Cannabinoid receptor 1 antagonists / inverse agonists and uses thereof

Abstract

Disclosed herein are compounds useful in the treatment of a condition, such as a diabetic condition, a dyslipidemia condition, a cardiovascular condition, an inflammatory condition, a liver condition, cancer, or obesity, or a complication thereof. Also disclosed are compositions comprising one or more of the compounds and the use of the compounds in the treatment of a disorder in a subject.

Description

Background Art

[0001] Obesity is associated with an increase in the total amount of adipose tissue (i.e., body fat), especially located in the abdominal area. Obesity has reached epidemic proportions in the United States. The prevalence of obesity has steadily increased over the years among all racial and ethnic groups. The latest data from the Centers for Disease Control and Prevention and the National Center for Health Statistics show that 66% of adults are overweight (BMI, 25.0-29.9), 31% are obese (BMI, 30-39.9), and 5% are extremely obese (BMI, > 40.0). Among children aged 6 to 19, 32% are overweight and 17% are obese. This means that 124 million Americans are medically overweight and 44 million of these are considered obese. Obesity kills over 300,000 people each year and will soon overtake tobacco use as the leading cause of preventable death in the United States. Obesity is a chronic disease that directly leads to many dangerous comorbidities, including type 2 diabetes, cardiometabolic disease, liver disease, cardiovascular disease, inflammatory disease, premature aging, and some forms of cancer. Type 2 diabetes, a serious and life-threatening disease, is increasing in prevalence in both adults and children and is currently the number one cause of death in the United States. 7 Obesity is a leading cause of death. With over 80% of people with type 2 diabetes being overweight, obesity is the greatest risk factor for developing type 2 diabetes. Growing clinical evidence suggests that the best way to manage type 2 diabetes is to lose weight. Therefore, there is a continuing need for improved medications to treat or prevent obesity.

[0002] The endocannabinoid system, composed of cannabinoid receptors (CB1 and CB2) and their endogenous ligands (e.g., cannabinoid 2-AG), plays an important role in controlling 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 many peripheral organs and tissues, including the thyroid, adrenal glands, reproductive organs, adipose tissue, liver, muscle, pancreas, kidney, and gastrointestinal tract. CB2 receptors are located almost exclusively on immune cells and blood cells (Endocrine Reviews 2006, 27, 73).

[0003] Plant-derived cannabinoid agonists Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), the main psychoactive component of cannabis, binds to CB1 and CB2 receptors. 9 -THC increases appetite and food intake (hyperphagia) in humans and animals. Selective CB1 receptor blockers (i.e., CB1 blockers) (e.g., rimonabant (SR141716A, )) pretreatment largely blocked this hyperphagia effect, strongly supporting the idea that CB1 receptor activation mediates Δ 9 - Views on the hyperphagia effects of THC (Endocrine Reviews 2006, 27, 73).

[0004] The CB1 receptor is one of the most abundant and widespread G protein-coupled receptors in the mammalian brain. It is now known that the appetite-suppressing properties of CB1 antagonists can be mediated by direct action on CB1 receptors in brain regions associated with hunger and satiety (e.g., the hypothalamus, mesolimbic region), or by direct action on CB1 receptors in peripheral tissues (e.g., adipose tissue, kidney) [J. Clin Invest 2010, 120:2953; Obesity 2011, 19:1325]. However, CB1 receptors are much more widely distributed in the brain (e.g., neocortex, hippocampus, thalamus, cerebellum, and pituitary gland), and while interacting with targeted CB1 receptors in the hypothalamus and mesolimbic region to suppress appetite, CB1 antagonists can also access non-targeted CB1 receptors, which have little effect on appetite control. Binding to non-targeted receptors can often lead to adverse side effects of CNS drugs (Endocrine Reviews 2006, 27:73). For example, the CB1 blockers rimonabant and tarenabant produce psychiatric and neurological side effects, including depression, anxiety, irritability, insomnia, dizziness, headache, seizures, and suicidal tendencies.

[0005] These side effects are dose-related and are evident at the most effective weight-loss doses of rimonabant and tarenabant (JAMA 2006, 311, 323; Cell Metabolism 2008, 7, 68). The occurrence of both therapeutic efficacy (appetite suppression) and side effects within the same dose range strongly suggests that both effects are mediated by simultaneous antagonism of CB1 receptors in both 'targeted' and 'untargeted' brain regions, as brain-penetrant CB1 blockers do not selectively target CB1 receptors in the brain.

[0006] The beneficial effects of the CB1 antagonist rimonabant on weight, obesity, diabetes, and cardiometabolic risk factors (such as hypertension, insulin resistance, and blood lipids) cannot be explained solely by weight loss caused by CNS-mediated appetite suppression (JAMA 2006, 311, 323). Approximately 50% of the benefits may come from interactions with CB1 receptors in peripheral tissues known to play an active role in metabolism. These tissues include 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). In particular, hCB1B has an internal deletion of 33 amino acids at the N-terminus between Leu-21 and Gly-55 (Gonzalez-Mariscal, Krzysik-Walker, Doyle et al., 2016). Further studies have shown that the distribution of these splice variants (hCB1 and hCB1b) in human tissues differs significantly (Gonzalez-Mariscal, Krzysik-Walker, Doyle et al., 2016). Initially, the hCB1B isoform was found to be highly expressed in human liver (where it is the predominant isoform) and pancreatic β cells, but not in the brain. Second, expression in the liver and beta cells of obese individuals (BMI ≥ 30.0) is significantly increased compared to non-obese individuals (BMI ≤ 30.0). Since rimonabant binds to both receptors (hCB1 and hCB1b) with similar affinity (Gonzalez-Mariscal, Krzysik-Walker, Doyle et al., 2016), the ability to more selectively target hCB1b may offer additional benefits over compounds such as rimonabant.

[0008] Therefore, there is a continuing need to find potent and highly selective CB1 receptor blockers with limited or no adverse CNS side effects, including affective disorders. In particular, it is desirable to find 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 as cannabinoid 1 (CB1) receptor antagonists / inverse agonists, pharmaceutical compositions of such compounds, and uses of these compounds for treating diseases mediated by CB1 receptors.

[0010] In one aspect, the present disclosure provides a compound of formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from F, Cl, CN and OCH3; R 2 is C1-C6 alkyl or phenyl optionally substituted by F or CN; R 3is phenyl substituted by 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 group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group; R 4 、R 4 '、R 5 and R 5 ' are independently H or C1-C6 alkyl; R 6 and R 7 R6 and R7 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 group containing 1-2 nitrogen atoms and optionally substituted with C1-C6 alkyl; and R 8 is H or CH3, provided that at least one of the following is true: (i) R 1 is not 4-chlorophenyl or 4-methoxyphenyl; (ii) R 2 is C1-C6 alkyl or phenyl substituted by CN; (iii) R 3 is not 4-chlorophenyl, 3-cyanophenyl or 3-methoxyphenyl; (iv) R 4 and R 5 One of them is C1-C6 alkyl; (v) R 6 and R 7 One of them is not H; and (vi) R 8 It is CH3.

[0013] In some embodiments, the compound is of Formula (IA):

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein R 1a It is F, Cl, CN or OCH3.

[0016] In some embodiments, the compound is of Formula (IIA):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN or OCH3, and R 2a is H or CN. In some embodiments, R 2a is H. In other embodiments, R 2a It is CN.

[0019] In some embodiments, the compound is of formula (IIIA):

[0020]

[0021] or a pharmaceutically acceptable salt thereof, wherein R 1a It is F, Cl, CN or OCH3.

[0022] In some embodiments, the compound is of Formula (IB):

[0023]

[0024] or a pharmaceutically acceptable salt thereof, wherein R 1a It is F, Cl, CN or OCH3.

[0025] In some embodiments, the compound is of Formula (IIB):

[0026]

[0027] or a pharmaceutically acceptable salt thereof, wherein R 1a is F, Cl, CN or OCH3, and R 2a is H or CN. In some embodiments, R 2a is H. In other embodiments, R 2a It is CN.

[0028] In some embodiments, the compound is of Formula (IIIB):

[0029]

[0030] or a pharmaceutically acceptable salt thereof, wherein R 1a It is F, Cl, CN or OCH3.

[0031] In some embodiments of any aspect described herein (e.g., Formula (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 1a It's F.

[0032] In some embodiments of any aspect described herein (e.g., Formula (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 1a It's Cl.

[0033] In some embodiments of any aspect described herein (e.g., Formula (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 1a It is OCH3.

[0034] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 3 is a phenyl group substituted by one or two groups selected from F, Cl, CF3, CN, OCH3, C2-C6 alkynyl or C(O)NH2. For example, R 3 yes:

[0035] In some embodiments, R 3 yes

[0036] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 3 is a 5- or 6-membered heteroaryl group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group. For example, R 3 yes:

[0037]

[0038] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 4 It’s H.

[0039] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 4 is a C1-C6 alkyl group, such as methyl or isopropyl.

[0040] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 5 It’s H.

[0041] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 5 is a C1-C6 alkyl group, such as methyl or isopropyl.

[0042] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 It’s H.

[0043] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 is a C1-C6 alkyl group, for example, R 6 is methyl, ethyl or isopropyl.

[0044] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 It's OH.

[0045] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 7 It’s H.

[0046] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 7 is a C1-C6 alkyl group, such as methyl, ethyl or isopropyl.

[0047] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 7 It's OH.

[0048] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted by a C1-C6 alkyl group, for example,

[0049] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 8 It’s H.

[0050] In some embodiments of any aspect described herein (e.g., Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), and (IIIB)), R 8 It is CH3.

[0051] In some embodiments, the compound is selected from any one of compounds 1-86, 103-110, 155-172, 175-182 of Table 1, or a pharmaceutically acceptable salt thereof.

[0052] In another aspect, the present disclosure provides a compound of formula (II):

[0053]

[0054] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from halogen, C1-C6 alkoxy and CN; R 2 is C1-C6, 5- or 6-membered heteroaryl or phenyl optionally substituted by halogen or CN; R 3 is phenyl substituted by 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 group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by 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; L is (a) (b) (c) (d) R 8 is H or C1-C6 alkyl; R 4 、R 4 '、R 5 and R 5 ' is independently H or C1-C6 alkyl optionally substituted by C1-C6 alkoxy; X is O or NR 9 ; R 9 is H or C1-C6 alkyl; and y and z are independently 1, 2 or 3.

[0055] In some embodiments, the compound is of Formula (IVA):

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN or C1-C6 alkoxy.

[0058] In some embodiments, the compound is of formula (VA):

[0059]

[0060] 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. In some embodiments, R 2a is H. In other embodiments, R 2a It is CN.

[0061] In some embodiments, the compound is of formula (VIA):

[0062]

[0063] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN or C1-C6 alkoxy.

[0064] In some embodiments, the compound is of Formula (IVB):

[0065]

[0066] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN or C1-C6 alkoxy.

[0067] In some embodiments, the compound is of formula (VB):

[0068]

[0069] 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. In some embodiments, R 2a is H. In other embodiments, R 2a It is CN.

[0070] In some embodiments, the compound is of Formula (VIB):

[0071]

[0072] or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN or C1-C6 alkoxy.

[0073] In some embodiments of any aspect described herein (e.g., Formula (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 1a It's F.

[0074] In some embodiments of any aspect described herein (e.g., Formula (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 1a It's Cl.

[0075] In some embodiments of any aspect described herein (e.g., Formula (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 1a It is OCH3.

[0076] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 3 is phenyl substituted by one or two groups selected from halogen, CF3, CN, C1-C6 alkoxy, C2-C6 alkynyl or C(O)NH2. 3 yes:

[0077]

[0078] In some embodiments, R 3 yes

[0079] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 3 is a 5- or 6-membered heteroaryl group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group. For example, R 3 yes:

[0080]

[0081] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 4 It’s H.

[0082] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 4 is a C1-C6 alkyl group, such as methyl or isopropyl.

[0083] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 5 It’s H.

[0084] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 5 is a C1-C6 alkyl group, such as methyl or isopropyl.

[0085] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 It’s H.

[0086] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 is a C1-C6 alkyl group, for example, R 6 is methyl, ethyl or isopropyl.

[0087] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 It's OH.

[0088] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 7 It’s H.

[0089] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 7 is a C1-C6 alkyl group, such as methyl, ethyl or isopropyl.

[0090] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 7 It's OH.

[0091] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted by a C1-C6 alkyl group, for example,

[0092] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 8 It’s H.

[0093] In some embodiments of any aspect described herein (e.g., Formula (II), (IVA), (IVB), (VA), (VB), (VIA), and (VIB)), R 8 It is CH3.

[0094] In some embodiments, the compound is selected from any one of compounds 99-102, 111-154, 173-174, 183-250 of Table 1, or a pharmaceutically acceptable salt thereof.

[0095] In another aspect, the present disclosure provides a compound of formula (III):

[0096]

[0097] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from F, Cl, CN and OCH3; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted by F or CN; R 3 is phenyl substituted by 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 group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group; R 4 、R 4 '、R 5 and R 5 ' are independently H or C1-C6 alkyl; R 6 and R 7 R6 and R7 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 group 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.

[0098] In some embodiments, the compound is selected from any one of compounds 87-98 of Table 1, or a pharmaceutically acceptable salt thereof.

[0099] In another aspect, the present disclosure provides a pharmaceutical composition comprising any of the compounds described herein (e.g., any of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0100] In another aspect, the present disclosure provides a method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein (e.g., any one of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, wherein the disease is a diabetic disorder, a dyslipidemic disorder, a cardiovascular disorder, an inflammatory disorder, a liver disorder, or cancer.

[0101] In some embodiments, the disease is a diabetic condition, such as type 1 diabetes, type 2 diabetes, impaired glucose tolerance, or insulin resistance.

[0102] In some embodiments, the disease is a dyslipidemic disorder, such as undesirable blood lipid levels, low levels of high-density lipoprotein, high levels of low-density lipoprotein, high levels of triglycerides, or a combination thereof.

[0103] In some embodiments, the disease is a cardiovascular disorder, such as atherosclerosis, hypertension, stroke, or heart attack.

[0104] In some embodiments, the disease is an inflammatory disorder, such as osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, or obesity-related inflammation.

[0105] In some embodiments, the disease is a liver disorder, such as liver inflammation, liver fibrosis, nonalcoholic steatohepatitis, fatty liver, hepatomegaly, alcoholic liver disease, jaundice, cirrhosis, or hepatitis.

[0106] In some embodiments, the disease is cancer, such as colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, or hepatocellular carcinoma.

[0107] In another aspect, the present disclosure provides a method of treating obesity or a complication of obesity, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein (e.g., any one of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and compounds of Table 1), or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the obesity comorbidity is diabetes, dyslipidemia, metabolic syndrome, dementia, cardiovascular disease, or liver disease.

[0109] In some embodiments, the obesity comorbidity is hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous stasis ulcers; hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arteriosclerotic disease; pseudotumor cerebri; accident proneness; increased surgical risk; osteoarthritis; high cholesterol; or an increased incidence of malignant tumors of the ovary, cervix, uterus, breast, prostate, or gallbladder.

[0110] In another aspect, the present disclosure provides a method of reversing adipose tissue deposition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein (e.g., any one of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and compounds of Table 1), or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments of any of the methods described herein, the method further comprises administering to the subject a second therapeutic agent, e.g., a PPAR-γ agonist, a biguanide, insulin or an insulin mimetic, a sulfonylurea, an α-glucosidase inhibitor, an HMG-CoA reductase inhibitor, a sequestrant, nicotinic 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 dipeptidyl peptidase IV inhibitor, exenatide, or pramlin. Peptide, FBPase inhibitor, glucagon receptor antagonist, glucagon-like peptide 1, glucagon-like peptide 1 receptor agonist, growth hormone secretagogue, growth hormone secretagogue receptor agonist, growth hormone secretagogue receptor antagonist, melanocortin agonist, melanocortin 4 receptor agonist, beta-3 agonist, serotonin receptor 2C agonist, orexin antagonist, melanin-concentrating hormone 1 antagonist, melanin-concentrating hormone 2 agonist, melanin-concentrating hormone 2 antagonist, galanin antagonist, CCK agonist, CCK-A agonist, corticotropin-releasing hormone agonist, NPY 5 antagonist, NPY 1 antagonist, histamine receptor-3 modulator, histamine receptor-3 blocker, β-hydroxysteroid dehydrogenase-1 inhibitor, phosphodiesterase inhibitor, phosphodiesterase-3B inhibitor, norepinephrine transport inhibitor, non-selective serotonin / norepinephrine transport inhibitor, ghrelin antagonist, leptin derivative, bombesin receptor subtype 3 agonist, ciliary neurotrophic factor or its derivative, monoamine reuptake inhibitor, uncoupling protein-1 activator, uncoupling protein-2 activator, uncoupling protein-3 activator, 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 co-transporter, phosphate transporter inhibitors, serotonin reuptake inhibitors, thiazolidinediones, metformin, topiramate, opioid antagonists, non-selective transporter inhibitors or MAO inhibitors. In some embodiments, the second therapeutic agent is a glucagon-like peptide 1 receptor agonist (e.g., liraglutide, semaglutide, exenatide, lixisenatide, dulaglutide or tesiparatide).

[0112] In some embodiments of any of the methods described herein, the subject is a human.

[0113] In another aspect, the disclosure discloses the use of any of the compounds described herein (e.g., any of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and compounds of Table 1), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in any of the methods disclosed herein.

[0114] In another aspect, the disclosure provides a compound for use in any of the methods disclosed herein (e.g., any of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and the compounds of Table 1).

[0115] Table 1

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] definition

[0138] To facilitate understanding of the present invention, a number of terms are defined below. The terms defined herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention relates. Terms such as "a," "an," and "the" are not intended to refer to only a single entity, but rather to encompass general categories that may be illustrated using specific examples. The terms herein are used to describe specific embodiments of the present invention, but their use does not limit the present invention unless outlined in the claims.

[0139] As used herein, any value provided in a range of values ​​includes the upper and lower limits, and any value contained within the upper and lower limits.

[0140] As used herein, "compounds of the present disclosure" and similar terms, whether explicitly stated or not, refer to the CB1 antagonists or inverse agonists described herein, including compounds of Formula I and its subformulae, and compounds of Table 1, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.

[0141] Those skilled in the art will appreciate that certain compounds described herein may exist in one or more different isomers (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., wherein one or more atoms are replaced by different isotopes of atoms, such as hydrogen replacing deuterium). Unless otherwise indicated or clear from the context, depicted structures can be understood to represent any such isomers or isotopic forms, alone or in combination.

[0142] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are referred to. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are considered in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be separated as mixtures of isomers or as separated isomeric forms.

[0143] In some embodiments, one or more compounds described herein may exist in different tautomeric forms. It is clear from the context that, unless explicitly excluded, reference to such compounds encompasses all such tautomeric forms. In some embodiments, tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. In certain embodiments, the tautomeric form may be a proton tautomer, which is an isomeric protonation state with the same empirical formula and total charge as the reference form. Examples of moieties with proton tautomeric forms are keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms, in which protons can occupy two or more positions in a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms arise from acetal interconversion.

[0144] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compound that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic reaction. 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, (P.H. Stahl and C.G. Wermuth, eds.), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. These 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.

[0145] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to achieve beneficial or desired results, such as clinical results, and thus, a "therapeutically effective amount" depends on the context in which it is used.

[0146] As used herein and as is well known in the art, "to treat" a condition or "treatment" of various diseases and disorders is an approach to obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions; lessening of the extent of the disease, disorder, or condition; stabilization (i.e., not worsening) of the state of the disease, disorder, or condition; delaying or slowing the progression of the disease, disorder, or condition; amelioration or alleviation of the disease, disorder, or condition; and remission (partial or complete), whether detectable or undetectable. To "mitigate" a disease, disorder, or condition means that the extent and / or reduction in undesirable clinical manifestations of the disease, disorder, or condition and / or the time course of progression are slowed or prolonged compared to the extent or time course in the absence of treatment.

[0147] As used herein, the term "subject" can be a human, non-human primate, or other mammal, such as, but not limited to, dogs, cats, horses, cows, pigs, goats, monkeys, rats, mice, and sheep. In preferred embodiments, the subject is a human.

[0148] As used herein, the term "pharmaceutical composition" refers to an active compound formulated with one or more pharmaceutically acceptable excipients. In some embodiments, the compound of the present invention is present in a unit dose suitable for administration in a treatment regimen that, when administered to a relevant population, shows a statistically significant probability of achieving a predetermined therapeutic effect. In certain embodiments, the pharmaceutical composition can be specially formulated for administration in solid or liquid form, including forms suitable for: oral administration, for example, an infusion (aqueous or non-aqueous solution or suspension), a tablet or capsule; and parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection.

[0149] As used herein, the term "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is biocompatible and suitable for administration to a subject. Typical excipients include, for example, antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, softeners, emulsifiers, diluents, film formers or coatings, flavorings, fragrances, glidants, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Excipients include, but are not limited to, butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked polyvinyl pyrrolidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, 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 of ordinary skill in the art are familiar with the various agents and materials that can be used as excipients.

[0150] As used herein, the term "alkyl" refers to a branched or straight-chain monovalent saturated aliphatic group containing only C and H when unsubstituted. The monovalence of an alkyl group does not include optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, the monovalence of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group can contain, for example, 1-8, 1-6, 1-4, or 1-2 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.

[0151] As used herein, the term "alkynyl" refers to a branched or straight-chain monovalent aliphatic group containing at least one carbon-carbon triple bond and, when unsubstituted, containing only C and H. The monovalence of an alkynyl group does not include optional substituents on the alkyl group. For example, if an alkynyl group is attached to a compound, the monovalence of an alkynyl group refers to its attachment 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 comprise, for example, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-C8, C2-C6, C2-C4, or C2-C3). Examples include, but are not limited to, ethynyl and propynyl.

[0152] As used herein, the term "alkylene" refers to a divalent group obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalence of the alkylene group does not include optional substituents on the alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene.

[0153] 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. The heterocyclyl ring can have five to ten ring atoms (e.g., five, six, seven, eight, nine, or ten), wherein one or more (e.g., one, two, three, four, or five) ring atoms are heteroatoms independently selected from the group consisting of N, O, and S. For example, heterocycloalkyl can be a 5-membered ring (i.e., a 5-membered heterocycle) containing one or more (e.g., one, two, three, or four) ring atoms, wherein the one or more ring atoms are heteroatoms independently selected from the group consisting of N, O, and S. As another example, heterocycloalkyl can be a 6-membered ring (i.e., a 6-membered heterocycle) comprising one or more (e.g., one, two, three, or four) ring atoms, wherein the one or more ring atoms 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.

[0154] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or fused ring bicyclic or polycyclic system having at least one heteroatom as a ring atom. For example, a heterocyclic ring can have five to ten ring atoms (for example, five, six, seven, eight, nine or ten; i.e., 5, 6, 7, 8, 9 or 10 yuan of heteroaryl), wherein one or more (for example, one, two, three, four or five) ring atoms are independently selected from the heteroatoms of the group consisting of nitrogen, oxygen and sulfur. The example of heteroaryl includes but is 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.

[0155] As used herein, the phrase "optionally substituted X" is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). This does not mean that the feature "X" (e.g., alkyl) itself is 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" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, such as any substituent or group 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 can be substituted with more than one substituent selected from a particular group, the substituent at each position may be the same or different. The combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when placed under conditions that allow its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0156] The term "combination therapy" refers to a method of treatment comprising administering at least two therapeutic agents to a subject, optionally as one or more pharmaceutical compositions, as part of a treatment regimen. For example, combination therapy can include administering a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy can include administering two or more pharmaceutical compositions, each composition comprising one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Two or more agents can optionally be administered simultaneously (as a single or separate composition) or sequentially (as a separate composition). The therapeutic agent can be administered in an effective amount. The therapeutic agent can be administered in a therapeutically effective amount. In some embodiments, when used for combination therapy, the effective amount of one or more therapeutic agents can be lower than the therapeutic amount when the same therapeutic agent is used as a monotherapy, for example, due to the additive or synergistic effect of combining two or more therapeutic agents.

[0157] As used herein, the term "CB1" or "CB1 receptor" refers to cannabinoid receptor type 1. CB1 is a G protein-coupled cannabinoid receptor that, in humans, is encoded by the CNR1 gene. Human CB1 receptors are primarily found 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.

[0158] As used herein, the term "CB1 b ” refers to a splice variant of the human CB1 receptor. CB1 bIt is the preferentially expressed form of CB1 in beta cells and hepatocytes (e.g., particularly in obese individuals), but is not significantly expressed in the brain. b Described in, for example, patent publication number US20060115816. b Selective inhibition of CB1b in relevant conditions can reduce 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). BRIEF DESCRIPTION OF THE DRAWINGS

[0159] Figure 1 It is a graph showing changes in body weight of C57BL / 6J mice fed a high-fat diet and administered with Compound 9, semaglutide, tesiparatide, a combination of Compound 9 and semaglutide, and a combination of Compound 9 and tesiparatide.

[0160] Figure 2 Provided is a graph showing the brain / plasma ratio of orally administered Compound 9 (10 mg / kg) versus orally administered Rimonabant (10 mg / kg) in C57BL / 6J mice, as measured by the area under the curve (AUC 0-24 ) and maximum concentration (C max ) for measurement. DETAILED DESCRIPTION

[0161] Disclosed herein are compounds, pharmaceutical compositions, and uses of pharmaceutical compositions for treating a condition modulated by the cannabinoid 1 (CB1) receptor in a subject.

[0162] Compound

[0163] The present disclosure provides compounds (e.g., CB1 receptor modulators) that can be used to treat conditions mediated by the CB1 receptor. These compounds are generally described by formula (I):

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from F, Cl, CN and OCH3; R 2 is C1-C6 alkyl or phenyl optionally substituted by F or CN; R 3 is phenyl substituted by 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 group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group; R 4 、R 4 '、R 5 and R5 ' are independently H or C1-C6 alkyl; R 6 and R 7 R6 and R7 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, wherein the heteroaryl group is optionally substituted with C1-C6 alkyl; and R 8 is H or CH3, provided that at least one of the following is true: (i) R 1 is not 4-chlorophenyl or 4-methoxyphenyl; (ii) R 2 is C1-C6 alkyl or phenyl substituted by CN; (iii) R 3 is not 4-chlorophenyl, 3-cyanophenyl or 3-methoxyphenyl; (iv) R 4 and R 5 One of them is C1-C6 alkyl; (v) R 6 and R 7 One of them is not H; and (vi) R 8 It is CH3.

[0166] These compounds are also generally described by formula (II):

[0167]

[0168] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from halogen, C1-C6 alkoxy and CN; R 2 is C1-C6, 5- or 6-membered heteroaryl or phenyl optionally substituted by halogen or CN; R 3 is phenyl substituted by 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 group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by 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; L is (a) (b) (c) (d) R 8 is H or C1-C6 alkyl; R 4 、R 4 '、R 5 and R 5 ' is independently H or C1-C6 alkyl optionally substituted by C1-C6 alkoxy; X is O or NR9 ; R 9 is H or C1-C6 alkyl; and y and z are independently 1, 2 or 3.

[0169] These compounds are also generally described by formula (III):

[0170]

[0171] or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from F, Cl, CN and OCH3; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted by F or CN; R 3 is phenyl substituted by 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 group containing 1-3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group; R 4 、R 4 '、R 5 and R 5 ' are independently H or C1-C6 alkyl; R 6 and R 7 R6 and R7 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 group 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.

[0172] In some embodiments, the disclosure features compounds that are CB1 receptor inverse agonists.

[0173] In some embodiments, the disclosure features compounds that are CB1 receptor antagonists.

[0174] In some embodiments, the disclosure features compounds with increased affinity for the CB1 receptor compared to known CB1 modulators such as rimonabant, tylenabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1, the contents of which are herein incorporated by reference in their entireties.

[0175] In some embodiments, the disclosure features compounds with increased selectivity for the CB1 receptor compared to known CB1 modulators such as rimonabant, tarenabant, and International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0176] In some embodiments, the disclosure features compounds with increased affinity and increased selectivity for the CB1 receptor compared to known CB1 modulators such as rimonabant, tylenabant, and International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0177] In some embodiments, the disclosure features compounds that exhibit reduced blood-brain barrier penetration compared to known CB1 modulators such as rimonabant, tarenabant, and International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0178] In some embodiments, the disclosure features a compound that exhibits a brain to plasma ratio 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) in a subject when orally administered to a mouse at a dose of 10 mg / kg, as measured by the area under the curve (AUC 0-24 ) measured.

[0179] In some embodiments, the disclosure features a compound that exhibits a brain to plasma ratio 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) in a subject when orally administered to a mouse at a dose of 10 mg / kg, as measured by the maximum concentration (C max ) measured.

[0180] In some embodiments, the disclosure features compounds with increased oral bioavailability compared to known CB1 modulators such as rimonabant, tarenabant, and International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0181] In some embodiments, the disclosure features compounds with increased safety or efficacy profiles compared to known CB1 modulators such as rimonabant, tylenabant, and International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0182] 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., suicide) in treated subjects compared to subjects treated with known CB1 modulators, such as rimonabant, tylenabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0183] In some embodiments, the disclosure features compounds with an enhanced ability to lower leptin levels compared to known CB1 modulators such as rimonabant, tarenabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1.

[0184] In some embodiments, the present disclosure features, for example, improved CB1 activity at the CB1 receptor compared to known CB1 modulators such as rimonabant, tarenabant, and compounds disclosed in International Publications WO2007106721A2, WO2007131219A2, WO2009033125A1, WO2009059264A1, WO2011044370A1, WO2012068529A2, and WO2014018695A1. b Compounds with increased binding or higher specificity of splice variants. 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 that of the human CB1 receptor.

[0185] Exemplary compounds are shown in Table 1.

[0186] Pharmaceutical composition

[0187] The pharmaceutical compositions of the present disclosure comprise one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1) as therapeutic compounds. In addition to a therapeutically effective amount of the compound, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. In some embodiments, a pharmaceutical composition for the treatment of cancer comprises one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1), which may be formulated and / or administered with or without other therapeutic agents for a particular condition. Examples of such therapeutic agents (secondary therapeutic agents) are described herein.

[0188] The compounds disclosed herein (e.g., compounds of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III), and Table 1) can be used in the form of free bases, or in the form of salts, and as solvates. All forms are within the scope of the present disclosure.

[0189] Exemplary routes of administration for the pharmaceutical composition (or a 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.

[0190] Preparations for oral administration

[0191] The pharmaceutical compositions of the present invention include those formulated for oral administration ("oral dosage forms"). Oral dosage forms can be in the form of, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid or solid crystals, which contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives (including microcrystalline cellulose), starch (including potato starch), croscarmellose sodium, alginate or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone or polyethylene glycol); and lubricants, glidants and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients may be colorants, flavorings, plasticizers, humectants, buffers, etc.

[0192] Pharmaceutical compositions for oral administration may also be presented as chewable tablets, hard gelatin capsules (where 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 (where the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil). Powders, granules and pills can be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, for example, a mixer, fluidized bed equipment or spray drying equipment.

