Diaryl ureas as CB1 allosteric modulators

Abstract

To provide a new diarylurea derivative and its use.SOLUTION: A compound of formula (I) is provided. Compounds of formula (I) have been demonstrated to be allosteric modulators of the CB1 receptor and are therefore useful in the treatment of diseases and conditions mediated by CB1.SELECTED DRAWING: Figure 1

Description

Federally funded research

[0001] This invention was made with government support under award DA040693 from the NIH. The government has certain rights in this invention.

[0002] This patent application claims the benefit of U.S. Patent Application No. 62 / 505,383, filed May 12, 2017. No. 6,239,999, which is incorporated herein by reference in its entirety. [Technical Field]

[0003] The present invention relates to novel cannabinoid CB1 receptor allosteric modulator compounds and The compounds of the present invention have the effects of appetite control, cardiovascular regulation, metabolic syndrome, and the like, and uses thereof. Cannabinoid CB1 receptors, including those involved in neuromuscular disorders, pain regulation, learning and memory, and drug addiction Useful for treating diseases and conditions caused by physiological processes involving the body It is thought that this is the case. [Background technology]

[0004] 2014 National Survey on Drug Use and Health According to the National Social Security and Drug Administration (NSDUH), 45 million Americans age 12 and older will use cocaine in their lifetime. In 2014, 100% of cocaine users in the United States aged 12 and over reported ever using cocaine. There are currently (past month) an estimated 1.5 million people (0.6% of the population) with approximately 913,000 Americans Cocaine dependence or abuse (any form) in the last month The patient met the criteria of the Diagnostic and Statistical Manual of Mental Disorders. The National Institute of Drug Addiction (NIDA) is a global Large-scale, first-in-class cocaine addiction treatment could generate US$1.2 billion in annual revenue Substance Abuse and Mental Health Services Administration According to the SAMHSA, the overall market for addiction treatment is estimated at $35 billion per year. In 2014, the WHO estimated that more than 1.9 billion adults worldwide were overweight and Approximately 35% of the US adult population is obese (BMI > 30). (Flegal, KM. JAMA, 2012, 307(5), 491-497). Obesity in the Healthcare System The cost of this disease was estimated at US$147 billion (Finkelstein et al, Health Affairs 28, no. 5, 2009, w822-831).

[0005] Cannabinoid CB1 and CB2 receptors play important roles in cardiovascular regulation, learning and memory, appetite, and pain control. It is a component of the endocannabinoid system, which is involved in many important physiological processes such as See, e.g., Mackie, K. Cannabinoid receptors as therapeutic targets. Annu. Rev. Pharmacol. Toxicol. 2006,46, 101-122; Howlett, AC; Breivogel, CS; SR, C. ; Deadwyler, SA; Hampson, RE; Porrino, LJ Cannabinoid physiology and ph armacology: 30 years of progress. Neuropharmacology 2004, 47 Suppl 1, 345-358; and Di, M.; Bisogno, T.; De Petrocellis, L. Endocannabinoids: new targets for d See rug development. Curr Pharm Des 2000, 6, 1361-80; No. 6,299,523, filed on Dec. 1, 2003, which is incorporated herein by reference for its teaching of relevant background art.

[0006] CB1 receptors are abundantly expressed in the central nervous system, and are thought to play a role in obesity, drug addiction, and other conditions. including chronic conditions, pain, inflammation, gastrointestinal disorders, multiple sclerosis, psychosis, schizophrenia, and osteoporosis It has been shown to be a valid target in many disorders. Pertwee, RG Therapeutics ic potential of drugs that target cannabinoid receptors or modulate the tissue l See AAPS Journal 2005, 7, E625-54. ; the teachings of which are incorporated herein by reference. CB2 receptors are primarily immunoreactive. Found in immune cells, it is responsible for regulating cytokine release and immune cell migration. A wide range of selective and non-selective agonists and antagonists for CB1 and CB2 receptors are available. Currently, all approved cannabinoid medicines are derived primarily from the cannabis plant. The main psychoactive component is tetrahydrocannabinol (Δ 9 -THC), or its synthetic analogues (nabilone); however, it has potential side effects such as marijuana-like psychoactivity and dependence-proneness. It is prescribed with many limitations due to adverse effects. Rimonabant (SR141716A), a vasopressin agonist, is used to treat obesity. It was first approved for this purpose but was later withdrawn due to the risk of suicidal thoughts.

