (47) and (R,E)-3-(4-fluorophenyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (compound 47) [ka] To a stirred solution of 1-aminopropane-2-sulfonamide hydrochloride (0.14 g, 0.81 mmol, 1.5 equiv.) and triethylamine (0.23 mL, 1.6 mmol, 3.0 equiv.) in dichloromethane (3 mL) was added (E)-3-(4-fluorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.28 g, 0.54 mmol, 45.1) at room temperature. After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with aqueous ammonium chloride (15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a heptane / ethyl acetate mixture (100 / 0 to 60 / 40, v / v) to give a colorless oil as a mixture of diastereomers, which was separated by SFC.

[0323] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 2.5 mL / min CO2 (60%) / MeOH + 0.1% diethylamine, 35 °C, and 100 bar BPR. The DAD detector acquisition frequency was set at 220 nm. Absolute stereochemistry was not determined. Diastereomers with negative OR were arbitrarily assigned as S isomers.

[0324] Compound 47: (8.6 mg, 0.014 mmol, 3% yield, 99% purity, 99% ee, OR: -47.6). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 7.58-7.70 (m, 5H), 7.27-7.35 (m, 3H), 7.10-7.15 (m, 2H), 6.95-7.02 (m, 2H), 4.88 (br s, 2H), 4.70 (dd, J = 11.4, 5.3 Hz, 1H), 4.54 (t, J = 11.4 Hz, 1H), 3.92-4.14 (m, 3H), 3.51 (quind, J = 7.1, 4.0 Hz, 1H), 1.47 ppm (d, J = 7.1Hz, 3H). LC-MS (ESI+): 612.1 (M+H + ).

[0325] Compound 48: (5.9 mg, 0.010 mmol, 2% yield, 95% purity, 99% ee, OR: -62.5). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.62 (br dd, J = 8.6, 5.3 Hz, 3H), 7.28-7.36 (m, 3H), 7.13 (br d, J = 7.0 Hz, 2H), 6.99 (t, J = 8.5 Hz, 2H), 4.82 (br s, 2H), 4.71 (br dd, J = 10.9, 4.9 Hz, 1H), 4.52 (br t, J = 11.3 Hz, 1H), 4.05-4.15 (m, 2H), 3.93-4.03 (m, 1H), 3.50 (br s, 1H), 1.48 ppm (br d, J = 6.5 Hz, 3H). LC-MS (ESI+): 612.1 (M+H + ).

[0326] Compound 49: (11.3 mg, 0.018 mmol, 3% yield, 99% purity, 99% ee, OR: +99.5). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.2 Hz, 3H), 7.57-7.64 (m, 2H), 7.27-7.35 (m, 3H), 7.09-7.15 (m, 2H), 6.94-7.02 (m, 2H), 4.91 (br s, 2H), 4.70 (dd, J = 11.3, 5.2 Hz, 1H), 4.54 (t, J = 11.4 Hz, 1H), 3.93-4.14 (m, 3H), 3.51 (td, J = 7.2, 3.7 Hz, 1H), 1.47 ppm (d, J = 7.0 Hz, 3H). LC-MS (ESI+): 612.1 (M+H + ).

[0327] Compound 50: (10.9 mg, 0.018 mmol, 3% yield, 97% purity, 99% ee, OR: +103.4). 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 2H), 7.58-7.71 (m, 5H), 7.27-7.35 (m, 3H), 7.10-7.16 (m, 2H), 6.94-7.01 (m, 2H), 4.87 (br s, 2H), 4.71 (dd, J = 11.3, 5.4 Hz, 1H), 4.52 (t, J = 11.4 Hz, 1H), 4.05-4.13 (m, 2H), 3.92-4.02 (m, 1H), 3.50 (dt, J = 7.1, 4.0 Hz, 1H), 1.47 ppm (d, J = 7.0 Hz, 3H). LC-MS (ESI+): 612.1 (M+H + ).

[0328] Synthesis of (S)-3-(4-fluorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 51) and (R)-3-(4-fluorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 52) [ka] Synthesis of 51.1 Dimethyl ((4-fluorophenyl)sulfonyl)carbonimidodithioate (0.63 g, 2.24 mmol, 1 equiv.) and 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.54 g, 2.24 mmol, 43.0) in pyridine (3.3 mL) were refluxed at 120 °C for 18 h. The reaction mixture was concentrated to dryness and the crude product was purified by column chromatography (SiO2) eluting with heptane / ethyl acetate mixture (100 / 0 to 50 / 50) to give the desired product as a yellow sticky solid (0.37 g, 0.79 mmol, 35% yield). LC-MS (ESI+): 472.1 (M+H) + ).

[0329] Synthesis of compounds 51 and 52 2-Aminoethane-1-sulfonamide hydrochloride (613 mg, 3.8 mmol, 5 equiv.) was added to a stirred solution of methyl 3-(4-fluorophenyl)-N-((4-fluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (360 mg, 0.76 mmol, 51.1 mL) and triethylamine (0.64 mL, 4.6 mmol, 6 equiv.) in methanol (2.4 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with a dichloromethane / methanol mixture (100 / 0 to 90 / 10) to give a colorless oil, which was further subjected to SFC purification (Amylose-1, ISOC: 50% EtOH + 0.1% DEA) to separate the two enantiomers.

[0330] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / EtOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0331] Compound 51: (87.3 mg, 0.16 mmol, 21% yield, 99% purity, 99% ee, OR: -173.7). 1 H NMR (DMSO-d6, 400 MHz) δ 7.8-7.9 (m, 2H), 7.7-7.8 (m, 2H), 7.2-7.4 (m, 10H), 6.9-7.1 (m, 2H), 5.09 (dd, J=4.3, 11.1 Hz, 1H), 4.52 (t, J=11.2 Hz, 1H), 4.08 (dd, J=4.3, 11.1 Hz, 1H), 3.73 (br t, J=6.7 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 547.6 (M+H + ).

[0332] Compound 52: (77.4 mg, 0.14 mmol, 18% yield, 99% purity, 99% ee, OR: +110.9). 1 H NMR (DMSO-d6, 400 MHz) δ 7.8-7.9 (m, 2H), 7.78 (dd, J=5.5, 8.8 Hz, 2H), 7.0-7.4 (m, 12H), 5.08 (dd, J=4.3, 11.1 Hz, 1H), 4.52 (t, J=11.2 Hz, 1H), 4.07 (dd, J=4.3, 11.2 Hz, 1H), 3.74 (br t, J=6.8 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 547.6 (M+H + ).

[0333] Examples 53 to 56: (S,E)-3-(4-fluorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 53), (S,E)-3-(4-fluorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 5 4), Synthesis of (R,E)-3-(4-fluorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((R)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 55), and (R,E)-3-(4-fluorophenyl)-N'-((4-fluorophenyl)sulfonyl)-4-phenyl-N-((S)-2-sulfamoylpropyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 56) [ka] 1-Aminopropane-2-sulfonamide hydrochloride (194 mg, 1.11 mmol, 2.1 equiv.) was added to a stirred solution of methyl 3-(4-fluorophenyl)-N-((4-fluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (250 mg, 0.53 mmol, 51.1%) and triethylamine (0.23 mL, 1.64 mmol, 3.1 equiv.) in methanol (1.20 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated to dryness and purified by flash chromatography on silica eluting with a dichloromethane / methanol mixture (100 / 0 to 90 / 10) to give a yellowish oil as a mixture of diastereomers, which was further subjected to SFC separation.

[0334] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Cellulose-4) 100 mm long x 4.6 mm i.d., 3 μm particle size, in isocratic mode at 2.5 mL / min CO2 (60%) / EtOH-MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0335] Compound 53: (25.3 mg, 0.045 mmol, 8% yield, 99% purity, 99% ee, OR: -113.3). 1 H NMR (DMSO-d6, 400 MHz) δ 8.08 (br s, 1H), 7.8-7.9 (m, 2H), 7.78 (dd, J=5.5, 8.8 Hz, 2H), 7.2-7.4 (m, 9H), 6.97 (br s, 2H), 5.10 (dd, J=4.3, 11.2 Hz, 1H), 4.55 (t, J=11.2 Hz, 1H), 4.0-4.1 (m, 1H), 3.6-3.7 (m, 1H), 3.56 (br d, J=13.3 Hz, 1H), 3.23 (br d, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H). LC-MS (ESI+): 562.1 (M+H+ ).

[0336] Compound 54: (36.1 mg, 0.06 mmol, 12% yield, 97% purity, 99% ee, OR: -72.2). 1 H NMR (DMSO-d6, 400 MHz) δ 8.09 (br t, J=5.6 Hz, 1H), 7.8-7.9 (m, 2H), 7.79 (dd, J=5.5, 8.8 Hz, 1H), 7.2-7.4 (m, 10H), 6.98 (s, 2H), 5.11 (dd, J=4.4, 11.2 Hz, 1H), 4.54 (t, J=11.1 Hz, 1H), 4.14 (dd, J=4.3, 11.2 Hz, 1H), 3.6-3.8 (m, 1H), 3.56 (td, J=6.8, 13.9 Hz, 1H), 3.2-3.3 (m, 1H), 1.16 (d, J=7.0 Hz, 3H). LC-MS (ESI+): 562.1 (M+H + ).

[0337] Compound 55: (23.3 mg, 0.04 mmol, 8% yield, 98% purity, 99% ee, OR: +50.5). 1 H NMR (DMSO-d6, 400 MHz) δ 8.09 (br t, J=5.4 Hz, 1H), 7.8-7.9 (m, 2H), 7.8 (m, 2H), 7.2-7.4 (m, 9H), 6.97 (s, 2H), 5.11 (dd, J=4.3, 11.1 Hz, 1H), 4.56 (t, J=11.2 Hz, 1H), 4.08 (dd, J=4.3, 11.2 Hz, 1H), 3.6-3.8 (m, 1H), 3.5-3.6 (m, 1H), 3.2-3.3 (m, 1H), 1.17 (d, J=7.0 Hz, 3H). LC-MS (ESI+): 562.1 (M+H + ).

[0338] Compound 56: (23.2 mg, 0.04 mmol, 8% yield, 99% purity, 99% ee, OR: +139.1). 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (br d, J=1.4 Hz, 1H), 7.87 (dd, J=5.3, 8.8 Hz, 2H), 7.78 (dd, J=5.5, 8.7 Hz, 2H), 7.2-7.4 (m, 9H), 6.98 (br s, 2H), 5.10 (dd, J=4.2, 11.1 Hz, 1H), 4.54 (t, J=11.1 Hz, 1H), 4.13 (br dd, J=4.3, 11.0 Hz, 1H), 3.67 (br d, J=5.9 Hz, 1H), 3.55 (br dd, J=6.2, 13.6 Hz, 1H), 3.25 (br s, 1H), 1.16 (d, J=6.9 Hz, 3H). LC-MS (ESI+): 562.1 (M+H + ).

[0339] Synthesis of (S,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((R)-1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 57) and (R,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((R)-1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 58) [ka] To a solution of (R)-2-aminopropane-1-sulfonamide (131 mg, 0.95 mmol, 1.5 equiv., I8) and triethylamine (0.26 mL, 1.89 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (300 mg, 0.63 mmol, 51.1). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (25 mL) and washed with aqueous HCl (2 N, 20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 70 / 30, v / v) to give a colorless oil, which was further subjected to SFC separation to give the following two diastereomers:

[0340] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0341] Compound 57: (50.9 mg, 0.088 mmol, 14% yield, 99% purity, 99% ee, OR: -112.1). 11H NMR (DMSO-d6, 400 MHz) δ 7.94 (broad d, J = 8.1 Hz, 1H), 7.7 - 7.9 (multiplet, 4H), 7.54 (d, J = 8.6 Hz, 2H), 7.3 - 7.4 (multiplet, 2H), 7.2 - 7.3 (multiplet, 5H), 6.96 (singlet, 2H), 5.09 (doublet of doublets, J = 4.2, 11.1 Hz, 1H), 4.57 (triplet, J = 11.2 Hz, 1H), 4.3 - 4.5 (multiplet, 1H), 4.08 (broad doublet of doublets, J = 3.9, 10.9 Hz, 1H), 3.44 (doublet of doublets, J = 6.2, 14.1 Hz, 1H), 3.2 - 3.3 (multiplet, 1H), 1.26 (doublet, J = 6.7 Hz, 3H). LC-MS (ESI+): 578.1 (M+H + )。

[0342] Compound 58: (23.2 mg, 0.04 mol, 6% yield, 99% purity, 99% ee, OR: +65.6). 1 1H NMR (DMSO-d6, 400 MHz) δ 7.96 (broad d, J = 7.8 Hz, 1H), 7.7 - 7.8 (multiplet, 4H), 7.53 (d, J = 8.6 Hz, 2H), 7.3 - 7.4 (multiplet, 2H), 7.2 - 7.3 (multiplet, 5H), 6.94 (singlet, 2H), 5.10 (doublet of doublets, J = 4.3, 11.2 Hz, 1H), 4.52 (triplet, J = 11.1 Hz, 1H), 4.3 - 4.4 (multiplet, 1H), 4.13 (broad doublet of doublets, J = 3.7, 11.0 Hz, 1H), 3.4 (multiplet, 1H), 3.23 (broad singlet, 1H), 1.28 (broad doublet, J = 6.7 Hz, 3H). LC-MS (ESI+): 578.0 (M+H + )。

[0343] Synthesis of (S)-N'-((4-ethynylphenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 59) and (R)-N'-((4-ethynylphenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 60) [ka] Synthesis of 59.1 Dimethyl ((4-ethynylphenyl)sulfonyl)carbonimidodithioate (0.39 g, 1.37 mmol, I9) and 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.33 g, 1.37 mmol, 43.0) were mixed in pyridine (2.5 mL). After stirring at 120 °C for 72 h, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give the expected product as a colorless oil (0.092 g, 0.19 mmol, 14% yield). LC-MS (ESI+): 478.1 (M+H) + ).

[0344] Synthesis of compounds 59 and 60 2-Aminoethane-1-sulfonamide hydrochloride (93 mg, 0.58 mmol, 3 equiv.) was added to a stirred solution of methyl N-((4-ethynylphenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (92 mg, 0.19 mmol, 59.1 mL) and triethylamine (0.16 mL, 1.16 mmol, 6 equiv.) in methanol (1.9 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 80 / 20, v / v) to give a white solid, which was further subjected to SFC purification to separate the two enantiomers.

[0345] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0346] Compound 59: (18.4 mg, 0.033 mmol, 17% yield, 99% purity, 99% ee, OR: -47.3). 1 H NMR (DMSO-d6, 400 MHz) δ 8.16 (br t, J=5.5 Hz, 1H), 7.7-7.9 (m, 4H), 7.56 (d, J=8.4 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.02 (s, 2H), 5.09 (dd, J=4.3, 11.1 Hz, 1H), 4.52 (t, J=11.1 Hz, 1H), 4.39 (s, 1H), 4.08 (dd, J=4.3, 11.1 Hz, 1H), 3.73 (q, J=6.3 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 554.1 (M+H + ).