[0193] Liquid forms into which the compounds and compositions of the invention can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0194] Preparations for parenteral administration

[0195] As described herein, the pharmaceutical compositions of the present invention can be administered in the form of pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, subcutaneous, etc.) formulations. Pharmaceutical compositions can also be administered parenterally in the form of 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, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. For example, to prepare such a composition, the compound of the present invention can be dissolved or suspended in a liquid vehicle that is acceptable to the parenteral. Acceptable vehicles and solvents that can be used are water; water adjusted to a suitable pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer's solution; and isotonic sodium chloride solution. Aqueous formulations may also contain one or more preservatives, such as methylparaben, ethylparaben, or n-propylparaben. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), the entire contents of which are incorporated herein by reference.

[0196] Parenteral formulations can be any of five general types of preparations identified by USP-NF as suitable for parenteral administration:

[0197] (1) “Drug injection”: a liquid preparation of a drug substance (e.g., a compound of the present invention) or its solution;

[0198] (2) "Injectables": a drug substance (e.g., a compound of the present invention) in the form of a dry solid that is to be combined with an appropriate sterile vehicle for parenteral administration in the form of a pharmaceutical injection;

[0199] (3) “Drug injectable emulsion”: a liquid preparation of a drug substance (e.g., a compound of the present invention) dissolved or dispersed in a suitable emulsion medium;

[0200] (4) "Drug injectable suspension": a liquid preparation of a drug substance (e.g., a compound of the present invention) suspended in a suitable liquid medium; and

[0201] (5) "Injectable suspension": a drug substance (eg, a compound of the present invention) in the form of a dry solid to be combined with an appropriate sterile vehicle for parenteral administration in the form of a pharmaceutical injectable suspension.

[0202] The exemplary formulations for parenteral administration are included in solutions of compounds prepared in water suitably mixed with a surfactant (e.g., hydroxypropyl cellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and in oils. Under common storage and use conditions, these preparations may contain preservatives to prevent microbial growth. For example, in Remington: The Science and Practice of Pharmacy, 23rd edition, Adejare, Ed., Academic Press (2020) and The United States Pharmacopeia and National Formulary (USP-NF 2021 Phases 1-3) published in 2021, conventional procedures and compositions for selecting and preparing suitable formulations are described.

[0203] Preparations for parenteral administration can for example comprise sterile water, saline, polyalkylene glycol (e.g., polyethylene glycol), oil of plant origin or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be used for controlling the release of the compound. Other potential useful parenteral delivery systems of the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. Preparations for suction can comprise for example lactose, or can be aqueous solutions comprising for example polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can be oily solutions for use in nasal drops or gel form.

[0204] How to use

[0205] 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 restricted (i.e., unable or limited to cross the blood-brain barrier, or readily eliminated from the brain by active transport systems) and therefore produce no or limited CNS effects. Thus, the compounds of the present disclosure can provide peripherally mediated efficacy in the treatment of CB1-modulated conditions, such as diabetic conditions, dyslipidemic conditions, cardiovascular conditions, inflammatory conditions, liver conditions, cancer, and obesity, and their complications, with improved therapeutic safety, e.g., with respect to CNS effects.

[0206] Thus, in some embodiments, the present disclosure provides methods of treating a diabetic condition 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 of Table 1), or a pharmaceutically acceptable salt thereof. Examples of diabetic conditions include, but are not limited to, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, and insulin resistance. In some embodiments, the diabetic condition is type 1 diabetes. In some embodiments, the diabetic condition is type 2 diabetes. In some embodiments, the diabetic condition is impaired glucose tolerance. In some embodiments, the diabetic condition is type 1 diabetes. In some embodiments, the diabetic condition is impaired glucose tolerance. In some embodiments, the diabetic condition is type 2 diabetes. In some embodiments, the diabetic condition is impaired glucose tolerance. In some embodiments, the diabetic condition is type 1 diabetes. In some embodiments, the diabetic condition is impaired glucose tolerance. In some embodiments, the diabetic condition is insulin resistance.

[0207] In some embodiments, the present disclosure provides methods of treating a dyslipidemic condition 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 of Table 1), or a pharmaceutically acceptable salt thereof. Examples of dyslipidemic conditions 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 dyslipidemic condition is an undesirable blood lipid level. In some embodiments, the dyslipidemic condition is a low level of high-density lipoprotein. In some embodiments, the dyslipidemic condition is a high level of low-density lipoprotein. In some embodiments, the dyslipidemic condition is an undesirable blood lipid level.

[0208] In some embodiments, the present disclosure provides methods of treating a cardiovascular disorder 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 of Table 1), or a pharmaceutically acceptable salt thereof. Examples of cardiovascular disorders include, but are not limited to, atherosclerosis, hypertension, stroke, and heart attack. In some embodiments, the cardiovascular disorder is atherosclerosis. In some embodiments, the cardiovascular disorder is hypertension. In some embodiments, the cardiovascular disorder is stroke. In some embodiments, the cardiovascular disorder is heart attack.

[0209] In some embodiments, the present disclosure provides methods of treating an inflammatory condition 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 of Table 1), or a pharmaceutically acceptable salt thereof. Examples of inflammatory conditions include, but are not limited to, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, and obesity-related inflammation. In some embodiments, the inflammatory condition is osteoarthritis. In some embodiments, the inflammatory condition is osteoarthritis. In some embodiments, the inflammatory condition is rheumatoid arthritis. In some embodiments, the inflammatory condition is inflammatory bowel disease. In some embodiments, the condition is obesity-related inflammation.

[0210] In some embodiments, the present disclosure provides methods of treating a liver disorder 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 of Table 1), or a pharmaceutically acceptable salt thereof. Examples of liver disorders 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 disorder is liver inflammation. In some embodiments, the liver disorder is liver fibrosis. In some embodiments, the liver disorder is non-alcoholic steatohepatitis. In some embodiments, the liver disorder is fatty liver. In some embodiments, the liver disorder is hepatomegaly. In some embodiments, the liver disorder is alcoholic liver disease. In some embodiments, the liver disorder is jaundice. In some embodiments, the liver disorder is cirrhosis. In some embodiments, the liver disorder is hepatitis.

[0211] In some embodiments, the present disclosure provides methods of treating cancer 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 of 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.

[0212] In some embodiments, the present disclosure provides a method of treating obesity or a complication thereof 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 of Table 1), or a pharmaceutically acceptable salt thereof. Examples of complications of obesity include, but are not limited to, hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous stasis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arteriosclerotic disease; pseudotumor cerebri; accident proneness; increased surgical risk; osteoarthritis; high cholesterol; or increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies. In some embodiments, the complication of obesity is hypertension. In some embodiments, the complication of obesity is gallbladder disease. In some embodiments, the complication of obesity is gastrointestinal disorders. In some embodiments, a complication of obesity is menstrual irregularity. In some embodiments, a complication of obesity is degenerative arthritis. In some embodiments, a complication is venous stasis ulcers. In some embodiments, a complication of obesity is hypoventilation syndrome. In some embodiments, a complication of obesity is sleep apnea. In some embodiments, a complication of obesity is snoring. In some embodiments, a complication of obesity is coronary artery disease. In some embodiments, a complication of obesity is arteriosclerotic disease. In some embodiments, a complication of obesity is pseudotumor cerebri. In some embodiments, a complication of obesity is accident proneness. In some embodiments, a complication of obesity is increased surgical risk. In some embodiments, a complication of obesity is osteoarthritis. In some embodiments, a complication of obesity is high cholesterol. In some embodiments, a complication of obesity is an increased incidence of malignant tumors of the ovary, cervix, uterus, breast, prostate, or gallbladder.

[0213] The dosage of the compounds of the present invention depends on a variety of factors, including the route of administration, the disease to be treated, and the physical characteristics of the subject, such as age, weight, and general health. Generally, the amount of the compounds disclosed herein (e.g., compounds of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III) or compounds of Table 1) contained in a single dose can be an amount that is effective in treating the disease without inducing significant toxicity. Pharmaceutical compositions of the present invention containing one or more of the compounds disclosed herein (e.g., one or more of the compounds of Formula (I), (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (II), (IVA), (VA), (VIA), (IVB), (VB), (VIB), and (III) and Table 1) can be administered to a subject in need once or more daily or as medically necessary.

[0214] Combination therapy

[0215] 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 of Table 1), or a pharmaceutically acceptable salt thereof, is administered with a second therapeutic agent, e.g., a therapeutic agent useful for treating any of the diseases described herein.

[0216] 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 Table 1), or a pharmaceutically acceptable salt thereof, include, but are not limited to, a PPAR-γ agonist (e.g., a glitazone, such as troglitazone, pioglitazone, englitazone, MCC-555, and rosiglitazone), biguanides (e.g., metformin 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), nicotinic alcohol, nicotinic acid or its salts, PPAR-α agonists (e.g., fenofibric acid derivatives such as 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, semaglutide, exenatide, lixisenatide, dulaglutide, or tesiparatide), growth hormone secretagogues, growth hormone secretagogue receptor agonists, growth hormone secretagogue receptor antagonists, melanocortin agonists, melanocortin 4 receptor agonists, beta-3 agonists, serotonin receptor 2C 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, NPY 5 antagonists, NPY 1 antagonists, histamine receptor-3 modulators, histamine receptor-3 blockers, β-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, 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 co-transporter, phosphate transporter inhibitors, serotonin reuptake inhibitors, thiazolidinediones, metformin, topiramate, opioid antagonists (e.g., naltrexone), non-selective transport inhibitors (e.g., bupropion), or MAO inhibitors (e.g., moclobemide, brofaromine, BW A616U, Ro 41-1049, RS-2232, SR 95191, camalline, halman, amifampamide, BW1370U87, FLA 688, FLA788; difemerol, clorgyline, LY 51641, MDL 72,394, 5-(4-benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-one, 5-(4-arylmethoxyphenyl)-2-(2-cyanoethyl)tetrazole, lazabemide, Ro 16-6491, amoxicillin, XB308, RS-1636, RS-1653, NW-1015, SL 340026, L-selegiline, rasagiline, pargyline, AGN 1135, MDL 72,974, MDL 72,145, MDL 72,638, LY 54761, MD780236, MD 240931, difemelane, toloxatone, simoxadone, iproniazid, phenelzine, nyamidine, phenylhydrazine, 1-phenylcyclopropylamine, isocarboxazid, or tranylcypromine).

[0217] 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 semaglutide.

[0218] 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 tesiparatide.

[0219] 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), or (IIIB), or a compound of Table 1), or a pharmaceutically acceptable salt thereof, is administered with liraglutide.

[0220] 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.

[0221] 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 lixisenatide.

[0222] 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 dulaglutide.

[0223] Example

[0224] Example 1. Synthesis of intermediates

[0225] Synthesis of (S)-2-aminopropane-1-sulfonamide (I1)

[0226] Synthesis of (S)-propyl 2-(((benzyloxy)carbonyl)amino)methanesulfonate (I1.1):

[0227]

[0228] At 0 ° C, a solution of methanesulfonyl chloride (1.92 mL, 24.8 mmol, 1.04 equiv) in dichloromethane (48 mL) was added to a solution of (S)-(1-hydroxypropyl-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) for 30 minutes. After stirring at room temperature for 16 hours, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution (80 mL) and brine (80 mL). The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness to give the expected product (6.85 g, 23.8 mmol, 99% yield) as a white solid. LC-MS (ESI+): 288.1 (M+H + ).

[0229] Synthesis of (S)-S-(2-(((Benzyloxy)carbonyl)amino)propyl)ethanethiolate (I1.2):

[0230]

[0231] 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 collected organic phase was washed with brine (60 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark oil, which was purified by flash chromatography on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give a light brown solid (6.3 g, 23.7 mmol, 99% yield). LC-MS (ESI+): 268.1 (M+H + ).

[0232] Synthesis of benzyl (S)-(1-(chlorosulfonyl)propan-2-yl)carbamate (I1.3):

[0233]

[0234] 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)ethanethiolate (5.73 g, 21.4 mmol, 11.2) in acetic acid (36 mL). After stirring at room temperature for 18 hours, palladium / activated carbon was added to destroy excess peroxide, and the resulting mixture was filtered through a pad of celite. The filtrate was concentrated to dryness in vacuo.

[0235] The obtained brown oil was dissolved in 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 hours, the solvent was removed under reduced pressure, and the residue was eluted with a dichloromethane / methanol mixture (0 / 100 to 10 / 90, v / v) to obtain a beige solid (5.43 g, 18.7 mmol, 87% yield). LC-MS (ESI+): 292.0 (M+H + ).

[0236] Synthesis of (S)-(1-sulfamoylprop-2-yl)benzylcarbamate (I1.4):

[0237]

[0238] At room temperature, ammonia gas was bubbled through a stirred solution of (S)-(1-(chlorosulfonyl)propan-2-yl)benzylcarbamate (5.4 g, 18.5 mmol, 11.3) in dichloromethane (185 mL) for 15 minutes. Upon completion, the reaction mixture was concentrated in vacuo to dryness, and the resulting light 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 + ).

[0239] Synthesis of (S)-2-aminopropane-1-sulfonamide (I1):

[0240]

[0241] A solution of (S)-(1-sulfamoylpropane-2-yl)benzylcarbamate (5.3 g, 19.5 mmol, 11.4) and 10% palladium / carbon powder (Pd / C, 10 wt %) (2.0 g, 0.1 equivalent) in ethanol (195 mL) was first vacuum degassed and then saturated with hydrogen, repeated 3 times. After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered through a celite pad and concentrated in vacuo to give the expected compound (2.65 g, 98% yield) as a brownish white solid. LC-MS (ESI+): 139.0 (M+H + ).

[0242] Synthesis of N-(bis-methylsulfanyl-methylene)-3-trifluoromethyl-benzenesulfonamide (I2)

[0243]

[0244] To a solution of 3-(trifluoromethyl)benzenesulfonamide (5.0 g, 22.2 mmol, 12.0) and carbon disulfide (2.18 mL, 36.4 mmol, 1.6 equivalents) in dimethylformamide (74 mL) cooled in an ice bath was added a solution of potassium hydroxide (2.94 g, 52.4 mmol, 2.4 equivalents) in water (11 mL), keeping the internal temperature below 10 ° C. After stirring at 0 ° C for 1 hour, iodomethane (3.2 mL, 51.5 mmol, 2.3 equivalents) was added dropwise while keeping the internal temperature below 10 ° C. After stirring at room temperature for 2 hours, water (35 mL) was added, and the mixture was extracted with ethyl acetate (2x50 mL). The combined organic layers were collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product (5.75 g, 17.5 mmol, 79% yield) without further purification as a light yellow solid. LC-MS (ESI+): 330.0 (M+H + ).

[0245] Synthesis of dimethyl ((2-chlorophenyl)sulfonyl)dithioimidocarbonate (I3)

[0246]

[0247] To a solution of 2-chlorobenzenesulfonamide (4.7g, 24.5mmol, 1 equivalent) and carbon disulfide (2.4mL, 40.2mmol, 1.6 equivalents) in dimethylformamide (87mL) cooled in an ice bath was added a solution of potassium hydroxide (3.2g, 57.8mmol, 2.4 equivalents) in water (13mL) while maintaining the internal temperature below 10°C. After stirring at 0°C for 1 hour, iodomethane (3.5mL, 56.9mmol, 2.3 equivalents) was added dropwise while maintaining the internal temperature below 10°C. After heating for 2 hours until room temperature, water (35mL) was added, and the mixture was extracted with ethyl acetate (2x50mL). The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product (6.0g, 20.3mmol, 83% yield) without further purification as a light yellow solid. LC-MS (ESI+): 295.9 (M+H + ).

[0248] Synthesis of dimethyl ((2-ethynylphenyl)sulfonyl)dithioimidocarbonate (I4)

[0249] Synthesis of 2-bromobenzenesulfonamide (I4.1):

[0250]

[0251] 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 pad of silica, washed with ethyl acetate, and concentrated under reduced pressure to afford a beige solid (4.4 g, 18.8 mmol, 95%) that was used directly without further purification. LC-MS (ESI+): 236.0 (M+H + ).

[0252] Synthesis of 2-((trimethylsilyl)ethynyl)benzenesulfonamide (I4.2)

[0253]

[0254] Bis(triphenylphosphine)palladium chloride (0.65g, 0.93mmol, 0.05 equivalent) and (trimethylsilyl)acetylene (3.3mL, 23.3mmol, 1.25 equivalent) are added to a solution of 2-bromobenzenesulfonamide (4.4g, 18.6mmol, 14.1) and copper (I) iodide (0.18g, 0.93mmol, 0.05 equivalent) in degassed triethylamine (78mL). The resulting mixture is refluxed at 90°C for 18 hours. Upon completion, the reaction mixture is filtered through a pad of celite, washed with ethyl acetate, concentrated, and purified by flash chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) on silica gel to give the desired compound (1.8g, 7.1mmol, 38% yield) as a beige solid. LC-MS (ESI+): 254.0 (M+H + ).

[0255] Synthesis of dimethyl ((2-ethynylphenyl)sulfonyl)dithioimidocarbonate (I4)

[0256]

[0257] 2-((trimethylsilyl)ethynyl)benzenesulfonamide (1.28g, 5.05mmol, 14.2) and carbon disulfide (0.5mL, 8.3mmol, 1.6 equivalents) are dissolved in dimethylformamide (9mL), and the mixture is cooled in an ice bath. Then, a solution of potassium hydroxide (0.67g, 11.9mmol, 2.4 equivalents) in water (3mL) is added dropwise while keeping the internal temperature below 10°C. The resulting mixture is stirred at 0°C for 1 hour. After this time, iodomethane (0.73mL, 11.7mmol, 2.3 equivalents) is added dropwise while keeping the internal temperature below 10°C, and the resulting mixture is stirred for 2 hours until room temperature. When the starting material is consumed, water (15mL) is added, and the mixture is extracted with ethyl acetate (2x20mL). The collected organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected compound (0.47 g, 1.6 mmol, 32% yield) as a light yellow solid. LC-MS (ESI+): 286.0 (M+H + ).

[0258] Synthesis of dimethyl ((3-ethynylphenyl)sulfonyl)dithioimidocarbonate (I5)

[0259] Synthesis of 3-((trimethylsilyl)ethynyl)benzenesulfonamide (I5.1):

[0260]

[0261] Bis(triphenylphosphine)palladium chloride (0.65g, 0.93mmol, 0.05 equivalent) and (trimethylsilyl)acetylene (3.3mL, 23.3mmol, 1.25 equivalent) are added to a solution of 3-bromobenzenesulfonamide (4.4g, 18.6mmol, 1.0 equivalent) and copper (I) iodide (0.18g, 0.93mmol, 0.05 equivalent) in degassed triethylamine (78mL). After stirring at 90°C for 18 hours, the reaction mixture is filtered through a celite pad, washed with ethyl acetate and concentrated. The residue is purified by flash chromatography using ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) eluted with silica gel to give the expected compound (4.45g, 17.6mmol, 94% yield) as a beige solid. LC-MS (ESI+): 254.0 (M+H + ).

[0262] Synthesis of dimethyl ((3-ethynylphenyl)sulfonyl)dithioimidocarbonate (I5)

[0263]

[0264] To a solution of 3-((trimethylsilyl)ethynyl)benzenesulfonamide (4.45 g, 17.6 mmol, 15.1) and carbon disulfide (1.7 mL, 28.8 mmol, 1.6 eq) in dimethylformamide (30 mL) cooled in an ice bath was added a solution of potassium hydroxide (2.3 g, 41.4 mmol, 2.4 eq) in water (10 mL) dropwise while maintaining the internal temperature below 10°C. After stirring at 0°C for 1 hour, iodomethane (2.5 mL, 40.7 mmol, 2.3 eq) was added dropwise while maintaining the internal temperature below 10°C. After warming to room temperature over 2 hours, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 50 / 50, v / v) to give the expected compound (2.65 g, 9.29 mmol, 53% yield) as a light yellow solid. LC-MS (ESI+): 286.0 (M+H + ).

[0265] Synthesis of Methyl ((2,4-difluorophenyl)sulfonyl)carbamate (I6)

[0266]

[0267] At 0 ° C, triethylamine (1.62 mL, 11.65 mmol, 2.5 equivalents) and methyl chloroformate (577.40 μL, 7.45 mmol, 1.6 equivalents) were added to a solution of I6.0 (0.9 g, 4.66 mmol, CAS No. 13656-60-5) in acetonitrile (15 mL). The resulting mixture was slightly warmed to room temperature and stirred at room temperature for 12 hours. 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 HCl aqueous solution (1 N). The suspension was filtered, and the filter cake was dried under high vacuum to give I6 (0.3 g, 1.19 mmol, 26%) as a white solid. 1 H NMR: 400MHz, DMSO-d6δppm 3.73 (s, 3H), 6.93-7.13 (m, 2H), 7.92 (br s, 1H), 8.11 (td, J=8.47, 6.05Hz, 1H)

[0268] Synthesis of I7: Methyl ((3,5-difluorophenyl)sulfonyl)carbamate (I7)

[0269]

[0270] To a solution of I7.0 (5 g, 25.88 mmol, 1 eq) in acetonitrile (50 mL) at 0 ° C., triethylamine (9.01 mL, 64.71 mmol, 2.5 eq) and methyl chloroformate (3.21 mL, 41.41 mmol, 1.6 eq) were added. After stirring at room temperature for 12 hours, 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 solution (1 N). The suspension was filtered and the filter cake was dried under high vacuum to give I7 (2 g, 7.56 mmol, 29%) as a white solid. LCMS (ESI+): m / z 239.1 (M+H) + ; 1 H NMR: 400MHz, DMSO-d6δppm 3.60 (s, 3H), 7.58 (br d, J = 4.77Hz, 2H), 7.73 (br t, J = 9.29Hz, 1H).

[0271] Synthesis of (R)-2-aminopropane-1-sulfonamide (I8)

[0272] Synthesis of benzyl (R)-(1-hydroxypropyl-2-yl)carbamate (I8.1)

[0273]

[0274] To a solution of D-alaninol (2.0 g, 26.6 mmol, 18.0) and potassium carbonate (7.4 g, 53.5 mmol, 2.01 equiv) in tetrahydrofuran / water (50 mL, 1:1) at 0°C was added benzyl chloroformate (4.2 mL, 29.3 mmol, 1.1 equiv). After stirring at room temperature for 1 hour, the reaction mixture was extracted with ethyl acetate (75 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a white solid (5.5 g, 26.3 mmol, 98% yield) that was used in the next step without further purification. LC-MS (ESI+): 210.1 (M+H + ).

[0275] Synthesis of (R)-2-(((Benzyloxy)carbonyl)amino)propyl methanesulfonate (I8.2)

[0276]

[0277] At 0 ° C, a solution of methanesulfonyl chloride (2.12 mL, 27.3 mmol, 1.04 equivalents) in dichloromethane (52 mL) was added to a solution of (R)-(1-hydroxypropyl-2-yl)benzylcarbamate (5.5 g, 26.3 mmol, 18.1) and triethylamine (4.03 mL, 28.9 mmol, 1.1 equivalents) in dichloromethane (104 mL). After stirring in an ice bath for 30 minutes, the mixture was stirred at room temperature for another 30 minutes. Upon completion, the reaction mixture was subsequently washed with saturated sodium bicarbonate aqueous solution (80 mL) and brine (80 mL). The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness to give the expected product (7.5 g, 26.2 mmol, 99% yield) as a white solid. LC-MS (ESI+): 288.1 (M+H + ).

[0278] Synthesis of (R)-S-(2-(((Benzyloxy)carbonyl)amino)propyl)ethanethiolate (I8.3)

[0279]

[0280] 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) 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 in vacuo to give a dark oil, which was purified by flash chromatography on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give a light brown oil (6.74 g, 25.2 mmol, 96% yield). LC-MS (ESI+): 268.1 (M+H + ).

[0281] Synthesis of benzyl (R)-(1-(chlorosulfonyl)propan-2-yl)carbamate (I8.4)

[0282]

[0283] 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)ethanethiolate (6.74 g, 25.2 mmol, 18.3) in acetic acid (40 mL). After stirring at room temperature for 18 hours, palladium / activated carbon was added to destroy excess peroxide, and the resulting mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to dryness.

[0284] The brown oil was dissolved in dichloromethane (120 mL) and triphosgene (10.4 g, 35.3 mmol, 1.4 equivalents), followed by dimethylformamide (3.5 mL). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was eluted with dichloromethane / methanol mixture (0 / 100 to 10 / 90, v / v) and chromatographed on silica gel to give a beige solid (5.9 g, 20.3 mmol, 80% yield). LC-MS (ESI+): 292.0 (M+H + ).

[0285] Synthesis of benzyl (R)-(1-sulfamoylpropan-2-yl)carbamate (I8.5)

[0286]

[0287] At room temperature, ammonia gas was bubbled through a stirred solution of (R)-(1-(chlorosulfonyl)propan-2-yl)benzylcarbamate (5.9 g, 20.2 mmol, 18.4) in dichloromethane (200 mL) for 15 minutes. Upon completion, the reaction mixture was concentrated in vacuo to dryness, and the resulting light 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 + ).

[0288] Synthesis of (R)-2-aminopropane-1-sulfonamide (I8)

[0289]

[0290] To a solution of (R)-(1-sulfamoylpropyl-2-yl)benzylcarbamate (5.48 g, 20.2 mmol, 18.5) in ethanol (200 mL) was added 10% palladium / carbon powder (Pd / C, 10 wt %) (2.0 g, 0.1 equivalent). The mixture was degassed in vacuo and then saturated with hydrogen, repeated 3 times. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. Upon completion, the mixture was filtered through a celite pad and concentrated in vacuo to give the expected compound (2.7 g, 19.6 mmol, 97% yield) as a brown solid. LC-MS (ESI+): 139.0 (M+H + ).

[0291] Synthesis of dimethyl ((4-ethynylphenyl)sulfonyl)dithioimidocarbonate (I9)

[0292] Synthesis of ((trimethylsilyl)ethynyl)benzenesulfonamide (I9.1)

[0293]

[0294] Bis(triphenylphosphine)palladium chloride (0.45g, 0.63mmol, 0.05 equivalent) and (trimethylsilyl)acetylene (2.26mL, 15.9mmol, 1.25 equivalent) are added to a solution of 4-bromobenzenesulfonamide (3.0g, 12.7mmol, 19.0) and copper (I) iodide (0.12g, 0.63mmol, 0.05 equivalent) in triethylamine (48mL). After stirring at 90°C for 18 hours, the reaction mixture is filtered through a diatomaceous earth pad, washed with ethyl acetate and concentrated to dryness. The residue is purified by flash chromatography with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) eluted with silica gel to give a beige solid (2.8g, 11.1mmol, 87% yield). LC-MS(ESI+): 254.1(M+H + ).

[0295] Synthesis of dimethyl ((4-ethynylphenyl)sulfonyl)dithioimidocarbonate (I9)

[0296]

[0297] 4-((trimethylsilyl)ethynyl)benzenesulfonamide (0.8 g, 3.16 mmol, 19.1) and carbon disulfide (0.31 mL, 5.18 mmol, 1.6 equiv) dissolved in DMF (4.5 mL) in an ice bath were added, and a solution of potassium hydroxide (0.42 g, 7.4 mmol, 2.4 equiv) in water (1.5 mL) was added dropwise while maintaining the internal temperature below 10°C. After stirring at 0°C for 1 hour, iodomethane (0.46 mL, 7.3 mmol, 2.3 equiv) was added dropwise while maintaining the internal temperature below 10°C. After stirring for 2 hours until room temperature, the reactant was diluted with water (15 mL) and extracted with ethyl acetate (2x20 mL). The collected organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using an ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) eluted with silica gel. The desired fractions were collected and concentrated in vacuo to give the expected compound (0.39 g, 1.37 mmol, 43% yield) as an orange solid. LC-MS (ESI+): 286.0 (M+H + ).

[0298] Synthesis of (S)-2-amino-3-methylbutane-1-sulfonamide (I10)

[0299] Synthesis of (S)-2-(1-hydroxy-3-methylbutan-2-yl)isoindoline-1,3-dione (I10.1)

[0300]

[0301] At 140 ° C, (S)-valinol (5.00 g, 48.4 mmol, 1 equivalent) and phthalic anhydride (7.54 g, 50.9 mmol, 1.05 equivalents) were melted in a closed capped flask under stirring for 18 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (75 mL) and then washed with saturated sodium bicarbonate aqueous solution (60 mL), water (50 mL), 10% citric acid aqueous solution (50 mL) and brine (50 mL). The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo to give an oily crude product, which was purified by silica gel column chromatography eluting with a heptane / ethyl acetate mixture to give (S)-2-(1-hydroxy-3-methylbutan-2-yl)isoindoline-1,3-dione (10.2 g, 43.8 mmol, 90% yield) as a light yellow oil. LC-MS (ESI+): 234.112 (M+H + ).

[0302] Synthesis of (S)-S-(2-(1,3-dioxoisoindolin-2-yl)-3-methylbutyl)ethanethiol salt (I10.2)

[0303]

[0304] To a solution of diethyl azodicarboxylate in toluene (40%, 2.15 mL, 4.71 mmol, 2.2 equiv) and triphenylphosphine (1.24 g, 4.71 mmol, 2.2 equiv) in THF (10 mL) at room temperature were 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). 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 magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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)ethanethiolate (I10.2) (0.51 g, 1.75 mmol, 82% yield) as a yellow oil. LC-MS (ESI+): 292.1 (M+H + ).

[0305] Synthesis of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonic acid (I10.3)

[0306]

[0307] A mixture of hydrogen peroxide and acetic acid (1: 2, v / v) (9.30mL) was added to a solution of (S) -S- (2- (1,3-dioxoisoindolin-2-yl) -3-methylbutyl) ethanethiolate (1.03g, 3.53mmol, 110.2) in acetic acid (3mL). After stirring at room temperature for 18 hours, palladium / activated carbon was added to destroy excess peroxide. The resulting mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The oily residue was co-evaporated with toluene (2x10mL) and concentrated to dryness to give a brown oil (0.99g, 3.33mmol, 94% yield) which was used in the next step without further purification. LC-MS (ESI +): 298.074 (M + H + ).

[0308] Synthesis of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonyl chloride (I10.4):

[0309]

[0310] (S) -2- (1,3-dioxoisoindolin-2-yl) -3-methylbutane-1-sulfonic acid (0.94 g, 3.17 mmol, 110.3) was refluxed in thionyl chloride (3 mL) at 80 ° C for 16 hours. 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 110.4 (0.55 g, 1.75 mmol, 55% yield) as a light yellow viscous oil. LC-MS (ESI +): 316.040 (M + H + ).

[0311] Synthesis of (S)-2-(1,3-dioxoisoindolin-2-yl)-3-methylbutane-1-sulfonamide (I10.5)

[0312]

[0313] At room temperature, 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) in dichloromethane (15 mL) until no more precipitate formed. Upon completion, the reaction mixture was concentrated to dryness in vacuo, and the obtained 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 + ).