[0007] Another approach to targeting CB1-mediated signaling pathways is orthosteriotropy. Allosteric modulators that bind to binding sites distinct from the orthosteric site The goal is to develop a new ligand that is more efficient than the orthosteric ligand. Orthosteric modulators are those that mediate signal transduction through orthosteric pathways. Better spatial and temporal selectivity due to dependence on the presence of an agonist The allosteric binding site is more conserved than the orthosteric site. The absence of ribonucleotides provides better subtype selectivity and a "ceiling" effect. The benefits of this approach include improved safety profile due to the effectiveness of the drug. s, A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 2002, 1, 198-210; and Bridges, TM; Lindsley, CW G-protein-coupled receptors: from classical modes of modulation to allost See ACS Chem. Biol. 2008, 3, 530-541; Recently, calcium-sensing receptors (CasRs, GPCRs) have been reported. C family member), a positive allosteric modulator (PAM) of Cinacalcet (Sensipar / Mimpara; Amgen) and CCR5 receptor negative Maraviroc (Celsentri / se), a novel antiallosteric modulator (NAM), Several allosteric modulators are available as therapeutic agents, including Benzyl Alcohol (Baltimore; Pfizer). are now on the market, and allosteric modulation offers a safe and therapeutic approach for targeting GPCRs. For example, Harrington, PE; sch, C. Calcium sensing receptor activators: calcimimetics. Curr Med Chem 2007, 14, 3027-34; Dorr, P.; Westby, M.; Dobbs, S.; Griffin, P.; Irvine, B.; Macartney , M.; Mori, J.; Rickett, G.; Smith-Burchnell, C.; Napier, C.; Webster, R.; Armou r, D.; Price, D.; Stammen, B.; Wood, A.; Perros, M. Maraviroc (UK-427,857), a po tent, orally bioavailable, and selective small-molecule inhibitor of chemokine r eceptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activi ty. Antimicrob Agents Chemother 2005, 49, 4721-32; Bridges, TM; Lindsley, C. W. G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem Biol 2008, 3, 530-41; and Conn, PJ; Christopoulos, A.; Lindsley, CW Allosteric modulators of GPCRs: a novel approach for the treatm ent of CNS disorders. Nat. Rev. Drug. Discov. 2009, 8, 41-54; is incorporated herein by reference for teaching such background art.

[0008] Since 2005, when the first CB1 modulator (A) Org27569 was discovered: [ka] Several negative and positive allosteric modulators have been reported. This includes NAMs PSNCBAM-1(B): [ka] Cannabidiol (C): [ka] Fenofibrate (D): [ka] and PAMs such as ZCZ011(E): [ka] Among them, A and B are two small molecule CB1 NAMs that have been better characterized. Both intracellular calcium mobilization, 35 S]GTP-γ-S binding, cAMP, and β-arrestin recruitment In the assay, it enhances the level of radioligand binding, but does not act as an orthosteric It has been reported that ERK suppresses responses stimulated by thrombolytic (antithrombotic) agonists. Unlike A, which shows agonist activity in several assays, B has not been shown to In many assays studied, orthosteric agonists In its absence, it showed little or no activity. Horswill, J.; Bali, U.; Shaaban, S.; Keily, J.; Jeevaratnam, P.; Babbs, A.; Reynet, C.; In, PWK PSNCBAM-1, a no vel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects i n rats. Br J Pharmacol 2007, 152, 805-814; Laprairie, RB; Bagher, AM; Kell y, M. E.; Denovan-Wright, E. M. Cannabidiol is a negative allosteric modulator o f the type 1 cannabinoid receptor. Br J Pharmacol 2015, 172, 4790-4805; Priestle y, R. S. N., Sarah A.; Alexander, Stephen P. H.; Kendall, David A. A potential r ole for cannabinoid receptors in the therapeutic action of fenofibrate. FASEB J 2015, 29, 1446-1455; Ignatowska-Jankowska, B. M.; Baillie, G. L.; Kinsey, S.; Cr owe, M.; Ghosh, S.; Owens, R. A.; Damaj, I. M.; Poklis, J.; Wiley, J. L.; Zanda, M.; Zanato, C.; Greig, I. R.; Lichtman, A. H.; Ross, R. A. A Cannabinoid CB1 Re ceptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. Neuropsychopharmacol 2015, 40, 2948-2959; Baillie, G. L .; Horswill, J. G.; Anavi-Goffer, S.; Reggio, P. H.; Bolognini, D.; Abood, M. E. ; McAllister, S.; Strange, PG; Stephens, GJ; Pertwee, RG; Ross, RA C B1 Receptor Allosteric Modulators Display Both Agonist and Signaling Pathway Spe cificity. Mol Pharmacol 2013, 83, 322-338; and Khajehali, E.; Malone, DT; Gl ass, M.; Sexton, PM; Christopoulos, A.; Leach, K. Biased agonism and biased a llosteric modulation at the CB1 cannabinoid receptor. Mol Pharmacol 2015, 88, 36 8-379; each of which is incorporated by reference for teaching such background art. For recent reviews on this topic, see Nguyen, T.; Li , JX; Thomas, BF; Wiley, JL; Kenakin, TP; Zhang, Y. Allosteric Modul ation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor. Med Res Rev 2017, 37, 441-474.

[0009] Cannabinoid CB1 receptors are involved in many conditions, including drug addiction, pain, obesity, inflammation, anxiety, and depression. It has been suggested that it plays an important role in many conditions, including obesity treatment and smoking cessation in humans. Despite the clinical efficacy of SR141716A, rimonabant ), Acomplia, and Zilmulti, known as CB1 selective antagonists / inverse antagonists. Agonist: [ka] was withdrawn from the European market due to the risk of suicidal thoughts. Another approach to targeting the CB1 pathway with neurosteroid modulators is Orthos. Avoid the side effects of orthosteric antagonists / inverse agonists However, it has emerged as a promising strategy for modulating the CB1 receptor that could be therapeutically valuable.