[0347] Compound 60: (17.6 mg, 0.032 mmol, 17% yield, 99% purity, 99% ee, OR: +146.9). 1H NMR (DMSO-d6, 400 MHz) δ 8.16 (br t, J=5.5 Hz, 1H), 7.7-7.8 (m, 4H), 7.56 (d, J=8.4 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.02 (s, 2H), 5.09 (dd, J=4.3, 11.1 Hz, 1H), 4.52 (t, J=11.2 Hz, 1H), 4.39 (s, 1H), 4.08 (dd, J=4.3, 11.0 Hz, 1H), 3.73 (q, J=6.3 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 554.1 (M+H + ).

[0348] Synthesis of (S,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 61) and (R,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(1-sulfamoylpropan-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 62) [ka] To a solution of (S)-2-aminopropane-1-sulfonamide (87 mg, 0.63 mmol, 1.5 equiv.) and triethylamine (0.18 mL, 1.26 mmol, 3.0 equiv.) in dichloromethane / methanol (3:1) (4 mL) was added (Z)-N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (200 mg, 0.42 mmol, 51.1). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 80 / 20, v / v) to give a white solid, which was further subjected to SFC purification to separate the two enantiomers.

[0349] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Cellulose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0350] Compound 61: (20.8 mg, 0.036 mol, 9% yield, 96% purity, 99% de, OR: -84.4). 1 H NMR (DMSO-d6, 400 MHz) δ 7.8 (m, 4H), 7.6-7.7 (m, 2H), 7.3-7.4 (m, 3H), 7.23 (t, J=8.6 Hz, 6H), 5.02 (dd, J=4.2, 11.2 Hz, 1H), 4.27 (t, J=11.3 Hz, 1H), 3.9-4.0 (m, 1H), 3.77 (dd, J=4.2, 11.3 Hz, 1H), 3.3-3.4 (m, 2H), 2.88 (dd, J=11.0, 13.3 Hz, 1H), 1.42 (d, J=6.5 Hz, 3H). LC-MS (ESI+): 578.0 (M+H + ).

[0351] Compound 62: (32.1 mg, 0.056 mmol, 13% yield, 98% purity, 99% de, OR: +198.1). 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (br d, J=8.3 Hz, 1H), 7.7-7.9 (m, 4H), 7.54 (d, J=8.5 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 6.96 (s, 2H), 5.09 (dd, J=4.1, 11.1 Hz, 1H), 4.57 (t, J=11.2 Hz, 1H), 4.3-4.5 (m, 1H), 4.08 (br dd, J=4.0, 11.2 Hz, 1H), 3.44 (dd, J=6.3, 14.1 Hz, 1H), 3.25 (dd, J=6.1, 14.1 Hz, 1H), 1.26 (d, J=6.7 Hz, 3H). LC-MS (ESI+): 578.1 (M+H + ).

[0352] Synthesis of (S,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-methoxyphenyl)-N-((S)-3-methyl-1-sulfamoylbutan-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 63) and (R,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-methoxyphenyl)-N-((S)-3-methyl-1-sulfamoylbutan-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 64) [ka] To a solution of (S)-2-amino-3-methylbutane-1-sulfonamide (94 mg, 0.57 mmol, 1.1 equiv., I10) and triethylamine (0.21 mL, 1.49 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-methoxyphenyl)-4-phenyl-N-((4-(chlorophenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (250 mg, 0.51 mmol, 63.0 equiv., CAS number: 1309 448-30-3) was added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was diluted with dichloromethane (25 mL) and washed with aqueous HCl (2N, 20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to give the following two diastereomers:

[0353] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0354] Compound 63: (7.1 mg, 0.011 mmol, 3% yield, 99% purity, 99% ee, OR: -91.8). 11H NMR (DMSO-d6, 400 MHz) δ 7.81 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.2 - 7.3 (m, 3H), 6.92 (d, J = 9.0 Hz, 2H), 6.86 (br s, 2H), 5.09 (br d, J = 3.9 Hz, 1H), 4.47 (br t, J = 11.0 Hz, 1H), 4.2 - 4.4 (m, 1H), 3.9 - 4.1 (m, 1H), 3.74 (s, 3H), 3.4 - 3.5 (m, 2H), 3.2 - 3.2 (m, 1H), 1.90 (br d, J = 1.0 Hz, 1H), 0.7 - 0.8 (m, 6H). LC-MS (ESI+): 618.1 (M + H + )。

[0355] Compound 64: (22.3 mg, 0.04 mol, 7% yield, 99% purity, 99% ee, OR: +105.5). 1 1H NMR (DMSO-d6, 400 MHz) δ 7.8 - 7.9 (m, 2H), 7.70 (d, J = 8.9 Hz, 2H), 7.5 - 7.6 (m, 2H), 7.31 (d, J = 7.1 Hz, 2H), 7.2 - 7.3 (m, 3H), 6.93 (d, J = 8.9 Hz, 2H), 6.88 (br s, 2H), 5.04 (br d, J = 9.9 Hz, 1H), 4.6 - 4.8 (m, 1H), 3.9 - 4.2 (m, 2H), 3.75 (s, 3H), 3.45 (br dd, J = 9.0, 13.6 Hz, 1H), 3.1 - 3.3 (m, 1H), 1.7 - 2.0 (m, 1H), 0.76 (br d, J = 6.7 Hz, 6H). LC-MS (ESI+): 618.172 (M + H + )。

[0356] Synthesis of (S)-3-(4-chlorophenyl)-4-phenyl-N'-(pyridin-3-ylsulfonyl)-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 65) and (R)-3-(4-chlorophenyl)-4-phenyl-N'-(pyridin-3-ylsulfonyl)-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 66) [ka] Synthesis of 65.1 Dimethyl (pyridin-3-ylsulfonyl)carbonimidodithioate (0.12 g, 0.47 mmol, CAS number: 76511-39-2) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.12 g, 0.47 mmol, 21.0) were mixed in pyridine (1 mL). After refluxing for 18 h, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography eluting with an ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) to give the expected product as a colorless oil (0.11 g, 0.23 mmol, 50% yield). LC-MS (ESI+): 471.0 (M+H + ).

[0357] Synthesis of compounds 65 and 66 2-Aminoethane-1-sulfonamide hydrochloride (76 mg, 0.5 mmol, 2 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-4-phenyl-N-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidothioate (112 mg, 0.24 mmol, 65.1%) and triethylamine (0.1 mL, 0.7 mmol, 3 equiv.) in methanol (2.3 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50) to give a colorless oil, which was further subjected to SFC purification (Amylose-1, ISOC: 60% MeOH + 0.1% DEA) to give the two enantiomers.

[0358] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0359] Compound 65: (33.0 mg, 0.06 mmol, 25% yield, 95% purity, 99% ee, OR: -68.2). 1 H NMR (DMSO-d6, 400 MHz) δ 8.98 (d, J=2.2 Hz, 1H), 8.71 (dd, J=1.2, 4.8 Hz, 1H), 8.2 (m, 2H), 7.72 (d, J=8.6 Hz, 2H), 7.52 (dd, J=4.9, 8.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 7.00 (s, 2H), 5.11 (dd, J=4.4, 11.2 Hz, 1H), 4.56 (t, J=11.2 Hz, 1H), 4.10 (dd, J=4.4, 11.1 Hz, 1H), 3.7-3.8 (m, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 547.0 (M+H+).

[0360] Compound 66: (16.6 mg, 0.03 mmol, 13% yield, 99% purity, 99% ee, OR: +102.5). 1H NMR (DMSO-d6, 400 MHz) δ 8.98 (d, J=2.1 Hz, 1H), 8.71 (dd, J=1.4, 4.8 Hz, 1H), 8.20 (td, J=1.8, 8.1 Hz, 2H), 7.72 (d, J=8.7 Hz, 2H), 7.53 (dd, J=4.8, 7.9 Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 3H), 7.00 (s, 2H), 5.11 (dd, J=4.4, 11.2 Hz, 1H), 4.56 (t, J=11.2 Hz, 1H), 4.10 (dd, J=4.4, 11.1 Hz, 1H), 3.74 (q, J=6.3 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 547.0 (M+H+).

[0361] Synthesis of (S)-3-(4-chlorophenyl)-N'-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 67) and (R)-3-(4-chlorophenyl)-N'-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 68) [ka] Synthesis of 67.1 Dimethyl ((1-methyl-1H-imidazol-4-yl)sulfonyl)carbonimidodithioate (65 mg, 0.24 mmol, I11) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (63 mg, 0.24 mmol, 21.0) were mixed in pyridine (1.5 mL). After stirring at reflux for 18 hours, the reaction mixture was concentrated to dryness to give the expected product as a yellowish oil (110 mg, 0.23 mmol, 95% yield). LC-MS (ESI+): 474.1 (M+H +).

[0362] Synthesis of compounds 67 and 68 2-Aminoethane-1-sulfonamide hydrochloride (75 mg, 0.5 mmol, 2 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((1-methyl-1H-imidazol-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (110 mg, 0.23 mmol, 67.1) and triethylamine (0.1 mL, 0.7 mmol, 3 equiv.) in methanol (1.5 mL) at room temperature. After stirring for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 60 / 40). The product was repurified by flash chromatography on silica gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v). The resulting colorless oil was further subjected to SFC purification to give two enantiomers.

[0363] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0364] Compound 67: (8.4 mg, 0.015 mmol, 7% yield, 99% purity, 99% ee, OR: -43.9). 1H NMR (CDCl3, 400 MHz) δ 7.8-8.1 (m, 2H), 7.53 (br d, J=8.4 Hz, 2H), 7.44 (s, 1H), 7.33 (m, 1H), 7.2-7.3 (m, 4H), 7.11 (br d, J=7.2 Hz, 2H), 6.35 (br s, 2H), 4.6-4.7 (m, 2H), 4.14 (br s, 3H), 3.7-3.8 (m, 3H), 3.55 (br s, 2H). LC-MS (ESI+): 550.0 (M+H + ).

[0365] Compound 68: (5.6 mg, 0.01 mmol, 5% yield, 97% purity, 99% ee, OR: +27.4). 1 H NMR (CDCl3, 400 MHz) δ 7.9-8.3 (m, 2H), 7.4-7.6 (m, 3H), 7.1-7.3 (m, 7H), 6.3-6.6 (m, 2H), 4.6-4.8 (m, 2H), 4.0-4.2 (m, 3H), 3.74 (br s, 3H), 3.5-3.6 (m, 2H). LC-MS (ESI+): 550.0 (M+H + ).

[0366] Synthesis of (S)-3-(4-fluorophenyl)-4-phenyl-N'-(pyridin-3-ylsulfonyl)-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 69) and (R)-3-(4-fluorophenyl)-4-phenyl-N'-(pyridin-3-ylsulfonyl)-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 70) [ka] Synthesis of 69.1 Dimethyl (pyridin-3-ylsulfonyl)carbonimidodithioate (0.27 g, 1.04 mmol, 1 equiv.) and 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.25 g, 1.04 mmol, 43.0) in pyridine (5 mL) were refluxed at 120° C. for 18 h. Upon completion, the reaction mixture was concentrated to dryness and the crude yellowish oil was used in the next step without further purification (0.47 g, 1.03 mmol, 99% yield). LC-MS (ESI+): 455.1 (M+H + ).

[0367] Synthesis of compounds 69 and 70: 2-Aminoethane-1-sulfonamide hydrochloride (332 mg, 2.07 mmol, 2 equiv.) was added to a stirred solution of methyl 3-(4-fluorophenyl)-4-phenyl-N-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidothioate (470 mg, 1.03 mmol, 69.1%) and triethylamine (0.43 mL, 3.1 mmol, 3 equiv.) in methanol (6 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC purification to separate the two enantiomers.

[0368] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0369] Compound 69: (26.7 mg, 0.05 mmol, 5% yield, 98% purity, 99% ee, OR: -108.9). 11H NMR (DMSO-d6, 400 MHz) δ 8.98 (d, J=2.2 Hz, 1H), 8.71 (dd, J=1.4, 4.8 Hz, 1H), 8.20 (td, J=1.8, 8.0 Hz, 2H), 7.77 (dd, J=5.6, 8.7 Hz, 2H), 7.52 (dd, J=4.9, 8.0 Hz, 1H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 5H), 7.02 (br s, 2H), 5.11 (dd, J=4.2, 11.1 Hz, 1H), 4.55 (t, J=11.1 Hz, 1H), 4.10 (dd, J=4.3, 11.1 Hz, 1H), 3.7-3.8 (m, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 531.1 (M+H + )。

[0370] Compound 70: (75.2 mg, 0.14 mmol, 14% yield, 99% purity, 99% ee, OR: +66.7). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.98 (d, J=2.1 Hz, 1H), 8.71 (dd, J=1.3, 4.8 Hz, 1H), 8.20 (td, J=1.8, 8.0 Hz, 1H), 7.77 (dd, J=5.6, 8.6 Hz, 2H), 7.52 (dd, J=4.9, 8.0 Hz, 1H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 6H), 6.9-7.2 (m, 2H), 5.11 (dd, J=4.3, 11.2 Hz, 1H), 4.54 (t, J=11.2 Hz, 1H), 4.10 (dd, J=4.3, 11.1 Hz, 1H), 3.74 (br t, J=6.7 Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 531.1 (M+H + )。

[0371] Synthesis of (S)-3-(4-chlorophenyl)-N'-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 71) and (R)-3-(4-chlorophenyl)-N'-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 72) [ka] Synthesis of 71.1 Dimethyl ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (1.45 g, 4.9 mmol, I12) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (1.3 g, 4.9 mmol, 21.0) in pyridine (7 mL) were refluxed at 120 °C for 18 h. Upon completion, the reaction mixture was concentrated to dryness and the residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected product as a yellow oil (1.09 g, 2.2 mmol, 44% yield). LC-MS (ESI+): 503.1 (M+H + ).

[0372] Synthesis of compounds 71 ​​and 72 2-Aminoethane-1-sulfonamide hydrochloride (0.2 g, 1.24 mmol, 2.5 equiv.) was added to a stirred solution of methyl (Z)-3-(4-chlorophenyl)-N-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (0.25 g, 0.5 mmol, 71.1) and triethylamine (0.24 mL, 1.74 mmol, 3.5 equiv.) in methanol (2 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give a colorless oil, which was further subjected to SFC purification to separate the two enantiomers.