[0314] Synthesis of (S)-2-amino-3-methylbutane-1-sulfonamide (I10)

[0315]

[0316] 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, 110.5) in ethanol (8.5 mL). After stirring at reflux for 5 hours, the reaction mixture was filtered and washed with ethanol. The filtrate was concentrated in vacuo to dryness to give (S) -2-amino-3-methylbutane -1- sulfonamide 110.6 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 + ).

[0317] Synthesis of dimethyl ((1-methyl-1H-imidazol-4-yl)sulfonyl)dithioimidocarbonate (I11)

[0318]

[0319] To 1-methyl isophthalic acid H-imidazole-4-sulfonamide (0.47g, 2.9mmol, 1 equivalent) and carbon disulfide (0.29mL, 4.8mmol, 1.6 equivalents) in the DMF (10mL) that is dissolved in ice bath cooling, drip solution of potassium hydroxide (0.39g, 6.9mmol, 2.4 equivalents) in water (2mL), keep internal temperature lower than 10 ℃ simultaneously.After stirring at 0 ℃ for 1 hour, drip iodomethane (0.42mL, 6.8mmol, 2.3 equivalents), keep internal temperature lower than 10 ℃ simultaneously.After stirring 1 hour until room temperature, reactant is diluted with water (15mL) and extracted with ethyl acetate (30mL x2).Collected organic layer, through dried over magnesium sulfate, filter and vacuum concentration.Resistates is carried out purification through silica gel wash-out with methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) by flash chromatography. The desired fractions were collected and concentrated in vacuo to give the expected compound (65 mg, 0.25 mmol, 8% yield) as a white solid. LC-MS (ESI+): 265.9 (M+H + ).

[0320] Synthesis of dimethyl ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)dithioimidocarbonate (I12):

[0321] Synthesis of 4-(Benzylthio)-1H-1,2,3-triazole (I12.1)

[0322]

[0323] 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) at 0 ° C. over 5 minutes. After warming to room temperature and stirring for 1 hour, the solvent was removed under reduced pressure. The residue was diluted with a saturated solution of sodium bicarbonate (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 in vacuo to give the expected compound (7.7 g, 40.31 mmol, 99%) as a white solid. LC-MS (ESI+): 192.1 (M+H + ).

[0324] Synthesis of intermediate 4-(benzylthio)-2-isopropyl-2H-1,2,3-triazole (I12.2 to I12.4)

[0325]

[0326] At 0 ° C, 2-iodopropane (8.05 mL, 80.5 mmol, 2.0 equivalents) was added dropwise 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 equivalents). After warming to room temperature and stirring for more than 18 hours, the solvent was partially removed. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2x50 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil, which was purified by flash chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) to give the corresponding triazole regioisomer as a colorless oil.

[0327] 4-(Benzylthio)-2-isopropyl-2H-1,2,3-triazole (I12.2) -5.36g, 57%. LC-MS (ESI+): 234.1 (M+H + ); 1H NMR (400MHz, DMSO-d6, 25°C): δ = 7.65 (s, 1H), 7.19-7.29 (m, 5H), 4.69-4.81 (m, 1H), 4.16 (s, 2H), 1.43ppm (d, J = 6.7Hz, 6H).

[0328] 5-(Benzylthio)-1-isopropyl-1H-1,2,3-triazole (I12.3) -1.04 g, 11%. LC-MS (ESI+): 234.1 (M+H + ); 1H NMR (400MHz, DMSO-d6, 25℃): δ=7.76 (s, 1H), 7.21-7.30 (m, 3H), 7.17 (dd, J=7. 7, 1.4Hz, 2H), 4.59 (spt, J = 6.7Hz, 1H), 4.10 (s, 2H), 1.28ppm (d, J = 6.8Hz, 6H).

[0329] 4-(Benzylthio)-1-isopropyl-1H-1,2,3-triazole (I12.4) -1.95 g, 21%. LC-MS (ESI+): 234.1 (M+H +); 1H NMR (400MHz, DMSO-d6, 25℃): δ = 8.07 (s, 1H), 7.18-7.28 (m, 5H), 4.75 (spt, J = 6.7Hz, 1H), 4.09-4.12 (m, 2H), 1.43ppm (d, J = 6.8Hz, 6H).

[0330] Synthesis of 2-isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride (I12.5)

[0331]

[0332] At 0 ° C, to a solution of 4- (benzylthio) -2-isopropyl -2H-1,2,3-triazole (5.36 g, 23.0 mmol, 112.5) in a mixture of AcOH / H2O (46 / 23 mL) was added N-chlorosuccinimide (12.3 g, 91.9 mmol, 4.0 equivalents). After stirring at room temperature for 18 hours, 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 in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) to give the expected sulfonyl chloride (4.1 g, 19.6 mmol, 85%) as a colorless oil. LC-MS (ESI +): 210.0 (M + H + ).

[0333] Synthesis of 2-isopropyl-2H-1,2,3-triazole-4-sulfonamide (I12.6)

[0334]

[0335] At room temperature, 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) in dichloromethane (100 mL) for 10 minutes. Upon completion, the solvent was removed under reduced pressure, and the resulting slurry was ground with ethyl acetate. The precipitate was removed by filtration through a pad of celite, and the filtrate was concentrated in vacuo to give sulfonamide (4.2 g, 22.1 mmol, 98% yield) as a yellow oil which was used in the next step without further purification. LC-MS (ESI+): 191.1 (M+H + ).

[0336] Synthesis of dimethyl ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)dithioimidocarbonate (I12)

[0337]

[0338] To a solution of 2-isopropyl-2H-1,2,3-triazole-4-sulfonamide (4.2 g, 22.1 mmol, 112.6) 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) 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 for 2 hours until room temperature, 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 in vacuo. The residue was purified by flash chromatography using ethyl acetate / heptane mixtures (0 / 100 to 30 / 70, v / v) to give the expected compound (2.9 g, 9.86 mmol, 45% yield) as a white solid. LC-MS (ESI+): 295.0 (M+H + ).

[0339] Synthesis of dimethyl ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)dithioimidocarbonate (I13)

[0340]

[0341] Synthesis of 113.1, 113.2 and 113.3.

[0342] At 0 ° C, 2-iodomethane (5.04 mL, 81.0 mmol, 2.0 equivalents) was added dropwise to a solution of 4- (benzylthio) -1H-1,2,3-triazole (7.75 g, 40.5 mmol, 113.0) in dimethylformamide (80 mL) containing potassium carbonate (12.3 g, 89.1 mmol, 2.2 equivalents) and added to the mixture at 0 ° C. After stirring at room temperature for 18 hours, the solvent was partially removed. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2x50 mL). The organic phase was collected, dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil, which was purified by flash chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) to give the corresponding triazole regioisomer as a colorless oil.

[0343] 4-(Benzylthio)-2-methyl-2H-1,2,3-triazole (I13.1)—3.02 g, 36%. 1H NMR (400MHz, DMSO-d6, 25℃): 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).

[0344] 5-(Benzylthio)-1-methyl-1H-1,2,3-triazole (I13.2) - 1.04 g, 11%. 1 H NMR (400MHz, 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).

[0345] 4-(Benzylthio)-1-methyl-1H-1,2,3-triazole (I13.3) - 1.95 g, 21%. 1 H NMR (400MHz, 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).

[0346] Synthesis of 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (I13.4)

[0347]

[0348] 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) at 0 ° C., N-chlorosuccinimide (7.8 g, 58.8 mmol, 4.0 equiv.) was added. After stirring at room temperature for 18 hours, 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 in vacuo to give the expected sulfonyl chloride (2.5 g, 13.8 mmol, 95%) as a colorless oil that was used without further purification. LC-MS (ESI+): 182.1 (M+H+ ).

[0349] Synthesis of 2-methyl-2H-1,2,3-triazole-4-sulfonamide (I13.5)

[0350]

[0351] At room temperature, 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) in dichloromethane (100 mL) for 10 minutes. Upon completion, the solvent was removed under reduced pressure, and the resulting slurry was ground with ethyl acetate. The precipitate was removed by filtration through a pad of celite, and the filtrate was concentrated in vacuo to give sulfonamide (2.2 g, 13.6 mmol, 97% yield) as a yellow oil which was used in the next step without further purification. LC-MS (ESI+): 163.0 (M+H + ).

[0352] Dimethyl ((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)dithioimidocarbonate (I13)

[0353]

[0354] To a solution of 2-methyl-2H-1,2,3-triazole-4-sulfonamide (2.2 g, 13.7 mmol, 113.5) 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 while 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 while maintaining the internal temperature below 10 ° C. After stirring for 2 hours until room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate / heptane mixtures (0 / 100 to 30 / 70, v / v) to give the expected compound (1.17 g, 4.4 mmol, 32% yield) as a light yellow viscous oil. LC-MS (ESI+): 267.0 (M+H + ).

[0355] Synthesis of the intermediate ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)dimethyl dithioimidocarbonate (I14)

[0356] 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)

[0357]

[0358] At 0 ° C, 5- (benzylthio) -1- isopropyl -1H-1,2,3- triazole (1.04g, 4.5mmol, 112.3) in acetic acid (8mL) and water (4mL) solution was added N- chlorosuccinimide (2.4g, 17.8mmol, 4.0 equivalents). After stirring at room temperature for 18 hours, the reaction mixture was diluted with water (10mL) and extracted with ethyl acetate (30mL). The organic phase was washed with saturated sodium bicarbonate solution (25mL) and brine (25mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v) to give the expected sulfonyl chloride (0.62g, 2.9mmol, 67%) as a white solid. LC-MS (ESI+): 210.0 (M+H + ).

[0359] Synthesis of 1-isopropyl-1H-1,2,3-triazole-5-sulfonamide (I14.2)

[0360]

[0361] At room temperature, 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) for 10 minutes. Upon completion, the solvent was removed under reduced pressure, and the resulting slurry was ground with ethyl acetate. The precipitate was removed by filtration through a pad of celite, and the filtrate was concentrated in vacuo to give sulfonamide (0.55 g, 2.89 mmol, 97% yield) as a yellow oil which was used in the next step without further purification. LC-MS (ESI+): 191.0 (M+H + ).

[0362] Synthesis of dimethyl ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)dithioimidocarbonate (I14)

[0363]

[0364] To a solution of 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) 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 for 2 hours until room temperature, 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 in vacuo. The residue was purified by flash chromatography using ethyl acetate / heptane mixtures (0 / 100 to 30 / 70, v / v) to give the expected compound (0.29 g, 0.97 mmol, 34% yield) as a colorless oil. LC-MS (ESI+): 295.0 (M+H + ).

[0365] Synthesis of methyl ((1-methyl-1H-pyrazol-4-yl)sulfonyl)carbamate (I15)

[0366]

[0367] 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 chloroformate (230.67 μL, 2.98 mmol, 1.6 equiv) at 0 ° C. After stirring at room temperature for 12 hours, 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 solution (1 N) 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) + .

[0368] Synthesis of 3-amino-2-methylpropane-1-sulfonamide (I16)

[0369] Synthesis of benzyl (3-hydroxy-2-methylpropyl)carbamate (16.1)

[0370]

[0371] 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 hour, 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane (0 / 100 to 100 / 0, v / v). The desired fractions were collected and concentrated in vacuo to give the expected compound (0.6 g, 6% yield) as a colorless oil. LC-MS (ESI+): 224.1 (M+H + ).

[0372] Synthesis of 3-(((Benzyloxy)carbonyl)amino)-2-methylpropyl methanesulfonate (I16.2)

[0373]

[0374] 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) at 0 ° C., methanesulfonyl chloride (0.2 mL, 2.6 mmol, 1.05 equiv) was added. After stirring at room temperature for 1 hour, 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 in vacuo to give the desired product (0.73 g, 97% yield) as a colorless oil. LC-MS (ESI+): 302.7 (M+H + ).

[0375] Synthesis of S-(3-(((Benzyloxy)carbonyl)amino)-2-methylpropyl)ethanethiolate (I16.3)

[0376]

[0377] 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, 116.2) in dimethylformamide (9 mL). After stirring at room temperature for 18 hours, 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 magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 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 (0.49 g, 71% yield) as a yellow oil. LC-MS (ESI+): 281.9 (M+H + ).

[0378] Synthesis of benzyl (2-methyl-3-sulfamoylpropyl)carbamate (I16.4)

[0379]

[0380] To a solution of N-chlorosuccinimide (0.93 g, 7.0 mmol, 4.0 equiv) and 2M hydrochloric acid solution (1.02 mL, 2.04 mmol, 1.2 equiv) in acetonitrile (29 mL) was added dropwise a solution of S-(3-(((benzyloxy)carbonyl)amino)-2-methylpropyl)ethanethiolate (0.49 g, 1.7 mmol, 116.3) in acetonitrile (29 mL) at 0°C. After stirring at room temperature for 1 hour, 25% aqueous ammonia (29 mL) was added. After stirring at room temperature for 2 hours, 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 in vacuo. 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 in vacuo to give the expected compound (0.45 g, 90% yield) as a white solid. LC-MS (ESI+): 286.9 (M+H + ).

[0381] Synthesis of 3-amino-2-methylpropane-1-sulfonamide (I16)

[0382]

[0383] To a solution of benzyl (2-methyl-3-sulfamoylpropyl)carbamate (0.5 g, 1.7 mmol, 116.4) 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 in vacuo and saturated with hydrogen (repeated 3 times). After stirring at room temperature for 4 hours under a hydrogen atmosphere, the suspension was filtered through a pad of celite and concentrated under reduced pressure to give the desired amine (0.185 g, 70% yield) as a brown solid. LC-MS (ESI+): 153.0 (M+H + ).

[0384] Synthesis of 4-aminobutane-2-sulfonamide (I17)

[0385] Synthesis of 3-(Benzyloxy)butyronitrile (I17.1)

[0386]

[0387] Under nitrogen atmosphere, benzyl alcohol (3.62 g, 33.45 mmol, 1.0 equiv) and but-3-enenitrile (2.74 mL, 33.45 mmol, 1.0 equiv) were added to potassium tert-butoxide (0.04 g, 0.335 mmol, 0.01 equiv). After stirring at room temperature for 16 hours, the mixture was neutralized, subjected to aqueous workup, dried, filtered, and concentrated. The residue was purified on silica gel using ethyl acetate / heptane mixture (0 / 100 to 40 / 60, v / v) to give the desired product (3.56 g, 20.3 mmol, 61% yield) as a colorless oil. LC-MS (ESI+): 176.2 (M+H + ).

[0388] Synthesis of intermediate 3-(benzyloxy)butan-1-amine (I17.2)

[0389]

[0390] A solution of 3-(benzyloxy)butanenitrile (3.24 g, 18.5 mmol, 117.1) and platinum (IV) oxide (0.21 g, 0.92 mmol, 0.05 equiv) in ethanol (185 mL) was vacuum degassed and saturated with hydrogen (repeated 3 times). After stirring at room temperature for 72 hours under a hydrogen atmosphere, the suspension was filtered through a pad of celite and concentrated under reduced pressure to give the desired amine (3.3 g, 22.1 mmol, quantitative yield) as a colorless oil. LC-MS (ESI+): 180.3 (M+H + ).

[0391] Synthesis of 2-(3-(Benzyloxy)butyl)isoindoline-1,3-dione (I17.3)

[0392]

[0393] Phthalic anhydride (3.3 g, 22.1 mmol, 1.1 equivalents) and 3- (benzyloxy) butan-1-amine (3.6 g, 20.1 mmol, 117.2) were dissolved in acetic acid. After stirring at reflux for 16 hours, the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 20 / 80, v / v). The desired fractions were collected and concentrated under reduced pressure to give the expected product (3.05 g, 9.8 mmol, 49% yield) as a colorless oil. LC-MS (ESI+): 309.9 (M+H + ).

[0394] Synthesis of 2-(3-hydroxybutyl)isoindoline-1,3-dione (I17.4)

[0395]

[0396] A solution of 2-(3-(benzyloxy)butyl)isoindoline-1,3-dione (3.05 g, 9.8 mmol, 117.3) and palladium on carbon (10 wt%) (1.0 g, 0.98 mmol, 0.1 eq) in ethanol (100 mL) was vacuum degassed and then saturated with hydrogen, 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 desired alcohol (2.1 g, 9.7 mmol, quantitative yield) as a brown solid. LC-MS (ESI+): 219.9 (M+H + ).

[0397] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butan-2-yl methanesulfonate (I17.5)

[0398]

[0399] At 0 ° C, to a mixture of 2- (3-hydroxybutyl) isoindoline -1,3-dione (2.1 g, 9.7 mmol, 117.4) 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). After stirring at room temperature for 1 hour, 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 in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give the expected compound (1.3 g, 4.37 mmol, 45% yield) as a colorless oil. LC-MS (ESI+): 297.9 (M+H + ).

[0400] Synthesis of S-(4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)ethanethiol salt (I17.6)

[0401]

[0402] Potassium thioacetate (2.5 g, 21.9 mmol, 5.0 equivalents) is added to a solution of 4- (1,3- dioxoisoindolin-2-yl) butan-2-yl methanesulfonate (1.3 g, 4.37 mmol, 117.5) in dimethylformamide (15 mL). After stirring at room temperature for 18 hours, the solvent is partially removed under reduced pressure. The residue is diluted with ethyl acetate (40 mL) and washed with water (30 mL) and brine (30 mL). The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is eluted with ethyl acetate / heptane mixture (0 / 100 to 70 / 30, v / v) on silica gel for chromatographic separation. The desired fractions are collected and concentrated under reduced pressure to give the expected compound (0.94 g, 3.4 mmol, 77% yield) as a yellow oil. LC-MS (ESI+): 277.9 (M+H + ).

[0403] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonic acid (I17.7)

[0404]

[0405] To a solution of S-(4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)ethanethiolate (0.94 g, 3.4 mmol, 117.6) in acetic acid (4 mL) was added a mixture of hydrogen peroxide (30% w / w aqueous solution) (4 mL) in acetic acid (8 mL). After stirring at room temperature for 16 hours, palladium / carbon (10% weight, 50% wet) was added to destroy excess peroxide. The resulting suspension was filtered through a pad of celite and concentrated in vacuo. The residue was co-evaporated with toluene (x3) and concentrated to dryness under reduced pressure to give a brown solid (0.82 g, 2.9 mmol, 85% yield) which was used in the next step without further purification. LC-MS (ESI +): 283.8 (M + H + ).

[0406] Synthesis of (1,3-dioxoisoindolin-2-yl)butane-2-sulfonyl chloride (I17.8)

[0407]

[0408] A solution of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonic acid (0.82 g, 2.9 mmol, 117.7) in thionyl chloride (10 mL) was refluxed at 80 ° C for 16 hours. Upon completion, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v). The desired fractions were collected and concentrated in vacuo to give the expected compound (0.38 g, 1.25 mmol, 43% yield) as a colorless oil. LC-MS (ESI+): 301.8 (M+H + ).

[0409] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonamide (I17.9)

[0410]

[0411] A solution of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonyl chloride (0.38 g, 1.25 mmol, 117.8 g) in tetrahydrofuran (5 mL) was bubbled with ammonia for 10 minutes. Upon completion, the reaction mixture was filtered and concentrated in vacuo to afford the desired sulfonamide (0.35 g, 1.24 mmol, quantitative yield) as a white solid. LC-MS (ESI+): 282.9 (M+H + ).

[0412] Synthesis of 4-aminobutane-2-sulfonamide (I17)

[0413]

[0414] To a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-2-sulfonamide (0.35 g, 1.24 mmol, 117.9) 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 hours, the reaction was cooled and diluted with cold ethanol (10 mL). The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give a white solid (0.19 g, 1.25 mmol, quantitative yield) that was used in the next step without further purification. LC-MS (ESI+): 153.0 (M+H + ).

[0415] Synthesis of 4-aminobutane-1-sulfonamide (I18)

[0416] Synthesis of S-(4-(1,3-dioxoisoindolin-2-yl)butyl)ethanethiol salt (I18.1)

[0417]

[0418] Potassium thioacetate (12.1 g, 106.3 mmol, 3.0 equivalents) was added to a stirred solution of N-(4-bromobutyl)phthalimide (10 g, 35.4 mmol, 1.0 equivalents) in tetrahydrofuran (350 mL). After stirring at 85 ° C for 5 hours, 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 magnesium sulfate, filtered and concentrated in vacuo. The residue was eluted with ethyl acetate / heptane mixture (0 / 100 to 30 / 70, v / v) for silica gel chromatography to obtain the expected product (7.3 g, 26.3 mmol, 74% yield) as a pink solid. LC-MS (ESI+): 278.0 (M+H + ).

[0419] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonic acid (I18.2)

[0420]

[0421] A mixture of hydrogen peroxide (30% w / w aqueous solution) (23 mL) and acetic acid (46 mL) was added to a solution of S-(4-(1,3-dioxoisoindolin-2-yl)butyl)ethanethiolate (7.3 g, 26.3 mmol, 1.0 equiv) in acetic acid (23 mL). After stirring at room temperature for 16 hours, palladium on carbon (10 wt %) was added to destroy excess peroxide. The resulting mixture was filtered through a pad of celite and concentrated under reduced pressure. The oily residue was evaporated with toluene (x2) and then concentrated in vacuo to dryness to give a beige solid (7.1 g, 25.1 mmol, 96% yield) which was used in the next step without further purification. LC-MS (ESI+): 284.0 (M+H + ).

[0422] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonyl chloride (I18.3)

[0423]

[0424] To a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonic acid (7.18 g, 25.3 mmol, 118.2) in thionyl chloride (25 mL) was added dimethylformamide (1 mL). After stirring at 80 ° C for 16 hours, 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 magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 40 / 60, v / v) to give the expected sulfonyl chloride (5.22 g, 17.3 mmol, 68% yield) as a beige solid. LC-MS (ESI+): 302.1 (M+H + ).

[0425] Synthesis of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonamide (I18.4)

[0426]

[0427] Ammonia gas was bubbled through a solution of 4-(1,3-dioxoisoindolin-2-yl)butane-1-sulfonyl chloride (5.22 g, 17.3 mmol, 118.3) in tetrahydrofuran (100 mL) for 10-15 minutes. Upon completion, the reaction mixture was filtered through a pad of celite, washed with more tetrahydrofuran (35 mL) and concentrated in vacuo to afford a beige solid (4.80 g, 17.0 mmol, 98% yield) which was used in the next step without further purification. LC-MS (ESI+): 283.0 (M+H + ).

[0428] Synthesis of 4-aminobutane-1-sulfonamide (I18)

[0429]

[0430] 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 hours, the reaction mixture was cooled and diluted with cold ethanol (50 mL). The filtrate was concentrated under reduced pressure to give the expected compound (2.2 g, 14.5 mmol, 85% yield) as a white solid which was used in the next step without further purification. LC-MS (ESI+): 153.1 (M+H + ).

[0431] Synthesis of Intermediate 3-(4-chlorophenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole (I19)

[0432]

[0433] Synthesis of intermediate (I19.1)

[0434] A mixture of I19.0 (15 g, 76.27 mmol, 1 eq), dimethylamine hydrochloride (24.88 g, 305.08 mmol, 4 eq), acetic acid (1.96 mL, 34.32 mmol, 0.45 eq) and formaldehyde (5.25 mL, 190.67 mmol, 2.5 eq). After stirring at 80 ° C for 18 hours, the mixture was treated with dimethylformamide (20 mL) and heated to 120 ° C. After stirring at 120 ° C for 2 hours in a microwave reactor, the mixture was cooled to room temperature, quenched with saturated NH4Cl (100 mL aqueous solution), and extracted with dichloromethane (50 mL × 3). The combined organic phases were 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) +1 H NMR: 400MHz, CDCl3δppm 1.05(d,J=6.79Hz,6H),2.95(quin,J=6.91Hz,1H),5.38(s,11H),5.66(d,J=1.31Hz,1H),7.34(d,J=8.58Hz,2H),7.59-7.70(m,2H).

[0435] Synthesis of intermediate I19

[0436] To a solution of I19.1 (3 g, 14.38 mmol, 1 eq) in ethanol (30 mL) was added hydrazine monohydrate (3.49 mL, 71.88 mmol, 5 eq) 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 afford I19 (1 g, 4.04 mmol, 28%) as a white solid. LCMS (ESI+): m / z 223.1 (M+H) +1 H NMR: 400MHz, DMSO-d6δppm 0.66(d,J=6.79Hz,3H),0.92(d,J=6.91Hz,3H),1.96(td,J=6.85,3.58Hz,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).

[0437] Example 2. Synthesis of compounds

[0438] 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)

[0439]

[0440] To a solution of (S)-2-aminopropane-1-sulfonamide (105 mg, 0.76 mmol, 1.5 equiv, 11) 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-carboximidoyl chloride (250 mg, 0.51 mmol, 1.0, CAS No. 1148142-85-1). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (25 mL) and washed with aqueous HCl (2N, 20 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) to give a colorless oil (a mixture of two diastereomers). A second chromatography was performed using a slow gradient of acetic acid / heptane mixture (0 / 100 to 70 / 30, v / v) to separate the diastereomers, yielding two fractions.

[0441] Compound 1: (26.1 mg, 0.044 mmol, 9% yield, 97% purity, 94% de, OR: -35.4). 1 H NMR(DMSO-d6,400MHz)δ7.98(br s,1H),7.8-7.9(m,2H),7.72(d,J=8.6Hz,2H),7.5-7.6(m,2H),7.45(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,3H),6.93(br s,2H),5.10(dd,J=4.4,11.2Hz,1H),4.53(t,J=11.2Hz,1H),4.40(br s,1H),4.13(br dd,J=3.9,11.0Hz,1H),3.4(m,1H),3.22(dd,J=6.3,14.1Hz,1H),1.28(d,J=6.7Hz,3H).LC-MS(ESI+):594.0(M+H + ).

[0442] Compound 2: (46.7 mg, 0.08 mol, 16% yield, 99% purity, 99% ee, OR: +116.8). 1H NMR(DMSO-d6,400MHz)δ7.96(br d,J=8.3Hz,1H),7.8-7.9(m,2H),7.74(d,J=8.7Hz,2H),7.5-7.6(m,2H),7.45(d,J=8.6Hz,2H),7.3-7.4(m,2H ),7.2-7.3(m,3H),6.95(s,2H),5.09(dd,J=4.3,11.2Hz,1H),4.58(t,J=11.3Hz,1H),4.3-4.5(m,1H),4.08(br dd,J=4.2,11.2Hz,1H),3.44(dd,J=6.3,14.1Hz,1H),3.24(dd,J=6.1,14.1Hz,1H),1.26(d,J=6.7Hz,3H).LC-MS(ESI+):594.0(M+H + ).

[0443] (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)

[0444]

[0445] 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-carboximidoyl 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 flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 80 / 20, v / v) to give a colorless oil, which was further separated by SFC to give the following two different diastereomers.

[0446] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0447] Compound 3: (32.0 mg, 0.05 mmol, 9% yield, 99% purity, 99% ee, OR: -79.1). 1 H NMR(DMSO-d6,400MHz)δ7.96(br d,J=1.1Hz,1H),7.8-7.9(m,2H),7.74(d,J=8.6Hz,2H),7.5-7.6(m,2H),7.45(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,3H),6.96(br s,2H),5.09(dd,J=4.3,11.2Hz,1H),4.58(t,J=11.2Hz,1H),4.41(br s,1H),4.09(br dd,J=4.1,11.1Hz,1H),3.44(dd,J=6.3,14.1Hz,1H),3.25(dd,J=6.1,14.1Hz,1H),1.26(d,J=6.7Hz,3H).LC-MS(ESI+):596.1(M+H + ).

[0448] Compound 4: (28.1 mg, 0.05 mol, 8% yield, 99% purity, 99% ee, OR: +48.4). 1H NMR(DMSO-d6,400MHz)δ7.98(br d,J=7.8Hz,1H),7.82(d,J=8.6Hz,2H),7.72(d,J=8.6Hz,2H),7.53(d,J=8.6Hz,2H),7.45(d,J=8.7Hz,2H) ,7.33(s,2H),7.2-7.3(m,3H),6.93(s,2H),5.10(dd,J=4.2,11.1Hz,1H),4.53(t,J=11.2Hz,1H),4.40(br d,J=4.0Hz,1H),4.13(br dd,J=3.5,11.0Hz,1H),3.37(br d,J=6.3Hz,1H),3.2(m,1H),1.28(d,J=6.6Hz,3H).LC-MS(ESI+):596.0(M+H + ).

[0449] (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), ( 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)

[0450]

[0451] To 1-aminopropane-2-sulfonamide hydrochloride (0.18g, 1.02mmol, 1.5 equivalents) and triethylamine (0.28mL, 2.05mmol, 3.0 equivalents) in a stirred solution of dichloromethane (3.5mL) was added (E) -3- (4- chlorophenyl) -N- ((4- chlorophenyl) sulfonyl) -4- phenyl -4,5- dihydro -1H- pyrazole -1- carbonimido chloride (0.34g, 0.68mmol, 1.0). After stirring at room temperature for 18 hours, the reactant was diluted with dichloromethane (20mL) and washed with ammonium chloride (15mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a heptane / ethyl acetate mixture (100 / 0 to 60 / 40, v / v) to obtain a colorless oil in the form of a mixture, which was further separated by SFC to obtain four isomers.

[0452] 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 with 2.5 mL / min of CO2 (60%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0453] Compound 5: (16.1 mg, 0.03 mmol, 4% yield, 99% purity, 99% ee, OR: -63.0). 1 H NMR(CDCl3,400MHz)δ7.85(br d,J=8.3Hz,2H),7.66(br s,1H),7.53(br d,J=8.3Hz,2H),7.39(br d,J=8.3Hz,2H),7.3-7.4(m,3H),7.25(s,2H),7.12(br d,J=7.0Hz,2H),4.95(br s,2H),4.70(br dd,J=4.4,10.2Hz,1H),4.53(br t,J=11.2Hz,1H),3.9-4.1(m,3H),3.51(br s,1H),1.46(br d,J=6.2Hz,3H).LC-MS(ESI+):594.1(M+H + ).

[0454] Compound 6: (27.0 mg, 0.045 mmol, 7% yield, 99% purity, 99% ee, OR: -97.8).1 H NMR(DMSO-d6,400MHz)δ8.13(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=7.1Hz,1H),4.55(br t,J=11.0Hz,1H),4.13(br d,J=7.2Hz,1H),3.70(br d,J=12.5Hz,1H),3.56(br d,J=6.4Hz,1H),2.8-3.0(m,1H),1.17(br d,J=6.5Hz,3H).LC-MS(ESI+):594.0(M+H + ).

[0455] Compound 7: (52.1 mg, 0.09 mmol, 13% yield, 98% purity, 99% ee, OR: +111.1). 1 H NMR(DMSO-d6,400MHz)δ8.1-8.2(m,1H),7.83(d,J=8.6Hz,2H),7.74(d,J=8.6Hz,2H),7.54( d,J=8.5Hz,2H),7.47(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,3H),6.98(s,2H),5.11( dd,J=4.3,11.2Hz,1H),4.58(t,J=11.2Hz,1H),4.08(dd,J=4.2,11.1Hz,1H),3.7(m,1H),3. 57(td,J=6.8,13.9Hz,1H),3.2-3.3(m,1H),1.18(d,J=7.0Hz,3H).LC-MS(ESI+):594.0(M+H + ).