[0010] Recently, a review of national trend data has revealed that opioid abuse is also associated with the rise of There have been warnings that cocaine-related overdose deaths are on the rise. There are no FDA-approved drugs to treat cocaine, and its recurrence rate remains at 40 to 60%. The in vivo efficacy of this drug in reducing relapse to drug cravings CB1 allosteric modulators prevent relapse to cocaine dependence and abuse This may be a promising candidate for developing therapeutic agents for the treatment of rheumatoid arthritis, which is a currently unmet need. There is an urgent need for more. See, e.g., McCall Jones, C.; Baldwin, GT; Compton, WM Recent Increases in Cocaine-Related Overdose Deaths and the Role of Opioids. Am J Public Health 2017, 107, 430-432; and McLellan, AT; Lewis, DC; O'Brien , CP; Kleber, HD Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. See JAMA 2000, 284, 1689-95. each of which is incorporated herein by reference for teaching such background art. To be incorporated. Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention describes diaryl ureas as CB1 negative allosteric modulators. The development of this compound is described below. Compared with PSNCBAM-1(B) exemplified above in this specification, this compound The product has good pharmacokinetic properties, similar in vitro potency, and is similar to cocaine self-administration. Drug-induced relapse in pretrained rats after extinction of their cocaine-seeking behavior The compounds of the present invention show greater efficacy in reducing the incidence of drug addiction. Efficacy is demonstrated in an in vivo model.

[0012] The compounds of the present invention act on the same biological target as the compounds described above: CB1 receptor signaling. Antagonism of this transmission, as exemplified by rimonabant, has been shown to be effective in treating obesity. Furthermore, rimonabant has also been shown to reduce cocaine-seeking responses and smoking habits. Reduced relapse and the atrophic and psychoactive effects of marijuana By allosterically modulating the CB1 receptor, the compounds of the present invention inhibited While retaining the potential therapeutic value of rimonabant, it is possible to avoid its undesirable effects. The compounds of the present invention may also be of great value to obese patients with addiction problems. I guess so. [Means for solving the problem]

[0013] One embodiment of the present invention is a compound of formula (I): [ka] where: R 1 is O-(C 1-6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 2 )2, (C 1-8 Archi L) x -(5- to 13-membered aryl), (C 1-8 alkyl) x -(5- to 13-membered heteroaryl), Or (C 1-8 alkyl) x -(4- to 13-membered heterocyclyl), wherein each aryl, Each heteroaryl and heterocyclyl is optionally substituted with one or more of the following: It has been: R 2 , OR 2 , C(O)R 2 , C(O)OR 2 , NO2, halogen, or C 1-6 Haloalkyl; R 2 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, or 5- to 13-membered alkenyl It is a reel; R 3 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C1-6 Alkynyl, halogen, C 1-6 Haloal Kill, NO2, or CN; each x is independently 0 or 1; and n is 1, 2 or 3; or a pharmaceutically acceptable salt or solvate thereof, Includes:

[0014] An embodiment of the present invention is a compound where n is 1. An aspect of this embodiment is a compound where R 3 Gaha An aspect of this embodiment is where R 3 is Cl.

[0015] One embodiment of the present invention is 1 is a 5- to 13-membered heteroaryl, and optionally one More than R 2 An aspect of this embodiment is that R 1 is phenyl, and optionally One or more R 2 An aspect of this embodiment is that R 1 is unsubstituted phenyl Another aspect of this embodiment is R 1 is one R 2 In this embodiment, the phenyl is substituted with The embodiment is R 1 There are two R 2 An aspect of this embodiment is phenyl substituted with R 2 Gaha It's Rogen.

[0016] One embodiment of the present invention is 1 is 5- to 13-membered aryl, and optionally one or more R 2 An aspect of this embodiment is that R 1 Furan, thiophene, pyrrole, iridium Midazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isopropyl alcohol isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridine Dazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxa azole, benzothiophene, indole, indazole, benzimidazole, imidazoline pyridine, pyrazolopyridine and pyrazolopyrimidine, each optionally containing one More than R 2 An aspect of this embodiment is that R 1 is pyridine, and optionally One or more R 2 An aspect of this embodiment is that R 1 is thiophene, and any Optionally, one or more R 2 An aspect of this embodiment is that R 1 is azetidine optionally one or more R 2 is replaced by .

[0017] In one embodiment of the present invention, x is 0.

[0018] One embodiment of the present invention provides a method for blocking CB1 receptors comprising administering an effective amount of a compound of the present invention. The present invention provides a method for treating a disease in a mammal susceptible to the disease. The disease is withdrawal, drug addiction, smoking cessation, addiction, opioid addiction, cocaine addiction , relapse in cocaine addiction, tobacco addiction, alcohol addiction, inhibition of angiogenesis, tumor growth Inhibition of cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer , lung cancer, prostate cancer, desmotrophic small round cell tumor cell tumors) and renal cell carcinoma, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain Pain, neuropathic pain, inflammatory pain, infertility, memory loss, cognitive dysfunction, Alzheimer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, Atherosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia disease, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite behavior or weight loss,

[0019] Certain embodiments of the present invention include compositions comprising a compound of the present invention and one or more pharmaceutically acceptable carriers. A pharmaceutical composition.

[0020] Certain embodiments of the present invention provide a method for treating CB1-sensitive disorders comprising administering an effective amount of a compound. Use of a compound of the present invention for preparing a medicament for treating a disease in a mammal In one aspect of this embodiment, the disease is withdrawal, drug dependence, smoking cessation, addiction, or Drug addiction, cocaine addiction, relapse in cocaine addiction, tobacco addiction, alcohol addiction Survival, inhibition of angiogenesis, inhibition of tumor growth, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, Breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmotrophic small round cell Tumors (desmotrophic small round cell tumors) and renal cell carcinoma, analgesia, pain, chronic sexual pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, memory loss, cognitive Intellectual disability, Alzheimer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia , amyotrophic lateral sclerosis, stroke, atherosclerosis, hypertension, hemorrhagic shock, cardiogenic shock Sexual shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal These include: impaired bowel movement, obesity, appetite behavior or weight loss.