[0373] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0374] Compound 71: (30.1 mg, 0.052 mmol, 10% yield, 95% purity, 99% ee, OR: -92.3). 11H NMR (DMSO-d6, 400 MHz) δ 8.01 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.31 - 7.36 (m, 2H), 7.21 - 7.28 (m, 3H), 5.10 (dd, J = 11.2, 4.2 Hz, 1H), 4.79 (spt, J = 6.6 Hz, 1H), 4.53 (t, J = 11.2 Hz, 1H), 4.09 (br dd, J = 11.1, 4.1 Hz, 1H), 3.77 (br t, J = 6.8 Hz, 2H), 3.27 (m, 5H), 1.43 (dd, J = 6.7, 2.1 Hz, 6H) ppm. LC-MS (ESI+): 579.1 (M+H + )。

[0375] Compound 72: (28.8 mg, 0.05 mmol, 10% yield, 98% purity, 99% ee, OR: +97.1). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.01 (s, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.29 - 7.35 (m, 2H), 7.20 - 7.29 (m, 3H), 5.08 (dd, J = 11.2, 4.2 Hz, 1H), 4.79 (spt, J = 6.6 Hz, 1H), 4.53 (t, J = 11.3 Hz, 1H), 4.08 (br dd, J = 11.2, 4.1 Hz, 1H), 3.77 (br t, J = 6.8 Hz, 2H), 3.26 - 3.29 (m, 5H), 1.43 (dd, J = 6.7, 2.0 Hz, 6H) ppm. LC-MS (ESI+): 579.1 (M+H + )。

[0376] Synthesis of (S)-3-(4-chlorophenyl)-N'-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 73) and (R)-3-(4-chlorophenyl)-N'-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 74) [ka] Synthesis of methyl 3-(4-chlorophenyl)-N-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (73.1) Dimethyl ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (1.17 g, 4.4 mmol, I13) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (1.1 g, 4.4 mmol, 21.0) in pyridine (6 mL) were refluxed at 120 °C for 18 h. Upon completion, the reaction mixture was concentrated to dryness. The residue was purified by flash chromatography on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected product as a yellow oil (0.64 g, 1.4 mmol, 31% yield). LC-MS (ESI+): 475.1 (M+H + ).

[0377] Synthesis of compounds 73 and 74 2-Aminoethane-1-sulfonamide hydrochloride (0.54 g, 3.35 mmol, 2.5 equiv.) was added to a stirred solution of methyl (Z)-3-(4-chlorophenyl)-N-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (0.64 g, 1.3 mmol, 73.1) and triethylamine (0.65 mL, 4.7 mmol, 3.5 equiv.) in methanol (2 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC purification and resolved into two enantiomers as white solids.

[0378] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0379] Compound 73: (27.6 mg, 0.05 mmol, 4% yield, 97% purity, 99% ee, OR: -50.7). 1 H NMR (DMSO-d6, 400 MHz) δ 8.30 (br s, 1H), 8.03 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.30-7.37 (m, 2H), 7.22-7.30 (m, 3H), 7.03 (s, 2H), 5.13 (dd, J = 11.2, 4.3 Hz, 1H), 4.57 (t, J = 11.2 Hz, 1H), 4.09-4.20 (m, 4H), 3.76 (q, J = 6.3 Hz, 2H), 3.25-3.31 (m, 2H) ppm. LC-MS (ESI+): 551.0 (M+H+ ).

[0380] Compound 74: (32.4 mg, 0.06 mmol, 4% yield, 94% purity, 99% ee, OR: +94.6). 1 H NMR (DMSO-d6, 400 MHz) δ 8.30 (br s, 1H), 8.03 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.31-7.37 (m, 2H), 7.23-7.29 (m, 3H), 7.03 (s, 2H), 5.13 (dd, J = 11.2, 4.4 Hz, 1H), 4.57 (t, J = 11.2 Hz, 1H), 4.10-4.18 (m, 4H), 3.76 (q, J= 6.3 Hz, 2H), 3.30 (br s, 2H) ppm. LC-MS (ESI+): 551.0 (M+H + ).

[0381] Synthesis of (S)-3-(4-chlorophenyl)-N'-((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 75) and (R)-3-(4-chlorophenyl)-N'-((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 76) [ka] Synthesis of methyl 3-(4-chlorophenyl)-N-((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (75.1) Dimethyl ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)carbonimidodithioate (0.29 g, 0.98 mmol, I14) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.25 g, 0.098 mmol, 21.0) in pyridine (3 mL) were refluxed at 120 °C for 18 h. Upon completion, the reaction mixture was concentrated to dryness and the residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected product as a yellow oil (0.1 g, 0.19 mmol, 20% yield). LC-MS (ESI+): 503.1 (M+H + ).

[0382] Synthesis of compounds 75 and 76 2-Aminoethane-1-sulfonamide hydrochloride (78 mg, 0.5 mmol, 2.5 equiv.) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate (98 mg, 0.2 mmol, 75.1) and triethylamine (0.1 mL, 0.7 mmol, 3.5 equiv.) in methanol (2 mL). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a yellowish oil, which was further subjected to SFC purification and resolved into two enantiomers as an off-white solid.

[0383] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm i.d., 5 μm particle size, in isocratic mode at 3 mL / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0384] Compound 75: (7.4 mg, 0.013 mmol, 6% yield, 99% purity, 99% ee, OR: -60.9). 1 H NMR (DMSO-d6, 400 MHz) δ 8.30 (br s, 1H), 8.00 (s, 1H), 7.73 (br d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.30-7.37 (m, 2H), 7.21-7.29 (m, 3H), 7.05 (s, 2H), 5.21 (dt, J = 13.2, 6.5 Hz, 1H), 5.13 (br dd, J = 11.3, 3.6 Hz, 1H), 4.54 (br t, J = 11.2 Hz, 1H), 4.03 (br dd, J = 11.0, 4.1 Hz, 1H), 3.74 (br s, 2H), 3.26 (br s, 2H), 1.52 (br d, J = 6.6 Hz, 6H) ppm. LC-MS (ESI+): 579.1 (M+H + ).

[0385] Compound 76: (9.7 mg, 0.017 mmol, 9% yield, 98% purity, 99% ee, OR: +73.3). 1 H NMR (DMSO-d6, 400 MHz) δ 8.31 (br s, 1H), 8.00 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.31-7.37 (m, 2H), 7.22-7.28 (m, 3H), 7.05 (s, 2H), 5.21 (dt, J = 13.3, 6.6 Hz, 1H), 5.14 (br dd, J = 11.1, 4.3 Hz, 1H), 4.54 (t, J = 11.2 Hz, 1H), 4.03 (br dd, J = 10.9, 4.2 Hz, 1H), 3.74 (br d, J = 5.4 Hz, 2H), 3.28 (br s, 2H), 1.52 (br d, J = 6.5 Hz, 6H) ppm. LC-MS (ESI+): 579.1 (M+H + ).

[0386] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-(3-cyanophenyl)-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 77) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-(3-cyanophenyl)-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 78) [ka] Synthesis of 77.2 To a solution of 77.1 (300 mg, 1.06 mmol, 1 equiv) in toluene (3 mL) was added 77.0 (265.85 mg, 1.06 mmol, CAS number: 34543-04-9) at room temperature. After stirring at 110 °C for 10 h, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (10 mL) to give 77.2 (500 mg, 901.14 μmol, 85%) as a white solid. LCMS (ESI+): m / z 499.0 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 3.73 (dd, J=11.38, 5.07 Hz, 1H), 4.28 (t, J=11.50 Hz, 1H), 5.08 (dd, J=11.50, 4.95 Hz, 1H), 7.40-7.54 (m, 4H), 7.67-7.82 (m, 6H), 7.94-8.06 (m, 2H), 11.18-11.94 (m, 1H).

[0387] Synthesis of 77.3 To a solution of 77.2 (300 mg, 600.76 μmol, 1 equiv.) in toluene (4 mL) was added N,N-diisopropylethylamine (116.47 mg, 901.14 μmol, 156.96 μL, 1.5 equiv.) and phosphorus oxychloride (72.58 μL, 780.99 μmol, 1.3 equiv.) at room temperature. After stirring at 85° C. for 16 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (10 mL) to give 77.3 (220 mg, 361.13 μmol, 60%) as a yellow solid. LCMS (ESI+): m / z 519.0 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 4.00 (dd, J=12.53, 5.56 Hz, 1H), 4.65 (br t, J=11.92 Hz, 1H), 5.36 (dd, J=11.25, 5.75 Hz, 1H), 7.46-7.55 (m, 3H), 7.59-7.77 (m, 6H), 7.90-7.94 (m, 2H), 11.62 (br d, J=4.16 Hz, 1H).

[0388] Synthesis of compounds 77 and 78 To a solution of 77.3 (220 mg, 424.86 μmol, 1 equiv.) in dichloromethane (3 mL) was added triethylamine (236.54 μL, 1.70 mmol, 4 equiv.) and 2-aminoethanesulfonamide (79.13 mg, 637.29 μmol, 1.5 equiv.) at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (10 mL) to give the racemic compound (220 mg, 363.33 μmol, 86%) as a white solid. LCMS (ESI+): m / z 605.1 (M+H) + . 1H NMR: 400 MHz, DMSO-d6δ ppm 3.28 (br t, J=6.60 Hz, 2H), 3.67-3.80 (m, 2H), 3.99-4.11 (m, 1H), 4.54 (t, J=11.19 Hz, 1H), 5.19 (dd, J=11.19, 4.34 Hz, 1H), 5.76 (s, 1H), 7.03 (s, 2H), 7.41-7.61 (m, 6H), 7.69-7.88 (m, 6H), 8.21 (br t, J=5.01 Hz, 1H).

[0389] The compound 77 (40 mg, 65.53 μmol, 20%) and the compound 78 (34 mg, 56.15 μmol, 17%) were obtained as white solids by SFC separation.

[0390] SFC method: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase A: CO2; mobile phase B: IPA (0.1% IPAm, v / v); B%: 55%; running time: 10 minutes.

[0391] Compound 77: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.24-3.31 (m, 2H), 3.66-3.80 (m, 2H), 4.07 (dd, J=11.27, 4.23 Hz, 1H), 4.54 (t, J=11.32 Hz, 1H), 5.14-5.24 (m, 1H), 7.04 (br s, 2H), 7.47 (d, J=8.70 Hz, 2H), 7.51-7.58 (m, 4H), 7.69-7.77 (m, 3H), 7.79-7.87 (m, 3H), 8.22 (br s, 1H). LCMS (ESI+): m / z 605 (M+H) + .OR:-143.00.

[0392] Compound 78: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.29 (s, 2H), 3.74 (br d, J=4.28 Hz, 2H), 4.07 (br dd, J=11.31, 4.22 Hz, 1H), 4.54 (t, J=11.25 Hz, 1H), 5.19 (dd, J=11.13, 4.40 Hz, 1H), 7.03 (s, 1H), 7.44-7.57 (m, 6H), 7.70-7.86 (m, 6H), 8.15-8.26 (m, 1H). LCMS (ESI+): m / z 604.90 (M+H) + . OR:141.40.

[0393] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 81) and (R,Z)-3-(4-chlorophenyl)-N'-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 82) [ka] Synthesis of 81.1 To a solution of 21.0 (157 mg, 716.18 μmol, 1 equiv.) in toluene (2 mL) was added I15 (183.87 mg, 716.18 μmol, 1 equiv.) at room temperature. After stirring at 110° C. for 10 h, the mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (5 mL) to give 81.1 (127 mg, 257.49 μmol, 36%) as a white solid. LCMS (ESI+): m / z 443.9 (M+H) + . 1H NMR: 400 MHz, DMSO-d6δ ppm 3.71 (dd, J=11.21, 4.77 Hz, 1H), 3.90 (s, 3H), 4.30 (t, J=11.38 Hz, 1H), 4.98 (dd, J=11.38, 4.71 Hz, 1H), 7.16-7.25 (m, 3H), 7.30 (br d, J=7.51 Hz, 2H), 7.42 (d, J=8.58 Hz, 2H), 7.78-7.87 (m, 3H), 8.41 (s, 1H), 11.32 (s, 1H).

[0394] Synthesis of 81.2 To a solution of 81.1 (157 mg, 353.68 μmol, 1 equiv.) in toluene (4 mL) was added N,N-diisopropylethylamine (92.40 μL, 530.52 μmol, 92.40 μL, 1.5 equiv.) and phosphorus oxychloride (42.73 μL, 459.78 μmol, 1.3 equiv.) at room temperature. After stirring at 85° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (10 mL) to give 81.2 (400 mg, 809.16 μmol, 77%) as a yellow solid, which was used in the next step without further purification. LCMS (ESI+): m / z 461.9 (M+H) + .

[0395] Synthesis of 81 and 82: To a solution of 81.2 (157 mg, 339.57 μmol, 1 equiv.) in dichloromethane (5 mL), triethylamine (236.32 μL, 1.70 mmol, 5 equiv.) and 2-aminoethanesulfonamide (63.24 mg, 393.72 μmol, 1.16 equiv.) were added at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a mixture of enantiomers (60 mg, 109.08 μmol, 32%) as a white solid. LCMS (ESI+): m / z 550.0 (M+H) + . 1H NMR: 400 MHz, DMSO-d6δ ppm 3.17 (s, 3H), 3.30 (br s, 1H), 3.80 (br s, 1H), 3.82 (s, 3H), 4.01-4.19 (m, 2H), 4.53 (t, J=11.25 Hz, 1H), 5.08 (dd, J=11.13, 4.28 Hz, 1H), 7.19-7.37 (m, 6H), 7.45 (d, J=8.56 Hz, 2H), 7.69 (s, 1H), 7.74 (d, J=8.56 Hz, 2H), 8.12 (s, 1H). The mirror-image opposite body (130 mg, 236.34 μmol, 1 equivalent) was separated into SFC, and compound 81 (15 mg, 27.27 μmol, 12%) and compound 82 (15 mg, 27.27 μmol, 12%) were obtained as white solids.

[0396] SFC method: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase A: CO2; mobile phase B: IPA (0.1% IPAm, v / v); B%: 55%; running time: 10 minutes.

[0397] Compound 81: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (br s, 2H), 3.72-3.87 (m, 5H), 4.13 (br dd, J=10.76, 4.03 Hz, 1H), 4.54 (br t, J=11.25 Hz, 1H), 5.09 (dd, 7.69 (s, 1H), 7.75 (d, J=8.56 Hz, 2H), 8.04 (br s, 1H), 8.13 (s, 1H). LCMS (ESI+): m / z 550.0 (M+H) + .OR:-111.80.

[0398] Compound 82: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.29 (s, 2H), 3.72-3.90 (m, 5H), 4.05-4.19 (m, 1H), 4.54 (t, J=11.25 Hz, 1H), 5.08 (dd, J=11.25, 4.40 Hz, 1H), 7.05 (s, 2H), 7.21-7.29 (m, 3H), 7.30-7.37 (m, 2H), 7.43-7.49 (m, 2H), 7.69 (s, 1H), 7.72-7.80 (m, 2H), 8.03 (br t, J=5.07 Hz, 1H), 8.13 (s, 1H). LCMS (ESI+): m / z 550.0 (M+H) + . OR:118.20.

[0399] Synthesis of (S,E)-3-(4-methoxyphenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 83) and (S,E)-3-(4-methoxyphenyl)-4-phenyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 84) [ka] To a solution of (S)-2-aminopropanamide hydrochloride (0.085 g, 0.53 mmol, 1.1 equiv.) and triethylamine (0.2 mL, 1.4 mmol, 3 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-methoxyphenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (0.25 mg, 0.5 mmol, 1 equiv.). After stirring at room temperature for 18 h, the reaction was diluted with dichloromethane (20 mL) and washed with 2 N HCl (15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give the expected compound as a colorless oil. This racemate was further subjected to SFC to separate the enantiomers.