[0456] Compound 8: (55.2 mg, 0.093 mmol, 14% yield, 99% purity, 99% ee, OR: +102.2). 1H NMR(DMSO-d6,400MHz)δ8.07(br s,1H),7.7-7.8(m,2H),7.66(d,J=8.7Hz,2H),7.5(m,2H),7.39(d,J=8.7Hz,2H),7.2-7.3(m ,2H),7.2(m,3H),6.92(s,2H),5.04(dd,J=4.4,11.2Hz,1H),4.48(t,J=11.1Hz,1H),4.07(br dd,J=4.2,11.0Hz,1H),3.63(br d,J=13.3Hz,1H),3.4-3.5(m,1H),3.2(m,1H),1.10(d,J=6.9Hz,3H).LC-MS(ESI+):594.0(M+H + ).

[0457] 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)

[0458]

[0459] 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) at room temperature was added (Z)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidyl chloride (0.25 g, 0.47 mmol, 9.0, CAS No. 2561196-52-7). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (20 mL) and washed with HCl (2N, 15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to give a colorless oil.The racemic mixture was further subjected to SFC separation conditions.

[0460] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Cellulose-4) 100 mm long x 4.6 mm ID 3 μm particle size in isocratic mode with 2.5 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0461] Compound 9: (54.1 mg, 0.09 mmol, 19% yield, 98% purity, 99% ee). 1 H NMR (400MHz, DMSO) δ8.23(s,1H),8.03(d,J=8.2Hz,2H),7.84(d,J=8.3Hz,2H),7.70(d ,J=8.3Hz,2H),7.44(d,J=8.6Hz,2H),7.33(t,J=7.3Hz,2H),7.25(ddd,J=11.6,6.7,4. 1Hz,3H),7.02(s,2H),5.09(dd,J=11.0,4.1Hz,1H),4.54(t,J=11.1Hz,1H),4.05(dd, J=11.0,4.2Hz,1H),3.73(t,J=6.6Hz,2H),3.35–3.20(m,2H).LC-MS(ESI+):614.0(M+H + ).

[0462] Compound 10: (57.8 mg, 0.09 mmol, 20% yield, 99% purity, 99% ee). 1 H NMR (400MHz, DMSO) δ8.23(s,1H),8.03(d,J=8.2Hz,2H),7.84(d,J=8.3Hz,2H),7.70(d ,J=8.6Hz,2H),7.45(d,J=8.7Hz,2H),7.33(t,J=7.3Hz,2H),7.25(ddd,J=11.4,6.7,4. 1Hz,3H),7.02(s,2H),5.10(dd,J=11.1,4.3Hz,1H),4.54(t,J=11.1Hz,1H),4.05(dd, J=10.9,4.1Hz,1H),3.73(t,J=6.7Hz,2H),3.30–3.23(m,2H).LC-MS(ESI+):614.0(M+H + ).

[0463] 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)

[0464] Synthesis of compound 11.1

[0465]

[0466] 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, CAS# 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 in vacuo to give a brown foam (0.73 g, 1.54 mmol, 78% yield). LC-MS (ESI+): 476.040 (M+H + ).

[0467] Synthesis of compounds 11 and 12

[0468]

[0469] To a stirred solution of 2-aminoethane-1-sulfonamide hydrochloride (0.1 g, 0.63 mmol, 1.5 equivalents) and triethylamine (0.2 mL, 1.4 mmol, 3.0 equivalents) in dichloromethane (4 mL) was added (E)-3-(4-chlorophenyl)-N-((4-fluorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonimidoyl chloride (0.2 g, 0.42 mmol, 11.1). After stirring at room temperature for 18 hours, the reactant was diluted with dichloromethane (20 mL) and washed with aqueous ammonium chloride (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50, v / v) to give a colorless oil in the form of a racemic mixture, which was further subjected to SFC separation conditions:

[0470] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 2.5 ml / min of CO2 (60%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0471] Compound 11: (21.4 mg, 0.04 mmol, 9% yield, 99% purity, 99% ee, OR: -114.8). 1 H NMR (400MHz, CDCl3) δ7.92(dd,J=5.1,8.8Hz,2H),7.65(br s,1H),7.52(d,J=8.6Hz,2H),7.3(m,3H),7.2(m,2H),7.1(m,4H),5.37(br s,2H),4.67(dd,J=5.3,11.3Hz,1H),4.53(t,J=11.5Hz,1H),4.18(q,J=5.9Hz,2H),4.05(dd,J=5.4,11.5Hz,1H),3.54(br t,J=5.8Hz,2H).LC-MS(ESI+):564.0(M+H + ).

[0472] Compound 12: (19.8 mg, 0.035 mmol, 8% yield, 97% purity, 99% ee, OR: +85.1). 1 H NMR (400MHz, CDCl3) δ7.93(dd,J=5.1,8.8Hz,2H),7.62(br s,1H),7.53(d,J=8.5Hz,2H),7.4(m,3H),7.3(m,2H),7.1(m,4H),5.14(br s,2H),4.70(dd,J=5.3,11.3Hz,1H),4.55(t,J=11.4Hz,1H),4.20(q,J=5.8Hz,2H),4.07(dd,J=5.3,11.5Hz,1H),3.54(br t,J=5.8Hz,2H).LC-MS(ESI+):564.1(M+H + ).

[0473] (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), ( 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)

[0474]

[0475] 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-carbonimidoyl chloride (0.38 g, 0.8 mmol, 11.1). After stirring at room temperature for 18 hours, the reactant was diluted with dichloromethane (20 mL) and washed with aqueous ammonium chloride (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a heptane / ethyl acetate mixture (100 / 0 to 60 / 40, v / v) to give a colorless oil in the form of a racemic mixture, which was further subjected to SFC separation conditions.

[0476] 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 with 2.5 ml / min of CO2 (60%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0477] Compound 13: (14.3 mg, 0.025 mmol, 3% yield, 97% purity, 99% ee, OR: -99.2).1 H NMR (400MHz, CDCl3) δ7.9(m,2H),7.62(br t,J=6.0Hz,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=5.4,11.4Hz,1H),4.5(m,1H),4.1(m,3H),3.5(m,1H),1.47(d,J=7.1Hz,3H).LC-MS(ESI+):578.1(M+H + ).

[0478] Compound 14: (12.5 mg, 0.022 mmol, 3% yield, 96% purity, 99% ee, OR: -120.8). 1 H NMR (400MHz, CDCl3) δ7.9(m,2H),7.62(br t,J=6.0Hz,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=5.4,11.4Hz,1H),4.54(t,J=11.5Hz,1H),3.9-4.1(m,3H),3.5(m,1H),1.46(d,J=7.0Hz,3H).LC-MS(ESI+):578.1(M+H) + ).

[0479] Compound 15: (7.7 mg, 0.013 mmol, 2% yield, 99% purity, 99% ee, OR: +87.05). 1 H NMR (400MHz, CDCl3) δ7.95(m,2H),7.62(br t,J=6.0Hz,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=5.3,11.4Hz,1H),4.55(m,1H),3.9-4.1(m,3H),3.51(dt,J=4.0,7.2Hz,1H),1.47(d,J=7.0Hz,3H).LC-MS(ESI+):578.1(M+H) + ).

[0480] Compound 16: (9.7 mg, 0.017 mmol, 2% yield, 99% purity, 99% ee, OR: +77.4). 1H NMR (400MHz, CDCl3) δ7.95(m,2H),7.61(br t,J=6.0Hz,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=5.4,11.4Hz,1H),4.54(t,J=11.5Hz,1H),3.9-4.2(m,3H), 3.51(dt,J=4.1,7.2Hz,1H),1.47(d,J=7.1Hz,3H,).LC-MS(ESI+):578.1(M+H + ).

[0481] (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), ( 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)

[0482]

[0483] 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) at room temperature was added (E)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (0.23 g, 0.43 mmol, 9.0 equiv). 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 magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with heptane / ethyl acetate mixtures (100 / 0 to 60 / 40, v / v) to give a colorless oil as a racemic mixture, which was further subjected to SFC separation conditions.

[0484] 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 with 2.5 ml / min of CO2 (60%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0485] Compound 17: (22.1 mg, 0.035 mmol, 8% yield, 95% purity, 99% ee, OR: -96.0). 1 H NMR(400MHz, CDCl3)δ8.04(d,J=8.2Hz,2H),7.63-7.73(m,3H),7.54(d,J=8 .6Hz,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=11.4,5.4Hz,1H),4.54(t,J=11.5Hz,1H),3.93-4.14(m,3 H),3.46-3.57(m,1H),1.47ppm(d,J=7.0Hz,3H).LC-MS(ESI+):628.1127(M+H + ).

[0486] Compound 18: (14.3 mg, 0.022 mmol, 5% yield, 99% purity, 99% ee, OR: -90.7). 1 H NMR(400MHz, CDCl3)δ8.04(d,J=8.1Hz,2H),7.63-7.73(m,3H),7.51-7.58(m,2 H),7.27-7.36(m,3H),7.23-7.27(m,2H),7.12(dd,J=7.9,1.3Hz,2H),4.88(br s,2H),4.70(dd,J=11.3,5.4Hz,1H),4.52(t,J=11.5Hz,1H),4.04-4.13(m,2H),3.93 -4.03(m,1H),3.45-3.56(m,1H),1.47ppm(d,J=7.0Hz,3H).LC-MS(ESI+):628.0(M+H + ).

[0487] Compound 19: (25.8 mg, 0.04 mmol, 10% yield, 99% purity, 99% ee, OR: +81.8). 1 H NMR (400MHz, CDCl3) δ8.04 (d, J = 8.1Hz, 2H), 7.68 (br d,J=8.3Hz,3H),7.54(d,J=8.7Hz,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=11.4,5.5Hz,1H),4.52(t,J=11.5Hz,1H),4.04-4.13(m,2H),3.92 -4.02(m,1H),3.46-3.55(m,1H),1.46ppm(d,J=7.0Hz,3H).LC-MS(ESI+):628.0(M+H + ).

[0488] Compound 20: (17.7 mg, 0.03 mmol, 7% yield, 99% purity, 99% ee, OR: +102.7). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=8.1Hz,2H),7.68(d,J=8.2Hz,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=5.3,11.3Hz,1H),4.54(t,J=11.5Hz,1H),3.9-4.1(m,3H),3.5(m,1H),1.48(d,J=7.0Hz,3H).LC-MS(ESI+):628.0(M+H + ).

[0489] 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)

[0490] Synthesis of compound 22.1

[0491]

[0492] By ((4-ethynylphenyl) sulfonyl) dimethyl dithioimidocarbonate (0.43g, 1.5mmol, 1 equivalent) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.39g, 1.5mmol, 21.0, CAS#59074-26-9) in pyridine (7.5mL) mix. After stirring at 120 ° C for 18 hours, 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 (0.35g, 0.71mmol, 47% yield) as a yellow oil. LC-MS (ESI+): 494.1 (M+H + ).

[0493] Synthesis of compounds 21 and 22

[0494]

[0495] 2-aminoethane-1-sulfonamide hydrochloride (230mg, 1.44mmol, 2 equivalents) is added to 3-(4-chlorophenyl)-N-((4-ethynylphenyl) sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazoles-1-thioimidocarboxylic acid methyl ester (355mg, 0.72mmol, 21.1) and triethylamine (0.3mL, 2.16mmol, 3 equivalents) in the stirred solution of methyl alcohol (3.6mL).After at room temperature stirring for 18 hours, decompression removal of solvent, and crude product is eluted with ethyl acetate / heptane mixture (0 / 100 to 60 / 40) and carried out silica gel chromatography separation.Collect required fraction, and carry out repurification by flash chromatography on silica gel with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) wash-out, obtain colorless oil, it is further carried out SFC purification to split two enantiomers.

[0496] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0497] Compound 21: (63.6 mg, 0.11 mmol, 16% yield, 99% purity, 99% ee, OR: -85.6). 1H NMR(DMSO-d6,400MHz)δ8.18(br s,1H),7.81(d,J=8.4Hz,2H),7.72(d,J=8.6Hz,2H),7.57(d,J=8.4Hz,2H),7.45(d,J=8.6Hz,2H),7.3-7.4(m, 2H),7.2-7.3(m,3H),7.03(s,2H),5.09(dd,J=4.3,11.2Hz,1H),4.53(t,J=11.2Hz,1H),4.39(s,1H),4.08(br dd,J=4.3,11.1Hz,1H),3.7-3.8(m,2H),3.3(m,2H).LC-MS(ESI+):570.0(M+H + ).

[0498] 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=4.3,11.2Hz,1H),3.73(q,J=6.2Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):570.0(M+H + ).

[0499] 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)

[0500]

[0501] 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-carboximidoyl chloride (300 mg, 0.57 mmol, 9.0 equiv). After stirring at room temperature for 18 h, the reaction was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40, v / v) to give a colorless oil, which was further separated by SFC to give the following two different isomers.

[0502] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0503] Compound 23: (30.0 mg, 0.05 mol, 8% yield, 99% purity, 99% ee, OR: -71.4). 1 H NMR(DMSO-d6,400MHz)δ8.03(br d,J=8.2Hz,3H),7.86(d,J=8.3Hz,2H),7.72(d,J=8.5Hz,2H),7.45(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,3H),6.96(br s,2H),5.10(dd,J=4.2,11.2Hz,1H),4.59(br t,J=11.2Hz,1H),4.39(br s,1H),4.08(br dd,J=4.1,11.1Hz,1H),3.45(dd,J=6.3,14.1Hz,1H),3.2-3.3(m,1H),1.25(d,J=6.7Hz,3H).LC-MS(ESI+):628.0(M+H + ).

[0504] Compound 24: (16.4 mg, 0.026 mmol, 4% yield, 99% purity, 99% ee, OR: +53.2). 1H NMR(DMSO-d6,400MHz)δ8.03(br d,J=8.2Hz,3H),7.85(d,J=8.3Hz,2H),7.70(d,J=8.5Hz,2H),7.44(d,J=8.7Hz,2H),7.3-7.4(m, 2H),7.2-7.3(m,3H),6.93(s,2H),5.11(dd,J=4.2,11.2Hz,1H),4.54(t,J=11.1Hz,1H),4.40(br d,J=6.0Hz,1H),4.11(br dd,J=4.4,11.0Hz,1H),3.4(m,1H),3.21(br dd,J=6.2,14.1Hz,1H),1.27(br d,J=6.7Hz,3H).LC-MS(ESI+):628.0(M+H + ).

[0505] 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)

[0506]

[0507] 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-carboximidoyl chloride (250 mg, 0.47 mmol, 9.0 equiv). After stirring at room temperature for 18 h, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel 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 resolve the two diastereomers.

[0508] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) 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 of CO2 (40%)– i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0509] Compound 25: (13.2 mg, 0.02 mol, 4% yield, 99% purity, 99% deuterated, OR: +202.1). 1 H NMR(DMSO-d6,400MHz)δ8.0-8.1(m,3H),7.86(d,J=8.4Hz,2H),7.72(d,J=8.5Hz,2H),7.45(d,J=8.5Hz,2H), 7.3-7.4(m,2H),7.2-7.3(m,3H),6.96(s,2H),5.10(dd,J=4.2,11.1Hz,1H),4.59(t,J=11.2Hz,1H),4.39(br d,J=5.1Hz,1H),4.08(br dd,J=4.1,11.1Hz,1H),3.45(dd,J=6.3,14.1Hz,1H),3.24(dd,J=6.1,14.0Hz,1H),1.25(d,J=6.7Hz,3H).LC-MS(ESI+):628.0(M+H + ).

[0510] Compound 26: (16.1 mg, 0.026 mmol, 5% yield, 92% purity, 99% de, OR: -63.4). 1 H NMR (DMSO-d6, 400MHz) δ8.03(br d,J=8.2Hz,3H),7.85(d,J=8.3Hz,2H),7.70(d,J=8.6Hz,2H),7.44(d,J=8.6Hz,2H),7.32(br d,J=7.2Hz,2H),7.2-7.3(m,3H),6.94(s,2H),5.11(dd,J=4.1,11.2Hz,1H),4.54(t,J=11.1Hz,1H),4.39(br s,1H),4.11(br dd,J=3.9,10.9Hz,1H),3.4(m,1H),3.2-3.3(m,1H),1.27(d,J=6.7Hz,3H).LC-MS(ESI+):628.1(M+H +).

[0511] 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)

[0512] Synthesis of compound 27.1

[0513]

[0514] N-(Bis-methylsulfanyl-methylene)-3-trifluoromethyl-benzenesulfonamide (0.54 g, 1.63 mmol, 12 and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.42 g, 1.63 mmol, 1 eq) were refluxed (120 ° C.) in pyridine (5 mL) for 18 hours. 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 desired product (0.6 g, 1.12 mmol, 69% yield) as a yellow foam. LC-MS (ESI+): 538.1 (M+H + ).

[0515] Synthesis of compounds 27 and 28

[0516]

[0517] 2-Aminoethane-1-sulfonamide hydrochloride (90 mg, 0.56 mmol, 1.2 equiv) was added to a stirred solution of N-{[3-(4-chloro-phenyl)-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 hours, the solvent was removed under reduced pressure. The residue was eluted with ethyl acetate / heptane mixture (0 / 100 to 60 / 40, v / v) for silica gel chromatography to give a colorless oil, which was further subjected to SFC purification to split the two enantiomers.

[0518] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) 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 of CO2 (40%)– i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0519] Compound 27: (65.0 mg, 0.10 mmol, 23% yield, 99% purity, 99% ee, OR: -109.5). 1 H NMR(DMSO-d6,400MHz)δ8.16(br s,1H),8.08(br d,J=7.9Hz,1H),7.97(s,1H),7.85(br d,J=7.8Hz,1H),7.60-7.72(m,3H),7.38(d,J=8.6Hz,2H),7.23-7.30(m,2H),7.13-7.22(m,3H),6.9 4(s,2H),5.04(dd,J=11.2,4.3Hz,1H),4.48(t,J=11.2Hz,1H),4.00(dd,J=11.0,4.3Hz,1H),3.66(br d,J=3.5Hz,2H),3.17-3.21ppm(m,2H).LC-MS(ESI+):614.0(M+H + ).

[0520] Compound 28: (66.3 mg, 0.11 mmol, 23% yield, 99% purity, 99% ee, OR: +86.7). 1 H NMR(DMSO-d6,400MHz)δ8.22(br s,1H),8.15(br d,J=7.9Hz,1H),8.04(s,1H),7.92(br d,J=7.8Hz,1H),7.67-7.78(m,3H),7.45(d,J=8.6Hz,2H),7.30-7.36(m,2H),7.20-7.29(m,3H),7.00(br s,2H),5.10(dd,J=11.1,4.3Hz,1H),4.54(t,J=11.2Hz,1H),4.07(dd,J=11.0,4.3Hz,1H),3.72(br s,2H),3.23-3.28ppm(m,2H).LC-MS(ESI+):614.0(M+H + ).

[0521] 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)

[0522] Synthesis of 29.1

[0523]

[0524] By N- (bis-methylsulfanyl-methylene) -2-chloro-benzenesulfonamide (0.5g, 1.69mmol, 13) and 3- (4-chlorophenyl) -4-phenyl -4,5-dihydro -1H- pyrazole (0.42g, 1.63mmol, 21.0) in pyridine (6mL) reflux (120 DEG C) 18 hours. Upon completion, the reaction mixture was concentrated to dryness, and the residue was purified by column chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 40 / 60, v / v) to give the desired product (0.58g, 1.15mmol, 71% yield) as a yellow foam. LC-MS (ESI+): 504.0 (M+H + ).

[0525] Synthesis of compounds 29 and 30

[0526]

[0527] 2-Aminoethane-1-sulfonamide hydrochloride (368 mg, 2.29 mmol, 2 eq) was added to a stirred solution of methyl 3-(4-chlorophenyl)-N-((2-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thioimidocarbamate (578 mg, 1.15 mmol, 29.1) and triethylamine (0.5 mL, 3.4 mmol, 3 eq) in methanol (4 mL). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) to give a colorless oil which was further purified by SFC to separate the two enantiomers.

[0528] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0529] Compound 29: (61.7 mg, 0.11 mmol, 9% yield, 99% purity, 99% ee, OR: -90.0). 1 H NMR(DMSO-d6,400MHz)δ8.16(br t,J=5.1Hz,1H),8.02(dd,J=1.5,7.7Hz,1H),7.73(d,J=8.6Hz,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=4.3,11.2Hz,1H),4.54(t,J=11.2Hz,1H),4.0-4.1(m,1H),3.77(q,J=6.3Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):580.2(M+H) + ).

[0530] Compound 30: (59.4 mg, 0.10 mmol, 9% yield, 99% purity, 99% ee, OR: +100.6). 1 H NMR(DMSO-d6,400MHz)δ8.16(br t,J=5.3Hz,1H),8.02(dd,J=1.3,7.7Hz,1H),7.73(d,J=8.6Hz,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=4.3,11.2Hz,1H),4.53(t,J=11.2Hz,1H),4.0-4.1(m,1H),3.77(q,J=6.4Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):580.2(M+H) + ).

[0531] 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)

[0532]

[0533] 2-Aminoethane-1-sulfonamide hydrochloride (0.2g, 1.2mmol, 1.2 equivalents) is added to 3-(4-chlorophenyl)-N-((3-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thioimidocarboxylic acid methyl ester (0.51g, 1.011mmol, CAS#656827-47-3) and triethylamine (0.42mL, 3.03mmol, 3 equivalents) in a stirred solution of methanol (5mL). After stirring at room temperature for 18 hours, the solvent is removed under reduced pressure. The residue is eluted with ethyl acetate / heptane mixture (0 / 100 to 80 / 20) for silica gel chromatography to obtain a colorless oil, which is further subjected to SFC purification to split the two enantiomers in a white solid.

[0534] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) 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 of CO2 (40%)– i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0535] Compound 31: (72.3 mg, 0.12 mmol, 12% yield, 99% purity, 99% ee, OR: -99.1). 1H NMR(DMSO-d6,400MHz)δ8.19(br t,J=5.3Hz,1H),7.76-7.81(m,2H),7.71(d,J=8.6Hz,2H),7.58-7.62(m,1H),7.49-7.55(m,1H),7.45(d,J=8.6Hz,2H),7.30-7.37(m,2 H),7.20-7.28(m,3H),7.01(s,2H),5.09(dd,J=11.2,4.4Hz,1H),4.53(t,J=11.2Hz,1H),3.99-4.10(m,1H),3.69-3.80(m,2H),3.27(br s,2H)ppm.LC-MS(ESI+):580.04(M+H + ).

[0536] Compound 32: (80.4 mg, 0.14 mmol, 14% yield, 99% purity, 99% ee, OR: +111.9). 1 H NMR(DMSO-d6,400MHz)δ8.19(br t,J=5.2Hz,1H),7.77-7.82(m,2H),7.71(d,J=8.6Hz,2H),7.57-7.62( m,1H),7.49-7.55(m,1H),7.45(d,J=8.6Hz,2H),7.30-7.36(m,2H),7.2 0-7.29(m,3H),7.01(s,2H),5.09(dd,J=11.1,4.2Hz,1H),4.53(t,J=11.2Hz,1H),4.06(dd,J=11.4,4.6Hz,1H),3.74(q,J=6.1Hz,2H),3.27(br s,2H)ppm.LC-MS(ESI+):580.04(M+H + ).

[0537] 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)

[0538] Synthesis of 33.1

[0539]

[0540] A solution of dimethyl ((2-ethynylphenyl)sulfonyl)carbonimidodithioate (0.47 g, 1.63 mmol, 14) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.42 g, 1.63 mmol, 21.0) in pyridine (3 mL) was heated at 120 ° C for 18 hours. Upon completion, the reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50) to give the desired product (0.24 g, 0.49 mmol, 30% yield) as a yellow solid. LC-MS (ESI+): 494.0 (M+H + ).

[0541] Synthesis of compounds 33 and 34

[0542]

[0543] 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-thioimidocarbamate (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 gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give a colorless oil, which was further purified by SFC to separate the two enantiomers as a white solid.

[0544] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) 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 of CO2 (40%)– i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0545] Compound 33: (52.2 mg, 0.09 mmol, 19% yield, 95% purity, 99% ee, OR: -61.9). 1H NMR(DMSO-d6,400MHz)δ8.06(br s,1H),7.91-7.96(m,1H),7.73(d,J=8.7Hz,2H),7.58-7.63(m,1H),7.47-7.5 4(m,2H),7.45(d,J=8.7Hz,2H),7.30-7.36(m,2H),7.21-7.28(m,3H),7.02(br s,2H),5.07(br dd,J=11.2,4.5Hz,1H),4.53(br t,J=11.3Hz,1H),4.47(s,1H),4.01-4.08(m,1H),3.81(br s,2H),3.28-3.30(m,2H)ppm.LC-MS(ESI+):570.9(M+H + ).

[0546] Compound 34: (56.6 mg, 0.10 mmol, 20% yield, 96% purity, 99% ee, OR: +89.9). 1 H NMR(DMSO-d6,400MHz)δ8.06(br s,1H),7.91-7.96(m,1H),7.73(d,J=8.7Hz,2H),7.58-7.64(m,1H),7.47-7.5 5(m,2H),7.45(d,J=8.7Hz,2H),7.30-7.35(m,2H),7.22-7.28(m,3H),7.02(br s,2H),5.07(br dd,J=11.3,4.4Hz,1H),4.53(br t,J=11.3Hz,1H),4.47(s,1H),4.05(br dd,J=11.1,4.3Hz,1H),3.81(br s,2H),3.28-3.30(m,2H)ppm.LC-MS(ESI+):570.9(M+H + ).

[0547] 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)

[0548] Synthesis of 35.1

[0549]

[0550] A solution of dimethyl ((3-ethynylphenyl)sulfonyl)carbonimidodithioate (2.65 g, 9.28 mmol, 15) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (2.4 g, 9.28 mmol, 21.0) in pyridine (18 mL) was heated at 120 ° C for 18 hours. Upon completion, the reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50) to give the desired product (1.94 g, 3.94 mmol, 42% yield) as a yellow solid. LC-MS (ESI+): 494.0 (M+H + ).

[0551] Synthesis of compounds 35 and 36

[0552]

[0553] 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-thioimidocarbamate (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 gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give a colorless oil, which was further purified by SFC to separate the two enantiomers as a white solid.

[0554] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) 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 of CO2 (40%)– i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0555] Compound 35: (38.2 mg, 0.07 mmol, 12% yield, 97% purity, 99% ee, OR: -98.8). 1H NMR(DMSO-d6,400MHz)δ7.97-8.44(m,1H),7.78-7.89(m,2H),7.66-7.74(m,J=8.4Hz,2H),7.57-7.64(m,1H),7.48-7.54(m,1H),7.44(br d,J=8.6Hz,2H),7.30-7.36(m,2H),7.20-7.28(m,3H),7.01(br s,2H),5.08(br dd,J=11.2,4.1Hz,1H),4.52(br t,J=11.1Hz,1H),4.32(s,1H),4.05(br dd,J=11.0,4.1Hz,1H),3.74(br t,J=6.5Hz,2H),3.27(br d,J=7.3Hz,2H)ppm.LC-MS(ESI+):570.9(M+H + ).

[0556] Compound 36: (17.1 mg, 0.03 mmol, 5% yield, 97% purity, 99% ee, OR: +68.0). 1 H NMR(DMSO-d6,400MHz)δ8.17(br s,1H),7.79-7.90(m,2H),7.70(br d,J=8.4Hz,2H),7.62(brd,J=7.7Hz,1H),7.50(t,J=7.8Hz,1H),7.44(d,J=8.6Hz,2H),7.30-7.37(m,2H),7.20-7.28(m,3H),7.01(br s,2H),5.08(br dd,J=11.3,4.1Hz,1H),4.52(br t,J=11.2Hz,1H),4.32(s,1H),4.05(br dd,J=11.3,3.9Hz,1H),3.74(br t,J=6.5Hz,2H),3.26ppm(brs,2H).LC-MS(ESI+):570.9(M+H + ).

[0557] 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)

[0558]

[0559] Synthesis of 37.1

[0560] To a solution of I6 (580 mg, 2.26 mmol, 1 eq) 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 hours, 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: 400MHz, DMSO-d6δppm 3.67(dd,J=11.27,4.83Hz,1H),4.27(t,J=11.38Hz,1H),4.98(dd,J=11.44,4.77Hz,1H),7.15-7.37(m,6H),7.43 (d,J=8.70Hz,2H),7.52-7.64(m,1H),7.85(d,J=8.58Hz,2H),8.02(td,J=8.64,6.44Hz,1H),11.83-12.19(m,1H)

[0561] Synthesis of 37.2

[0562] To a solution of 37.1 (500 mg, 1.05 mmol, 1 eq) in toluene (5 mL) was added N,N-diisopropylethylamine (274.51 μL, 1.58 mmol, 1.5 eq) and phosphorus oxychloride (126.93 μL, 1.37 mmol, 1.3 eq) at room temperature. After stirring at 85 ° C for 16 hours, 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.

[0563] Synthesis of compounds 37 and 38

[0564] At room temperature, triethylamine (319.32 mg, 3.16 mmol, 439.24 μL, 4 equivalents) and 2-aminoethanesulfonamide (146.93 mg, 1.18 mmol, 1.5 equivalents) were added to a solution of 37.2 (390 mg, 788.93 μmol, 1 equivalent) in dichloromethane (5 mL). 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 a racemate (380 mg, 652.87 μmol, 83%) as a white solid. The racemate was separated by SFC to obtain compound 37 (22 mg, 35.15 μmol, 5%) and compound 38 (29 mg, 49.82 μmol, 8%) as a white solid.

[0565] 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

[0566] Compound 37: 1 H NMR(400MHz,DMSO-d6)δppm 3.22-3.27(m,2H),3.71(q,J=6.32Hz,2H),4.06(dd,J=11.00,4.40Hz,1H),4.54(t,J=11.19Hz,1H),5.11(dd,J=11.31,4.34Hz,1H),7.01(s,2 H),7.15(td,J=8.44,2.32Hz,1H),7.21-7.28(m,3H),7.30-7.37(m,3H) ,7.46(d,J=8.56Hz,2H),7.71-7.76(m,2H),7.84-7.91(m,1H),8.23(br t,J=5.50Hz,1H); LCMS(ESI+):m / z 582.0(M+H) + ;OR:-118.40

[0567] Compound 38: 1H NMR(400MHz,DMSO-d6)δppm 3.22-3.28(m,2H),3.71(q,J=6.40Hz,2H),4.06(dd,J=11.07,4.34Hz,1H),4.54(t,J=11.19Hz,1H),5.11(dd,J=11.19,4.46Hz,1H),6.96-7.04 (m,2H),7.15(td,J=8.50,2.08Hz,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=5.20Hz,1H); LCMS(ESI+):m / z 582.0(M+H) + ;OR:116.0.