[0021] One embodiment of the present invention is a compound of the present invention for use as an active therapeutic substance. is.

[0022] One embodiment of the present invention provides a compound for use in treating CB1 mediated diseases. In one aspect of this embodiment, the disease is withdrawal, drug addiction, , smoking cessation, addiction, opioid addiction, cocaine addiction, cocaine addiction relapse, tobacco addiction Alcoholism, angiogenesis inhibition, tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma cystic cancer, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmotrophic Fick small round cell tumors (desmotrophic small round cell tumors) and renal cell carcinoma, Analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, pain Pregnancy, memory loss, cognitive impairment, Alzheimer's disease, Tourette's syndrome, dyskinesia, Tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis, hypertension, Hemophilic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite behavior or weight loss.

[0023] One embodiment of the present invention provides a method for treating withdrawal, drug use, or other conditions comprising administering an effective amount of a compound of the present invention. Addiction, smoking cessation, addiction, opioid addiction, cocaine addiction, cocaine addiction relapse, Bacoism, alcoholism, inhibition of angiogenesis, inhibition of tumor growth, cancer, endometrial cancer , hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, death Desmotrophic small round cell tumors and renal cell Cancer, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain Pain, infertility, memory loss, cognitive impairment, Alzheimer's disease, Tourette's syndrome, dyskinesia Diarrhea, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis, hypertension hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, omentum One of the following: membranes, glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, obesity, appetite behavior, or weight loss A method for treating one or more species.

[0024] In one embodiment of the present invention, a method for treating withdrawal, drug dependence, or the like, comprising administering an effective amount of the compound. disease, smoking cessation, addiction, opioid addiction, cocaine addiction, cocaine addiction relapse, tobacco Addiction, alcoholism, inhibition of angiogenesis, inhibition of tumor growth, cancer, endometrial cancer, liver Cellular cancer, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmo Desmotrophic small round cell tumors and renal cell carcinoma , analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, Infertility, memory loss, cognitive impairment, Alzheimer's disease, Tourette's syndrome, dyskinesia , tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis, hypertension, Hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy , glaucoma, anxiety, gastrointestinal disorders, intestinal hypomotility, obesity, appetite behavior, or weight loss and the use of a compound of the present invention for the preparation of a medicament for the treatment of the above.

[0025] Certain embodiments of the present invention are directed to the treatment of withdrawal, drug addiction, smoking cessation, addiction, opioid addiction, cocaine addiction, Alcoholism, cocaine addiction, relapse, tobacco addiction, and angiogenesis inhibition , tumor growth inhibition, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, Colorectal cancer, lung cancer, prostate cancer, desmotrophic small round cell tumor mall round cell tumors) and renal cell carcinoma, analgesia, pain, chronic pain, acute pain, Sexual pain, visceral pain, neuropathic pain, inflammatory pain, infertility, memory loss, cognitive impairment, Alzheimer's Immer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis , stroke, atherosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, high cholesterol Hypertension, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, A method of treating obesity, appetite, or weight loss comprising administering to a subject therapies of the present invention. Compound.

[0026] Preferably, the compounds of the present invention provide drugs at the CB1 receptor that exhibit greater efficacy and fewer side effects. This is expected to result in improved efficacy, pharmacokinetics, and safety through reduced use of It may be used as such.

[0027] The compounds are intended to treat diseases and conditions caused by modulation of CB1 receptors. Although it is believed that such compounds are useful in treating cancer, the invention should not be limited thereto.

[0028] The scope of the present invention includes all combinations of aspects, embodiments, and preferences described herein. nothing. [Brief explanation of the drawings]

[0029] [Figure 1] Figure 1 is an illustration of the effect of compounds of the present invention compared to known compound B, showing their effectiveness in reducing the binding level of [35S]GTP-γ-S activated by CP55,940. Binding levels in the presence of an allosteric modulator are expressed as a percentage compared to binding levels in the absence of the allosteric modulator. Symbols represent the mean ± SEM of at least three independent experiments performed in duplicate. [Figure 2] FIG. 2 is a graphical illustration showing that compounds B and 34 attenuate the relapse of extinguished cocaine-seeking behavior in rats. DETAILED DESCRIPTION OF THE INVENTION

[0030] Detailed Description of the Invention The following definitions are intended to clarify, but not limit, the terms defined. Unless a particular term is used herein and not otherwise defined, such Terms should not be considered undefined; rather, terms should be considered within the scope of their accepted meanings. Used within.

[0031] As used throughout this specification, preferred numbers of atoms, such as carbon atoms, are, for example, As defined herein, the phrase "C" refers to an alkyl group containing a specific number of carbon atoms. x-y The same applies to other preferred terms and ranges. Therefore, for example, C 1-4 Alkyl is a straight or branched chain alkyl group containing 1 to 4 carbon atoms. Represents hydrogen chloride.

[0032] As used herein, the term "alkyl" alone or in combination with any other term means In combination, the term "alkyl" refers to a straight or branched chain hydrocarbon. Examples of "alkyl" as used herein include: is, but is not limited to, methyl, ethyl, propyl, isopropyl, isobutyl , n-butyl, tert-butyl, sec-butyl, iso-pentyl, n-pentyl, n-hexyl, etc. Includes:

[0033] As used herein, the term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. This refers to a straight or branched chain aliphatic hydrocarbon containing, which may be optionally substituted and may contain multiple Examples of "alkenyl" as used herein include, but are not limited to, Examples include, but are not limited to, vinyl and allyl.