[0400] SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm internal diameter, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / iPrOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0401] Compound 83: (103.5 mg, 0.17 mmol, 36% yield, 99% purity, 99% ee). 11H NMR (400 MHz, DMSO-d6) δ 8.18 (broad d, J = 6.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 7.03 (broad s, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.06 (dd, J = 4.1, 10.9 Hz, 1H), 4.49 (t, J = 11.1 Hz, 1H), 4.02 (dd, J = 4.0, 11.2 Hz, 1H), 3.75 (s, 3H), 3.72 (broad s, 2H), 3.29 (broad d, J = 7.2 Hz, 2H). LC-MS (ESI+): 610.2 (M+H + )。

[0402] Compound 84: (103.3 mg, 0.17 mmol, 36% yield, 99% purity, 99% ee). 1 1H NMR (400 MHz, DMSO-d6) δ 8.16 (broad s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.64 (broad d, J = 8.7 Hz, 2H), 7.3 - 7.4 (m, 2H), 7.2 - 7.3 (m, 3H), 7.02 (broad s, 2H), 6.91 (d, J = 8.9 Hz, 2H), 5.05 (dd, J = 4.0, 11.0 Hz, 1H), 4.48 (t, J = 11.2 Hz, 1H), 4.01 (dd, J = 4.0, 11.2 Hz, 1H), 3.74 (s, 3H), 3.71 (broad s, 2H), 3.3 (m, 3H). LC-MS (ESI+): 610.2 (M+H + )。

[0403] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 85) and (R,Z)-3-(4-chlorophenyl)-N'-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 86) [ka] Synthesis of 85.1 To a solution of 21.0 (365 mg, 1.67 mmol, 1 equiv.) in toluene (3 mL) was added methyl ((1-methyl-1H-pyrazol-3-yl)sulfonyl)carbamate (427.46 mg, 1.67 mmol, 1 equiv.) at room temperature. After stirring at 110° C. for 10 hours, the mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (5 mL) to give 85.1 (300 mg, 608.24 μmol, 37%) as a white solid. LCMS (ESI+): m / z 443.9 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 3.69 (dd, J=11.37, 4.65 Hz, 1H), 3.94 (s, 3H), 4.27 (t, J=11.37 Hz, 1H), 4.98 (dd, J=11.43, 4.71 Hz, 1H), 6.71-6.81 (m, 1H), 7.16-7.26 (m, 2H), 7.28-7.36 (m, 2H), 7.42 (d, J=8.68 Hz, 2H), 7.84 (d, J=8.68 Hz, 2H), 7.87-7.91 (m, 1H), 11.54 (br s, 1H), 12.09 (br s, 1H).

[0404] Synthesis of 85.2 To a solution of 85.1 (300 mg, 675.82 μmol, 1 equiv.) in toluene (7 mL) was added N,N-diisopropylethylamine (176.57 μL, 1.01 mmol, 1.5 equiv.) and phosphorus oxychloride (134.71 mg, 878.56 μmol, 81.64 μL, 1.3 equiv.) at room temperature. After stirring at 85° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (10 mL) to give 85.2 (300 mg, 551.53 μmol, 82%) as a yellow solid, which was used in the next step without further purification. LCMS (ESI+): m / z 461.9 (M+H) + .

[0405] Synthesis of Compounds 85 and 86 To a solution of 85.2 (300 mg, 648.86 μmol, 1 equiv.) in dichloromethane (3 mL), triethylamine (451.56 μL, 3.24 mmol, 5 equiv.) and 2-aminoethanesulfonamide (80.56 mg, 648.86 μmol, 1 equiv.) were added at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give the racemic compound (30 mg, 51.81 μmol, 8%) as a white solid. LCMS (ESI+): m / z 550.0 (M+H) + The racemate (30 mg, 51.81 μmol, 8%) was separated by SFC to give compound 85 (5 mg, 9.09 μmol, 1.40%) and compound 86 (7 mg, 12.73 μmol, 2%) as white solids.

[0406] SFC method: Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); Mobile phase A: CO2; Mobile phase B: IPA (0.1% IPAm, v / v); B%: 55%; Run time: 10 min.

[0407] Compound 85: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.26-3.31 (m, 2H), 3.74-3.88 (m, 5H), 4.13 (br dd, J=10.57, 3.81 Hz, 1H), 4.54 (br t, J=11.32 Hz, 1H), 5.09 (dd, J=11.19, 4.32 Hz, 1H), 6.51 (d, J=2.25 Hz, 1H), 7.02 (s, 2H), 7.21-7.37 (m, 5H), 7.46 (d, J=8.63 Hz, 2H), 7.69-7.81 (m, 3H), 8.15 (br s, 1H). LCMS (ESI+): m / z 550.0 (M+H) + .

[0408] Compound 86: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (br s, 2H), 3.81 (s, 5H), 4.00-4.18 (m, 1H), 4.49 (br t, J=11.01 Hz, 1H), 5.04 (br dd, J=10.57, 3.69 Hz, 1H), 6.49 (d, J=2.13 Hz, 1H), 7.20-7.35 (m, 6H), 7.45 (d, J=8.63 Hz, 2H), 7.69-7.76 (m, 3H). LCMS (ESI+): m / z 550.0 (M+H) + .

[0409] Synthesis of (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2,2-dimethyl-3-sulfamoylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 87) and (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-(2,2-dimethyl-3-sulfamoylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 88) [ka] Synthesis of compounds 87 and 88: To a solution of 3-amino-2,2-dimethylpropane-1-sulfonamide (126 mg, 0.76 mmol, 1.5 equiv.) and triethylamine (0.21 mL, 1.5 mmol, 3.0 equiv.) in dichloromethane (3 mL) was added (E)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (250 mg, 0.51 mmol, 1.0). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to give the following enantiomers as white solids: Compound 87 (85.4 mg, 0.14 mmol, 27% yield, 99% purity, 99% ee, OR: −84.9) and Compound 88 (80.6 mg, 0.13 mol, 26% yield, 99% purity, 99% ee, OR: +77.1).

[0410] SFC method: SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm id, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / EtOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0411] Compound 87: 11H NMR (DMSO-d6, 400 MHz) δ 7.85 (broad singlet, 1H), 7.80 (doublet, J = 8.6 Hz, 2H), 7.73 (doublet, J = 8.7 Hz, 2H), 7.56 (doublet, J = 8.6 Hz, 2H), 7.45 (doublet, J = 8.6 Hz, 2H), 7.31 - 7.37 (multiplet, 2H), 7.22 - 7.29 (multiplet, 3H), 6.98 (singlet, 2H), 5.10 (doublet of doublets, J = 11.1, 4.1 Hz, 1H), 4.57 (triplet, J = 11.2 Hz, 1H), 4.08 (broad doublet of doublets, J = 11.0, 3.8 Hz, 1H), 3.37 (broad singlet, 1H), 3.30 (singlet, 1H), 3.03 (singlet, 2H), 1.01 (singlet, 6H) ppm. LC-MS (ESI+): 622.0 (M+H+).

[0412] Compound 88: 1 1H NMR (DMSO-d6, 400 MHz) δ 7.85 (broad singlet, 1H), 7.80 (doublet, J = 8.6 Hz, 2H), 7.73 (doublet, J = 8.6 Hz, 2H), 7.56 (doublet, J = 8.7 Hz, 2H), 7.45 (doublet, J = 8.7 Hz, 2H), 7.31 - 7.37 (multiplet, 2H), 7.21 - 7.29 (multiplet, 3H), 6.98 (singlet, 2H), 5.10 (doublet of doublets, J = 11.1, 4.1 Hz, 1H), 4.57 (triplet, J = 11.2 Hz, 1H), 4.08 (broad doublet of doublets, J = 11.1, 3.8 Hz, 1H), 3.43 (broad singlet, 1H), 3.29 (singlet, 1H), 3.03 (singlet, 2H), 1.01 (singlet, 6H) ppm. LC-MS (ESI+): 622.0 (M+H+).

[0413] Synthesis of (S,E)-N'-((4-chlorophenyl)sulfonyl)-N-(2,2-dimethyl-3-sulfamoylpropyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 89) and (R,E)-N'-((4-chlorophenyl)sulfonyl)-N-(2,2-dimethyl-3-sulfamoylpropyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 90) [ka] Synthesis of Compounds 89 and 90 To a solution of 3-amino-2,2-dimethylpropane-1-sulfonamide (121 mg, 0.72 mmol, 1.5 equiv.) and triethylamine (0.2 mL, 1.5 mmol, 3.0 equiv.) in dichloromethane (3 mL) was added 4-chloro-N-{chloro-[3-(4-fluoro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene}-benzenesulfonamide (230 mg, 0.48 mmol, 1.0 equiv.). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to give two different enantiomers as white solids: compound 89 (71.5 mg, 0.12 mmol, 25% yield, 99% purity, 99% ee, OR: −130.5) and compound 90 (73.4 mg, 0.12 mol, 25% yield, 99% purity, 99% ee, OR: +98.5).

[0414] SFC method: SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm id, 5 μm particle size, in isocratic mode at 3 ml / min CO2 (40%) / MeOH + 0.1% diethylamine, 35 °C, BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm.

[0415] Compound 89: 1 H NMR (DMSO-d6, 400 MHz) δ 7.74-7.88 (m, 5H), 7.53-7.59 (m, 2H), 7.31-7.37 (m, 2H), 7.20-7.29 (m, 5H), 6.98 (s, 2H), 5.10 (br dd, J = ppm. LC-MS (ESI+): 606.1 (M+H+).

[0416] Compound 90: 1 H NMR (DMSO-d6, 400 MHz) δ 7.74-7.85 (m, 5H), 7.56 (d, J = 8.7 Hz, 2H), 7.30-7.37 (m, 2H), 7.19-7.29 (m, 5H), 6.98 (br s, 2H), 5.10 (br ppm. LC-MS (ESI+): 606.1 (M+H+).

[0417] (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-((S)-2-methyl-3-sulfamoylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 91), (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-((R)-2-methyl-3-sulfamoylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 92), (R Synthesis of (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-((S)-2-methyl-3-sulfamoylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 93) and (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-((R)-2-methyl-3-sulfamoylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 94) [ka] Synthesis of compounds 91-94 To a stirred solution of 3-amino-2-methylpropane-1-sulfonamide (185 mg, 1.22 mmol, 2.0 equiv., I16) and triethylamine (0.26 mL, 1.83 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (300 mg, 0.61 mmol, 1.0). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40) to give a colorless oil, which was further subjected to SFC purification to separate the four diastereomers as white solids: Compound 91 (9.7 mg, 0.016 mmol, % yield, 99% purity, 99% ee, OR: −50.9), Compound 92 (8.1 mg, 0.013 mmol, % yield, 99% purity, 99% ee, OR: −59.2), Compound 93 (8.3 mg, 0.013 mmol, % yield, 99% purity, 99% ee, OR: +29.0), and Compound 94 (12.3 mg, 0.020 mmol, % yield, 98% purity, 99% ee, OR: +41.7).

[0418] SFC method: SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The reaction was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm. Absolute stereochemistry was not determined. Diastereomers with negative OR were arbitrarily assigned as S isomers.

[0419] Compound 91: 11H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.17 - 7.37 (m, 7H), 4.94 (dd, J = 11.3, 4.7 Hz, 1H), 4.54 (t, J = 11.3 Hz, 1H), 4.10 (dd, J = 11.3, 4.7 Hz, 1H), 3.41 - 3.60 (m, 2H), 3.23 (dd, J = 14.3, 5.0 Hz, 1H), 2.98 (dd, J = 14.3, 7.4 Hz, 1H), 2.37 - 2.52 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0420] Compound 92: 1 1H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.17 - 7.37 (m, 7H), 4.94 (dd, J = 11.2, 4.6 Hz, 1H), 4.55 (t, J = 11.3 Hz, 1H), 4.09 (dd, J = 11.2, 4.6 Hz, 1H), 3.50 (br d, J = 6.1 Hz, 2H), 3.23 (dd, J = 14.3, 4.9 Hz, 1H), 2.97 (dd, J = 14.3, 7.3 Hz, 1H), 2.38 - 2.51 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0421] Compound 93: 11H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.17 - 7.37 (m, 7H), 4.94 (dd, J = 11.2, 4.7 Hz, 1H), 4.54 (t, J = 11.3 Hz, 1H), 4.10 (dd, J = 11.3, 4.7 Hz, 1H), 3.41 - 3.59 (m, 2H), 3.23 (dd, J = 14.3, 4.9 Hz, 1H), 2.98 (dd, J = 14.3, 7.4 Hz, 1H), 2.37 - 2.51 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0422] Compound 94: 1 1H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.16 - 7.38 (m, 7H), 4.94 (dd, J = 11.2, 4.6 Hz, 1H), 4.55 (t, J = 11.3 Hz, 1H), 4.08 (dd, J = 11.3, 4.6 Hz, 1H), 3.50 (br d, J = 6.2 Hz, 2H), 3.23 (dd, J = 14.3, 4.9 Hz, 1H), 2.97 (dd, J = 14.3, 7.4 Hz, 1H), 2.45 (br dd, J = 12.2, 6.7 Hz, 1H), 1.10 (d, J = 6.8 Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0423] (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((R)-3-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 95), (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((S)-3-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 96), (R Synthesis of (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((R)-3-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 97) and (R,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((S)-3-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 98) [ka] Synthesis of compounds 95-98 To a stirred solution of 4-aminobutane-2-sulfonamide (185 mg, 1.22 mmol, 2.0 equiv.) and triethylamine (0.26 mL, 1.83 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (300 mg, 0.61 mmol, 1.0). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40) to give a colorless oil, which was further purified by SFC to separate the four diastereomers as white solids: Compound 95 (14.2 mg, 0.023 mmol, 4% yield, 99% purity, 99% ee, OR: −33.9), Compound 96 (11.7 mg, 0.019 mmol, 3% yield, 99% purity, 99% ee, OR: −59.1), Compound 97 (6.0 mg, 0.010 mmol, 2% yield, 99% purity, 99% ee, OR: +19.1), and Compound 98 (12.6 mg, 0.021 mmol, 4% yield, 99% purity, 99% ee, OR: +78.1).

[0424] SFC method: SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-3) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 mL / min of CO2 (40%) / i The reaction was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The DAD detector acquisition frequency was set at 220 nm. Absolute stereochemistry was not determined. Diastereomers with negative OR were arbitrarily assigned as S isomers.