[0568] 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)

[0569]

[0570] Synthesis of 39.1

[0571] To a solution of 21.0 (1 g, 3.90 mmol, 1 eq) 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) + ; 1H NMR: 400MHz, DMSO-d6δppm3.70 (dd, J=11.27, 4.95Hz, 1H), 4.30 (t, J=11.32Hz, 1H), 4.99(dd,J=11.44,4.77Hz,1H),7.12-7.34(m,7H),7.44(d,J=8.70Hz,2H),7.67(br d,J=5.36Hz,2H),7.73-7.83(m,2H),11.43-12.04(m,1H).

[0572] Synthesis of 39.2

[0573] To a solution of 39.1 (500 mg, 1.05 mmol, 1 eq) in toluene (5 mL) was added N,N-diisopropylethylamine (274.51 μL, 1.58 mmol, 1.5 eq) and phosphorus oxychloride (126.93 μL, 1.37 mmol, 1.3 eq) 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 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 HNMR:400MHz,DMSO-d6δppm 4.03(dd,J=12.59,5.26Hz,1H), 4.68(t,J=11.80Hz,1H), 5.28(dd,J=10.94,5.07Hz,1H), 7.24-7.36(m,6H),7.47(d,J=8.56Hz,2H),7.63(t,J=4.22Hz,2H),7.71(d,J=8.56Hz,2H)

[0574] Synthesis of compounds 39 and 40

[0575] To a solution of 39.2 (300 mg, 606.87 μmol, 1 eq) in dichloromethane (5 mL) at room temperature were added triethylamine (84.47 μL, 606.87 μmol, 1 eq) and 2-aminoethanesulfonamide (113.03 mg, 910.31 μmol, 1.5 eq). 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 racemate (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 afford compound 39 (35 mg, 60.13 μmol, 18%) and compound 40 (54 mg, 92.78 μmol, 27%) as white solids.

[0576] 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

[0577] Compound 39: 1 H NMR(400MHz,DMSO-d6)δppm 3.23-3.29(m,2H),3.71(br s,2H),4.06(dd,J=11.13,4.40Hz,1H),4.54(t,J=11.19Hz,1H),5.11(dd,J=11.13,4.40Hz,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=8.68Hz,2H),8.25(br d,J=1.22Hz,1H).LCMS(ESI+):m / z 582.0(M+H) + OR:-124.60.

[0578] Compound 40: 1 H NMR(400MHz,DMSO-d6)δppm 3.23-3.29(m,2H),3.72(br t,J=6.72Hz,2H),4.06(dd,J=11.07,4.34Hz,1H),4.53(t,J=11.13Hz,1H),5.10(dd,J=11.19,4.34Hz,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=8.56Hz,2H),8.10-8.38(m,1H); LCMS(ESI+):m / z 582.10(M+H) + OR:118.00.

[0579] 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)

[0580]

[0581] Synthesis of 41.1

[0582] To a solution of 41.0 (1 g, 3.48 mmol, 1 eq) in toluene (20 mL) was added 21.0 (891.5 mg, 3.48 mmol, 1 eq) 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: 400MHz, DMSO-d6δppm1.34(t,J=7.09Hz,3H),3.67(dd,J=11.31,4.83Hz,1H),4.27(t,J=11.37Hz,1H),4.33-4.43(m,2H),4. 98(dd,J=11.43,4.83Hz,1H),7.15-7.27(m,4H),7.27-7.35(m,2H),7.41-7.48(m,2H),7.81(d,J=8.56Hz,2H),8.11-8.23(m,4H).

[0583] Synthesis of 41.2

[0584] To a solution of 41.1 (1.5 g, 2.93 mmol, 1 eq) in toluene (10 mL) was added N,N-diisopropylethylamine (765.45 μL, 4.40 mmol, 1.5 eq) and phosphorus oxychloride (853.95 μL, 3.80 mmol, 1.3 eq) 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 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) + .

[0585] Synthesis of 41.3

[0586] 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 by silica 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) + .

[0587] Synthesis of 41.4

[0588] To a solution of ethyl 41.3 (800 mg, 1.29 mmol, 1 eq.) in tetrahydrofuran (40 mL) and H2O (10 mL) was added LiOH.H2O (108.64 mg, 2.59 mmol, 2 eq.) at room temperature. After stirring at room temperature for 7 hours, 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) + .

[0589] Synthesis of compounds 41 and 42

[0590] At 0 ° C, to a solution of 41.4 (500 mg, 847.36 μmol, 1 equivalent) in dichloromethane (5 mL) was added 2-methylpropyl chloroformate (127.30 mg, 932.09 μmol, 122.41 μL, 1.1 equivalents) and 4-methylmorpholine (257.12 mg, 2.54 mmol, 279.48 μL, 3 equivalents). After stirring at room temperature for 1 hour. NH3 / THF (6 M) was added. After stirring at room temperature for 1 hour, 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 a racemate (80 mg, 108.64 μmol, 13%) as a white solid. LCMS (ESI+): m / z 589.9 (M+H) +1H NMR: 400MHz, DMSO-d6δppm 3.16-3.22(m,2H),3.54(d,J=6.68Hz,2H),3.59-3.72(m,2H),3.94-4.11(m,1H),4.41-4.58(m,1H) ,5.07(dd,J=11.03,4.23Hz,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) 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 a white solid.

[0591] Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system; Mobile phase: A: TFA / H2O = 0.075% v / v; B: CAN; Column: C18-1 150*30mm*5μm; Flow rate: 25mL / min; Monitoring wavelength: 220&254nm;

[0592]

[0593] SFC method: column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase A: CO 2 ; mobile phase B: [0.1% NH 3 H 2 O ethanol]; B%: 50%, running time: 12 minutes.

[0594] Compound 41: 1H NMR(400MHz,DMSO-d6)δppm 3.25-3.31(m,2H),3.67-3.83(m,2H),4.11(br dd,J=11.19,4.19Hz,1H),4.55(t,J=11.13Hz,1H),5.10(dd,J=11.19,4.19Hz,1H),7.03(s,2H),7.20-7.29(m,3H),7.30- 7.39(m,2H),7.46(d,J=8.50Hz,2H),7.53(brs,1H),7.72(d,J=8.50Hz,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) + .

[0595] Compound 42: 1 H NMR (400MHz, DMSO-d6) δppm 3.28 (br s, 2H), 3.74 (br t, J = 6.00Hz, 2H), 4.09 (br dd, J = 10.51, 2.88Hz, 1H), 4.53 (br t, J = 11.38Hz, 1H), 5.09 (br dd,J=10.82,3.56Hz,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=8.25Hz,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) + .

[0596] 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)

[0597]

[0598] Synthesis of 43.2

[0599] A solution of 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.8 g, 3.3 mmol, 43.0, CAS No. 69433-60-9) and methyl ((4-(trifluoromethyl)phenyl)sulfonyl)carbamate (1.04 g, 3.7 mmol, 43.1, CAS No. 1042414-31-2) in toluene (30 mL) was stirred at 120 ° C for 16 hours. Upon completion, the solvent was removed under reduced pressure, and the resulting slurry was chromatographed on silica gel eluted with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50, v / v) to give the title product (1.47 g, 2.9 mmol, 91% yield) as a brown foam. LC-MS (ESI+): 492.0 (M+H + ).

[0600] Synthesis of 43.3

[0601] At room temperature, 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) in toluene (6 mL) was added phosphorus pentachloride (685 mg, 3.29 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 filtered and purified by flash chromatography on silica gel eluting with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50, v / v) to give the expected compound (0.7 g, 1.4 mmol, 46% yield) as a white solid. LC-MS (ESI+): 510.00 (M+H + ).

[0602] Synthesis of compounds 43 and 44

[0603] 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) at room temperature was added (Z)-3-(4-fluorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (0.25 g, 0.5 mmol, 43.3). 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 magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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 2 enantiomers.

[0604] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0605] Compound 43: (33.7 mg, 0.06 mmol, 12% yield, 98% purity, 99% ee). 1 H NMR(DMSO-d6,400MHz)δ8.22(br s,1H),8.0-8.1(d,J=8.2Hz,2H),7.84(d,J=8.3Hz,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=4.2,11.1Hz,1H),4.53(s,1H),4.06(br dd,J=4.2,11.1Hz,1H),3.73(br d,J=6.3Hz,2H),3.3-3.3(m,2H).LC-MS(ESI+):598.2(M+H + ).

[0606] Compound 44: (28.4 mg, 0.05 mmol, 10% yield, 99% purity, 99% ee). 1 H NMR(DMSO-d6,400MHz)δ8.1-8.3(s,1H),8.03(d,J=8.2Hz,2H),7.8-7.9(d,J=8.3Hz,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=6.3Hz,2H),3.3-3.3(m,2H).LC-MS(ESI+):598.3(M+H + ).

[0607] 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)

[0608]

[0609] Synthesis of 45.1

[0610] 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 No. 656827-57-5) in toluene (32 mL) was added phosphorus pentachloride (2.9 g, 13.9 mmol, 1.1 equivalents) 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 dried in vacuo to give the expected compound (1.45 g, 3.05 mmol, 24% yield) as a light white solid which was used in the next step without further purification. LC-MS (ESI+): 476.040 (M+H + ).

[0611] Synthesis of compounds 45 and 46

[0612] 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) at room temperature was added (Z)-N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride (0.25 g, 0.53 mmol, 45.1). 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 magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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 2 enantiomers.

[0613] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0614] Compound 45: (21.4 mg, 0.04 mmol, 7% yield, 99% purity, 99% ee, OR: -70.5). 1 H NMR(DMSO-d6,400MHz)δ8.1-8.2(s,1H),7.7-7.9(m,4H),7.53(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H), 7.03(s,2H),5.10(dd,J=4.4,11.1Hz,1H),4.52(t,J=11.2Hz,1H),4.07(dd,J=4.1,11.1Hz,1H),3.7-3.8(m,2H),S 3.2-3.3(m,2H).LC-MS(ESI+):564.0(M+H + ).

[0615] Compound 46: (19.8 mg, 0.035 mmol, 7% yield, 99% purity, 99% ee, OR: +19.8). 1 H NMR(DMSO-d6,400MHz)δ8.16(br s,1H),7.7-7.9(m,4H),7.53(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H),7.03(s ,2H),5.10(dd,J=4.3,11.2Hz,1H),4.52(s,1H),4.07(dd,J=4.4,11.1Hz,1H),3.73(br d,J=5.9Hz,2H),S 3.2-3.3(m,2H).LC-MS(ESI+):564.0(M+H + ).

[0616] (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)

[0617]

[0618] 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) at room temperature was added (E)-3-(4-fluorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidyl chloride (0.28 g, 0.54 mmol, 45.1). 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 magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with heptane / ethyl acetate mixtures (100 / 0 to 60 / 40, v / v) to give a colorless oil as a mixture of diastereomers which are separated by SFC.

[0619] 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 with 2.5 ml / min of CO2 (60%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0620] Compound 47: (8.6 mg, 0.014 mmol, 3% yield, 99% purity, 99% ee, OR: -47.6). 1 H NMR (400MHz, CDCl3) δ8.04 (d, J = 8.1Hz, 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=11.4,5.3Hz,1H),4.54(t,J=11.4Hz,1H),3.92-4.14(m,3H),3 .51(quind,J=7.1,4.0Hz,1H),1.47ppm(d,J=7.1Hz,3H).LC-MS(ESI+):612.1(M+H + ).

[0621] Compound 48: (5.9 mg, 0.010 mmol, 2% yield, 95% purity, 99% ee, OR: -62.5). 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.1Hz,2H),7.69(d,J=8.1Hz,2H),7.62(br dd,J=8.6,5.3Hz,3H),7.28-7.36(m,3H),7.13(br d,J=7.0Hz,2H),6.99(t,J=8.5Hz,2H),4.82(brs,2H),4.71(br dd,J=10.9,4.9Hz,1H),4.52(br t,J=11.3Hz,1H),4.05-4.15(m,2H),3.93-4.03(m,1H),3.50(br s,1H),1.48ppm(br d,J=6.5Hz,3H).LC-MS(ESI+):612.1(M+H + ).

[0622] Compound 49: (11.3 mg, 0.018 mmol, 3% yield, 99% purity, 99% ee, OR: +99.5). 1H NMR (400MHz, CDCl3) δ8.04(d,J=8.1Hz,2H),7.67(d,J=8.2Hz,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=11.3,5.2Hz,1H),4.54(t,J=11.4Hz,1H),3.93-4.14(m,3H), 3.51(td,J=7.2,3.7Hz,1H),1.47ppm(d,J=7.0Hz,3H).LC-MS(ESI+):612.1(M+H + ).

[0623] Compound 50: (10.9 mg, 0.018 mmol, 3% yield, 97% purity, 99% ee, OR: +103.4). 1 H NMR (400MHz, CDCl3) δ8.04(d,J=8.2Hz,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=11.3,5.4Hz,1H),4.52(t,J=11.4Hz,1H),4.05-4.13(m,2H),3.92-4.0 2(m,1H),3.50(dt,J=7.1,4.0Hz,1H),1.47ppm(d,J=7.0Hz,3H).LC-MS(ESI+):612.1(M+H + ).

[0624] 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)

[0625]

[0626] Synthesis of 51.1

[0627] A solution of 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) was refluxed at 120 ° C for 18 hours. The reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (SiO ) eluted with a heptane / ethyl acetate mixture (100 / 0 to 50 / 50) to give the desired product (0.37 g, 0.79 mmol, 35% yield) as a yellow sticky solid. LC-MS (ESI+): 472.1 (M+H + ).

[0628] Synthesis of compounds 51 and 52

[0629] 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-thioimidocarboxylate (360 mg, 0.76 mmol, 51.1) and triethylamine (0.64 mL, 4.6 mmol, 6 equiv) in methanol (2.4 mL). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a dichloromethane / methanol mixture (100 / 0 to 90 / 10) to give a colorless oil, which was further purified by SFC (Amylose-1, ISOC. 50% EtOH + 0.1% DEA) to resolve the two enantiomers.

[0630] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-EtOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0631] Compound 51: (87.3 mg, 0.16 mmol, 21% yield, 99% purity, 99% ee, OR: -173.7). 1H NMR(DMSO-d6,400MHz)δ7.8-7.9(m,2H),7.7-7.8(m,2H),7.2-7.4(m,10H),6.9-7.1(m,2H), 5.09(dd,J=4.3,11.1Hz,1H),4.52(t,J=11.2Hz,1H),4.08(dd,J=4.3,11.1Hz,1H),3.73(br t,J=6.7Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):547.6(M+H + ).

[0632] Compound 52: (77.4 mg, 0.14 mmol, 18% yield, 99% purity, 99% ee, OR: +110.9). 1 H NMR(DMSO-d6,400MHz)δ7.8-7.9(m,2H),7.78(dd,J=5.5,8.8Hz,2H),7.0-7.4(m,12H),5.08(dd,J=4.3,11.1Hz,1H),4 .52(t,J=11.2Hz,1H),4.07(dd,J=4.3,11.2Hz,1H),3.74(brt,J=6.8Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):547.6(M+H + ).

[0633] Examples 53-56; (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 54); 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)

[0634]

[0635] 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-thioimidocarbamate (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 hours, the reaction mixture was concentrated to dryness and purified by flash chromatography on silica gel eluting with a dichloromethane / methanol mixture (100 / 0 to 90 / 10) to give a yellow oil in the form of a mixture of diastereomers, which was further separated by SFC.

[0636] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Cellulose-4) 100 mm long x 4.6 mm ID 3 μm particle size in isocratic mode with 2.5 ml / min of CO2 (60%)-EtOH-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0637] Compound 53: (25.3 mg, 0.045 mmol, 8% yield, 99% purity, 99% ee, OR: -113.3). 1 H NMR(DMSO-d6,400MHz)δ8.08(br s,1H),7.8-7.9(m,2H),7.78(dd,J=5.5,8.8Hz,2H),7.2-7.4(m,9H),6.97(br s,2H),5.10(dd,J=4.3,11.2Hz,1H),4.55(t,J=11.2Hz,1H),4.0-4.1(m,1H),3.6-3.7(m,1H),3.56(br d,J=13.3Hz,1H),3.23(br d,J=6.8Hz,1H),1.16(d,J=6.8Hz,3H).LC-MS(ESI+):562.1(M+H + ).

[0638] Compound 54: (36.1 mg, 0.06 mmol, 12% yield, 97% purity, 99% ee, OR: -72.2). 1H NMR(DMSO-d6,400MHz)δ8.09(br t,J=5.6Hz,1H),7.8-7.9(m,2H),7.79(dd,J=5.5,8.8Hz,1H),7.2-7.4(m,10H),6.98(s,2H),5.11(dd,J=4.4,11.2Hz,1H),4.54(t,J=11.1Hz,1 H),4.14(dd,J=4.3,11.2Hz,1H),3.6-3.8(m,1H),3.56(td,J=6.8,13.9Hz,1H),3.2-3.3(m,1H),1.16(d,J=7.0Hz,3H).LC-MS(ESI+):562.1(M+H) + ).

[0639] Compound 55: (23.3 mg, 0.04 mmol, 8% yield, 98% purity, 99% ee, OR: +50.5). 1 H NMR(DMSO-d6,400MHz)δ8.09(br t,J=5.4Hz,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=4.3,11.1Hz,1H),4.56(t,J=11.2Hz,1H) ,4.08(dd,J=4.3,11.2Hz,1H),3.6-3.8(m,1H),3.5-3.6(m,1H),3.2-3.3(m,1H),1.17(d,J=7.0Hz,3H).LC-MS(ESI+):562.1(M+H + ).

[0640] Compound 56: (23.2 mg, 0.04 mmol, 8% yield, 99% purity, 99% ee, OR: +139.1). 1H NMR(DMSO-d6,400MHz)δ8.08(br d,J=1.4Hz,1H),7.87(dd,J=5.3,8.8Hz,2H),7.78(dd,J=5.5,8.7Hz,2H),7.2-7.4(m,9H),6.98(br s,2H),5.10(dd,J=4.2,11.1Hz,1H),4.54(t,J=11.1Hz,1H),4.13(br dd,J=4.3,11.0Hz,1H),3.67(br d,J=5.9Hz,1H),3.55(br dd,J=6.2,13.6Hz,1H),3.25(br s,1H),1.16(d,J=6.9Hz,3H).LC-MS(ESI+):562.1(M+H + ).

[0641] 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)

[0642]

[0643] To a solution of (R)-2-aminopropane-1-sulfonamide (131 mg, 0.95 mmol, 1.5 equiv, 18) 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-carboximidoyl 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 (2N, 20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 70 / 30, v / v) to give a colorless oil, which was further separated by SFC to give the following two diastereomers.

[0644] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0645] Compound 57: (50.9 mg, 0.088 mmol, 14% yield, 99% purity, 99% ee, OR: -112.1). 1 H NMR(DMSO-d6,400MHz)δ7.94(br d,J=8.1Hz,1H),7.7-7.9(m,4H),7.54(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H),6 .96(s,2H),5.09(dd,J=4.2,11.1Hz,1H),4.57(t,J=11.2Hz,1H),4.3-4.5(m,1H),4.08(br dd,J=3.9,10.9Hz,1H),3.44(dd,J=6.2,14.1Hz,1H),3.2-3.3(m,1H),1.26(d,J=6.7Hz,3H).LC-MS(ESI+):578.1(M+H + ).

[0646] Compound 58: (23.2 mg, 0.04 mol, 6% yield, 99% purity, 99% ee, OR: +65.6). 1 H NMR(DMSO-d6,400MHz)δ7.96(br d,J=7.8Hz,1H),7.7-7.8(m,4H),7.53(d,J=8.6Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H),6 .94(s,2H),5.10(dd,J=4.3,11.2Hz,1H),4.52(t,J=11.1Hz,1H),4.3-4.4(m,1H),4.13(br dd,J=3.7,11.0Hz,1H),3.4(m,1H),3.23(br s,1H),1.28(br d,J=6.7Hz,3H).LC-MS(ESI+):578.0(M+H + ).

[0647] 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)

[0648]

[0649] Synthesis of 59.1

[0650] By ((4-ethynylphenyl) sulfonyl) dimethyl dithioimidocarbonate (0.39g, 1.37mmol, 19) and 3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.33g, 1.37mmol, 43.0) in pyridine (2.5mL) mix. After stirring at 120 DEG C for 72 hours, 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 (0.092g, 0.19mmol, 14% yield) as a colorless oil. LC-MS (ESI+): 478.1 (M+H + ).

[0651] Synthesis of compounds 59 and 60

[0652] 2-Aminoethane-1-sulfonamide hydrochloride (93mg, 0.58mmol, 3 equivalents) is added to the stirred solution of N-((4-ethynylphenyl) sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazoles-1-thioimidocarboxylic acid methyl ester (92mg, 0.19mmol, 59.1) and triethylamine (0.16mL, 1.16mmol, 6 equivalents) in methanol (1.9mL).After at room temperature stirring for 18 hours, decompression removal of solvent.Residue is eluted with ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) and carried out silica gel chromatography separation, obtain white solid, it is further carried out SFC purification to separate two enantiomers.

[0653] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) 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 of CO2 (40%)– iPrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0654] Compound 59: (18.4 mg, 0.033 mmol, 17% yield, 99% purity, 99% ee, OR: -47.3). 1 H NMR(DMSO-d6,400MHz)δ8.16(br t,J=5.5Hz,1H),7.7-7.9(m,4H),7.56(d,J=8.4Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H),7.02(s,2H),5.09(dd,J=4.3,11.1Hz,1H) ,4.52(t,J=11.1Hz,1H),4.39(s,1H),4.08(dd,J=4.3,11.1Hz,1H),3.73(q,J=6.3Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):554.1(M+H + ).

[0655] Compound 60: (17.6 mg, 0.032 mmol, 17% yield, 99% purity, 99% ee, OR: +146.9). 1 H NMR(DMSO-d6,400MHz)δ8.16(br t,J=5.5Hz,1H),7.7-7.8(m,4H),7.56(d,J=8.4Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H),7.02(s,2H),5.09(dd,J=4.3,11.1Hz,1H) ,4.52(t,J=11.2Hz,1H),4.39(s,1H),4.08(dd,J=4.3,11.0Hz,1H),3.73(q,J=6.3Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):554.1(M+H + ).

[0656] 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)

[0657]

[0658] To (S)-2-aminopropane-1-sulfonamide (87 mg, 0.63 mmol, 1.5 equivalents) and triethylamine (0.18 mL, 1.26 mmol, 3.0 equivalents) in a solution of dichloromethane / methanol (3: 1) (4 mL) was added (Z)-N-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbonimido chloride (200 mg, 0.42 mmol, 51.1). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) to give a white solid, which was further subjected to SFC purification to separate the two enantiomers.

[0659] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Cellulose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0660] Compound 61: (20.8 mg, 0.036 mol, 9% yield, 96% purity, 99% deuterated, OR: -84.4). 1 H NMR(DMSO-d6,400MHz)δ7.8(m,4H),7.6-7.7(m,2H),7.3-7.4(m,3H),7.23(t,J=8.6Hz,6H),5.02(dd,J=4.2,11.2Hz,1H),4.27(t,J=11.3Hz,1H ),3.9-4.0(m,1H),3.77(dd,J=4.2,11.3Hz,1H),3.3-3.4(m,2H),2.88(dd,J=11.0,13.3Hz,1H),1.42(d,J=6.5Hz,3H).LC-MS(ESI+):578.0(M+H) + ).

[0661] Compound 62: (32.1 mg, 0.056 mmol, 13% yield, 98% purity, 99% deuterated, OR: +198.1). 1H NMR(DMSO-d6,400MHz)δ7.94(br d,J=8.3Hz,1H),7.7-7.9(m,4H),7.54(d,J=8.5Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,5H),6 .96(s,2H),5.09(dd,J=4.1,11.1Hz,1H),4.57(t,J=11.2Hz,1H),4.3-4.5(m,1H),4.08(br dd,J=4.0,11.2Hz,1H),3.44(dd,J=6.3,14.1Hz,1H),3.25(dd,J=6.1,14.1Hz,1H),1.26(d,J=6.7Hz,3H).LC-MS(ESI+):578.1(M+H + ).

[0662] 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)

[0663]

[0664] To a solution of (S)-2-amino-3-methylbutane-1-sulfonamide (94 mg, 0.57 mmol, 1.1 equiv, 110) 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-carboximidoyl chloride (250 mg, 0.51 mmol, 63. 0, CAS No. 1309448-30-3). After stirring at room temperature for 18 hours, the reaction was diluted with dichloromethane (25 mL) and washed with HCl aqueous solution (2N, 20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) to obtain a colorless oil, which was further subjected to SFC separation conditions to obtain the following two diastereomers.

[0665] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0666] Compound 63: (7.1 mg, 0.011 mmol, 3% yield, 99% purity, 99% ee, OR: -91.8). 1 H NMR(DMSO-d6,400MHz)δ7.81(d,J=8.7Hz,2H),7.66(d,J=8.9Hz,2H),7.55(d,J=8 .7Hz,2H),7.32(d,J=7.3Hz,2H),7.2-7.3(m,3H),6.92(d,J=9.0Hz,2H),6.86(br s,2H),5.09(brd,J=3.9Hz,1H),4.47(br t,J=11.0Hz,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=1.0Hz,1H),0.7-0.8(m,6H).LC-MS(ESI+):618.1(M+H + ).

[0667] Compound 64: (22.3 mg, 0.04 mol, 7% yield, 99% purity, 99% ee, OR: +105.5). 1 H NMR(DMSO-d6,400MHz)δ7.8-7.9(m,2H),7.70(d,J=8.9Hz,2H),7.5-7.6(m,2H),7.31(d,J=7.1Hz,2H),7.2-7.3(m,3H),6.93(d,J=8.9Hz,2H),6.88(br s,2H),5.04(br d,J=9.9Hz,1H),4.6-4.8(m,1H),3.9-4.2(m,2H),3.75(s,3H),3.45(br dd,J=9.0,13.6Hz,1H),3.1-3.3(m,1H),1.7-2.0(m,1H),0.76(br d,J=6.7Hz,6H).LC-MS(ESI+):618.172(M+H + ).

[0668] Synthesis of (S)-3-(4-chlorophenyl)-4-phenyl-N'-(pyridin-3-ylsulfonyl)-N-(2-sulfamoyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 65) and (R)-3-(4-chlorophenyl)-4-phenyl-N'-(pyridin-3-ylsulfonyl)-N-(2-sulfamoyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 66)

[0669]

[0670] Synthesis of 65.1

[0671] By (pyridin-3-ylsulfonyl) dimethyl dithioimidocarbonate (0.12g, 0.47mmol, CAS#76511-39-2) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.12g, 0.47mmol, 21.0) in pyridine (10mL) mix. After refluxing for 18 hours, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography eluting with ethyl acetate / heptane mixture (0 / 100 to 80 / 20, v / v) to obtain the expected product (0.11g, 0.23mmol, 50% yield) as a colorless oil. LC-MS (ESI+): 471.0 (M+H + ).

[0672] Synthesis of compounds 65 and 66

[0673] 2-Aminoethane-1-sulfonamide hydrochloride (76 mg, 0.5 mmol, 2 eq) was added to a stirred solution of methyl 3-(4-chlorophenyl)-4-phenyl-N-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-pyrazole-1-thioimidocarboxylate (112 mg, 0.24 mmol, 65.1) and triethylamine (0.1 mL, 0.7 mmol, 3 eq) in methanol (2.3 mL). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with an ethyl acetate / heptane mixture (0 / 100 to 50 / 50) to give a colorless oil, which was further purified by SFC (Amylose-1, ISOC. 60% MeOH + 0.1% DEA) to give both enantiomers.

[0674] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0675] Compound 65: (33.0 mg, 0.06 mmol, 25% yield, 95% purity, 99% ee, OR: -68.2). 1 H NMR(DMSO-d6,400MHz)δ8.98(d,J=2.2Hz,1H),8.71(dd,J=1.2,4.8Hz,1H),8.2(m,2H),7 .72(d,J=8.6Hz,2H),7.52(dd,J=4.9,8.0Hz,1H),7.45(d,J=8.5Hz,2H),7.3-7.4(m,2H) ,7.2-7.3(m,3H),7.00(s,2H),5.11(dd,J=4.4,11.2Hz,1H),4.56(t,J=11.2Hz,1H),4.1 0 (dd, J=4.4, 11.1Hz, 1H), 3.7-3.8 (m, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 547.0 (M+H+).

[0676] Compound 66: (16.6 mg, 0.03 mmol, 13% yield, 99% purity, 99% ee, OR: +102.5). 1 H NMR(DMSO-d6,400MHz)δ8.98(d,J=2.1Hz,1H),8.71(dd,J=1.4,4.8Hz,1H),8.20(td,J=1.8,8 .1Hz,2H),7.72(d,J=8.7Hz,2H),7.53(dd,J=4.8,7.9Hz,1H),7.45(d,J=8.7Hz,2H),7.3-7.4( m,2H),7.2-7.3(m,3H),7.00(s,2H),5.11(dd,J=4.4,11.2Hz,1H),4.56(t,J=11.2Hz,1H),4.1 0 (dd, J=4.4, 11.1Hz, 1H), 3.74 (q, J=6.3Hz, 2H), 3.2-3.3 (m, 2H). LC-MS (ESI+): 547.0 (M+H+).

[0677] 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)

[0678]

[0679] Synthesis of 67.1

[0680] Dimethyl ((1-methyl-1H-imidazol-4-yl)sulfonyl)carbonimidodithioate (65 mg, 0.24 mmol, 111) 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 desired product (110 mg, 0.23 mmol, 95% yield) as a light yellow oil. LC-MS (ESI+): 474.1 (M+H + ).

[0681] Synthesis of compounds 67 and 68

[0682] At room temperature, 2-aminoethane-1-sulfonamide hydrochloride (75mg, 0.5mmol, 2 equivalents) is added to 3-(4-chlorophenyl)-N-((1-methyl isophthalic acid H-imidazoles-4-yl) sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazoles-1-thioimidocarboxylic acid methyl ester (110mg, 0.23mmol, 67.1) and triethylamine (0.1mL, 0.7mmol, 3 equivalents) in the stirred solution of methyl alcohol (1.5mL).After stirring for 18 hours, removal of solvent under reduced pressure.Residue is eluted with ethyl acetate / heptane mixture (0 / 100 to 60 / 40) and carried out silica gel chromatography separation.The product obtained is eluted with methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) by flash chromatography on silica gel and is purified again.The colorless oil obtained is further carried out SFC purification, obtain two enantiomers.

[0683] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0684] Compound 67: (8.4 mg, 0.015 mmol, 7% yield, 99% purity, 99% ee, OR: -43.9). 1 H NMR(CDCl3,400MHz)δ7.8-8.1(m,2H),7.53(br d,J=8.4Hz,2H),7.44(s,1H),7.33(m,1H),7.2-7.3(m,4H),7.11(br d,J=7.2Hz,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 + ).

[0685] Compound 68: (5.6 mg, 0.01 mmol, 5% yield, 97% purity, 99% ee, OR: +27.4). 1 H NMR(CDCl3,400MHz)δ7.9-8.3(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 + ).