[0034] As used herein, the term "alkylene" refers to an optionally substituted straight chain dialkyl Examples of "alkylene" as used herein include, but are not limited to, Examples include, but are not limited to, methylene, ethylene, n-propylene, and n-butylene.

[0035] As used herein, the term "alkynyl" refers to a group having one or more carbon-carbon triple bonds. and optionally substituted and polysubstituted straight or branched chain aliphatic hydrocarbons containing Examples of "alkynyl" as used herein include, but are not limited to, alkyl, alkynyl ... It contains ethynyl, but not all of them.

[0036] As used herein, the term "cycloalkyl" refers to a group that is fully saturated and optionally optionally substituted monocyclic, bicyclic, bridged, or spirocyclic hydrocarbon rings; Multiple degrees of substitution are permissible. Exemplary "cycloalkyl" groups as used herein include: Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Examples include cyclohexyl, cyclohexyl, and cycloheptyl.

[0037] As used herein, the term "heterocyclyl" refers to a heterocyclyl that is fully saturated and optionally optionally substituted monocyclic, bicyclic, bridged, or spirocyclic hydrocarbon rings; Multiple degrees of substitution are permitted, with one or more atoms selected from nitrogen, sulfur, and / or oxygen atoms. Containing hetero atoms, N-oxides, sulfur oxides, and dioxides are acceptable. Exemplary "heterocyclyl" groups of use include, but are not limited to, azetidine, Pyrrolidinyl, piperidinyl, piperazinyl, hexahydroazepine, and morpholinyl Includes:

[0038] As used herein, the term "aryl" refers to a single benzene ring, fused, bridged, or a spirocyclic benzene ring system, which may be optionally substituted. Multiple degrees of substitution are permitted. Examples of "aryl" groups that may be used include, but are not limited to: but includes phenyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene Preferred aryl rings have 5 to 10 members.

[0039] As used herein, fused benzene ring systems encompassed within the term "aryl" include: including condensed polycyclic hydrocarbons, i.e., cyclic hydrocarbons having less than the maximum number of non-cumulative double bonds; For example, a saturated hydrocarbon ring (cycloalkyl, e.g., a cyclopentyl ring) may be substituted with an aromatic ring (aryl benzene ring) to form, for example, indanyl and acenaphthalenyl. forming groups, and non-limiting examples include dihydronaphthalene and tetrahydronaphthalene. Also included are groups such as len.

[0040] As used herein, the term "heteroaryl" refers to a monocyclic 5- to 7-membered aromatic heterocyclic ring. The ring may be optionally substituted, with multiple degrees of substitution permitted. Aromatic ring systems containing two or more rings, which may be fused, bridged, or spirocyclic. Typically, such rings are 5- to 10-membered. These heteroaryl rings may contain one or more nitrogen atoms. , sulfur, and / or oxygen atoms, N-oxides, sulfur oxides, and dioxides are permitted. Examples of "heteroaryl" groups as used herein include: Non-limiting examples include furan, thiophene, pyrrole, imidazole, and pyrazole. , triazole, tetrazole, thiazole, oxazole, isoxazole, oxazole Diazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyridyl amide, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene Indoles, indazoles, benzimidazoles, imidazopyridines, pyrazolopyridines pyrazolopyrimidines, and pyrazolopyrimidines.

[0041] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. Point.

[0042] As used herein, the term "haloalkyl" refers to an alkyl group containing at least one halogen. As used herein, branched or Examples of straight chain "haloalkyl" groups include, but are not limited to, groups containing one or more halogens methyl, ethyl, independently substituted with fluoro, chloro, bromo, and iodo; The term "haloalkyl" includes propyl, isopropyl, n-butyl, and t-butyl. , and perfluoroalkyl groups such as -CF3.

[0043] Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention. Salts of the compounds of the present invention may include acid addition salts. Representative salts include acetate salts, benzene salts, and the like. Sulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, edetate potassium Calcium, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate Salt, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamine Phosphate, glycollylarsanilate, hexylresulcinate (hexylresorcinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate , iodide, isethionate, lactate, lactobionate, laurate, malate, Maleate, mandelate, mesylate, methyl sulfate, monopotassium maleate, Sodium phosphate, sodium phosphate, nitrate, N-methylglucamine, oxalate, pamoate (en carbonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate Salicylate, Potassium, Salicylate, Sodium, Stearate, Acetate, Amber Acid salts, sulfates, tannates, tartrates, teoclates, tosylates late), trithiodide, trimethylammonium, and valerate salts. Other salts, although not necessarily acceptable, may be useful in preparing the compounds of this invention. and the like, which are believed to form further aspects of the invention.

[0044] The compounds of formula (I) may crystallize in more than one form (a characteristic known as polymorphism). Such polymorphic forms ("polymorphs") have the formula ( Polymorphism generally occurs as a response to changes in temperature, pressure, or both. Polymorphism can also arise from variations in the crystallization process. Polymorphism can be classified into various forms known in the art, such as X-ray diffraction patterns, solubilities, and melting points. They can be distinguished by their physical properties.

[0045] As used herein, the term "effective amount" refers to the amount of a substance that is effective for a particular purpose, e.g., as determined by a researcher or clinician. The amount of a drug or pharmaceutical product that induces a biological or medical response in a tissue, system, animal, or human The term "therapeutically effective amount" means a therapeutically effective amount relative to a corresponding subject not receiving such amount. and the treatment, cure, prevention, or amelioration of a disease, disorder, or side effect resulting from ... The term also refers to any amount that results in a reduction in the rate of progression of a disease or disorder. Included within the range are amounts effective to enhance physiological function.