[0425] Compound 95: 11H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.14 - 7.37 (m, 7H), 4.93 (dd, J = 11.2, 4.6 Hz, 1 ), 化合物7.14 (7.37 米, 7H), 4.93 (dd, J = 11.2, 4.6 Hz, 1H), 4.53 (t, J = 图11.3 Hz, 1H), 4.08 (dd, J = 11.5, 5.0 Hz, 1H), 3.62 (br t, J = 7.1 Hz, 2H), 2.97 - 3.10 (m, 1H), 2.22 - 2.34 (m, 1H), 1.79 (dq, J = 14.3, 7.1 Hz, 1H), 1.31 (d, J = 6.8 Hz, 3H) ppm。LC-MS (ESI+): 608.0 (M+H+)。

[0426] Compound 96: 1 1H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.17 - 7.35 (m, 7H), 4.93 (dd, J = 11.2, 4.6 Hz, 1H), 4.54 (t, J = 11.3 Hz, 1H), 4.07 (dd, J = 11.3, 4.6 Hz, 1H), 3.50 - 3.72 (m, 2H), 2.98 - 3.10 (m, 1H), 2.21 - 2.36 (m, 1H), 1.73 - 1.86 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H) ppm。LC-MS (ESI+): 608.1 (M+H+)。

[0427] Compound 97: 1H NMR (MeOD-d4, 400 MHz) δ 7.82-7.88 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 8.7, 2.0 Hz, 2H), 7.16-7.36 (m, 7H), 4.90-4.97 (m, 1H), 4.54 (td, J = 11.3, 6.0 Hz, 1H), 4.04-4.12 (m, 1H), 3.52-3.70 (m, 2H), 2.98-3.09 (m, 1H), 2.22-2.34 (m, 1H), 1.74-1.85 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0428] Compound 98: 1 H NMR (MeOD-d4, 400 MHz) δ 7.85 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.18-7.35 (m, 7H), 4.93 (dd, J = 11.2, 4.6 Hz, 1H), 4.54 (t, J = 11.3 Hz, 1H), 4.07 (dd, J = 11.3, 4.6 Hz, 1H), 3.52-3.73 (m, 2H), 2.98-3.09 (m, 1H), 2.24-2.35 (m, 1H), 1.74-1.86 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H) ppm. LC-MS (ESI+): 608.1 (M+H+).

[0429] Synthesis of (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-(4-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 99) and (S,E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-(4-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 100) [ka] Synthesis of Compounds 99 and 100 To a stirred solution of 4-aminobutane-1-sulfonamide (85 mg, 0.56 mmol, 1.1 equiv.) and triethylamine (0.21 mL, 1.5 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (250 mg, 0.51 mmol, 1.0). After stirring at room temperature for 18 hours, the reaction mixture was diluted with dichloromethane (15 mL) and washed with ammonium chloride (20 mL) and water (20 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil, which was further subjected to SFC separation conditions: Compound 99 (13.6 mg, 0.022 mmol, 5% yield, 98% purity, 99% ee, OR: -60.7) and Compound 100 (13.4 mg, 0.022 mmol, 5% yield, 99% purity, 99% ee, OR: +60.1).

[0430] SFC method: SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0431] Compound 99: (13.6 mg, 0.022 mmol, 5% yield, 98% purity, 99% ee, OR: -60.7). 11H NMR (CDCl3, 400 MHz) δ 7.80 - 7.90 (m, 2H), 7.53 (br d, J = 5.7 Hz, 2H), 7.42 (br d, J = 4.9 Hz, 2H), 7.33 (br d, J = 4.6 Hz, 5H), 7.13 (br s, 2H), 6.98 - 7.09 (m, 1H), 4.76 (br s, 2H), 4.62 - 4.71 (m, 1H), 4.49 - 4.61 (m, 1H), 4.01 - 4.18 (m, 1H), 3.63 - 3.79 (m, 2H), 3.18 (br d, J = 7.1 Hz, 2H), 2.02 (br d, J = 5.3 Hz, 2H), 1.83 - 1.94 (m, 2H) ppm. LC-MS (ESI+): 608.0 (M+H+). HPLC RT: 3.867 min (Method: VILLA).

[0432] Compound 100: (13.4 mg, 0.022 mmol, 5% yield, 99% purity, 99% ee, OR: +60.1). 1 1H NMR (CDCl3, 400 MHz) δ 7.81 - 7.89 (m, 2H), 7.51 (br d, J = 5.0 Hz, 2H), 7.37 - 7.44 (m, 2H), 7.27 - 7.36 (m, 5H), 7.12 (br s, 2H), 7.05 (br dd, J = 2.7, 1.1 Hz, 1H), 4.75 (br d, J = 2.1 Hz, 2H), 4.61 - 4.71 (m, 1H), 4.49 - 4.59 (m, 1H), 4.05 - 4.17 (m, 1H), 3.71 (br d, J = 4.3 Hz, 2H), 3.12 - 3.24 (m, 2H), 2.00 (br s, 2H), 1.83 - 1.94 (m, 2H) ppm. LC-MS (ESI+): 608. (M+H+). HPLC RT: 3.867 min (Method: VILLA).

[0433] Synthesis of (S,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(4-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 101) and (R,E)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-(4-sulfamoylbutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 102) [ka] Synthesis of Compounds 101 and 102 To a stirred solution of 4-aminobutane-1-sulfonamide (88 mg, 0.58 mmol, 1.1 equiv.) and triethylamine (0.22 mL, 1.6 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added (Z)-N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidoyl chloride (250 mg, 0.52 mmol, 51.1). After stirring at room temperature for 18 hours, the reaction mixture was diluted with dichloromethane (20 mL) and washed with ammonium chloride (20 mL) and water (20 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / heptane mixtures (0 / 100 to 70 / 30, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to resolve the following two enantiomers as white solids: Compound 101 (25.2 mg, 0.04 mmol, 8% yield, 95% purity, 99% ee, OR: −103.5) and Compound 102 (38.4 mg, 0.06 mmol, 12% yield, 93% purity, 99% ee, OR: +89.9).

[0434] SFC method: SFC purification was performed on a Jasco 4000 Parallel SFC System (4 channels: 3 UV + 1 DAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm inner diameter, 5 μm particle size, in isocratic mode with 3 ml / min CO2 (40%) / i The analysis was carried out in PrOH + 0.1% diethylamine at 35°C and BPR: 100 bar. The acquisition frequency of the DAD detector was set at 220 nm.

[0435] Compound 101: 1 H NMR (DMSO-d6, 400 MHz) δ 8.12 (br s, 1H), 7.79 (dt, J = 8.7, 2.5 Hz, 4H), 7.54 (d, J = 8.6 Hz, 2H), 7.30-7.38 (m, 2H), 7.19-7.28 (m, 5H), 6.76 (s, 2H), 5.06 (dd, J = 11.1, 4.3 Hz, 1H), 4.50 (t, J = 11.2 Hz, 1H), 4.03 (br dd, J = 11.1, 4.3 Hz, 1H), 3.18 (br s, 2H), 2.90-3.00 (m, 2H), 1.54-1.74 (m, 4H) ppm. LC-MS (ESI+): 592.1 (M+H+).

[0436] Compound 102: 1 H NMR (DMSO-d6, 400 MHz) δ 8.12 (br s, 1H), 7.75-7.84 (m, 4H), 7.54 (d, J = 8.5 Hz, 2H), 7.29-7.36 (m, 2H), 7.19-7.27 (m, 5H), 6.76 (s, 2H), 5.06 (dd, J = 11.1, 4.2 Hz, 1H), 4.50 (t, J = 11.2 Hz, 1H), 3.99-4.05 (m, 1H), 3.28-3.31 (m, 2H), 2.95 (br t, J = 7.3 Hz, 2H), 1.54-1.74 (m, 4H) ppm. LC-MS (ESI+): 592.1 (M+H+).

[0437] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-isopropyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 103) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-isopropyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 104) [ka] Synthesis of 103.1 To a solution of I19 (370 mg, 1.66 mmol, 1 equiv) in dioxane (4 mL) and pyridine (1 mL) was added methyl ((4-chlorophenyl)sulfonyl)carbamate (435.53 mg, 1.74 mmol, 1.05 equiv) at room temperature. After stirring at 100 °C for 8 h, the reaction mixture was concentrated under reduced pressure to give a residue which was triturated with methyl tert-butyl ether (5 mL) to give 103.1 (150 mg, 306.58 μmol, 18%) as a white solid. LCMS (ESI+): m / z 223.1 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 0.51 (d, J=6.85 Hz, 3H), 0.91 (d, J=6.85 Hz, 3H), 1.97 - 2.09 (m, 1H), 3.71 - 3.86 (m, 3H), 7.54 (d, J=8.56 Hz, 2H), 7.71 (d, J=8.56 Hz, 2H), 7.95 (dd, J=13.75, 8.62 Hz, 4H), 11.34 (br s, 1H).

[0438] Synthesis of 103.2 To a solution of 103.1 (150 mg, 340.64 μmol, 1 equiv.) in toluene (2 mL), diisopropylethylamine (77.13 μL, 442.84 μmol, 1.3 equiv.) and phosphorus oxychloride (37.99 μL, 408.77 μmol, 1.2 equiv.) were added at room temperature. After stirring at 80° C. for 6 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL×2). The combined organic layers were washed with brine (5 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with ethanol (5 mL) to give 103.2 (120 mg, 235.40 μmol, 69%) as a white solid. LCMS (ESI+): m / z 459.9 (M+H) + . 1 H NMR: 400 MHz, DMSO-d6δ ppm 0.52 - 0.60 (m, 3 H), 0.97 (d, J=6.79 Hz, 3 H), 2.08 (td, J=6.94, 3.16 Hz, 1 H), 3.97 - 4.22 (m, 3 H), 7.59 (d, J=8.58 Hz, 2 H), 7.64 - 7.71 (m, 2 H), 7.84 (d, J=8.58 Hz, 2 H), 7.90 - 7.96 (m, 2 H).

[0439] Synthesis of Compounds 103 and 104 To a solution of 103.1 (120 mg, 261.56 μmol, 1 equiv.) in dichloromethane (2 mL), 2-aminoethane-1-sulfonamide (50.41 mg, 313.87 μmol, 1.2 equiv., HCl salt) and triethylamine (66.17 mg, 653.89 μmol, 2.5 equiv.) were added at room temperature. After stirring at room temperature for 10 hours, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (5 / 1, v / v) to give the racemic compound (110 mg, 191.19 μmol, 77%) as a white solid, which was further separated by SFC to give compound 104 (16 mg, 27.81 μmol, 11%) as a white solid and compound 103 (18 mg, 32.94 μmol, 12%) as a white solid. LCMS (ESI+): m / z 546.0 (M+H) + .

[0440] SFC method: Column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); Mobile phase A: CO2; Mobile phase B: [0.1% NH3H2O ​​in IPA]; % of mobile phase B: 50%; Run time: 12 min.

[0441] Compound 103: 11H NMR: 400 MHz, DMSO-d6 δ ppm 0.55 (d, J = 6.79 Hz, 3H), 0.91 (d, J = 6.79 Hz, 3H), 2.01 (ddd, J = 9.83, 6.62, 3.34 Hz, 1H), 3.20 (br t, J = 6.85 Hz, 2H), 3.66 (br d, J = 3.46 Hz, 2H), 3.86 - 3.93 (m, 1H), 3.95 - 4.04 (m, 1H), 4.15 (br dd, J = 10.91, 2.92 Hz, 1H), 7.00 (s, 2H), 7.57 (dd, J = 8.40, 5.54 Hz, 4H), 7.87 (dd, J = 8.58, 2.27 Hz, 4H), 8.02 (br s, 1H). LCMS (ESI+): m / z 546.0 (M+H) + 。OR: -1.60。

[0442] Compound 104: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 0.55 (d, J = 6.79 Hz, 3H), 0.91 (d, J = 6.79 Hz, 3H), 1.96 - 2.05 (m, 2H), 3.20 (t, J = 6.97 Hz, 2H), 3.60 - 3.71 (m, 2H), 3.86 - 3.94 (m, 1H), 3.95 - 4.03 (m, 1H), 4.15 (dd, J = 11.15, 3.28 Hz, 1H), 7.00 (s, 2H), 7.52 - 7.62 (m, 4H), 7.82 - 7.92 (m, 4H), 8.02 (br t, J = 5.54 Hz, 1H). LCMS (ESI+): m / z 546.0 (M+H) + 。OR: 1.80。

[0443] Examples 105 and 106: Synthesis of (S,Z)-3-(4-chlorophenyl)-4-isopropyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (105) and (S,Z)-3-(4-chlorophenyl)-4-isopropyl-N-(2-sulfamoylethyl)-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (106) [ka] Synthesis of 105.1 To a solution of I19 (414 mg, 1.86 mmol) in toluene (5 mL) was added 43.1 (579.13 mg, 2.04 mmol, 1.1 equiv) at room temperature. After stirring at 110 °C for 10 h, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (5 mL) to give 105.1 (270 mg, 512.77 μmol, 27%) as a white solid. 1 H NMR: 400 MHz CDCl3δ ppm 0.64 (d, J=6.91 Hz, 3H), 0.98 (d, J=6.79 Hz, 3H), 2.14 (dtt, J=10.26, 6.81, 6.81, 3.44, 3.44 Hz, 1H), 3.63 - 3.72 (m, 1H), 3.81 (t, J=11.44 Hz, 1H), 3.88 - 3.95 (m, 1H), 7.40 - 7.47 (m, 2H), 7.58 - 7.67 (m, 2H), 7.82 (d, J=8.34 Hz, 2H), 8.29 (d, J=8.23 Hz, 2H), 8.66 (s, 1H).

[0444] Synthesis of 105.2 To a solution of 105.1 (270 mg, 0.57 mmol, 1 equiv) in toluene (5 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.85 mmol, 1.5 equiv) at room temperature. After stirring at room temperature for 1 hour, phosphorus oxychloride (0.11 g, 0.74 mmol, 0.07 mL, 1.3 equiv) was added at room temperature. After stirring at 85 °C for 16 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give 105.2 (610 mg, 557.54 μmol, 98%) as a yellow solid. LCMS (ESI+): m / z 491.9 (M+H) + .

[0445] Synthesis of Compounds 105 and 106 To a solution of 105.2 (610 mg, 1.24 mmol, 1 equiv.) in dichloromethane (6 mL), triethylamine (626.85 mg, 6.19 mmol, 0.86 mL, 5 equiv.) and 2-aminoethane-1-sulfonamide (230.75 mg, 1.86 mmol, 1.5 equiv.) were added at room temperature. After stirring at room temperature for 10 h, the reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (5 / 1, v / v) to give the racemic compound, which was separated by SFC to give compound 105 (76.70 mg, 128.26 μmol, 10%) as a white solid and compound 106 (73.50 mg, 126.71 μmol, 10%) as a white solid.

[0446] SFC method: Column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 µm); Mobile phase A: CO2; Mobile phase B: [IPA with 0.1% NH3·HO]; B%: 37%–37%, Run time: 10 min.