[0686] 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)

[0687]

[0688] Synthesis of 69.1

[0689] A solution of 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) was refluxed at 120 ° C for 18 hours. Upon completion, the reaction mixture was concentrated to dryness, and the pale yellow crude 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 + ).

[0690] Synthesis of compounds 69 and 70:

[0691] 2-aminoethane-1-sulfonamide hydrochloride (332mg, 2.07mmol, 2 equivalents) is added to 3-(4-fluorophenyl)-4-phenyl-N-(pyridin-3-ylsulfonyl)-4,5-dihydro-1H-pyrazoles-1-thioimidomethyl formate (470mg, 1.03mmol, 69.1) and triethylamine (0.43mL, 3.1mmol, 3 equivalents) in the stirred solution of methanol (6mL).After stirring at room temperature for 18 hours, decompression removal of solvent.Residue is eluted with methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) and carried out silica gel chromatography separation, obtain colorless oil, it is further carried out SFC purification to split two enantiomers.

[0692] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0693] Compound 69: (26.7 mg, 0.05 mmol, 5% yield, 98% purity, 99% ee, OR: -108.9). 1H NMR(DMSO-d6,400MHz)δ8.98(d,J=2.2Hz,1H),8.71(dd,J=1.4,4.8Hz,1H),8.20(td,J=1.8,8.0Hz,2H ),7.77(dd,J=5.6,8.7Hz,2H),7.52(dd,J=4.9,8.0Hz,1H),7.3-7.4(m,2H),7.2-7.3(m,5H),7.02(br s,2H),5.11(dd,J=4.2,11.1Hz,1H),4.55(t,J=11.1Hz,1H),4.10(dd,J=4.3,11.1Hz,1H),3.7-3.8(m,2H),3.2-3.3(m,2H).LC-MS(ESI+):531.1(M+H) + ).

[0694] Compound 70: (75.2 mg, 0.14 mmol, 14% yield, 99% purity, 99% ee, OR: +66.7). 1 H NMR(DMSO-d6,400MHz) δ8.98(d,J=2.1Hz,1H),8.71(dd,J=1.3,4.8Hz,1H),8.20(td,J=1.8,8.0Hz,1H),7.77(dd,J=5.6,8.6Hz,2H),7.52(dd,J=4.9,8. 0Hz,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 ,11.2Hz,1H),4.54(t,J=11.2Hz,1H),4.10(dd,J=4.3,11.1Hz,1H),3.74(br t,J=6.7Hz,2H),3.2-3.3(m,2H).LC-MS(ESI+):531.1(M+H + ).

[0695] 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)

[0696]

[0697] Synthesis of 71.1

[0698] A solution of dimethyl ((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)carbonimidodithioate (1.45 g, 4.9 mmol, 112) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (1.3 g, 4.9 mmol, 21.0) in pyridine (7 mL) was refluxed at 120 ° C for 18 hours. Upon completion, the reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give the desired product (1.09 g, 2.2 mmol, 44% yield) as a yellow oil. LC-MS (ESI+): 503.1 (M+H + ).

[0699] Synthesis of compounds 71 ​​and 72

[0700] 2-Aminoethane-1-sulfonamide hydrochloride (0.2g, 1.24mmol, 2.5 equivalents) is added to a stirred solution of (Z)-3-(4-chlorophenyl)-N-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thioimidocarboxylic acid methyl ester (0.25g, 0.5mmol, 71.1) and triethylamine (0.24mL, 1.74mmol, 3.5 equivalents) in methanol (2mL). After stirring at room temperature for 18 hours, the solvent is removed under reduced pressure. The residue is eluted with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) for silica gel chromatography to give a colorless oil, which is further subjected to SFC purification to split the two enantiomers.

[0701] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0702] Compound 71: (30.1 mg, 0.052 mmol, 10% yield, 95% purity, 99% ee, OR: -92.3). 1H NMR(DMSO-d6,400MHz)δ8.01(s,1H),7.74(d,J=8.6Hz,2H),7.46(d,J=8.6Hz,2H),7.31-7.36(m,2H),7. 21-7.28(m,3H),5.10(dd,J=11.2,4.2Hz,1H),4.79(spt,J=6.6Hz,1H),4.53(t,J=11.2Hz,1H),4.09(br dd,J=11.1,4.1Hz,1H),3.77(br t,J=6.8Hz,2H),3.27(m,5H),1.43(dd,J=6.7,2.1Hz,6H)ppm.LC-MS(ESI+):579.1(M+H + ).

[0703] Compound 72: (28.8 mg, 0.05 mmol, 10% yield, 98% purity, 99% ee, OR: +97.1). 1 H NMR(DMSO-d6,400MHz)δ8.01(s,1H),7.73(d,J=8.6Hz,2H),7.45(d,J=8.6Hz,2H),7.29-7.35(m,2H),7. 20-7.29(m,3H),5.08(dd,J=11.2,4.2Hz,1H),4.79(spt,J=6.6Hz,1H),4.53(t,J=11.3Hz,1H),4.08(br dd,J=11.2,4.1Hz,1H),3.77(br t,J=6.8Hz,2H),3.26-3.29(m,5H),1.43(dd,J=6.7,2.0Hz,6H)ppm.LC-MS(ESI+):579.1(M+H + ).

[0704] 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)

[0705]

[0706] 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-thioimidocarbamate (73.1)

[0707] By ((2- methyl -2H-1,2,3- triazole -4- bases) sulfonyl) dimethyl dithioimidocarbonate (1.17g, 4.4mmol, 113) and 3- (4- chlorophenyl) -4-phenyl -4,5- dihydro -1H- pyrazole (1.1g, 4.4mmol, 21.0) pyridine (6mL) solution was refluxed at 120 DEG C for 18 hours. Upon completion, the reaction mixture was concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give the expected product (0.64g, 1.4mmol, 31% yield) as a yellow oil. LC-MS (ESI+): 475.1 (M+H + ).

[0708] Synthesis of compounds 73 and 74

[0709] 2-Aminoethane-1-sulfonamide hydrochloride (0.54g, 3.35mmol, 2.5 equivalents) is added to (Z) -3- (4- chlorophenyl) -N- ((2- methyl -2H-1,2,3- triazole -4- bases) sulfonyl) -4- phenyl -4,5- dihydro -1H- pyrazole -1- thioimidocarboxylic acid methyl ester (0.64g, 1.3mmol, 73.1) and triethylamine (0.65mL, 4.7mmol, 3.5 equivalents) in a stirred solution of methanol (2mL). After stirring at room temperature for 18 hours, the solvent is removed under reduced pressure. Residue is eluted with methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) and silica gel chromatography is performed to obtain a colorless oil, which is further subjected to SFC purification to split the two enantiomers in a white solid.

[0710] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0711] Compound 73: (27.6 mg, 0.05 mmol, 4% yield, 97% purity, 99% ee, OR: -50.7). 1H NMR(DMSO-d6,400MHz)δ8.30(br s,1H),8.03(s,1H),7.76(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H),7.30-7.37(m,2H),7.22-7.30(m,3H),7.03(s,2H),5.13(dd,J=1 1.2,4.3Hz,1H),4.57(t,J=11.2Hz,1H),4.09-4.20(m,4H),3.76(q,J=6.3Hz,2H),3.25-3.31(m,2H)ppm.LC-MS(ESI+):551.0(M+H + ).

[0712] Compound 74: (32.4 mg, 0.06 mmol, 4% yield, 94% purity, 99% ee, OR: +94.6). 1 H NMR(DMSO-d6,400MHz)δ8.30(br s,1H),8.03(s,1H),7.76(d,J=8.6Hz,2H),7.47(d,J=8.5Hz,2H),7.31-7.37(m,2H),7.23-7.29(m,3H),7.03( s,2H),5.13(dd,J=11.2,4.4Hz,1H),4.57(t,J=11.2Hz,1H),4.10-4.18(m,4H),3.76(q,J=6.3Hz,2H),3.30(br s,2H)ppm.LC-MS(ESI+):551.0(M+H + ).

[0713] 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)

[0714]

[0715] 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-thioimidate (75.1):

[0716] A solution of dimethyl ((1-isopropyl-1H-1,2,3-triazol-5-yl)sulfonyl)carbonimidodithioate (0.29 g, 0.98 mmol, 114) and 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (0.25 g, 0.098 mmol, 21.0) in pyridine (3 mL) was refluxed at 120 ° C for 18 hours. Upon completion, the reaction mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate / heptane mixture (0 / 100 to 50 / 50, v / v) to give the desired product (0.1 g, 0.19 mmol, 20% yield) as a yellow oil. LC-MS (ESI+): 503.1 (M+H + ).

[0717] Synthesis of compounds 75 and 76

[0718] 2-Aminoethane-1-sulfonamide hydrochloride (78mg, 0.5mmol, 2.5 equivalents) is added to 3-(4-chlorophenyl)-N-((1-isopropyl-1H-1,2,3-triazole-5-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thioimidocarboxylic acid methyl ester (98mg, 0.2mmol, 75.1) and triethylamine (0.1mL, 0.7mmol, 3.5 equivalents) in a stirred solution of methanol (2mL). After stirring at room temperature for 18 hours, the solvent is removed under reduced pressure. The residue is eluted with methanol / dichloromethane mixture (0 / 100 to 10 / 90, v / v) for silica gel chromatography to obtain a light yellow oil, which is further subjected to SFC purification to split the two enantiomers in a light yellowish white solid.

[0719] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0720] Compound 75: (7.4 mg, 0.013 mmol, 6% yield, 99% purity, 99% ee, OR: -60.9). 1H NMR(DMSO-d6,400MHz)δ8.30(br s,1H),8.00(s,1H),7.73(br d,J=8.3Hz,2H),7.46(d,J=8.6Hz,2H),7.30-7.37(m,2H),7.21-7.29(m,3H),7.05(s,2H),5.21(dt,J=13.2,6.5Hz,1H),5.13(br dd,J=11.3,3.6Hz,1H),4.54(br t,J=11.2Hz,1H),4.03(br dd,J=11.0,4.1Hz,1H),3.74(br s,2H),3.26(br s,2H),1.52(br d,J=6.6Hz,6H)ppm.LC-MS(ESI+):579.1(M+H + ).

[0721] Compound 76: (9.7 mg, 0.017 mmol, 9% yield, 98% purity, 99% ee, OR: +73.3). 1 H NMR(DMSO-d6,400MHz)δ8.31(br s,1H),8.00(s,1H),7.73(d,J=8.5Hz,2H),7.46(d,J=8.6Hz,2H),7.31-7.37( m,2H),7.22-7.28(m,3H),7.05(s,2H),5.21(dt,J=13.3,6.6Hz,1H),5.14(br dd,J=11.1,4.3Hz,1H),4.54(t,J=11.2Hz,1H),4.03(br dd,J=10.9,4.2Hz,1H),3.74(br d,J=5.4Hz,2H),3.28(br s,2H),1.52(br d,J=6.5Hz,6H)ppm.LC-MS(ESI+):579.1(M+H + ).

[0722] 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)

[0723]

[0724] Synthesis of 77.2

[0725] 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# 34543-04-9) at room temperature. After stirring at 110°C for 10 hours, 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: 400MHz, DMSO-d6δppm3.73(dd,J=11.38,5.07Hz,1H),4.28(t,J=11.50Hz,1H),5.08(dd,J=1 1.50,4.95Hz,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)

[0726] Synthesis of 77.3

[0727] 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: 400MHz, DMSO-d6δppm 4.00 (dd, J=12.53, 5.56Hz, 1H), 4.65 (br t,J=11.92Hz,1H),5.36(dd,J=11.25,5.75Hz,1H),7.46-7.55(m,3H),7.59-7.77(m,6H),7.90-7.94(m,2H),11.62(br d,J=4.16Hz,1H).

[0728] Synthesis of compounds 77 and 78

[0729] To a solution of 77.3 (220 mg, 424.86 μmol, 1 eq) in dichloromethane (3 mL) was added triethylamine (236.54 μL, 1.70 mmol, 4 eq) and 2-aminoethanesulfonamide (79.13 mg, 637.29 μmol, 1.5 eq) 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 a racemate (220 mg, 363.33 μmol, 86%) as a white solid. LCMS (ESI+): m / z 605.1 (M+H) + ; 1 H NMR: 400MHz, DMSO-d6δppm 3.28(br t,J=6.60Hz,2H),3.67-3.80(m,2H),3.99-4.11(m,1H),4.54(t,J=11.19Hz,1H),5.19(dd,J= 11.19,4.34Hz,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) The racemate (200 mg, 330.30 μmol, 1 eq) was separated by SFC to give compound 77 (40 mg, 65.53 μmol, 20%) and compound 78 (34 mg, 56.15 μmol, 17%) as white solids.

[0730] 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%, running time: 10 minutes.

[0731] Compound 77: 1 H NMR(400MHz,DMSO-d6)δppm 3.24-3.31(m,2H),3.66-3.80(m,2H),4.07(dd,J=11.27,4.23Hz,1H),4.54(t,J=11.32Hz,1H),5.14-5.24(m,1H),7.04(br s,2H),7.47(d,J=8.70Hz,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.

[0732] Compound 78: 1 H NMR (400MHz, DMSO-d6) δppm 3.29 (s, 2H), 3.74 (br d, J = 4.28Hz, 2H), 4.07 (br dd,J=11.31,4.22Hz,1H),4.54(t,J=11.25Hz,1H),5.19(dd,J=11.13,4.40Hz,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 / z604.90(M+H) + ;OR:141.40.

[0733] 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)

[0734]

[0735] Synthesis of 81.1

[0736] To a solution of 21.0 (157 mg, 716.18 μmol, 1 eq) in toluene (2 mL) was added 115 (183.87 mg, 716.18 μmol, 1 eq) 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 81.1 (127 mg, 257.49 μmol, 36%) as a white solid. LCMS (ESI+): m / z 443.9 (M+H) + . 1 H NMR: 400MHz, DMSO-d6δppm 3.71(dd,J=11.21,4.77Hz,1H),3.90(s,3H),4.30(t,J=11.38Hz,1H),4.98(dd,J=11.38,4.71Hz,1H),7.16- 7.25(m,3H),7.30(brd,J=7.51Hz,2H),7.42(d,J=8.58Hz,2H),7.78-7.87(m,3H),8.41(s,1H),11.32(s,1H).

[0737] Synthesis of 81.2

[0738] To a solution of 81.1 (157 mg, 353.68 μmol, 1 eq) in toluene (4 mL) was added N,N-diisopropylethylamine (92.40 μL, 530.52 μmol, 92.40 μL, 1.5 eq) and phosphorus oxychloride (42.73 μL, 459.78 μmol, 1.3 eq) 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) + .

[0739] Synthesis of 81 and 82:

[0740] To a solution of 81.2 (157 mg, 339.57 μmol, 1 eq) in dichloromethane (5 mL) was added triethylamine (236.32 μL, 1.70 mmol, 5 eq) and 2-aminoethanesulfonamide (63.24 mg, 393.72 μmol, 1.16 eq) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by 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) + . 1 H NMR: 400MHz, DMSO-d6δppm 3.17(s,3H),3.30(br s, 1H), 3.80 (brs, 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 enantiomers (130 mg, 236.34 μmol, 1 equiv) were separated by SFC to give compound 81 (15 mg, 27.27 μmol, 12%) and compound 82 (15 mg, 27.27 μmol, 12%) as two white solids.

[0741] 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%, running time: 10 minutes.

[0742] Compound 81: 1 H NMR (400MHz, DMSO-d6) δppm 3.30 (br s, 2H), 3.72-3.87 (m, 5H), 4.13 (br dd, J=10.76, 4.03Hz, 1H), 4.54 (br t,J=11.25Hz,1H),5.09(dd,J=11.31,4.34Hz,1H),7.05(s,2H),7.21-7.29(m,3H),7.32(br d,J=7.34Hz,2H),7.46(d,J=8.56Hz,2H),7.69(s,1H),7.75(d,J=8.56Hz,2H),8.04(br s,1H),8.13(s,1H)LCMS(ESI+):m / z 550.0(M+H) + OR:-111.80.

[0743] Compound 82: 1 H NMR(400MHz,DMSO-d6)δppm 3.29(s,2H),3.72-3.90(m,5H),4.05-4.19(m,1H),4.54(t,J=11.25Hz,1H),5.08(dd,J=11.25,4.40Hz,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(brt,J=5.07Hz,1H),8.13(s,1H).LCMS(ESI+):m / z 550.0(M+H) + .OR:118.20.

[0744] 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)

[0745]

[0746] To a solution of (S)-2-aminopropionamide 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-carbonimidoyl chloride (0.25 mg, 0.5 mmol, 1 equiv). After stirring at room temperature for 18 hours, the reactant was diluted with dichloromethane (20 mL) and washed with 2N HCl (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a methanol / dichloromethane mixture (0 / 100 to 10 / 90) to give the desired compound as a colorless oil. The racemic compound was further subjected to SFC to separate the enantiomers.

[0747] SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-iPrOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0748] Compound 83: (103.5 mg, 0.17 mmol, 36% yield, 99% purity, 99% ee). 1 H NMR(400MHz,DMSO-d6)δ8.18(br d,J=6.1Hz,1H),8.03(d,J=8.1Hz,2H),7.84(d,J=8.4Hz,2H),7.65(d,J=8.7Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,3H),7.03(br s,2H),6.92(d,J=8.9Hz,2H),5.06(dd,J=4.1,10.9Hz,1H),4.49(t,J=11.1Hz,1H),4.02(dd,J=4.0,11.2Hz,1H),3.75(s,3H),3.72(br s,2H),3.29(br d,J=7.2Hz,2H).LC-MS(ESI+):610.2(M+H + ).

[0749] Compound 84: (103.3 mg, 0.17 mmol, 36% yield, 99% purity, 99% ee). 1 H NMR (400MHz, DMSO-d6) δ8.16(br s,1H),8.02(d,J=8.2Hz,2H),7.83(d,J=8.4Hz,2H),7.64(br d,J=8.7Hz,2H),7.3-7.4(m,2H),7.2-7.3(m,3H),7.02(br s,2H),6.91(d,J=8.9Hz,2H),5.05(dd,J=4.0,11.0Hz,1H),4.48(t,J=11.2Hz,1H),4.01(dd,J=4.0,11.2Hz,1H),3.74(s,3H),3.71(br s,2H),3.3(m,3H).LC-MS(ESI+):610.2(M+H + ).

[0750] 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)

[0751]

[0752] Synthesis of 85.1

[0753] To a solution of 21.0 (365 mg, 1.67 mmol, 1 eq) in toluene (3 mL) was added methyl ((1-methyl-1H-pyrazol-3-yl)sulfonyl)carbamate (427.46 mg, 1.67 mmol, 1 eq) 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 85.1 (300 mg, 608.24 μmol, 37%) as a white solid. LCMS (ESI+): m / z 443.9 (M+H) + . 1H NMR: 400MHz, DMSO-d6δppm3.69(dd,J=11.37,4.65Hz,1H),3.94(s,3H),4.27(t,J=11.37Hz,1H),4.98(dd,J=11.43,4.71Hz,1H),6. 71-6.81(m,1H),7.16-7.26(m,2H),7.28-7.36(m,2H),7.42(d,J=8.68Hz,2H),7.84(d,J=8.68Hz,2H),7.87-7.91(m,1H),11.54(br s,1H),12.09(br s,1H).

[0754] Synthesis of 85.2

[0755] To a solution of 85.1 (300 mg, 675.82 μmol, 1 eq) in toluene (7 mL) was added N,N-diisopropylethylamine (176.57 μL, 1.01 mmol, 1.5 eq) and phosphorus oxychloride (134.71 mg, 878.56 μmol, 81.64 μL, 1.3 eq) 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) + .

[0756] Synthesis of compounds 85 and 86

[0757] To a solution of 85.2 (300 mg, 648.86 μmol, 1 eq) in dichloromethane (3 mL) was added triethylamine (451.56 μL, 3.24 mmol, 5 eq) and 2-aminoethanesulfonamide (80.56 mg, 648.86 μmol, 1 eq) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a racemate (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.

[0758] SFC method: column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase A: CO 2 ; mobile phase B: IPA (0.1% IPAm, v / v); B%: 55%, running time: 10 minutes.

[0759] Compound 85: 1 H NMR (400MHz, DMSO-d6) δppm 3.26-3.31(m,2H),3.74-3.88(m,5H),4.13(br dd,J=10.57,3.81Hz,1H),4.54(br t,J=11.32Hz,1H),5.09(dd,J=11.19,4.32Hz,1H),6.51(d,J=2.25Hz,1H),7.0 2(s,2H),7.21-7.37(m,5H),7.46(d,J=8.63Hz,2H),7.69-7.81(m,3H),8.15(br s,1H); LCMS(ESI+):m / z 550.0(M+H) + .

[0760] Compound 86: 1 H NMR (400MHz, DMSO-d6) δppm 3.27 (br s, 2H), 3.81 (s, 5H), 4.00-4.18 (m, 1H), 4.49 (br t, J=11.01Hz, 1H), 5.04 (br dd,J=10.57,3.69Hz,1H),6.49(d,J=2.13Hz,1H),7.20-7.35(m,6H),7.45(d,J=8.63Hz,2H),7.69-7.76(m,3H); LCMS(ESI+):m / z 550.0(M+H) + .

[0761] 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)

[0762]

[0763] Synthesis of compounds 87 and 88:

[0764] 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-carboximidoyl chloride (250 mg, 0.51 mmol, 1.0 equiv). After stirring at room temperature for 18 hours, 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 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).

[0765] SFC method: SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-EtOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0766] Compound 87: 1 H NMR(DMSO-d6,400MHz)δ7.85(br s,1H),7.80(d,J=8.6Hz,2H),7.73(d,J=8.7Hz,2H),7.56(d,J=8.6Hz,2H),7.45(d,J=8.6Hz,2H),7.31-7.37(m,2H),7.22 -7.29(m,3H),6.98(s,2H),5.10(dd,J=11.1,4.1Hz,1H),4.57(t,J=11.2Hz,1H),4.08(brdd,J=11.0,3.8Hz,1H),3.37(br s,1H),3.30(s,1H),3.03(s,2H),1.01(s,6H)ppm.LC-MS(ESI+):622.0(M+H+).

[0767] Compound 88: 1H NMR(DMSO-d6,400MHz)δ7.85(br s,1H),7.80(d,J=8.6Hz,2H),7.73(d,J=8.6Hz,2H),7.56(d,J=8.7Hz,2H),7.45(d,J=8.7Hz,2H),7.31-7.37(m,2H),7.21 -7.29(m,3H),6.98(s,2H),5.10(dd,J=11.1,4.1Hz,1H),4.57(t,J=11.2Hz,1H),4.08(brdd,J=11.1,3.8Hz,1H),3.43(br s,1H),3.29(s,1H),3.03(s,2H),1.01(s,6H)ppm.LC-MS(ESI+):622.0(M+H+).

[0768] 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)

[0769]

[0770] Synthesis of compounds 89 and 90

[0771] To a solution of 3-amino-2,2-dimethylpropane-1-sulfonamide (121 mg, 0.72 mmol, 1.5 eq) and triethylamine (0.2 mL, 1.5 mmol, 3.0 eq) 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 eq). After stirring at room temperature for 18 hours, 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 60 / 40, v / v) to give a colorless oil, which was further subjected to SFC separation conditions to give the following 2 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).

[0772] SFC method: SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV + 1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with 3 ml / min of CO2 (40%)-MeOH + 0.1% diethylamine at 35°C and a BPR of 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0773] Compound 89: 1 H NMR(DMSO-d6,400MHz)δ7.74-7.88(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=11.0,4.1Hz,1H),4.56(br t,J=11.1Hz,1H),4.08(br dd, J=11.0, 3.7Hz, 1H), 3.30 (s, 2H), 3.03 (s, 2H), 1.01 (s, 6H) ppm. LC-MS (ESI+): 606.1 (M+H+).

[0774] Compound 90: 1 H NMR(DMSO-d6,400MHz)δ7.74-7.85(m,5H),7.56(d,J=8.7Hz,2H),7.30-7.37(m,2H),7.19-7.29(m,5H),6.98(br s,2H),5.10(br dd,J=11.2,4.1Hz,1H),4.56(t,J=11.1Hz,1H),4.07(br dd, J=10.9, 3.6Hz, 1H), 3.30 (s, 2H), 3.03 (s, 2H), 1.01 (s, 6H) ppm. LC-MS (ESI+): 606.1 (M+H+).

[0775] (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), ( 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)

[0776]

[0777] Synthesis of compounds 91-94

[0778] 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-carboximidoyl chloride (300 mg, 0.61 mmol, 1.0 equiv). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel 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 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).

[0779] SFC method: SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with a CO2 (40%) flow rate of 3 ml / min. i PrOH + 0.1% diethylamine was carried out at 35°C and BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0780] Compound 91: 1 H NMR(MeOD-d4,400MHz)δ7.85(d,J=8.6Hz,2H),7.69(d,J=8.6Hz,2H),7.48(d,J=8.6Hz ,2H),7.17-7.37(m,7H),4.94(dd,J=11.3,4.7Hz,1H),4.54(t,J=11.3Hz,1H),4.10(dd ,J=11.3,4.7Hz,1H),3.41-3.60(m,2H),3.23(dd,J=14.3,5.0Hz,1H),2.98(dd,J=14.3 ,7.4Hz,1H),2.37-2.52(m,1H),1.10(d,J=6.9Hz,3H)ppm.LC-MS(ESI+):608.0(M+H+).

[0781] Compound 92: 1 H NMR(MeOD-d4,400MHz)δ7.85(d,J=8.5Hz,2H),7.70(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),7.17-7.3 7(m,7H),4.94(dd,J=11.2,4.6Hz,1H),4.55(t,J=11.3Hz,1H),4.09(dd,J=11.2,4.6Hz,1H),3.50(br d, J=6.1Hz, 2H), 3.23 (dd, J=14.3, 4.9Hz, 1H), 2.97 (dd, J=14.3, 7.3Hz, 1H), 2.38-2.51 (m, 1H), 1.11 (d, J=6.8Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0782] Compound 93: 1H NMR(MeOD-d4,400MHz)δ7.85(d,J=8.6Hz,2H),7.69(d,J=8.6Hz,2H),7.48(d,J=8.6Hz ,2H),7.17-7.37(m,7H),4.94(dd,J=11.2,4.7Hz,1H),4.54(t,J=11.3Hz,1H),4.10(dd ,J=11.3,4.7Hz,1H),3.41-3.59(m,2H),3.23(dd,J=14.3,4.9Hz,1H),2.98(dd,J=14.3 ,7.4Hz,1H),2.37-2.51(m,1H),1.10(d,J=6.9Hz,3H)ppm.LC-MS(ESI+):608.0(M+H+).

[0783] Compound 94: 1 H NMR(MeOD-d4,400MHz)δ7.85(d,J=8.6Hz,2H),7.70(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),7.16-7.3 8(m,7H),4.94(dd,J=11.2,4.6Hz,1H),4.55(t,J=11.3Hz,1H),4.08(dd,J=11.3,4.6Hz,1H),3.50(br d,J=6.2Hz,2H),3.23(dd,J=14.3,4.9Hz,1H),2.97(dd,J=14.3,7.4Hz,1H),2.45(br dd, J=12.2, 6.7Hz, 1H), 1.10 (d, J=6.8Hz, 3H) ppm. LC-MS (ESI+): 608.0 (M+H+).

[0784] (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), ( 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)

[0785]

[0786] Synthesis of compounds 95-98

[0787] 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-carboximidoyl chloride (300 mg, 0.61 mmol, 1.0 equiv). After stirring at room temperature for 18 hours, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate / heptane mixtures (0 / 100 to 60 / 40) to give a colorless oil, which was further purified by SFC to separate 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).

[0788] SFC method: SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) using a Phenomenex column (Lux Amylose-3) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode at 3 ml / min of CO2 (40%)– i PrOH + 0.1% diethylamine was carried out at 35°C and BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0789] 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, 1H), 4.53 (t, J = 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+).

[0790] 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. March 5 (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+).

[0791] Compound 97: 1 1H NMR (MeOD-d4, 400 MHz) δ 7.82 - 7.88 (m, 2H), 7.70 (d, J = 8.4 Hz, 2H), x0000465 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+).

[0792] Compound 98: 1H NMR(MeOD-d4,400MHz)δ7.85(d,J=8.6Hz,2H),7.70(d,J=8.7Hz,2H),7.48(d,J=8 .5Hz,2H),7.18-7.35(m,7H),4.93(dd,J=11.2,4.6Hz,1H),4.54(t,J=11.3Hz,1H ),4.07(dd,J=11.3,4.6Hz,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 = 6.9Hz, 3H) ppm. LC-MS (ESI+): 608.1 (M+H+).

[0793] 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)

[0794]

[0795] Synthesis of compounds 99 and 100

[0796] 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-carboximidoyl chloride (250 mg, 0.51 mmol, 1.0 equiv). After stirring at room temperature for 18 hours, the mixture was diluted with dichloromethane (15 mL) and washed with ammonium chloride (20 mL) and water (20 mL). The organic extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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).

[0797] SFC method: SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with a CO2 (40%) flow rate of 3 ml / min. i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0798] Compound 99: (13.6 mg, 0.022 mmol, 5% yield, 98% purity, 99% ee, OR: -60.7). 1 H NMR (CDCl3, 400MHz) δ7.80-7.90(m,2H),7.53(br d,J=5.7Hz,2H),7.42(br d,J=4.9Hz,2H),7.33(br d,J=4.6Hz,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=7.1Hz,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).

[0799] Compound 100: (13.4 mg, 0.022 mmol, 5% yield, 99% purity, 99% ee, OR: +60.1). 1H NMR(CDCl3,400MHz)δ7.81-7.89(m,2H),7.51(br d,J=5.0Hz,2H),7.37-7.44(m,2H),7.27-7.36(m,5H),7.12(br s,2H),7.05(br dd,J=2.7,1.1Hz,1H),4.75(br d,J=2.1Hz,2H),4.61-4.71(m,1H),4.49-4.59(m,1H),4.05-4.17(m,1H),3.71(br d,J=4.3Hz,2H),3.12-3.24(m,2H),2.00(br s, 2H), 1.83-1.94 (m, 2H) ppm. LC-MS (ESI+): 608.0 (M+H+); HPLC RT: 3.867 min (method; VILLA).

[0800] 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)

[0801]

[0802] Synthesis of compounds 101 and 102

[0803] 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-carboximidoyl chloride (250 mg, 0.52 mmol, 51.1). After stirring at room temperature for 18 hours, the mixture was diluted with dichloromethane (20 mL) and washed with ammonium chloride (20 mL) and water (20 mL). The organic extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel 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 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).

[0804] SFC method: SFC purification was performed on a Jasco 4000 parallel SFC system (4x channels 3xUV+1xDAD) using a Phenomenex column (Lux Amylose-1) 150 mm long x 4.6 mm ID 5 μm particle size in isocratic mode with a CO2 (40%) flow rate of 3 ml / min. i PrOH + 0.1% diethylamine was carried out at 35° C., BPR 100 bar. The DAD detector was set to an acquisition frequency of 220 nm.