[0046] For use in therapy, a therapeutically effective amount of a compound of formula (I), as well as salts or solvates thereof In addition, active ingredients may be administered as pharmaceutical compositions. It may be presented as follows.

[0047] Accordingly, the present invention further provides a method for treating a rheumatoid arthritis comprising administering to a patient a therapeutically effective amount of one or more compounds of formula (I), or a salt or solution thereof. Pharmaceutical compositions comprising a vehicle and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compound of formula (I) or a salt or solvate thereof may be used as described herein. The carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and must be compatible with the pharmaceutical composition. It must be acceptable in the sense of not being harmful to the recipients of the composition.

[0048] The compounds of the present invention can be prepared by a variety of methods, including well-known standard synthetic methods. Exemplary general synthetic methods are described below, followed by specific methods for the synthesis of the compounds of the present invention. The compounds are prepared in the examples.

[0049] In all examples described below, protecting groups for sensitive or reactive groups are used. Protecting groups are used where necessary in accordance with the general principles of synthetic chemistry. Therefore, treat (TW Green and PGM Wuts (1999) Protecting Groups in Organic Synthetic (Thesis, 3rd Edition, John Wiley & Sons, regarding protecting groups, which is incorporated by reference). These groups can be removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and the order of their execution are dependent on the compound of the present invention. There should be no inconsistencies with the preparation.

[0050] The present invention also relates to methods for the synthesis of compounds of formula (I) and synthetic intermediates in the preparation of compounds of the invention. The present invention provides a method for synthesizing novel compounds useful as ligands.

[0051] The compounds can be prepared according to the methods described below using readily available starting materials and reagents. These reactions are well known to those skilled in the art, but may be more specifically Variations not mentioned in detail may be used.

[0052] Unless otherwise stated, structures depicted herein may be isotopically enriched or enriched in one or more isotopically enriched forms. It is also intended to include compounds which differ only in the presence of hydrogen atoms. Deuterium or tritium substitution, or carbon atoms 13 C- or 14 C-enriched carbon Compounds having the present structures except as substituted are within the scope of this invention. For example, Deuterium is widely used to study the pharmacokinetics and metabolism of biologically active compounds. Deuterium behaves similarly to hydrogen from a chemical point of view, but the deuterium-carbon bond and hydrogen There is a significant difference in bond energy and bond length between the carbon and hydroxyl groups. The substitution of hydrogen for deuterium in biologically active compounds generally improves their biochemical potency and selectivity. It retains selectivity but exhibits significantly different absorption, distribution, and metabolism compared to its isotope-free counterpart. Deuterium substitution can result in compounds that exhibit improved metabolic and / or excretory (ADME) properties. For certain biologically active compounds, improved drug efficacy, safety, and / or tolerability Tolerance may be achieved.

[0053] According to another aspect of the present invention, there is provided a compound of formula (I) or a salt, solvate thereof, and a compound thereof which acts on a physiological function. The active ingredient may be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. Also provided are methods for preparing pharmaceutical formulations, including:

[0054] The therapeutically effective amount of a compound of the invention will depend on many factors, including the species and age of the recipient, and body weight, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration. are all factors to be considered. The therapeutically effective amount is ultimately at the discretion of the attending physician or veterinarian. Nevertheless, the compounds of formula (I) for treating infirm humans The effective amount of the compound is generally in the range of 0.1 to 100 mg per kg of body weight of the recipient (mammal) per day. More generally, the effective dose should be in the range of 0.1 to 20 mg / kg body weight / day. Therefore, for a 70 kg adult mammal, an example of a practical daily amount would typically be 10 to 20 00 mg. This amount may be administered in a single dose per day or in multiple doses per day (e.g., 2, 3, 4, 5, or more times daily, resulting in The effective amount of the compound of formula (I) itself or its salt or solvate will be the same. The dosage may be determined in proportion to the effective amount of the active ingredient. Similar dosages are used in the methods mentioned herein. It should also be suitable for the treatment of other conditions. It may be provided in the form of a unit dose containing the active ingredient. Such units may include, but are not limited to: Typical examples include the use of a steroid drug depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. A preferred unit dose formulation may contain 1 mg to 2 g of a compound of formula (I). A daily dose or sub-dose, as recited hereinabove, or an appropriate fraction thereof, of the active ingredient(s) may be administered. Such pharmaceutical preparations may be prepared by any method known in the pharmaceutical arts. It may be prepared.

[0055] Pharmaceutical formulations can be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical, or intravenous. oral (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) Such formulations may be adapted for administration by any route known in the pharmaceutical arts. The active ingredient may be prepared in any manner, for example, by bringing the active ingredient into association with a carrier or excipient. By way of example, and not meant to limit the invention, For certain conditions and disorders for which a compound is believed to be useful, certain pathways may be involved in the synthesis of other pathways. In addition, delayed or extended exposure may improve treatment. In appropriate circumstances, pharmaceutical preparations may be used to delay exposure to the compounds of formula (I) or It may be possible to extend it.