[0447] Compound 105: 11H NMR: 400 MHz DMSO-d6 δ ppm 8.06 (d, J=8.11 Hz, 2H), 7.82 - 7.93 (m, 4 H), 7.56 (d, J=8.58 Hz, 2H), 6.76 - 7.24 (m, 2H), 4.05 - 4.14 (m, 1H), 3.99 (t, J=10.91 Hz, 1H), 3.85 - 3.93 (m, 1H), 3.58 - 3.75 (m, 2H), 3.21 (t, J=7.03 Hz, 2H), 2.01 (dq, J=9.95, 6.74 Hz, 1H), 0.89 (d, J=6.79 Hz, 3H), 0.53 (d, J=6.79 Hz, 3H). LCMS (ESI+): m / z 580.0 (M+H) + 。OR: -1.90。

[0448] Compound 106: 1 1H NMR: 400 MHz DMSO-d6 δ ppm 8.07 (d, J=8.13 Hz, 2H), 7.82 - 7.94 (m, 4H), 7.57 (d, J=8.63 Hz, 2H), 7.00 (br s, 2 H), 4.06 - 4.16 (m, 1 H), 4.00 (t, J=10.94 Hz, 1H), 3.87 - 3.94 (m, 1H), 3.67 (br s, 2H), 3.22 (t, J=7.00 Hz, 2H), 1.95 - 2.07 (m, 1H), 0.90 (d, J=6.88 Hz, 3H), 0.54 (d, J=6.75 Hz, 3H). LCMS (ESI+): m / z 580.0 (M+H) + 。OR: 1.80。

[0449] Synthesis of (S,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-N-methyl-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 107) and (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-N-methyl-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 108) [ka] Synthesis of Compounds 107 and 108 To a solution of 2-(methylamino)ethane-1-sulfonamide (300 mg, 1.72 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (1.2 mL, 8.59 mmol, 5 equiv.) and 45.1 (1.23 g, 2.58 mmol, 1.2 equiv.) at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate to give the racemic compound (400 mg, 733 μmol, 42%) as a white solid. LCMS (ESI+): m / z 578.3 (M+H) + .

[0450] The racemate (400 mg, 733 μmol, 1 equiv.) was separated by SFC to give compound 107 (103 mg, 183.25 μmol, 11%) and compound 108 (80.9 mg, 138.39 μmol, 8%) as white solids.

[0451] SFC method: Column: DAICEL CHIRALCEL o1 (250 mm*30 mm, 10 μm); Mobile phase A: CO2; Mobile phase B: MeOH with 0.1% NH3H2O; B%: 50%; Run time: 15 min.

[0452] Compound 107: 1H NMR: 400 MHz, DMSO-d6δ ppm 2.07 (s, 1H) 3.10 (s, 3 H) 3.36 - 3.51 (m, 2 H) 3.72 - 3.92 (m, 3H) 4.56 (t, J=11.15 Hz, 1H) 5.03 (dd, J=11.27, 5.07 Hz, 1H) 6.99 (s, 2H) 7.15 - 7.27 (m, 3H) 7.28 - 7.35 (m, 4H) 7.52 (d, J=8.58 Hz, 2H) 7.66 (dd, J=8.70, 5.60 Hz, 2H) 7.80 (d, J=8.58 Hz, 2H). LCMS (ESI+): m / z 578.2 (M+H) + . OR:-122.60.

[0453] Compound 108: 1 H NMR: 400 MHz, DMSO-d6δ ppm 2.07 (s, 1 H) 3.10 (s, 3H) 3.35 - 3.51 (m, 2H) 3.73 - 3.91 (m, 3H) 4.56 (t, J=11.09 Hz, 1H) 5.03 (dd, 7.77 - 7.83 (m, 2H). LCMS (ESI+): m / z 578.2 (M+H) + . OR:114.40.

[0454] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-methyl-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 109) and (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N-methyl-4-phenyl-N-(2-sulfamoylethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 110) [ka] Synthesis of Compounds 109 and 110 To a solution of 1.0 (1.27 g, 2.58 mmol, 1.5 equiv.) in dichloromethane (10 mL), triethylamine (869.08 g, 8.59 mmol, 1.20 mL, 5 equiv.) and 2-(methylamino)ethane-1-sulfonamide (300 mg, 1.72 mmol, 1 equiv.) were added at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give the racemic compound (900 mg, 908.28 μmol, 60%) as a white solid. LCMS (ESI+): m / z 593.07.0 (M+H) + .

[0455] The racemate (200 mg, 336.40 μmol, 1 equiv.) was separated by SFC to give compound 109 (100 mg, 168.82 μmol, 96%) as a white solid and compound 110 (100 mg, 158.61 μmol, 94%) as a white solid.

[0456] SFC method: Column: Chiralpak AD-3, 50 × 4.6 mm i.d., 3 μm; Mobile phase A: CO2; Mobile phase B: isopropanol (0.1% isopropanol m, v / v); B%: 50%, Run time: 15 min.

[0457] Compound 109: 11H NMR (400 MHz, DMSO-d6) δ ppm 3.10 (s, 3H), 3.42 (td, J=8.85, 5.94 Hz, 2H), 3.72 - 3.89 (m, 3H), 4.57 (t, J=11.19 Hz, 1H), 5.04 (dd, J=11.32, 5.19 Hz, 1H), 6.98 (s, 2H), 7.21 - 7.27 (m, 1H), 7.28 - 7.35 (m, 4H), 7.41 (d, J=8.76 Hz, 2H), 7.50 - 7.55 (m, 2H), 7.61 (d, J=8.63 Hz, 2H), 7.77 - 7.84 (m, 2H). LCMS (ESI+): m / z 594.0 (M+H) + 。OR: - 98.70。

[0458] Compound 110: 1 1H NMR (400 MHz, DMSO-d6) δ ppm 3.10 (s, 3H), 3.38 - 3.49 (m, 2H), 3.74 - 3.89 (m, 3H), 4.57 (br t, J=11.21 Hz, 1H), 5.03 (br dd, J=11.32, 5.01 Hz, 1H), 6.98 (s, 2H), 7.25 (br d, J=6.32 Hz, 1H), 7.28 - 7.35 (m, 4H), 7.41 (br d, J=8.46 Hz, 2H), 7.53 (br d, J=8.46 Hz, 2H), 7.61 (br d, J=8.46 Hz, 2H), 7.80 (br d, J=8.46 Hz, 2H). LCMS (ESI+): m / z 594.0 (M+H) + 。OR: 94.60。

[0459] Synthesis of (S,Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)piperidine-4-sulfonamide (Compound 111) and (R,Z)-1-((((4-chlorophenyl)sulfonyl)imino)(3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)piperidine-4-sulfonamide (Compound 112) [ka] Synthesis of Compounds 111 and 112 To a solution of 45.1 (760 mg, 1.60 mmol, 1 equiv.) in dichloromethane (50 mL) was added triethylamine (1.11 mL, 7.98 mmol, 5 equiv.) and piperidine-4-sulfonamide (262.02 mg, 1.60 mmol, 1 equiv.) at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a racemic mixture, which was separated by SFC to give compound 111 (36.7 mg, 6.08 mmol, 4%) as a white solid and compound 112 (32.7 mg, 5.42 mmol, 3%) as a white solid.

[0460] SFC method: Column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 μm); A: CO2; Mobile phase B: [neutral isopropanol]; Ratio: 50%; Run time: 12 min.

[0461] Compound 111: 11H NMR: 400 MHz DMSO-d6 δ ppm 1.77 (qd, J=12.38, 3.87 Hz, 1 H), 1.89 - 2.03 (m, 1 H), 2.14 (br s, 2 H), 3.17 - 3.31 (m, 3 H), 3.63 (dd, J=11.27, 4.71 Hz, 1 H), 4.12 (br t, J=14.25 Hz, 2 H), 4.42 (t, J=11.27 Hz, 1 H), 4.96 (dd, J=11.21, 4.65 Hz, 1 H), 6.90 (s, 2 H), 7.17 - 7.27 (m, 5 H), 7.28 - 7.35 (m, 2 H), 7.51 (d, J=8.58 Hz, 2 H), 7.69 (dd, J=8.82, 5.48 Hz, 2 H), 7.77 (d, J=8.58 Hz, 2 H). LCMS (ESI+): m / z 604.0 (M+1) + 。OR: -89.68。

[0462] Compound 112: 1 1H NMR: 400 MHz DMSO-d6 δ ppm 1.77 (qd, J=12.36, 3.70 Hz, 1 H) 1.96 (qd, J=12.26, 3.99 Hz, 1 H) 2.14 (br s, 2 H) 3.17 - 3.30 (m, 3 H) 3.63 (dd, J=11.21, 4.65 Hz, 1 H) 4.12 (br t, J=14.25 Hz, 2 H) 4.42 (t, J=11.21 Hz, 1 H) 4.96 (dd, J=11.09, 4.65 Hz, 1 H) 6.90 (s, 2 H) 7.17 - 7.27 (m, 5 H) 7.31 (d, J=7.03 Hz, 2 H) 7.51 (d, J=8.58 Hz, 2 H) 7.69 (dd, J=8.70, 5.48 Hz, 2 H) 7.77 (d, J=8.46 Hz, 2 H). LCMS (ESI+): m / z 604.0 (M+1) + 。OR: 87.67。

[0463] Synthesis of (S,Z)-1-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide (Compound 113) and (S,Z)-1-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)piperidine-4-sulfonamide (Compound 114) [ka] Synthesis of Compounds 113 and 114 To a solution of 1.0 (500 mg, 1.01 mmol, 1 equiv.) in dichloromethane (5 mL), triethylamine (351.45 μL, 2.53 mmol, 2.5 equiv.) and piperidine-4-sulfonamide (202.69 mg, 1.01 mmol, 1 equiv., HCl) were added at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give the racemic compound (470 mg, 0.76 mmol, 75%) as a white solid. LCMS (ESI+): m / z 620.1 (M+1) + .

[0464] The racemate (300 mg, 483 μmol, 1 equiv.) was separated by SFC to give compound 113 (92.8 mg, 150 μmol, 31%) as a white solid and compound 114 (94.6 mg, 153 μmol, 32%) as a white solid.

[0465] SFC method: Column: DAICEL CHIRALCEL OD (250 mm x 50 mm, 10 μm); Mobile phase: [neutral isopropanol]; B%: 50%-50%, 10 min.

[0466] Compound 113: 11H NMR: 400 MHz DMSO-d6 δ 1.70 - 1.88 (m, 1H), 1.89 - 2.05 (m, 1H), 2.14 (br d, J = 1.59 Hz, 2H), 3.30 (br s, 3H), 3.65 (dd, J = 11.19, 4.83 Hz, 1H), 4.12 (br t, J = 14.06 Hz, 2H), 4.42 - 4.50 (m, 1H), 4.97 (dd, J = 11.31, 4.83 Hz, 1H), 6.91 (s, 2H), 7.21 - 7.29 (m, 3H), 7.29 - 7.36 (m, 2H), 7.44 (d, J = 8.68 Hz, 2H), 7.52 (d, J = 8.56 Hz, 2H), 7.64 (d, J = 8.68 Hz, 2H), 7.78 (d, J = 8.56 Hz, 2H). LCMS (ESI+): m / z 620.0 (M+1) + 。OR: -64.82。

[0467] Compound 114: 1H NMR: 400 MHz DMSO-d6 δ 1.69 - 1.86 (m, 1H), 1.89 - 2.04 (m, 1H), 2.07 - 2.22 (m, 2H), 3.19 - 3.32 (m, 3H), 3.65 (dd, J = 11.25, 4.89 Hz, 1H), 4.12 (br t, J = 14.00 Hz, 2H), 4.44 (t, J = 11.31 Hz, 1H), 4.97 (dd, J = 11.25, 4.89 Hz, 1H), 6.91 (s, 2H), 7.22 - 7.28 (m, 3H), 7.29 - 7.35 (m, 2H), 7.44 (d, J = 8.68 Hz, 2H), 7.52 (d, J = 8.56 Hz, 2H), 7.64 (d, J = 8.56 Hz, 2H), 7.78 (d, J = 8.56 Hz, 2H). LCMS (ESI+): m / z 620.0 (M+1) + 。OR: 74.73。

[0468] (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1r,3S)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 115), (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1s,3R)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (R,Z Synthesis of (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1r,3R)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (117) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1s,3S)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (compound 118) [ka] To a solution of 1.0 (1 g, 3.15 mmol, 1 equiv.) in dichloromethane (5 mL), triethylamine (706.10 μL, 5.07 mmol, 2.5 equiv.) and 3-aminocyclobutane-1-sulfonamide (378.77 mg, 2.03 mmol, 1 equiv.) were added at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a mixture of diastereomers (860 mg, 1.35 mmol, 66%) as a white solid. LCMS (ESI+): m / z 606.1.0 (M+H) + .

[0469] SFC Method: The diastereomers (800 mg, 1.32 mmol, 1 equiv.) were separated by a first SFC to give 115 (102 mg, 161.78 μmol, 12%) as a white solid, 116 (32 mg, 52.76 μmol, 4%) as a white solid, and a racemic mixture of 117 and 118. The racemic mixture of 117 and 118 was further separated by a second SFC to give 117 (135 mg, 222.57 μmol, 16%) as a white solid and 118 (78 mg, 127.44 μmol, 9%) as a white solid. Absolute stereochemistry was not determined. The diastereomer with a negative OR was appropriately assigned as the S isomer.

[0470] First SFC method: Column: REGIS (s,s) WHELK-O1 (250 mm x 30 mm, 10 μm); Mobile phase A: [NH3H2O ​​(0.1%) in ethanol]; Mobile phase B: CO2; B%: 60%; Run time: 10 min.

[0471] Second SFC method: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); Mobile phase A: [NH3H2O ​​(0.1%) in methanol]; Mobile phase B: CO2; B%: 65%; Run time: 20 min.

[0472] Compound 115: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.07 (s, 1H), 2.30 - 2.46 (m, 3H), 2.54 (s, 1H), 3.46 (quin, J = 8.44 Hz, 1H), 3.94 (dd, J = 11.25, 4.28 Hz, 1H), 4.14 - 4.32 (m, 1H), 4.48 (t, J = 11.31 Hz, 1H), 5.05 (dd, J = 11.19, 4.34 Hz, 1H), 6.80 (s, 2H), 7.18 - 7.35 (m, 5H), 7.45 (d, J = 8.68 Hz, 2H), 7.50 - 7.60 (m, 2H), 7.71 - 7.82 (m, 4H), 8.13 (br d, J = 5.50 Hz, 1H). LCMS (ESI+): m / z 606.0 (M + H) + . OR: -119.57.

[0473] Compound 116: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.55 - 2.71 (m, 4H), 3.50 - 3.67 (m, 1H), 3.96 (br dd, J = 11.25, 4.16 Hz, 1H), 4.38 - 4.69 (m, 2H), 5.06 (dd, J = 11.19, 4.34 Hz, 1H), 6.86 (s, 2H), 7.17 - 7.29 (m, 3H), 7.29 - 7.38 (m, 2H), 7.46 (d, J = 8.68 Hz, 2H), 7.53 (d, J = 8.56 Hz, 2H), 7.77 (dd, J = 16.26, 8.56 Hz, 4H), 8.19 (br d, J = 5.99 Hz, 1H). LCMS (ESI+): m / z 606.0 (M + H) + . OR: -105.34.