[0805] Compound 101: 1 H NMR(DMSO-d6,400MHz)δ8.12(br s,1H),7.79(dt,J=8.7,2.5Hz,4H),7.54(d,J=8.6Hz,2H),7.30-7.38(m,2H),7.19-7. 28(m,5H),6.76(s,2H),5.06(dd,J=11.1,4.3Hz,1H),4.50(t,J=11.2Hz,1H),4.03(br dd, J=11.1, 4.3Hz, 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+).

[0806] Compound 102: 1H NMR(DMSO-d6,400MHz)δ8.12(br s,1H),7.75-7.84(m,4H),7.54(d,J=8.5Hz,2H),7.29-7.36(m,2H),7.19-7.27(m,5H),6.76(s,2H), 5.06(dd,J=11.1,4.2Hz,1H),4.50(t,J=11.2Hz,1H),3.99-4.05(m,1H),3.28-3.31(m,2H),2.95(br t, J=7.3Hz, 2H), 1.54-1.74 (m, 4H)ppm. LC-MS (ESI+): 592.1 (M+H+).

[0807] 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)

[0808]

[0809] Synthesis of 103.1

[0810] To a solution of I19 (370 mg, 1.66 mmol, 1 eq) in dioxane (4 mL) and pyridine (1 mL) was added methyl ((4-chlorophenyl)sulfonyl)carbamate (435.53 mg, 1.74 mmol, 1.05 eq) 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: 400MHz, DMSO-d6δppm 0.51(d,J=6.85Hz,3H),0.91(d,J=6.85Hz,3H),1.97-2.09(m,1H),3.71-3.86(m,3H),7 .54(d,J=8.56Hz,2H),7.71(d,J=8.56Hz,2H),7.95(dd,J=13.75,8.62Hz,4H),11.34(br s,1H).

[0811] Synthesis of 103.2

[0812] To a solution of 103.1 (150 mg, 340.64 μmol, 1 eq) in toluene (2 mL) was added diisopropylethylamine (77.13 μL, 442.84 μmol, 1.3 eq) and phosphorus oxychloride (37.99 μL, 408.77 μmol, 1.2 eq) at room temperature. After stirring at 80 ° C for 6 hours, 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: 400MHz, DMSO-d6δppm 0.52-0.60(m,3H),0.97(d,J=6.79Hz,3H),2.08(td,J=6.94,3.16Hz,1H),3.97-4.22(m, 3H),7.59(d,J=8.58Hz,2H),7.64-7.71(m,2H),7.84(d,J=8.58Hz,2H),7.90-7.96(m,2H)

[0813] Synthesis of compounds 103 and 104

[0814] To a solution of 103.1 (120 mg, 261.56 μmol, 1 eq) in dichloromethane (2 mL) at room temperature were added 2-aminoethane-1-sulfonamide (50.41 mg, 313.87 μmol, 1.2 eq, HCl salt) and triethylamine (66.17 mg, 653.89 μmol, 2.5 eq). After stirring at room temperature for 10 hours, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL x 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 a racemate (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) + .

[0815] SFC method: column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase A: CO 2 , mobile phase B: [0.1% NH 3 H 2 O / IPA]; mobile phase B%: 50%; running time: 12 minutes.

[0816] Compound 103: 1 H NMR: 400MHz, DMSO-d6δppm 0.55(d,J=6.79Hz,3H),0.91(d,J=6.79Hz,3),2.01(ddd,J=9.83,6.62,3.34Hz,1H),3.20(br t,J=6.85Hz,2H),3.66(br d,J=3.46Hz,2H),3.86-3.93(m,1H),3.95-4.04(m,1H),4.15(br dd,J=10.91,2.92Hz,1H),7.00(s,2H),7.57(dd,J=8.40,5.54Hz,4H),7.87(dd,J=8.58,2.27Hz,4H),8.02(br s,1H); LCMS(ESI+):m / z 546.0(M+H) + .OR:-1.60.

[0817] Compound 104: 1 H NMR: 400MHz, DMSO-d6δppm 0.55(d,J=6.79Hz,3H),0.91(d,J=6.79Hz,3H),1.96-2.05(m,2H),3.20(t,J=6.97Hz,2H),3.60-3.71(m,2H),3.86-3.9 4(m,1H),3.95-4.03(m,1H),4.15(dd,J=11.15,3.28Hz,1H),7.00(s,2H),7.52-7.62(m,4H),7.82-7.92(m,4H),8.02(br t,J=5.54Hz,1H); LCMS(ESI+):m / z 546.0(M+H) + .OR:1.80.

[0818] 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)

[0819]

[0820] Synthesis of 105.1

[0821] 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 hours, the reaction mixture was concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether (5 mL) to afford 105.1 (270 mg, 512.77 μmol, 27%) as a white solid. 1 H NMR: 400MHz CDCl3δppm 0.64(d,J=6.91Hz,3H),0.98(d,J=6.79Hz,3H),2.14(dtt,J=10.26,6.81,6.81,3.44,3.44Hz,1H),3.63-3.72(m,1H),3.81(t,J=1 1.44Hz, 1H), 3.88-3.95 (m, 1H), 7.40-7.47 (m, 2H), 7.58-7.67 (m, 2H), 7.82 (d, J = 8.34Hz, 2H), 8.29 (d, J = 8.23Hz, 2H), 8.66 (s, 1H).

[0822] Synthesis of 105.2

[0823] To a solution of 105.1 (270 mg, 0.57 mmol, 1 eq) in toluene (5 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.85 mmol, 1.5 eq) at room temperature. After stirring at room temperature for 1 hour. Phosphorus oxychloride (0.11 g, 0.74 mmol, 0.07 mL, 1.3 eq) 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) + .

[0824] Synthesis of compounds 105 and 106

[0825] At room temperature, triethylamine (626.85 mg, 6.19 mmol, 0.86 mL, 5 equivalents) and 2-aminoethane -1- sulfonamide (230.75 mg, 1.86 mmol, 1.5 equivalents) were added to a solution of 105.2 (610 mg, 1.24 mmol, 1 equivalent) in dichloromethane (6 mL). After stirring at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (5 / 1, v / v) to obtain a racemate, which was separated by SFC to give compound 105 (76.70 mg, 128.26 μmol, 10%) and compound 106 (73.50 mg, 126.71 μmol, 10%) as a white solid.

[0826] SFC method: column; DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); mobile phase A: CO 2 ; mobile phase B: [0.1% NH 3 -H 2 O IPA]; B%: 37%-37%, run time: 10 minutes.

[0827] Compound 105: 1 H NMR:400MHz DMSO-d6δppm 8.06(d,J=8.11Hz,2H),7.82-7.93(m,4H),7.56(d,J=8.58Hz,2H),6.76 -7.24(m,2H),4.05-4.14(m,1H),3.99(t,J=10.91Hz,1H),3.85-3.93(m ,1H),3.58-3.75(m,2H),3.21(t,J=7.03Hz,2H),2.01(dq,J=9.95,6.74Hz,1H),0.89(d,J=6.79Hz,3H),0.53(d,J=6.79Hz,3H).LCMS(ESI+):m / z 580.0(M+H) + .OR:-1.90.

[0828] Compound 106: 1H NMR: 400MHz DMSO-d6δppm 8.07(d,J=8.13Hz,2H),7.82-7.94(m,4H),7.57(d,J=8.63Hz,2H),7.00(br s,2H),4.06-4.16(m,1H),4.00(t,J=10.94Hz,1H),3.87-3.94(m,1H),3.67(br s,2H),3.22(t,J=7.00Hz,2H),1.95-2.07(m,1H),0.90(d,J=6.88Hz,3H),0.54(d,J=6.75Hz,3H).LCMS(ESI+):m / z 580.0(M+H) + .OR:1.80.

[0829] 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)

[0830]

[0831] Synthesis of compounds 107 and 108

[0832] 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 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using ethyl acetate to give a racemate (400 mg, 733 μmol, 42%) as a white solid. LCMS (ESI+): m / z 578.3 (M+H) + .

[0833] The racemate (400 mg, 733 μmol, 1 eq) 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.

[0834] SFC method: column daicel chiralcel o1 (250 mm*30 mm, 10 μm); mobile phase A: CO2; mobile phase B: 0.1% NH3H2O ​​MeOH; B%: 50%, running time: 15 minutes.

[0835] Compound 107: 1 H NMR: 400MHz, DMSO-d6δppm 2.07(s,1H)3.10(s,3H)3.36-3.51(m,2H)3.72-3.92(m,3H)4.56(t,J=11.15Hz,1H)5.03(dd,J=11.27,5.07Hz,1H)6.99(s,2H)7 .15-7.27(m,3H)7.28-7.35(m,4H)7.52(d,J=8.58Hz,2H)7.66(dd,J=8.70,5.60Hz,2H)7.80(d,J=8.58Hz,2H); LCMS(ESI+):m / z 578.2(M+H) + .OR:-122.60.

[0836] Compound 108: 1 H NMR: 400MHz, DMSO-d6δppm 2.07(s,1H)3.10(s,3H)3.35-3.51(m,2H)3.73-3.91(m,3H)4.56(t,J=11.09Hz,1H)5.03(dd,J=11.32,5.13Hz,1H)6.98(s, 2H)7.15-7.27(m,3H)7.28-7.35(m,4H)7.49-7.55(m,2H)7.66(dd,J=8.82,5.48Hz,2H)7.77-7.83(m,2H); LCMS(ESI+):m / z 578.2(M+H) + ;OR:114.40.

[0837] 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)

[0838]

[0839] Synthesis of compounds 109 and 110

[0840] To a solution of 1.0 (1.27 g, 2.58 mmol, 1.5 equiv) in dichloromethane (10 mL) was added 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) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a racemate (900 mg, 908.28 μmol, 60%) as a white solid. LCMS (ESI+): m / z 593.07.0 (M+H) + .

[0841] 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.

[0842] SFC method: column: Chiralpak AD-3, 50×4.6 mm ID, 3 μm); mobile phase A: CO 2 ; mobile phase B: isopropanol (0.1% isopropanol m, v / v); B%: 50%, run time: 15 minutes.

[0843] Compound 109: 1 H NMR(400MHz,DMSO-d6)δppm 3.10(s,3H),3.42(td,J=8.85,5.94Hz,2H),3.72-3.89(m,3H),4.57(t,J=11.19Hz,1H),5.04(dd,J=11.32,5.19Hz,1H),6.98(s,2H),7.2 1-7.27(m,1H),7.28-7.35(m,4H),7.41(d,J=8.76Hz,2H),7.50-7.55(m,2H),7.61(d,J=8.63Hz,2H),7.77-7.84(m,2H); LCMS(ESI+):m / z 594.0(M+H) + ;OR:-98.70.

[0844] Compound 110: 1H NMR (400MHz, DMSO-d6) δppm 3.10 (s, 3H), 3.38-3.49 (m, 2H), 3.74-3.89 (m, 3H), 4.57 (br t, J=11.21Hz, 1H), 5.03 (br dd,J=11.32,5.01Hz,1H),6.98(s,2H),7.25(br d,J=6.32Hz,1H),7.28-7.35(m,4H),7.41(br d,J=8.46Hz,2H),7.53(brd,J=8.46Hz,2H),7.61(br d,J=8.46Hz,2H),7.80(br d,J=8.46Hz,2H); LCMS(ESI+):m / z 594.0(M+H) + ;OR:94.60.

[0845] 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)

[0846]

[0847] Synthesis of compounds 111 and 112

[0848] At room temperature, triethylamine (1.11mL, 7.98mmol, 5 equivalents) and piperidine-4-sulfonamide (262.02mg, 1.60mmol, 1 equivalent) are added to a solution of 45.1 (760mg, 1.60mmol, 1 equivalent) in dichloromethane (50mL). After stirring at room temperature for 12 hours, the mixture is concentrated under reduced pressure. The residue is purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to obtain a racemic mixture, which is separated by SFC to obtain compound 111 (36.7mg, 6.08mmol, 4%) as a white solid and compound 112 (32.7mg, 5.42mmol, 3%) as a white solid.

[0849] SFC method: column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 μm); A: CO 2 , mobile phase B: [Neu-isopropanol]; ratio: 50%, running time: 12 minutes.

[0850] Compound 111: 1H NMR: 400MHz DMSO-d6δppm 1.77(qd,J=12.38,3.87Hz,1H),1.89-2.03(m,1H),2.14(br s,2H),3.17-3.31(m,3H),3.63(dd,J=11.27,4.71Hz,1H),4.12(brt,J=14. 25Hz,2H),4.42(t,J=11.27Hz,1H),4.96(dd,J=11.21,4.65Hz,1H),6.90(s ,2H),7.17-7.27(m,5H),7.28-7.35(m,2H),7.51(d,J=8.58Hz,2H),7.69(d d,J=8.82,5.48Hz,2H),7.77(d,J=8.58Hz,2H); LCMS(ESI+):m / z604.0(M+1) + OR:-89.68.

[0851] Compound 112: 1 H NMR: 400MHz DMSO-d6δppm 1.77(qd,J=12.36,3.70Hz,1H)1.96(qd,J=12.26,3.99Hz,1H)2.14(br s,2H)3.17-3.30(m,3H)3.63(dd,J=11.21,4.65Hz,1H)4.12(br t,J=14.25Hz,2H)4.42(t,J=11.21Hz,1H)4.96(dd,J=11.09,4.65Hz,1H)6.90(s,2H)7.17-7.27(m,5H)7.31( d, J=7.03Hz, 2H) 7.51 (d, J=8.58Hz, 2H) 7.69 (dd, J=8.70, 5.48Hz, 2H) 7.77 (d, J=8.46Hz, 2H) LCMS (ESI+): m / z 604.0(M+1) + ;OR:87.67.

[0852] 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)

[0853]

[0854] Synthesis of compounds 113 and 114

[0855] To a solution of 1.0 (500 mg, 1.01 mmol, 1 equiv) in dichloromethane (5 mL) was added triethylamine (351.45 μL, 2.53 mmol, 2.5 equiv) and piperidine-4-sulfonamide (202.69 mg, 1.01 mmol, 1 equiv, HCl) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a racemate (470 mg, 0.76 mmol, 75%) as a white solid. LCMS (ESI+): m / z 620.1 (M+1) + .

[0856] The racemate (300 mg, 483 μmol, 1 eq) 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.

[0857] SFC method: column: DAICEL CHIRALCEL OD (250 mm×50 mm, 10 μm); mobile phase: [Neu-isopropanol]; B%: 50%-50%, 10 minutes.

[0858] Compound 113: 1 H NMR: 400MHz DMSO-d6δ1.70-1.88(m,1H),1.89-2.05(m,1H),2.14(br d,J=1.59Hz,2H),3.30(br s,3H),3.65(dd,J=11.19,4.83Hz,1H),4.12(br t,J=14.06Hz,2H),4.42-4.50(m,1H),4.97(dd,J=11.31,4.83Hz,1H),6.91(s,2H),7.21-7.29(m,3H),7.29-7.36(m, 2H),7.44(d,J=8.68Hz,2H),7.52(d,J=8.56Hz,2H),7.64(d,J=8.68Hz,2H),7.78(d,J=8.56Hz,2H); LCMS(ESI+):m / z 620.0(M+1) + OR:-64.82.

[0859] Compound 114: 1H NMR: 400MHz DMSO-d6δ1.69-1.86(m,1H),1.89-2.04(m,1H),2.07-2.22(m,2H),3.19-3.32(m,3H),3.65(dd,J=11.25,4.89Hz,1H),4.12(br t,J=14.00Hz,2H),4.44(t,J=11.31Hz,1H),4.97(dd,J=11.25,4.89Hz,1H),6.91(s,2H),7.22-7.28(m,3H),7.29-7.35 (m,2H),7.44(d,J=8.68Hz,2H),7.52(d,J=8.56Hz,2H),7.64(d,J=8.56Hz,2H),7.78(d,J=8.56Hz,2H); LCMS(ESI+):m / z 620.0(M+1) + ;OR:74.73.

[0860] (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, 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)

[0861]

[0862] To a solution of 1.0 (1 g, 3.15 mmol, 1 eq) in dichloromethane (5 mL) was added triethylamine (706.10 μL, 5.07 mmol, 2.5 eq) and 3-aminocyclobutane-1-sulfonamide (378.77 mg, 2.03 mmol, 1 eq) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a diastereomeric mixture (860 mg, 1.35 mmol, 66%) as a white solid. LCMS (ESI+): m / z 606.1.0 (M+H) + .

[0863] SFC method: The diastereomers (800 mg, 1.32 mmol, 1 equivalent) were separated by the first SFC to give compound 115 (102 mg, 161.78 μmol, 12%) as a white solid, compound 116 (32 mg, 52.76 μmol, 4%) as a white solid, and a racemic mixture of compound 117 and compound 118. The racemic mixture of compound 117 and compound 118 was further separated by the second SFC to give compound 117 (135 mg, 222.57 μmol, 16%) as a white solid and compound 118 (78 mg, 127.44 μmol, 9%) as a white solid. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0864] The first SFC method: column: REGIS (s,s) WHELK-O1 (250 mm × 30 mm, 10 μm); mobile phase A: [NH 3 H 2 O (0.1%) / ethanol]; mobile phase B: CO 2 ; B%: 60%, running time: 10 minutes.

[0865] Second SFC method: column; DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase A: [NH 3 H 2 O (0.1%) / methanol]; mobile phase B: CO 2 ; B%: 65%, run time; 20 minutes.

[0866] 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.

[0867] 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.

[0868] 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.

[0869] 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.

[0870] (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), ( 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)

[0871]

[0872] Synthesis of compounds 119-122

[0873] To a solution of 1.0 (2 g, 2.43 mmol, 1 eq) in dichloromethane (20 mL) was added triethylamine (1.23 g, 12.13 mmol, 1.69 mL, 5 eq) and 4-aminocyclohexane-1-sulfonamide (520.71 mg, 2.43 mmol, 1 eq) 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 two racemic mixtures as white solids. 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. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0874] Method for preparative HPLC: instrument: ACSTJ-GX-N; column: Phenomenex luna C18 250×50 mm×10 μm; mobile phase: A is H2O=(0.04% HCl) and B is acetonitrile; gradient: B from 60% to 80% in 10 minutes; flow rate: 80 mL / min; wavelength: 220 and 254 nm

[0875] SFC separation of compounds 119 and 121: Column: PHENOMENEX LUNA C18 (250 mm × 30 mm, 10 μm); Mobile phase A: [water (HCl) / ACN]; Mobile phase B: CO2; B%: 60%-80%, Run time: 10 min

[0876] SFC separation of compounds 120 and 122: Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Mobile phase A: [NH 3 H 2 O (0.1%) / ethanol]; Mobile phase B: CO 2; B%: 50%, Run time: 18 minutes

[0877] Compound 119: 1 H NMR: 400MHz, DMSO-d6; δppm 1.21-1.60 (m, 4H), 1.93 (br t, J=11.13Hz, 2H), 2.05-2.18 (m, 2H), 2.75 (br t,J=11.86Hz,1H),3.62-3.82(m,1H),3.90-4.09(m,1H),4.51(t,J=11.25Hz,1H),5.06(dd,J=11.07,4.34Hz,1H),6.72(s ,2H),7.19-7.30(m,3H),7.31-7.37(m,2H),7.46(d,J=8.68Hz,2H),7.52-7.59(m,2H),7.70-7.83(m,4H); LCMS(ESI+):m / z 634.0(M+H) + ; OR:-94.82

[0878] Compound 121: 1 H NMR: 400MHz, DMSO-d6δppm 1.19-1.60(m,4H),1.80-2.03(m,2H),2.03-2.17(m,2H),2.74(br t,J=11.74Hz,1H),3.56-3.82(m,1H),3.99(br d,J=7.58Hz,1H),4.50(t,J=11.25Hz,1H),5.05(br dd,J=11.13,4.28Hz,1H),6.72(s,2H),7.18-7.29(m,3H),7.30-7.37(m,2H),7. 45(d,J=8.56Hz,2H),7.55(d,J=8.56Hz,2H),7.70-7.82(m,4H); LCMS(ESI+):m / z 634.0(M+H) + OR:107.61

[0879] Compound 120: 1 H 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

[0880] Compound 122: 1 H NMR: ET51134 - 33 - P4N1, 400 MHz, DMSO-d6 δ 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

[0881] (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), ( 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)

[0882]

[0883] Synthesis of P1 and P2; Compounds 123-126

[0884] To a solution of 45.1 (2 g, 4.33 mmol, 1 eq) in dichloromethane (20 mL) was added triethylamine (3.01 mL, 21.65 mmol, 5 eq) and 4-aminocyclohexane-1-sulfonamide (926.67 mg, 4.33 mmol, 1 eq) 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 P1 (450 mg, 673.66 μmol, 15.6%) as a white solid and a racemic mixture P2 (200 mg, 315.16 μmol, 7.28%) as a white solid.

[0885] Method for preparative HPLC: instrument: ACSTJ-GX-N; column: Phenomenex luna C18 250×50 mm×10 μm; mobile phase: A is H2O=(0.04% HCl) and B is acetonitrile; gradient: B from 60% to 80% in 10 minutes; flow rate: 80 mL / min; wavelength: 220 and 254 nm

[0886] P1: 1H NMR: 400MHz, DMSO-d6δppm 1.27-1.57(m,4H),1.81-1.98(m,2H),2.04-2.17(m,2H),2.74(br t,J=11.74Hz,1H),3.53-3.82(m,1H),3.91-4.02(m,1H),4.50(t,J=11.21Hz,1H),5.06(dd,J=11.09 ,4.29Hz,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) + .

[0887] P2: 1 H NMR: 400MHz, DMSO-d6δppm 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=11.38Hz,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) + .

[0888]

[0889] P1 (450 mg, 1.05 mmol, 1 eq) 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.

[0890] SFC method used for P1 separation: Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Mobile phase A: [NH₃H₂O (0.1%) / ethanol] Mobile phase B: CO₂; B%: 50%-50%, Run time: 13 minutes. Absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0891] Compound 123: 1H NMR: 400MHz, DMSO-d6δppm 1.33(q,J=12.00Hz,2H),1.41-1.59(m,2H),1.91(br d,J=12.40Hz,2H),2.10(br d,J=11.32Hz,2H),2.74(br t,J=11.86Hz,1H),3.63-3.79(m,1H),3.92-4.08(m,1H),4.49(t,J=11.21Hz,1H),5.06(dd,J=11.15,4.35Hz, 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

[0892] Compound 124: 1 H NMR: 400MHz, DMSO-d6δppm 1.29-1.39(m,2H),1.44-1.54(m,2H),1.87-1.97(m,2H),2.10(br d,J=10.85Hz,2H),2.74(br t,J=11.80Hz,1H),3.71(br d,J=2.03Hz,1H),3.99(br d,J=7.51Hz,1H),4.49(br t,J=11.27Hz,1H),5.06(br dd,J=11.03,4.23Hz,1H),6.72(s,2H),7.20-7.27(m,5H),7.30-7.36(m,2H),7.55(d,J=8.46Hz,2H),7.78(br d,J=8.46Hz,4H); LCMS(ESI+):m / z 618.0(M+H) + ;OR:123.08

[0893] 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.

[0894]

[0895] SFC method for P2 separation: column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase A: [NH3H2O ​​(0.1%) / ethanol]; mobile phase B: CO2; B%: 50%-50%, run time: 15 min

[0896] Compound 125: 1 H NMR: 400MHz, DMSO-d6; δppm 1.63 (br d, J=2.86Hz, 2H), 1.80-1.99 (m, 6H), 2.90 (dt, J=12.10, 6.23Hz, 1H), 3.98 (br d, J=8.46Hz, 1H), 4.51 (br t,J=11.27Hz,1H),5.04(br dd,J=10.91,3.99Hz,1H),6.79(s,2H),7.18-7.27(m,5H),7.30-7.35(m,2H),7.56(d,J=8.58Hz,2H),7.61(br d,J=6.68Hz,1H),7.73(br dd,J=8.23,5.72Hz,2H),7.80(d,J=8.58Hz,2H); LCMS(ESI+):m / z 618.0(M+H) + ;OR:-150.19.

[0897] Compound 126: 1 H NMR: 400MHz, DMSO-d6δppm 1.64(br d,J=1.79Hz,2H),1.80-2.00(m,6H),2.85-2.96(m,1H),3.98(br d,J=7.51Hz,1H),4.51(br t,J=11.38Hz,1H),5.04(br dd,J=11.03,3.99Hz,1H),6.79(s,2H),7.17-7.28(m,5H),7.30-7.37(m,2H),7.56(d,J=8.46Hz,2H),7.59-7.67(m,1H),7.73(br dd,J=8.05,5.66Hz,2H),7.80(d,J=8.58Hz,2H); LCMS(ESI+):m / z 618.0(M+H) + ;OR:137.16.

[0898] (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), ( 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)

[0899]

[0900] Synthesis of compounds 127-130

[0901] To a solution of 45.1 (1.5 g, 3.15 mmol, 1 eq) in dichloromethane (5 mL) was added triethylamine (1.10 mL, 7.87 mmol, 2.5 eq) and 3-aminocyclobutane-1-sulfonamide (472.97 mg, 3.15 mmol, 1 eq) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give (780 mg, 1.26 mmol, 40%) as a white solid. LCMS (ESI+): m / z 590.1 (M+H) + .

[0902] The diastereomers (780 mg, 1.32 mmol, 1 equivalent) were separated by the first SFC to give compound 127 (85.8 mg, 0.14 mmol, 11%) as a white solid, compound 129 (120.9 mg, 0.21 mmol, 16%) as a white solid, and a racemic mixture of compound 128 and compound 130. The racemic mixture of compound 128 and compound 130 was further separated by the second SFC to give compound 128 (70 mg, 0.12 mmol, 8%) as a white solid and compound 130 (123.8 mg, 0.21 mmol, 15%) as a white solid. The absolute stereochemistry was not determined. The diastereomers with (-)OR were arbitrarily designated as S isomers.

[0903] First SFC method: column: REGIS (s,s) WHELK-O1 (250 mm × 30 mm, 10 μm); mobile phase A: [NH3H2O ​​(0.1%) / ethanol]; mobile phase B: CO2; B%: 55%, run time: 10 min

[0904] Second SFC method: column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase A: [NH 3 H 2 O (0.1%) / isopropanol]; mobile phase B: CO 2 ; B%: 50%, run time: 12 minutes.

[0905] Compound 127: 1 H NMR: 400MHz, DMSO-d6δppm 2.29-2.44(m,3H),2.54(s,1H),3.41-3.52(m,1H),3.94(dd,J=11.25,4.16Hz,1H),4.24(sxt,J=7.68Hz,1H),4.47(t,J=11 .19Hz,1H),5.05(dd,J=11.13,4.28Hz,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=5.87Hz, 1H); LCMS (ESI+): m / z 590.0 (M+H) + ;OR:-126.61.

[0906] Compound 129: 1 H NMR: 400MHz, DMSO-d6δppm 2.07(s,1H),2.55-2.74(m,4H),3.50-3.67(m,1H),3.96(br dd,J=11.07,3.97Hz,1H),4.40-4.68(m,2H),5.05(br dd,J=11.07,4.22Hz,1H),6.86(s,2H),7.15-7.39(m,7H),7.53(d,J=8.56Hz,2H),7.69-7.91(m,4H),8.16(br d,J=5.75Hz,1H); LCMS(ESI+):m / z 590.0(M+H) + ;OR:-118.48.

[0907] Compound 128: 1H NMR: 400MHz, DMSO-d6δppm 2.30-2.48(m,4H),3.46(quin,J=8.41Hz,1H),3.94(br dd,J=11.13,3.91Hz,1H),4.15-4.33(m,1H),4.47(br t,J=11.25Hz,1H),5.05(br dd,J=11.13,4.16Hz,1H),6.80(s,2H),7.16-7.38(m,7H),7.55(d,J=8.44Hz,2H),7.73-7.86(m,4H),8.10(br d, J=4.65Hz, 1H); LCMS (ESI+): m / z 590.0 (M+H) + ;OR:132.9.

[0908] Compound 130: 1 H NMR: 400MHz, DMSO-d6δppm 2.07(s,1H),2.53-2.73(m,4H),3.52-3.66(m,1H),3.96(br dd,J=11.13,4.03Hz,1H),4.40-4.66(m,2H),5.05(dd,J=11.07,4.22Hz,1H),6. 86(s,2H),7.16-7.37(m,7H),7.53(d,J=8.56Hz,2H),7.71-7.85(m,4H),8.16(br d, J=5.26Hz, 1H); LCMS (ESI+): m / z 590.0 (M+H) + ;OR:126.48.

[0909] (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); Synthesis of (S)-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)

[0910]

[0911] Synthesis of compounds 131-134

[0912] To a solution of 45.1 (1.5 g, 3.15 mmol, 1 eq) in dichloromethane (20 mL) was added triethylamine (1.59 g, 15.74 mmol, 2.19 mL, 5 eq) and pyrrolidine-3-sulfonamide (472.97 mg, 3.15 mmol, 1 eq) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a diastereomeric mixture (900 mg, 1.53 mmol, 44%) as a white solid.

[0913] The diastereomers (900 mg, 0.84 mmol, 1 equivalent) were separated by the first SFC to give compound 131 (57.8 mg, 0.09 mmol, 11%) as a white solid, compound 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 compound 133 and compound 134 was further separated by the second SFC to give compound 133 (48.1 mg, 0.08 mmol, 9%) as a white solid and compound 134 (44.6 mg, 0.07 mmol, 8%) as a white solid. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0914] First SFC method: column: Chiralpak IE-3, 50×4.6 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.

[0915] Second SFC method: column: Chiralpak AD-3, 50×4.6 mm ID, 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; 2.695 5; 3.0 95 5; flow rate; 3.4 mL / min; column temperature: 35°C; ABPR: 1800 psi.