[0056] Pharmaceutical preparations adapted for oral administration include capsules or tablets; powders or granules; Granules; solutions or suspensions in aqueous or non-aqueous liquids, respectively; edible foams or edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquids It may be provided as a separate unit such as a tablet or capsule. For oral administration in capsule form, the active drug ingredient is dissolved in ethanol, glycerol, , in combination with an oral, non-toxic, pharmaceutically acceptable inert carrier such as water. Generally, powders are prepared by comminuting the compound to a suitable fine size and adding the compound to a suitable pharmaceutical carrier, e.g. , and an edible carbohydrate (e.g., starch or mannitol) Flavoring, preservative, dispersing agent, and coloring agent can also be present.

[0057] Capsules are prepared by preparing a powder, liquid, or suspension mixture and filling it with gelatin or some other suitable Glidants and lubricants, e.g. Colloidal silica, talc, magnesium stearate, calcium stearate, or Alternatively, solid polyethylene glycol may be added to the mixture prior to encapsulation. Agar - Agar, with the addition of a disintegrant or solubilizer such as calcium carbonate or sodium carbonate This can also improve the availability of the drug when the capsule is ingested. When necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, glucose or beta-lacto. natural sugars such as corn sweeteners, gum arabic, gum tragacanth, and other natural and and synthetic rubber, or sodium alginate, carboxymethyl cellulose, polyethylene Lubricants useful in these unit doses include, for example, For example, sodium oleate, sodium stearate, magnesium stearate, benzoate Examples of tablet disintegrants include sodium carbonate, sodium acetate, sodium chloride, etc. Examples include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Gum, etc.

[0058] Tablets can be prepared, for example, by preparing a powder mixture, granulating or slugging, and then moistening the mixture. A lubricant and a disintegrant are added and the mixture is formulated by compressing into tablets. As described above, it is prepared by mixing the compound, which has been appropriately ground, with a diluent or base. Optional ingredients include carboxymethylcellulose, aliginate, , a binder such as gelatin or polyvinylpyrrolidone, a solution retarder such as paraffin, Absorption enhancers such as quaternary salts and / or bentonite, kaolin, or dicalcium phosphate The powder mixture may contain syrup, starch paste, red beans, etc. Wet granulate with a binder such as mucilage or a solution of a cellulosic or polymeric material and shake. Alternatively, the powder mixture may be passed through a tablet press. The result is imperfectly formed slugs broken into granules. Adhesion to tablet forming dies can be improved by adding stearate, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the invention can be combined with a free-flowing inert carrier and used in a granulation or slugging step. Sometimes they are compressed directly into tablets without going through the sealing step. a coating of sugar or polymeric material, and a polishing coating of wax. A clear or opaque protective coating may be provided to distinguish different unit doses. Additionally, pigments may be added to these coatings.

[0059] Oral fluids such as solutions, syrups, and elixirs are prepared by administering a given amount of the compound. Syrups may be prepared in dosage unit form, for example, by dissolving the compound in a suitable solution. can be prepared by dissolving it in a flavored aqueous solution, while an elixir The suspension is generally prepared by using a non-toxic alcoholic medium. The compound can be formulated by dispersing it in a non-toxic vehicle. Modified isostearyl alcohol and polyoxyethylene sorbitol ether any solubilizers and emulsifiers, preservatives; flavoring additives such as peppermint oil, or natural sweeteners; Saccharin or other artificial sweeteners may also be added.

[0060] Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation may also be prepared by, for example, coating particulate material with polymers, waxes, etc. The release can be extended or sustained by embedding the drug in a polymer, wax, etc. It may also be formulated as a

[0061] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and the like. illes), and mouthwashes.

[0062] The compounds of the present invention or salts or solvates thereof may be used alone or in combination with other therapeutic agents. The compounds of formula (I) and other pharmaceutically active agents may be used together or separately. The compounds may be administered separately, and when administered separately, administration may be simultaneous or in any order. Amounts and administration of the compound of formula (I) and other pharmaceutically active agents The relative timing of the administration of the compounds of formula (I) is selected to achieve the desired combined therapeutic effect. The administration of the compound or a salt or solvate thereof in combination with another therapeutic agent is (2) a single pharmaceutical composition containing a combination of the compounds; or (3) separate pharmaceutical compositions each containing one of the compounds. Alternatively, the combination may be administered in a manner in which one therapeutic agent is administered first. one treatment is administered first and the other treatment is administered second, or vice versa. Such sequential administration may be close in time or If so, it may be far away in time.

[0063] Those skilled in the art of organic synthesis will be able to prepare radioisotope-labeled compounds of the invention suitable for a variety of applications. It will be appreciated that there are multiple means for preparing the compound.