[0474] Compound 117: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.29 - 2.48 (m, 4H), 3.46 (m, J = 8.34 Hz, 1H), 3.94 (br dd, J = 11.19, 4.10 Hz, 1H), 4.24 (br s, 1H), 4.48 (br t, J = 11.25 Hz, 1H), 5.05 (br dd, J = 11.19, 4.22 Hz, 1H), 6.80 (br s, 2H), 7.17 - 7.37 (m, 5H), 7.45 (d, J = 8.56 Hz, 2H), 7.55 (d, J = 8.56 Hz, 2H), 7.69 - 7.84 (m, 4H), 8.13 (br s, 1H). LCMS (ESI+): m / z 606.0 (M + H) + 。OR: 116.16。

[0475] Compound 118: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.07 (s, 1H), 2.53 - 2.70 (m, 4H), 3.51 - 3.65 (m, 1H), 3.96 (br dd, J = 11.19, 4.22 Hz, 1H), 4.40 - 4.66 (m, 2H), 5.05 (dd, J = 11.19, 4.34 Hz, 1H), 6.86 (s, 2H), 7.17 - 7.28 (m, 3H), 7.28 - 7.37 (m, 2H), 7.45 (d, J = 8.56 Hz, 2H), 7.53 (d, J = 8.56 Hz, 2H), 7.76 (dd, J = 16.38, 8.56 Hz, 4H), 8.19 (br d, J = 5.75 Hz, 1H). LCMS (ESI+): m / z 606.0 (M + 1) + 。OR: 105.11。

[0476] (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1s,4R)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 119), (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1r,4S)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 120), (R Synthesis of (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1s,4S)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 121) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1r,4R)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 122) [ka] Synthesis of compounds 119-122 To a solution of 1.0 (2 g, 2.43 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (1.23 g, 12.13 mmol, 1.69 mL, 5 equiv.) and 4-aminocyclohexane-1-sulfonamide (520.71 mg, 2.43 mmol, 1 equiv.) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a racemic mixture of the two as a white solid. The two racemic mixtures were separated by SFC to give compound 119 (104.1 mg, 161.58 μmol, 7%) as a white solid, compound 121 (127.1 mg, 200.28 μmol, 8%) as a white solid, compound 120 (36.7 mg, 57.83 μmol, 2.3%) as a white solid, and compound 121 (46.4 mg, 73.12 μmol, 3%) as a white solid. Absolute stereochemistry was not determined. Diastereomers with negative OR were appropriately assigned as S isomers.

[0477] Preparative HPLC method: Instrument: ACSTJ-GX-N; Column: Phenomenex luna C18 250 x 50 mm x 10 μm; Mobile phase: H2O (0.04% HCl) A and acetonitrile B; Gradient: 60% to 80% B in 10 min; Flow rate: 80 mL / min; Wavelength: 220 and 254 nm

[0478] Method for SFC separation of compounds 119 and 121: Column: PHENOMENEX LUNA C18 (250 mm x 30 mm, 10 μm); Mobile phase A: [water (HCl) in ACN]; Mobile phase B: CO2; B%: 60%-80%; Run time: 10 min

[0479] Method for SFC separation of compounds 120 and 122: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); Mobile phase A: [NH₃H₂O (0.1%) in ethanol]; Mobile phase B: CO₂; B%: 50%; Run time: 18 min

[0480] Compound 119: 1 H NMR: 400 MHz, DMSO-d6;δ ppm 1.21-1.60 (m, 4H), 1.93 (br t, J=11.13 Hz, 2H), 2.05-2.18 (m, 2H), 2.75 (br t, J=11.86 Hz, 1H), 3.62-3.82 (m, 1H), 3.90-4.09 (m, 1H), 4.51 (t, J=11.25 Hz, 1H), 5.06 (dd, J=11.07, 4.34 Hz, 1H), 6.72 (s, 2H), 7.19-7.30 (m, 3H), 7.31-7.37 (m, 2H), 7.46 (d, J=8.68 Hz, 2H), 7.52-7.59 (m, 2H), 7.70-7.83 (m, 4H). LCMS (ESI+): m / z 634.0 (M+H) + . OR:-94.82.

[0481] Compound 121: 11H NMR: 400 MHz, DMSO-d6 δ ppm 1.19 - 1.60 (m, 4H), 1.80 - 2.03 (m, 2H), 2.03 - 2.17 (m, 2H), 2.74 (br t, J = 11.74 Hz, 1H), 3.56 - 3.82 (m, 1H), 3.99 (br d, J = 7.58 Hz, 1H), 4.50 (t, J = 11.25 Hz, 1H), 5.05 (br dd, J = 11.13, 4.28 Hz, 1H), 6.72 (s, 2H), 7.18 - 7.29 (m, 3H), 7.30 - 7.37 (m, 2H), 7.45 (d, J = 8.56 Hz, 2H), 7.55 (d, J = 8.56 Hz, 2H), 7.70 - 7.82 (m, 4H). LCMS (ESI+): m / z 634.0 (M+H) + 。OR: 107.61。

[0482] Compound 120: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 1.62 (br d, J = 0.86 Hz, 2H), 1.74 - 1.98 (m, 6H), 2.82 - 3.00 (m, 1H), 3.85 - 4.28 (m, 2H), 4.52 (br t, J = 11.37 Hz, 1H), 5.04 (br dd, J = 10.88, 4.03 Hz, 1H), 6.79 (s, 2H), 7.19 - 7.29 (m, 3H), 7.29 - 7.37 (m, 2H), 7.43 (d, J = 8.56 Hz, 2H), 7.56 (d, J = 8.56 Hz, 2H), 7.60 - 7.73 (m, 3H), 7.80 (d, J = 8.56 Hz, 2H). LCMS (ESI+): m / z 634.0 (M+H) + 。OR: -67.00。

[0483] Compound 122: 1H NMR: ET51134-33-P4N1, 400 MHz, DMSO-d6δ ppm 1.52-1.71 (m, 2H), 1.75-2.05 (m, 6H), 2.81-3.03 (m, 1H), 3.75-4.32 (m, 2H), 4.53 (br t, J=11.31 Hz, 1H), 5.05 (br dd, J=11.07, 3.85 Hz, 1H), 6.80 (s, 2H), 7.20-7.29 (m, 3H), 7.30-7.37 (m, 2H), 7.44 (d, J=8.68 Hz, 2H), 7.57 (d, J=8.56 Hz, 2H), 7.61-7.73 (m, 3H), 7.81 (d, J=8.56 Hz, 2H). LCMS (ESI+): m / z 634.0 (M+H) + OR: 64.20

[0484] (S,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1s,4R)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 123), (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1s,4S)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 124), (S Synthesis of (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1r,4S)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 125) and (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1r,4R)-4-sulfamoylcyclohexyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 126) [ka] Synthesis of P1 and P2, compounds 123-126 To a solution of 45.1 (2 g, 4.33 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (3.01 mL, 21.65 mmol, 5 equiv.) and 4-aminocyclohexane-1-sulfonamide (926.67 mg, 4.33 mmol, 1 equiv.) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give racemic mixture P1 (450 mg, 673.66 μmol, 15.6%) as a white solid and racemic mixture P2 (200 mg, 315.16 μmol, 7.28%) as a white solid.

[0485] Preparative HPLC method: Instrument: ACSTJ-GX-N; Column: Phenomenex luna C18 250 x 50 mm x 10 μm; Mobile phase: H2O (0.04% HCl) A and acetonitrile B; Gradient: 60% to 80% B in 10 min; Flow rate: 80 mL / min; Wavelength: 220 and 254 nm

[0486] P1: 1 H NMR: 400 MHz, DMSO-d6δ ppm 1.27-1.57 (m, 4H), 1.81-1.98 (m, 2H), 2.04-2.17 (m, 2H), 2.74 (br t, J=11.74 Hz, 1H), 3.53-3.82 (m, 1H), 3.91-4.02 (m, 1H), 4.50 (t, J=11.21 Hz, 1H), 5.06 (dd, J=11.09, 4.29 Hz, 1H), 6.72 (s, 2H), 7.18-7.37 (m, 7H), 7.50-7.59 (m, 2H), 7.74-7.83 (m, 4H). LCMS (ESI+): m / z 618.2 (M+H) + .

[0487] P2: 1H NMR: 400 MHz, DMSO-d6δ ppm 1.54-1.71 (m, 2H), 1.75-2.00 (m, 7H), 2.82-2.98 (m, 1H), 3.90-4.03 (m, 1H), 4.52 (br t, J=11.38 Hz, 1H), 4.96-5.14 (m, 1H), 6.80 (s, 2H), 7.17-7.29 (m, 5H), 7.30-7.38 (m, 2H), 7.52-7.65 (m, 3H), 7.67-7.85 (m, 4H). LCMS (ESI+): m / z 618.2 (M+H) + .

[0488] P1 (450 mg, 1.05 mmol, 1 equiv) was separated by SFC to give compound 123 (127 mg, 205.45 μmol, 28%) as a white solid and compound 124 (121.2 mg, 196.07 μmol, 27%) as a white solid. [ka]

[0489] SFC method for P1 separation: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); Mobile Phase A: [NH₃H₂O (0.1%) in ethanol]; Mobile Phase B: CO₂; B%: 50%–50%; Run Time: 13 min. Absolute stereochemistry was not determined. Diastereomers with negative OR were appropriately assigned as S isomers.

[0490] Compound 123: 11H NMR: 400 MHz, DMSO-d6 δ ppm 1.33 (q, J = 12.00 Hz, 2H), 1.41 - 1.59 (m, 2H), 1.91 (br d, J = 12.40 Hz, 2H), 2.10 (br d, J = 11.32 Hz, 2H), 2.74 (br t, J = 11.86 Hz, 1H), 3.63 - 3.79 (m, 1H), 3.92 - 4.08 (m, 1H), 4.49 (t, J = 11.21 Hz, 1H), 5.06 (dd, J = 11.15, 4.35 Hz, 1H), 6.72 (s, 2H), 7.19 - 7.28 (m, 5H), 7.29 - 7.37 (m, 2H), 7.52 - 7.57 (m, 2H), 7.75 - 7.81 (m, 4H). LCMS (ESI+): m / z 618.0 (M + H) + 。OR: - 128.72。

[0491] Compound 124: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 1.29 - 1.39 (m, 2H), 1.44 - 1.54 (m, 2H), 1.87 - 1.97 (m, 2H), 2.10 (br d, J = 10.85 Hz, 2H), 2.74 (br t, J = 11.80 Hz, 1H), 3.71 (br d, J = 2.03 Hz, 1H), 3.99 (br d, J = 7.51 Hz, 1H), 4.49 (br t, J = 11.27 Hz, 1H), 5.06 (br dd, J = 11.03, 4.23 Hz, 1H), 6.72 (s, 2H), 7.20 - 7.27 (m, 5H), 7.30 - 7.36 (m, 2H), 7.55 (d, J = 8.46 Hz, 2H), 7.78 (br d, J = 8.46 Hz, 4H). LCMS (ESI+): m / z 618.0 (M + H) + 。OR: 123.08。

[0492] P2 (200 mg, 1.05 mmol, 1 equiv) was separated by SFC to give 125 (33.3 mg, 53.87 μmol, 17%) as a white solid and 126 (35 mg, 56.52 μmol, 18%) as a white solid. [ka]

[0493] SFC method for P2 separation: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); Mobile phase A: [NH3H2O ​​(0.1%) in ethanol]; Mobile phase B: CO2; B%: 50%-50%; Run time: 15 min

[0494] Compound 125: 1 H NMR: 400 MHz, DMSO-d6;δ ppm 1.63 (br d, J=2.86 Hz, 2H), 1.80-1.99 (m, 6H), 2.90 (dt, J=12.10, 6.23 Hz, 1H), 3.98 (br d, J=8.46 Hz, 1H), 4.51 (br t, J=11.27 Hz, 1H), 5.04 (br dd, J=10.91, 3.99 Hz, 1H), 6.79 (s, 2H), 7.18-7.27 (m, 5H), 7.30-7.35 (m, 2H), 7.56 (d, J=8.58 Hz, 2H), 7.61 (br d, J=6.68 Hz, 1H), 7.73 (br dd, J=8.23, 5.72 Hz, 2H), 7.80 (d, J=8.58 Hz, 2H). LCMS (ESI+): m / z 618.0 (M+H) + . OR:-150.19.

[0495] Compound 126: 1H NMR: 400 MHz, DMSO-d6δ ppm 1.64 (br d, J=1.79 Hz, 2H), 1.80-2.00 (m, 6H), 2.85-2.96 (m, 1H), 3.98 (br d, J=7.51 Hz, 1H), 4.51 (br t, J=11.38 Hz, 1H), 5.04 (br dd, J=11.03, 3.99 Hz, 1H), 6.79 (s, 2H), 7.17-7.28 (m, 5H), 7.30-7.37 (m, 2H), 7.56 (d, J=8.46 Hz, 2H), 7.59-7.67 (m, 1H), 7.73 (br dd, J=8.05, 5.66 Hz, 2H), 7.80 (d, J=8.58 Hz, 2H). LCMS (ESI+): m / z 618.0 (M+H) + . OR:137.16.

[0496] (S,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1r,3S)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 127), (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1r,3R)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 128), (S Synthesis of (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1s,3R)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 129) and (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1s,3S)-3-sulfamoylcyclobutyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 130) [ka] Synthesis of compounds 127-130 To a solution of 45.1 (1.5 g, 3.15 mmol, 1 equiv.) in dichloromethane (5 mL), triethylamine (1.10 mL, 7.87 mmol, 2.5 equiv.) and 3-aminocyclobutane-1-sulfonamide (472.97 mg, 3.15 mmol, 1 equiv.) were added at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a white solid (780 mg, 1.26 mmol, 40%). LCMS (ESI+): m / z 590.1 (M+H) + .

[0497] The diastereomers (780 mg, 1.32 mmol, 1 equiv.) were separated by a first SFC to give 127 (85.8 mg, 0.14 mmol, 11%) as a white solid, 129 (120.9 mg, 0.21 mmol, 16%) as a white solid, and a racemic mixture of 128 and 130. The racemic mixture of 128 and 130 was further separated by a second SFC to give 128 (70 mg, 0.12 mmol, 8%) as a white solid and 130 (123.8 mg, 0.21 mmol, 15%) as a white solid. Absolute stereochemistry was not determined. The diastereomer with a negative OR was appropriately assigned as the S isomer.

[0498] First SFC method: Column: REGIS (s,s) WHELK-O1 (250 mm x 30 mm, 10 μm); Mobile phase A: [NH3H2O ​​(0.1%) in ethanol]; Mobile phase B: CO2; B%: 55%; Run time: 10 min.