[0916] Compound 131: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.18 - 2.28 (m, 2H) 3.71 - 3.85 (m, 3H) 3.95 (br d, J = 7.13 Hz, 2H) 4.06 (dd, J = 10.82, 4.94 Hz, 1H) 4.69 (t, J = 11.19 Hz, 1H) 5.07 (dd, J = 11.44, 4.94 Hz, 1H) 7.13 (s, 2H) 7.17 - 7.29 (m, 3H) 7.33 (d, J = 4.38 Hz, 4H) 7.50 - 7.56 (m, 2H) 7.68 (dd, J = 8.76, 5.50 Hz, 2H) 7.76 - 7.84 (m, 2H); LCMS (ESI+): m / z 590.0 (M + H) + ; OR: -95.36

[0917] Compound 132: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.20 - 2.31 (m, 2H) 3.63 - 3.73 (m, 1H) 3.74 - 3.82 (m, 1H) 3.84 - 3.96 (m, 2H) 3.97 - 4.12 (m, 2H) 4.69 (t, J = 11.13 Hz, 1H) 5.06 (dd, J = 11.38, 4.75 Hz, 1H) 7.14 (s, 2H) 7.17 - 7.28 (m, 3H) 7.30 - 7.35 (m, 4H) 7.50 - 7.58 (m, 2H) 7.66 - 7.71 (m, 2H) 7.78 - 7.84 (m, 2H); LCMS (ESI+): m / z 590.0 (M + 1) + ; OR: -111.20

[0918] Compound 133: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.27 (q, J = 7.00 Hz, 2H), 3.62 - 3.72 (m, 1H), 3.74 - 3.83 (m, 1H), 3.83 - 3.96 (m, 2H), 3.97 - 4.13 (m, 2H), 4.69 (t, J = 11.13 Hz, 1H), 5.06 (dd, J = 11.32, 4.69 Hz, 1H), 7.14 (s, 2H), 7.20 (t, J = 8.88 Hz, 2H), 7.23 - 7.29 (m, 1H), 7.30 - 7.35 (m, 4H), 7.51 - 7.57 (m, 2H), 7.65 - 7.73 (m, 2H), 7.78 - 7.84 (m, 2H); LCMS (ESI+): m / z 590.0 (M + 1) + ; OR: 102.2

[0919] Compound 134: 1 H NMR: 400MHz, DMSO-d6δppm 2.23(br dd,J=6.85,3.67Hz,2H),3.71-3.86(m,3H),3.95(br d,J=7.09Hz,2H),4.07(dd,J=10.82,4.83Hz,1H),4.69(brt,J=11.13Hz,1H),5.07(dd,J=11.37,4.89Hz,1H),7.14(s,2H),7.17-7 .28(m,3H),7.33(d,J=4.40Hz,4H),7.54(d,J=8.56Hz,2H),7.68(dd,J=8.80,5.50Hz,2H),7.80(d,J=8.56Hz,2H); LCMS(ESI+):m / z 590.0(M+H) + ;OR:89.9.

[0920] (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); ( 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)

[0921]

[0922] Synthesis of compounds 135-138

[0923] To a solution of 1.0 (2 g, 4.06 mmol, 1 eq) in dichloromethane (20 mL) was added triethylamine (2.82 mL, 20.29 mmol, 5 eq) and pyrrolidine-3-sulfonamide (731.48 mg, 4.87 mmol, 1.2 eq) at room temperature. After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 1, v / v) to give a diastereomeric mixture (400 mg, 659.48 μmol, 16%) as a white solid. LCMS (ESI+): m / z 606.1 (M+H)+.

[0924] The diastereomeric mixture (400 mg, 659.48 μmol, 1 equivalent) was separated by the first SFC to obtain 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 the second SFC to obtain 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 the third SFC to obtain 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. The absolute stereochemistry was not determined. The diastereomer with (-)OR was arbitrarily designated as the S isomer.

[0925] First SFC method: column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase A: [NH 3 H 2 O (0.1%) / ethanol]; mobile phase B: CO 2 ; B%: 50%-50%, running time: 7 minutes.

[0926] Second SFC method: column: REGIS (s,s) WHELK-O1 (250mm*30mm, 5μm); mobile phase A: [NH3H2O ​​(0.1%) / ethanol]; mobile phase B: CO2; B%: 50%-50%, running time: 16 minutes.

[0927] The third SFC method: column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase A: [NH3H2O ​​(0.1%) in ACN / IPA solution]; mobile phase B: CO2; B%: 50%-50%, running time: 10 minutes.

[0928] Compound 135: 11H NMR: 400 MHz, DMSO-d6 δ ppm 2.15 - 2.29 (m, 2H), 3.67 - 3.86 (m, 3H), 3.88 - 4.01 (m, 2H), 4.08 (dd, J = 10.88, 5.00 Hz, 1H), 4.70 (t, J = 11.19 Hz, 1H), 5.07 (dd, J = 11.44, 4.94 Hz, 1H), 7.14 (s, 2H), 7.21 - 7.29 (m, 1H), 7.30 - 7.37 (m, 4H), 7.42 (d, J = 8.50 Hz, 2H), 7.54 (d, J = 8.51 Hz, 2H), 7.63 (d, J = 8.50 Hz, 2H), 7.81 (d, J = 8.50 Hz, 2H); LCMS (ESI+): m / z 606.0 (M + H) + ; OR: -76.18

[0929] Compound 136: 1 1H NMR: 400 MHz, DMSO-d6 δ ppm 2.27 (q, J = 6.92 Hz, 2H), 3.62 - 3.72 (m, 1H), 3.78 (quin, J = 6.28 Hz, 1H), 3.83 - 3.95 (m, 2H), 3.98 - 4.11 (m, 2H), 4.70 (t, J = 11.19 Hz, 1H), 5.07 (dd, J = 11.51, 4.75 Hz, 1H), 7.14 (s, 2H), 7.25 (td, J = 5.35, 3.44 Hz, 1H), 7.29 - 7.36 (m, 4H), 7.42 (d, J = 8.63 Hz, 2H), 7.54 (d, J = 8.50 Hz, 2H), 7.63 (d, J = 8.50 Hz, 2H), 7.81 (d, J = 8.50 Hz, 2H); LCMS (ESI+): m / z 606.0 (M + H) + ; OR: -98.21

[0930] Compound 137: 1H NMR: 400MHz, DMSO-d6δppm 2.27(q,J=7.00Hz,2H),3.61-3.72(m,1H),3.74-3.82(m,1H),3.83-3.95(m,2H) ,3.97-4.11(m,2H),4.70(t,J=11.19Hz,1H),5.06(dd,J=11.44,4.82Hz,1H),7.1 4(s,2H),7.25(td,J=5.50,3.25Hz,1H),7.29-7.36(m,4H),7.42(d,J=8.63Hz,2H ),7.51-7.57(m,2H),7.63(d,J=8.63Hz,2H),7.78-7.83(m,2H); LCMS(ESI+):m / z 606.0(M+H) + ;OR:90.61.

[0931] Compound 138: 1 H NMR: 400MHz, DMSO-d6δppm 2.17-2.29(m,2H),3.71-3.86(m,3H),3.94(br d,J=7.13Hz,2H),4.07(dd,J=10.88,5.00Hz,1H),4.70(br t,J=11.26Hz,1H),5.07(dd,J=11.38,4.88Hz,1H),7.14(s,2H),7.22-7.29(m,1H),7.30-7.36(m,4H),7.42 (d,J=8.63Hz,2H),7.54(d,J=8.50Hz,2H),7.63(d,J=8.50Hz,2H),7.81(d,J=8.50Hz,2H); LCMS(ESI+):m / z 606.0(M+H) + ;OR:77.98.

[0932] Compound

[0933] The absolute stereochemistry of 3-aminocyclopentane-1-sulfonamide was arbitrarily assigned after separation of the four diastereomers. Therefore, the absolute stereochemistry of compounds 139-146 was arbitrarily assigned. The diastereomer with (-)OR was arbitrarily assigned as the S isomer.

[0934] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1S,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 139); (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1S,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 140)

[0935]

[0936] Synthesis of compounds 139 and 140

[0937] At room temperature, triethylamine (203.41 μ L, 1.46 mmol, 6 equivalents) and (1R, 3S) -3- aminocyclopentane -1- sulfonamide (40 mg, 243.57 μ mol, 1 equivalent) were added to a solution of 1.0 (180.05 mg, 365.35 μ mol, 1.5 equivalents) in dichloromethane (1 mL). After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 2, v / v) to obtain a crude product, which was further separated by SFC to obtain compound 139 (5.8 mg, 9.35 μ mol, 3%) and compound 140 (6.6 mg, 10.44 μ mol, 4%) as a white solid.

[0938] Compound 139: 1 H NMR: 400MHz, DMSO-d6δppm 7.85-7.70(m,5H),7.58-7.51(m,2H),7.44(d,J=8.6Hz,2H),7.38-7.29(m,2H),7.28-7.18(m,3H ),6.80(s,2H),5.06(dd,J=4.3,11.1Hz,1H),4.55(t,J=11.1Hz,1H),4.47-4.35(m,1H),4.00(br dd,J=3.5,10.9Hz,1H),3.66-3.52(m,1H),2.35-2.23(m,1H),2.11-1.90(m,3H),1.88-1.77(m,1H),1.73-1.58(m,1H).LCMS(ESI+):m / z 620.0(M+H) + ;OR:-100.44.

[0939] Compound 140: 1H NMR: 400 MHz, DMSO-d6δppm 7.83-7.68(m,4H),7.54(d,J=8.5Hz,2H),7.44(d,J=8.5Hz,2H),7.37-7.29(m, 2H),7.28-7.17(m,3H),6.80(s,2H),5.10-5.03(m,1H),4.57-4.47(m,1H),4.4 5-4.33(m,1H),4.10-4.01(m,1H),3.62-3.53(m,1H),2.27-2.21(m,1H),2.08- 1.94(m,3H),1.87-1.78(m,1H),1.75-1.66(m,1H); LCMS(ESI+):m / z620.0(M+H) + ;OR:103.39.

[0940] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1R,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (141) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1R,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (142)

[0941]

[0942] Synthesis of compounds 141 and 142

[0943] At room temperature, triethylamine (279.69 μ L, 2.01 mmol, 6 equivalents) and (1S, 3R) -3- aminocyclopentane -1- sulfonamide (55 mg, 334.91 μ mol, 1 equivalent) were added to a solution of 1.0 (247.56 mg, 502.36 μ mol, 1.5 equivalents) in dichloromethane (1 mL). After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 2, v / v) to obtain a racemate, which was further separated by SFC to obtain compound 141 (38.7 mg, 22.18 μ mol, 18%) and compound 142 (39 mg, 21.22 μ mol, 18%) as a white solid.

[0944] Compound 141: 1H NMR: 400MHz, DMSO-d6δppm 7.94(br s,1H)7.72-7.83(m,4H)7.54(d,J=7.76Hz,2H)7.44(d,J=8.58Hz,2H)7.19-7.36( m,5H)6.89(s,2H)5.07(dd,J=11.15,4.23Hz,1H)4.52(t,J=11.27Hz,1H)4.27(br s,1H)3.90-4.10(m,1H)3.41-3.51(m,1H)2.21-2.38(m,1H)1.82-2.08(m,4H)1.66-1.79(m,1H); LCMS(ESI+):m / z 620.0(M+H) + ;OR:-107.40.

[0945] Compound 142: 1 H NMR: 400MHz, DMSO-d6δppm 7.95(br s,1H)7.68-7.86(m,4H)7.55(d,J=8.58Hz,2H)7.44(d,J=8.58Hz,2H)7.30-7.39(m,2H)7.19-7.29(m,3H)6.88(s,2H)5.07(br dd,J=11.15,4.35Hz,1H)4.50(br t,J=11.21Hz,1H)4.28(br d,J=4.65Hz,1H)3.97-4.11(m,1H)3.41-3.50(m,1H)2.19-2.36(m,1H)1.71-2.09(m,5H); LCMS(ESI+):m / z620.0(M+H) + ;OR:82.50.

[0946] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1S,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 143) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1S,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 144)

[0947]

[0948] Synthesis of compounds 143 and 144

[0949] At room temperature, triethylamine (432.25 μ L, 3.11 mmol, 6 equivalents) and (1S, 3S) -3- aminocyclopentane -1- sulfonamide (85 mg, 517.58 μ mol, 1 equivalent) were added to a solution of 1.0 (382.60 mg, 776.37 μ mol, 1.5 equivalents) in dichloromethane (2 mL). After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 2, v / v) to obtain a racemate, which was further separated by SFC to obtain compound 143 (78.3 mg, 130.55 μ mol, 24.3%) and compound 144 (68.7 mg, 120.85 μ mol, 21.4%) as a white solid.

[0950] Compound 143: 1 H NMR: 400MHz, DMSO-d6δppm 7.68-7.89(m,5H)7.54(br d,J=8.34Hz,2H)7.44(br d,J=8.34Hz,2H)7.20-7.36(m,5H)6.81(br s,2H)4.97-5.16(m,1H)4.31-4.60(m,2H)4.06(br d,J=7.87Hz,1H)3.52-3.63(m,1H)2.25(dt,J=13.20,6.57Hz,1H)1.94-2.12(m,3H)1.78-1.91(m,1H)1.64-1.77(m,1H); LCMS(ESI+):m / z 620.0(M+H) + ;OR:-100.60.

[0951] Compound 144: 1 H NMR: 400MHz DMSO-d6δppm 7.66-7.89(m,5H)7.54(br d,J=8.34Hz,2H)7.44(br d,J=8.23Hz,2H)7.16-7.39(m,5H)6.81(br s,2H)5.06(br d,J=7.39Hz,1H)4.55(br t,J=11.27Hz,1H)4.42(br s,1H)4.00(br d,J=8.34Hz,1H)3.54-3.66(m,1H)2.22-2.37(m,1H)1.91-2.11(m,3H)1.77-1.91(m,1H)1.57-1.75(m,1H); LCMS(ESI+):m / z 620.0(M+1) + ;OR:90.60.

[0952] Synthesis of (S,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1R,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 145) and (R,Z)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-N-((1R,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compound 146)

[0953]

[0954] Synthesis of compounds 145 and 146

[0955] At room temperature, triethylamine (239.01 μ L, 1.72 mmol, 6 equivalents) and (1R, 3R) -3- aminocyclopentane -1- sulfonamide (47 mg, 286.19 μ mol, 1 equivalent) were added to a solution of 1.0 (211.56 mg, 429.29 μ mol, 1.5 equivalents) in dichloromethane (1 mL). After stirring at room temperature for 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column using petroleum ether and ethyl acetate (1 / 2, v / v) to obtain a racemate, which was further separated by SFC to obtain compound 145 (20.6 mg, 32.3 μ mol, 11%) and compound 146 (14.2 mg, 22.52 μ mol, 7%) as a white solid.

[0956] Compound 145: 1 H NMR: 400MHz, DMSO-d6δppm 7.95(br d,J=1.2Hz,1H),7.83-7.78(m,2H),7.74(d,J=8.6Hz,2H),7.58-7.52(m,2H),7.44(d,J =8.7Hz,2H),7.37-7.30(m,2H),7.28-7.20(m,3H),6.88(s,2H),5.07(dd,J=4.4,11.1H z,1H),4.51(t,J=11.2Hz,1H),4.35-4.22(m,1H),4.11-3.97(m,1H),3.52-3.40(m,1H) ,2.36-2.22(m,1H),2.12-1.83(m,4H),1.81-1.70(m,1H); LCMS(ESI+):m / z620.0(M+H) + ;OR:-157.42

[0957] Compound 146: 1H NMR:400MHz DMSO-d6δppm 8.03-7.87(m,1H),7.84-7.70(m,4H),7.54(d,J=8.5Hz,2H),7.44(d,J=8.7Hz,2H),7.38-7.29(m,2H),7.28-7.17(m,3H),6.89(s,2H),5.07(br dd,J=4.3,11.2Hz,1H),4.52(t,J=11.3Hz,1H),4.37-4.20(m,1H),4.07-3.94(m,1H),3.5 3-3.39(m,1H),2.37-2.22(m,1H),2.10-1.96(m,2H),1.94-1.68(m,3H); LCMS(ESI+):m / z 620.0(M+H) + ;OR:78.53.

[0958] (S,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1R,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1R,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (S,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1R,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1S,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1S,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (S,Z)-N '-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1S,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1S,3S)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (S,Z)-N'-(( Synthesis of (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1R,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide, (R,Z)-N'-((4-chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-4-phenyl-N-((1R,3R)-3-sulfamoylcyclopentyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide (Compounds 147-154):

[0959] The absolute stereochemistry of 3-aminocyclopentane-1-sulfonamide was arbitrarily assigned after separation of the four diastereomers. Therefore, the absolute stereochemistry of the following examples is arbitrarily assigned. The diastereomer with (-)OR is arbitrarily designated as the S isomer. The starting material for the following examples is 45.1.

[0960]

[0961] Compound 147: 1 H NMR: 400MHz, DMSO-d6δppm 7.87-7.73(m,5H),7.54(d,J=8.4Hz,2H),7.35-7.29(m,2H),7.28-7.16(m,5H),6.81(s,2H),5.06(br dd,J=4.1,11.1Hz,1H),4.54(br t,J=11.2Hz,1H),4.42(br s,1H),4.00(br dd,J=3.2,10.7Hz,1H),3.60(quin,J=7.8Hz,1H),2.29(td,J=7.0,13.6Hz,1 H),2.09-1.90(m,3H),1.89-1.77(m,1H),1.72-1.60(m,1H); LCMS(ESI+):m / z 604.0(...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from F, Cl, CN and OCH3; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted by F or CN; R 3 is phenyl substituted by 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 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted by C1-C6 alkyl; R 4 , R 4 '、R 5 and R 5 ' is independently H or C1-C6 alkyl; R 6 and R 7 are independently H, OH or C1-C6 alkyl; or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted with a C1-C6 alkyl group; and R 8 is H or CH3, The premise is that at least one of the following is true: (i)R 1 Not 4-chlorophenyl or 4-methoxyphenyl; (ii) R 2 is C1-C6 alkyl or phenyl substituted by CN; (iii) R 3 Not 4-chlorophenyl, 3-cyanophenyl or 3-methoxyphenyl; (iv) R 4 , R 4 '、R 5 and R 5 'At least one of them is C1-C6 alkyl; (v)R 6 and R 7 At least one of is not H; and (vi)R 8 It is CH3.

2. The compound of claim 1, wherein the compound is a compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein R 1a It is F, Cl, CN or OCH3.

3. The compound according to claim 2, wherein the compound is a compound of formula (IIA): or a pharmaceutically acceptable salt thereof, wherein R 2a is H or CN.

4. The compound as claimed in claim 3, wherein R 2a It's H.

5. The compound as claimed in claim 3, wherein R 2a It is CN.

6. The compound of claim 2, wherein the compound is a compound of formula (IIIA): or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is a compound of formula (IB): or a pharmaceutically acceptable salt thereof, wherein R 1a It is F, Cl, CN or OCH3.

8. The compound of claim 7, wherein the compound is a compound of formula (IIB): or a pharmaceutically acceptable salt thereof, wherein R 2a is H or CN.

9. The compound of claim 8, wherein R 2a It's H.

10. The compound of claim 8, wherein R 2a It is CN.

11. The compound of claim 7, wherein the compound is a compound of formula (IIIB): or a pharmaceutically acceptable salt thereof.

12. A compound as claimed in any one of claims 2 to 11, wherein R 1a It's F.

13. A compound as claimed in any one of claims 2 to 11, wherein R 1a It is Cl.

14. A compound as claimed in any one of claims 2 to 11, wherein R 1a It is OCH3.

15. A compound as claimed in any one of claims 1 to 14, wherein R 3 It is phenyl substituted by one or two groups selected from F, Cl, CF3, CN, OCH3, C2-C6 alkynyl or C(O)NH2.

16. The compound of claim 15, wherein R 3 yes:

17. The compound of claim 16, wherein R 3 yes 18. The compound of claim 16, wherein R 3 yes 19. The compound of claim 16, wherein R 3 yes 20. The compound of any one of claims 1 to 14, wherein R 3 is a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group.

21. The compound of claim 20, wherein R 3 yes:

22. A compound as described in any one of claims 1 to 21, wherein R 4 It's H.

23. A compound as described in any one of claims 1 to 21, wherein R 4 It is a C1-C6 alkyl group.

24. The compound of claim 23, wherein R 4 It's methyl.

25. The compound of claim 23, wherein R 4 It is isopropyl.

26. A compound as described in any one of claims 1 to 25, wherein R 5 It's H.

27. A compound as described in any one of claims 1 to 25, wherein R 5 It is a C1-C6 alkyl group.

28. The compound of claim 27, wherein R 5 It's methyl.

29. The compound of claim 27, wherein R 5 It is isopropyl.

30. A compound as described in any one of claims 1 to 29, wherein R 6 It's H.

31. A compound as described in any one of claims 1 to 29, wherein R 6 It is a C1-C6 alkyl group.

32. The compound of claim 31, wherein R 6 It is methyl, ethyl or isopropyl.

33. A compound as described in any one of claims 1 to 29, wherein R 6 It's OH.

34. A compound as described in any one of claims 1 to 33, wherein R 7 It's H.

35. A compound as described in any one of claims 1 to 33, wherein R 7 It is a C1-C6 alkyl group.

36. The compound of claim 35, wherein R 7 It is methyl, ethyl or isopropyl.

37. A compound as described in any one of claims 1 to 33, wherein R 7 It's OH.

38. A compound as described in any one of claims 1 to 29, wherein R 6 and R 7 Together with the nitrogen atom to which they are attached they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted by a C1-C6 alkyl group.

39. The compound of claim 38, wherein R 6 and R 7 Together with the nitrogen atom to which they are attached, they form:

40. A compound as described in any one of claims 1 to 39, wherein R 8 It's H.

41. A compound as described in any one of claims 1 to 39, wherein R 8 It is CH3.

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

43. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by 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 by halogen or CN; R 3 is phenyl substituted by 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 by C1-C6 alkyl; R 6 and R 7 are independently H, OH or C1-C6 alkyl; or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted with a C1-C6 alkyl group; L is R 8 is H or C1-C6 alkyl; R 4 , R 4 '、R 5 and R 5 ' is independently H or C1-C6 alkyl optionally substituted by C1-C6 alkoxy; X is O or NR 9 ; R 9 is H or C1-C6 alkyl; and y and z are independently 1, 2 or 3.

44. The compound of claim 43, wherein the compound is of formula (IVA): or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN or C1-C6 alkoxy.

45. The compound of claim 44, wherein the compound is of formula (VA): or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halogen, C1-C6 alkoxy or CN.

46. ​​The compound of claim 45, wherein R 2a It's H.

47. The compound of claim 45, wherein R 2a It is CN.

48. The compound of claim 44, wherein the compound is of formula (VIA): or a pharmaceutically acceptable salt thereof.

49. The compound of claim 43, wherein the compound is of formula (IVB): or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, CN or C1-C6 alkoxy.

50. The compound of claim 49, wherein the compound is of formula (VB): or a pharmaceutically acceptable salt thereof, wherein R 2a is H, halogen, C1-C6 alkoxy or CN.

51. The compound of claim 50, wherein R 2a It's H.

52. The compound of claim 50, wherein R 2a It is CN.

53. The compound of claim 49, wherein the compound is of formula (VIB): or a pharmaceutically acceptable salt thereof.

54. A compound as described in any one of claims 44 to 53, wherein R 1a It's F.

55. A compound as described in any one of claims 44 to 53, wherein R 1a It is Cl.

56. A compound as described in any one of claims 44 to 53, wherein R 1a It is OCH3.

57. A compound as described in any one of claims 43 to 56, wherein R 3 is phenyl substituted by one or more groups selected from halogen, CF3, CN, C1-C6 alkoxy, C2-C6 alkynyl or C(O)NH2.

58. The compound of claim 57, wherein R 3 yes:

59. The compound of claim 58, wherein R 3 yes 60. The compound of claim 58, wherein R 3 yes 61. The compound of claim 58, wherein R 3 yes 62. A compound as described in any one of claims 43 to 56, wherein R 3 is a 5- or 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, wherein the heteroaryl group is optionally substituted by a C1-C6 alkyl group.

63. The compound of claim 62, wherein R 3 yes:

64. A compound as described in any one of claims 43 to 63, wherein R 4 It's H.

65. A compound as described in any one of claims 43 to 63, wherein R 4 It is a C1-C6 alkyl group.

66. The compound of claim 65, wherein R 4 It's methyl.

67. The compound of claim 65, wherein R 4 It is isopropyl.

68. A compound as described in any one of claims 43 to 67, wherein R 5 It's H.

69. A compound as described in any one of claims 43 to 67, wherein R 5 It is a C1-C6 alkyl group.

70. The compound of claim 69, wherein R 5 It's methyl.

71. The compound of claim 69, wherein R 5 It is isopropyl.

72. A compound as described in any one of claims 43 to 71, wherein R 6 It's H.

73. A compound as described in any one of claims 43 to 71, wherein R 6 It is a C1-C6 alkyl group.

74. The compound of claim 73, wherein R 6 It is methyl, ethyl or isopropyl.

75. A compound as described in any one of claims 43 to 71, wherein R 6 It's OH.

76. A compound as described in any one of claims 43 to 75, wherein R 7 It's H.

77. A compound as described in any one of claims 43 to 75, wherein R 7 It is a C1-C6 alkyl group.

78. The compound of claim 77, wherein R 7 It is methyl, ethyl or isopropyl.

79. A compound as described in any one of claims 43 to 75, wherein R 7 It's OH.

80. A compound as described in any one of claims 43 to 71, wherein R 6 and R 7 Together with the nitrogen atom to which they are attached they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted by a C1-C6 alkyl group.

81. The compound of claim 80, wherein R 6 and R 7 Together with the nitrogen atom to which they are attached, they form:

82. The compound of any one of claims 43 to 81, wherein R 8 It's H.

83. The compound of any one of claims 43 to 81, wherein R 8 It is CH3.

84. The compound of claim 43, wherein the compound is selected from any one of compounds 99-102, 111-154, 173-174, 183-250, or a pharmaceutically acceptable salt thereof.

85. A compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted by one or more substituents selected from F, Cl, CN and OCH3; R 2 is C1-C6 alkyl, 5- or 6-membered heteroaryl, or phenyl optionally substituted by F or CN; R 3 is phenyl substituted by 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 1-3 nitrogen atoms, wherein the heteroaryl is optionally substituted by C1-C6 alkyl; R 4 , R 4 '、R 5 and R 5 ' is independently H or C1-C6 alkyl; R 6 and R 7 are independently H, OH or C1-C6 alkyl; or R 6 and R 7 Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocycloalkyl group containing 1-2 nitrogen atoms and optionally substituted with a C1-C6 alkyl group; R 8 is H or CH3; and n is 1, 2, or 3.

86. The compound of claim 85, wherein the compound is selected from any one of compounds 87-98 or a pharmaceutically acceptable salt thereof.

87. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

88. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof, wherein the disease is a diabetic disorder, a dyslipidemic disorder, a cardiovascular disorder, an inflammatory disorder, a liver disorder, or cancer.

89. The method of claim 88, wherein the disease is a diabetic condition.

90. The method of claim 89, wherein the diabetic condition is type 1 diabetes, type 2 diabetes, impaired glucose tolerance, or insulin resistance.

91. The method of claim 88, wherein the disease is a dyslipidemic disorder.

92. The method of claim 91, wherein the dyslipidemic condition is undesirable blood lipid levels, low levels of high-density lipoprotein, high levels of low-density lipoprotein, high levels of triglycerides, or a combination thereof.

93. The method of claim 88, wherein the disease is a cardiovascular disorder.

94. The method of claim 93, wherein the cardiovascular disorder is atherosclerosis, hypertension, stroke, or heart attack.

95. The method of claim 88, wherein the disease is an inflammatory disorder.

96. The method of claim 95, wherein the inflammatory disorder is osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, or obesity-related inflammation.

97. The method of claim 88, wherein the disease is a liver disorder.

98. The method of claim 97, wherein the liver disorder is liver inflammation, liver fibrosis, nonalcoholic steatohepatitis, fatty liver, hepatomegaly, alcoholic liver disease, jaundice, cirrhosis, or hepatitis.

99. The method of claim 88, wherein the disease is cancer.

100. The method of claim 99, wherein the cancer is colon cancer, breast cancer, thyroid cancer, alveolar rhabdomyosarcoma, or hepatocellular carcinoma.

101. A method for treating obesity or obesity complications, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 86 or a pharmaceutically acceptable salt thereof.

102. The method of claim 101, wherein the obesity comorbidity is diabetes, dyslipidemia, metabolic syndrome, dementia, cardiovascular disease, or liver disease.

103. The method of claim 101, wherein the obesity comorbidity is hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous stasis ulcers; hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; atherosclerotic disease; pseudotumor cerebri; accident proneness; increased surgical risk; osteoarthritis; high cholesterol; or an increased incidence of ovarian, cervical, uterine, breast, prostate, or gallbladder malignancies.

104. A method of reversing adipose tissue deposition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 86, or a pharmaceutically acceptable salt thereof.

105. The method of any one of claims 88 to 104, further comprising administering to the subject a second therapeutic agent.

106. The method of claim 105, wherein the second therapeutic agent is a PPAR-gamma agonist, a biguanide, insulin or an insulin mimetic, a sulfonylurea, an alpha-glucosidase inhibitor, an HMG-CoA reductase inhibitor, a sequestrant, nicotinic alcohol, nicotinic acid or a salt thereof, a PPAR-alpha agonist, a cholesterol absorption inhibitor, an acyl-CoA: cholesterol acyltransferase inhibitor, probucol, a PPAR-alpha / gamma agonist, an ileal bile acid transporter inhibitor, an insulin receptor activator, a dipeptidyl peptidase IV inhibitor, exenatide, pramlintide, a FBPase inhibitor , Glucagon receptor antagonist, Glucagon-like peptide 1, Glucagon-like peptide 1 receptor agonist, Growth hormone secretagogue, Growth hormone secretagogue receptor agonist, Growth hormone secretagogue receptor antagonist, Melanocortin agonist, Melanocortin 4 receptor agonist, Beta-3 agonist, Serotonin receptor 2C agonist, Orexin antagonist, Melanin concentrating hormone 1 antagonist, Melanin concentrating hormone 2 agonist, Melanin concentrating hormone 2 antagonist, Galanin antagonist, CCK agonist, CCK-A agonist, Corticotropin releasing hormone agonist, NPY5 antagonist, NPY 1 antagonist, histamine receptor-3 modulator, histamine receptor-3 blocker, β-hydroxysteroid dehydrogenase-1 inhibitor, phosphodiesterase inhibitor, phosphodiesterase-3B inhibitor, norepinephrine transport inhibitor, non-selective serotonin / norepinephrine transport inhibitor, ghrelin antagonist, leptin derivative, bombesin receptor subtype 3 agonist, ciliary neurotrophic factor or its derivative, monoamine reuptake inhibitor, uncoupling protein-1 activator, uncoupling protein-2 activator, uncoupling protein-3 activator, 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, dicarboxylate transporter inhibitors, glucose transporter inhibitors, sodium-glucose co-transporter, phosphate transporter inhibitors, serotonin reuptake inhibitors, thiazolidinediones, metformin, topiramate, opioid antagonists, nonselective transporter inhibitors, or MAO inhibitors.

107. The method of claim 106, wherein the second therapeutic agent is a glucagon-like peptide 1 receptor agonist.

108. The method of claim 107, wherein the second therapeutic agent is liraglutide, semaglutide, exenatide, lixisenatide, dulaglutide, or tesiparatide.

109. The method of claim 108, wherein the second therapeutic agent is semaglutide.

110. The method of claim 108, wherein the second therapeutic agent is tesiparatide.

111. The method of any one of claims 88 to 110, wherein the subject is a human.

112. The method of any one of claims 88 to 110, wherein the subject is a non-human mammal.

113. Use of a compound as claimed in any one of claims 1 to 86 for the preparation of a medicament for use in a method as claimed in any one of claims 88 to 112.

114. A compound as claimed in any one of claims 1 to 86 for use in a method as claimed in any one of claims 88 to 112.

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