[0499] Second SFC method: Column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); Mobile phase A: [NH₃H₂O (0.1%) in isopropanol]; Mobile phase B: CO₂; B%: 50%; Run time: 12 min

[0500] Compound 127: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.29 - 2.44 (m, 3H), 2.54 (s, 1H), 3.41 - 3.52 (m, 1H), 3.94 (dd, J = 11.25, 4.16 Hz, 1H), 4.24 (sxt, J = 7.68 Hz, 1H), 4.47 (t, J = 11.19 Hz, 1H), 5.05 (dd, J = 11.13, 4.28 Hz, 1H), 6.80 (s, 2H), 7.14 - 7.40 (m, 7H), 7.48 - 7.61 (m, 2H), 7.70 - 7.86 (m, 4H), 8.10 (br d, J = 5.87 Hz, 1H). LCMS (ESI+): m / z 590.0 (M+H) + 。OR: -126.61。

[0501] Compound 129: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.07 (s, 1H), 2.55 - 2.74 (m, 4H), 3.50 - 3.67 (m, 1H), 3.96 (br dd, J = 11.07, 3.97 Hz, 1H), 4.40 - 4.68 (m, 2H), 5.05 (br dd, J = 11.07, 4.22 Hz, 1H), 6.86 (s, 2H), 7.15 - 7.39 (m, 7H), 7.53 (d, J = 8.56 Hz, 2H), 7.69 - 7.91 (m, 4H), 8.16 (br d, J = 5.75 Hz, 1H). LCMS (ESI+): m / z 590.0 (M+H) + 。OR: -118.48。

[0502] Compound 128: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.30 - 2.48 (m, 4H), 3.46 (quin, J = 8.41 Hz, 1H), 3.94 (br dd, J = 11.13, 3.91 Hz, 1H), 4.15 - 4.33 (m, 1H), 4.47 (br t, J = 11.25 Hz, 1H), 5.05 (br dd, J = 11.13, 4.16 Hz, 1H), 6.80 (s, 2H), 7.16 - 7.38 (m, 7H), 7.55 (d, J = 8.44 Hz, 2H), 7.73 - 7.86 (m, 4H), 8.10 (br d, J = 4.65 Hz, 1H). LCMS (ESI+): m / z 590.0 (M+H) + 。OR: 132.9。

[0503] Compound 130: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.07 (s, 1H), 2.53 - 2.73 (m, 4H), 3.52 - 3.66 (m, 1H), 3.96 (br dd, J = 11.13, 4.03 Hz, 1H), 4.40 - 4.66 (m, 2H), 5.05 (dd, J = 11.07, 4.22 Hz, 1H), 6.86 (s, 2H), 7.16 - 7.37 (m, 7H), 7.53 (d, J = 8.56 Hz, 2H), 7.71 - 7.85 (m, 4H), 8.16 (br d, J = 5.26 Hz, 1H). LCMS (ESI+): m / z 590.0 (M+H) + 。OR: 126.48。

[0504] (S)-1-((Z)-(((4-chlorophenyl)sulfonyl)imino)((S)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)pyrrolidine-3-sulfonamide (Compound 131), (R)-1-((Z)-(((4-chlorophenyl)sulfonyl)imino)((S)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)pyrrolidine-3-sulfonamide (Compound 132), (S Synthesis of (R)-1-((Z)-(((4-chlorophenyl)sulfonyl)imino)((R)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)pyrrolidine-3-sulfonamide (Compound 133) and (R)-1-((Z)-(((4-chlorophenyl)sulfonyl)imino)((R)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)methyl)pyrrolidine-3-sulfonamide (Compound 134) [ka] Synthesis of compounds 131-134 To a solution of 45.1 (1.5 g, 3.15 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (1.59 g, 15.74 mmol, 2.19 mL, 5 equiv.) and pyrrolidine-3-sulfonamide (472.97 mg, 3.15 mmol, 1 equiv.) at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a mixture of diastereomers (900 mg, 1.53 mmol, 44%) as a white solid.

[0505] The diastereomers (900 mg, 0.84 mmol, 1 equiv.) were separated by a first SFC to give 131 (57.8 mg, 0.09 mmol, 11%) as a white solid, 132 (62.1 mg, 0.10 mmol, 12%) as a white solid, and a racemic mixture of 133 and 134. The resulting racemic mixture of 133 and 134 was further separated by a second SFC to give 133 (48.1 mg, 0.08 mmol, 9%) as a white solid and 134 (44.6 mg, 0.07 mmol, 8%) as a white solid. Absolute stereochemistry was not determined. The diastereomer with a negative OR was appropriately assigned as the S isomer.

[0506] First SFC method: Column: Chiralpak IE-3, 50 x 4.6 mm id, 3 μm; Mobile phase: A: hexane; B: ethanol (0.1% isopropanol m); Gradient: A:B = 60:40; Flow rate: 1 mL / min; Column temperature: 30 °C.

[0507] Second SFC method: Column: Chiralpak AD-3, 50 x 4.6 mm i.d., 3 μm; Mobile phase A: CO2; B: Isopropanol (0.1% isopropanol m, v / v); Gradient: Time A% B% 0.0 95 5; 0.2 95 5; 1.2 50 50; 2.2 50 50; 2.6 95 5; 3.0 95 5; Flow rate: 3.4 mL / min; Column temperature: 35 °C; ABPR: 1800 psi.

[0508] Compound 131: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.18 - 2.28 (m, 2 H) 3.71 - 3.85 (m, 3 H) 3.95 (br d, J=7.13 Hz, 2 H) 4.06 (dd, J=10.82, 4.94 Hz, 1 H) 4.69 (t, J=11.19 Hz, 1 H) 5.07 (dd, J=11.44, 4.94 Hz, 1 H) 7.13 (s, 2 H) 7.17 - 7.29 (m, 3 H) 7.33 (d, J=4.38 Hz, 4 H) 7.50 - 7.56 (m, 2 H) 7.68 (dd, J=8.76, 5.50 Hz, 2 H) 7.76 - 7.84 (m, 2 H). LCMS (ESI+): m / z 590.0 (M+H) + 。OR: -95.36。

[0509] Compound 132: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.20 - 2.31 (m, 2 H) 3.63 - 3.73 (m, 1 H) 3.74 - 3.82 (m, 1 H) 3.84 - 3.96 (m, 2 H) 3.97 - 4.12 (m, 2 H) 4.69 (t, J=11.13 Hz, 1 H) 5.06 (dd, J=11.38, 4.75 Hz, 1 H) 7.14 (s, 2 H) 7.17 - 7.28 (m, 3 H) 7.30 - 7.35 (m, 4 H) 7.50 - 7.58 (m, 2 H) 7.66 - 7.71 (m, 2 H) 7.78 - 7.84 (m, 2 H). LCMS (ESI+): m / z 590.0 (M+1) + 。OR: -111.20。

[0510] Compound 133: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.27 (q, J = 7.00 Hz, 2 H), 3.62 - 3.72 (m, 1 H), 3.74 - 3.83 (m, 1 H), 3.83 - 3.96 (m, 2 H), 3.97 - 4.13 (m, 2 H), 4.69 (t, J = 11.13 Hz, 1 H), 5.06 (dd, J = 11.32, 4.69 Hz, 1 H), 7.14 (s, 2 H), 7.20 (t, J = 8.88 Hz, 2 H), 7.23 - 7.29 (m, 1 H), 7.30 - 7.35 (m, 4 H), 7.51 - 7.57 (m, 2 H), 7.65 - 7.73 (m, 2 H), 7.78 - 7.84 (m, 2 H). LCMS (ESI+): m / z 590.0 (M + 1) + . OR: 102.2.

[0511] Compound 134: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.23 (br dd, J = 6.85, 3.67 Hz, 2 H), 3.71 - 3.86 (m, 3 H), 3.95 (br d, J = 7.09 Hz, 2 H), 4.07 (dd, J = 10.82, 4.83 Hz, 1 H), 4.69 (br t, J = 11.13 Hz, 1 H), 5.07 (dd, J = 11.37, 4.89 Hz, 1 H), 7.14 (s, 2 H), 7.17 - 7.28 (m, 3 H), 7.33 (d, J = 4.40 Hz, 4 H), 7.54 (d, J = 8.56 Hz, 2 H), 7.68 (dd, J = 8.80, 5.50 Hz, 2 H), 7.80 (d, J = 8.56 Hz, 2 H). LCMS (ESI+): m / z 590.0 (M + H) + . OR: 89.9.

[0512] (S)-1-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)pyrrolidine-3-sulfonamide (Compound 135), (R)-1-((Z)-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)pyrrolidine-3-sulfonamide (Compound 136), (R Synthesis of (S)-1-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)pyrrolidine-3-sulfonamide (Compound 137) and (S)-1-((Z)-((R)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-chlorophenyl)sulfonyl)imino)methyl)pyrrolidine-3-sulfonamide (Compound 138) [ka] Synthesis of compounds 135-138 To a solution of 1.0 (2 g, 4.06 mmol, 1 equiv.) in dichloromethane (20 mL) was added triethylamine (2.82 mL, 20.29 mmol, 5 equiv.) and pyrrolidine-3-sulfonamide (731.48 mg, 4.87 mmol, 1.2 equiv.) at room temperature. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a mixture of diastereomers (400 mg, 659.48 μmol, 16%) as a white solid. LCMS (ESI+): m / z 606.1 (M+H)+.

[0513] The mixture of diastereomers (400 mg, 659.48 μmol, 1 equiv.) was separated by a first SFC to give a racemic mixture of compounds 137 and 138 and a racemic mixture of compounds 135 and 136. The racemic mixture of compounds 137 and 138 was further separated by a second SFC to give compound 137 (55.8 mg, 92.0 μmol, 13%) as a white solid and compound 138 (52.5 mg, 86.56 μmol, 13%) as a white solid. The racemic mixture of compounds 135 and 136 was further separated by a third SFC to give compound 135 (48.9 mg, 80.62 μmol, 12%) as a white solid and compound 136 (56.5 mg, 93.15 μmol, 14%) as a white solid. Absolute stereochemistry was not determined. Diastereomers with negative OR were appropriately assigned as S isomers.

[0514] First SFC method: Column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); Mobile phase A: [NH3H2O ​​(0.1%) in ethanol]; Mobile phase B: CO2; B%: 50%~50%; Run time: 7 min.

[0515] Second SFC method: Column: REGIS (s,s) WHELK-O1 (250 mm*30 mm, 5 μm); Mobile phase A: [NH3HO (0.1%) in ethanol]; Mobile phase B: CO2; B%: 50%-50%; Run time: 16 min.

[0516] Third SFC method: Column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); Mobile phase A: [NH3H2O ​​(0.1%) in ACN / IPA]; Mobile phase B: CO2; B%: 50%~50%; Run time: 10 min.

[0517] Compound 135: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.15 - 2.29 (m, 2 H), 3.67 - 3.86 (m, 3 H), 3.88 - 4.01 (m, 2 ...

Claims

1. Equation (I): 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is R １ These are F, Cl, CN, and OCH ３ A phenyl compound optionally substituted with one or more substituents selected from the following: R ２ C １ ~C ６ Alkyl, 5-membered or 6-membered heteroaryl, or phenyl optionally substituted with F or CN, R ３ is phenyl substituted with one or two substituents selected from F, Cl, CF ３ , CN, OCH ３ , C ２ -C ６ alkynyl, and C(O)NH ２ , or a 5- or 6-membered heteroaryl containing 1 to 3 nitrogen atoms, wherein said heteroaryl is optionally substituted with C １ -C ６ alkyl, R ４ , R ４ ', R ５ , and R ５ ' is independently H or C １ ~C ６ It is alkyl, R ６ and R ７ These are independently H, OH, or C １ ~C ６ It is alkyl, or R ６ and R ７ It contains one to two nitrogen atoms along with the nitrogen atoms to which they are bonded, and C １ ~C ６ It forms a 5-membered or 6-membered heterocycloalkyl group that is optionally substituted with alkyl groups. R ８ is H or CH ３ And, however, (i) R １ It is not 4-chlorophenyl or 4-methoxyphenyl; (ii) R ２ C １ ~C ６ It is a phenyl molecule substituted with alkyl or CN; (iii) R ３ It is not 4-chlorophenyl, 3-cyanophenyl, or 3-methoxyphenyl; (iv)R ４ , R ４ ', R ５ , and R ５ At least one of ' is C １ ~C ６ It is alkyl; (v) R ６ and R ７ At least one of them is not H; and (vi)R ８ CH ３ It is; The compound or a pharmaceutically acceptable salt thereof, wherein at least one of the following is true.

2. The compound is of formula (IIA) or formula (IIB): 【Chemistry 2】 During the ceremony, R 1a is F, Cl, CN, or OCH3, R ２ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is H or CN; preferably, R 1a is Cl and R 2a is H.

3. R ３ However, F, Cl, CF ３ , CN, OCH ３ , C ２ ~C ６ Alkinyl, or C(O)NH ２ A phenyl compound substituted with one or two groups selected from: optionally, R3 is 【Transformation 3】 Preferably, R3 is 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ３ However, the heteroaryl is a 5-membered or 6-membered heteroaryl containing 1 to 3 nitrogen atoms, where the heteroaryl is C １ ~C ６ Optionally substituted with alkyl; optionally, R3 is 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ４ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is H, methyl, or isopropyl; preferably, R4 is H.

6. R ５ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R5 is H, methyl, or isopropyl; preferably, R5 is H.

7. R ６ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R6 is H, methyl, ethyl, isopropyl, or OH; preferably, R6 is H.

8. R ７ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R7 is H, methyl, ethyl, isopropyl, or OH; preferably, R7 is H.

9. R ６ and R ７ However, along with the nitrogen atoms to which they are bonded, they contain one or two nitrogen atoms, C １ ~C ６ It forms a 5-membered or 6-membered heterocycloalkyl group optionally substituted with alkyl; preferably, R6 and R7, together with the nitrogen atom to which they are bonded, 【Transformation 6】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which forms a compound.

10. R ８ The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is H or CH3; preferably, R8 is H.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of compounds 1 to 86, 103 to 110, 155 to 172, 175 to 182, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in a method of treating obesity in a subject for which such treatment is necessary.

14. The comorbidities of the obesity are diabetes, dyslipidemia, metabolic syndrome, dementia, cardiovascular disease, or liver disease; optionally, the comorbidities of the obesity are hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; osteoarthritis; venous congestive ulcers; pulmonary hypoventilation syndrome; Sleep apnea; snoring; Coronary artery disease; The pharmaceutical composition according to claim 13, wherein the increased incidence of arteriosclerotic disease; pseudobrain tumors; frequent accidents; increased risk associated with surgery; osteoarthritis; high cholesterol; or malignant tumors of the ovaries, cervix, uterus, breast, prostate, or gallbladder is a symptom of the pharmaceutical composition according to claim 13.

15. A pharmaceutical composition according to claim 13, further comprising a second therapeutic agent, The pharmaceutical composition wherein the second therapeutic agent is optionally a glucagon-like peptide 1 receptor agonist; preferably, the second therapeutic agent is liraglutide, semaglutide, exenatide, lixisenatide, dulaglutide, or tylzepatide.

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