[0064] Experimental Section Abbreviation: As used herein, the symbols used in these processes, schemes and examples and conventional expressions are found in modern scientific literature, e.g., Journal of the American Chemical Society The following are consistent with those used in the Journal of Biological Chemistry: The following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliter); psi (pounds per square inch). M (mol); mM (millimol); Hz (Hertz); MHz (Megahertz); mole (mol); mmol (millimol); RT or rt (room temperature); hr (hours); min (minutes); TLC (thin layer chromatography). mp (melting point); RP (reversed phase); T r (retention time) TFA (trifluoroacetic acid) ; TEA (triethylamine); THF (tetrahydrofuran); TFAA (trifluoroacetic anhydride); CD3OD (deuterated methanol); CDCl3 (deuterated chloroform); DMSO (dimethyl sulfoxide); SiO2 (silica gel); atm (atmospheric pressure); EtOAc (ethyl acetate); CHCl3 (chloroform); HCl (hydrochloric acid); Ac (acetyl); DMF (N,N-dimethylformamide); Me (methyl); Cs2CO3 (Cesium Carbonate); EtOH (Ethanol); Et (ethyl); t-Bu (tert-butyl); MeOH (methanol) p-TsOH (p-toluenesulfonic acid); DCM (dichloromethane) DCE (dichloroethane) Et2O (diethyl ether) K2CO3 (potassium carbonate); Na2CO3 (sodium carbonate); i-PrOH (isopropyl alcohol) NaHCO3 (sodium bicarbonate); ACN (acetonitrile); Pr (propyl); i-Pr (isopropyl); PE (petroleum ether); Hex (hexane); H2SO4 (sulfuric acid); HCl (hydrochloric acid); Et3N (triethylamine); Na2SO4 (sodium sulfate); MTBE (methyl tert-butyl ether); Boc (tert-butoxycarbonyl); DIPEA (Diisopropylethylamine); IPA (Isopropanol); HMDS (Hexamethyldisilazane) NH4Cl (Ammonium chloride) NH4CO3 (Ammonium carbonate) MgSO4 (Magnesium sulfate) NH4OH (Ammonium Hydroxide)

[0065] All solvents and chemicals were reagent grade. Unless otherwise stated, all reagents and The solvents and eluents were purchased from commercial vendors and used as delivered. Chromatography was performed using a Teledyne ISCO CombiFlash RF system using pre-packed columns. The solvents used were hexane, ethyl acetate (EtOAc), dichloromethane, ethanol, and chloroform / methanol / ammonium hydroxide (80:18:2) (CMA-80). The purity and identity of the compounds were determined by a combination of HPLC, TLC, mass spectrometry, and NMR analysis. Ta. 1 H and 13 C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer. chloroform-d, with tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as the internal standard. Measurements were made in DMSO-d6 or methanol-d4. Chemical shifts are expressed in ppm relative to the reference signal. Coupling constant (J) values ​​are expressed in Hertz (Hz). Thin layer chromatography (TLC) was performed on an EMD plate. Coated silica gel 60 F254 plates were used, and spots were visualized using UV light or iodine staining. Low-resolution mass spectra were obtained using a Waters Alliance HT / Micromass ZQ system (ESI). All test compounds were obtained using Agilent Zorbax SB-Phenyl, 2.1 mm x 150 mm, 5 μL A 1.0 m column was used, and gradient elution was performed with a mobile phase of (A) 0.1% CF3COOH in H2O and (B) MeCN. The purity was greater than 95% as determined by HPLC on an Agilent 1100 system at a flow rate of 1 L / min. there were.

[0066] Compounds of formula (I) are generally prepared by the methods disclosed in ND, Ann M.; Gilmour, Brian P.; Gay, El aine A.; Wiley, Jenny L.; Thomas, Brian F.; Zhang, Yanan. Diarylureas as Alloste ric Modulators of the Cannabinoid CB1 Receptor: Structure-Activity Relationship Studies on 1-(4-Chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1). Scheme according to the method previously described in J Med Chem 2014, 57, 7758-7769 1; see reference for teachings on such synthesis. Other compounds can be prepared as shown in Schemes 2 and 3. Cut.

[0067] Briefly, commercially available 3-nitrophenylboronic acid (10) was converted to a base by Pd(PPh3)4 catalysis. Suzuki coupling with the corresponding aryl bromide under neutral conditions gave intermediate 11. Transfer hydrogenation was carried out using hydrazine hydrate and Raney nickel in water. The nitro group in 11 was reduced to give the 3-substituted aniline 12 in good yield. The final diamine is obtained by reacting aniline with 4-chlorophenyl isocyanate. Alternatively, the anilines 14a-g were converted to the corresponding aryl ureas by the addition of 3-bromoaniline (13). can be prepared by Suzuki coupling between arylboronic acids and then 4-chloro This was converted to the final product (15-53) by reaction with phenyl isocyanate. The same three-step synthetic route (Suzuki coupling, transfer hydrogenation, and 4-chlorophenyl) Starting from 4-nitrophenylboronic acid (54) using the coupling with isocyanates Compound 57 was prepared by the reaction of 4-biphenylamine (58) and 4-chloroisocyanide. It was prepared by coupling with [ka] Scheme 1. Reagents and Conditions: (a) 3-Nitrophenylboronic Acid, Pd(PPh3)4, DME, NaHC1 O3 aqueous solution, reflux, 16 hours (b) Hydrazine hydrate, Raney Ni, ethanol, 50°C , 2 hours (c) 4-chlorophenyl isocyanate, chloroform, 50°C, 16 hours.

[0068] Compounds 63, 65, 68, and 72 were prepared according to Scheme 2. N-Noc-pyrrole-2-boronic acid Suzuki coupling of 1-bromo-3-nitrobenzene with Raney-Nitrobenzene gives intermediate 61. The nitro group was reduced with chlorine and hydrazine to give aniline 62. The Boc group of 62 was converted under basic conditions. The aniline 64 was obtained by cleavage under reduced pressure (Marzaro et al., JMC, 2014, 57, 4598-4605). Palladium-Catalyzed Direct Arylation between 3-Iodoaniline and N-Methylpyrrole (Beladhria et al., Synthesis-Stuttgart, 2012, 44, 2264- 2276). The imidazole ring in 70 is formed by the reaction of 3-nitrobenzonitrile with aminoacetaldehyde dimer. methyl acetal (Hah et al., 2011, WO 2011049274 A1 ) Reduction of the nitro group by typical transfer hydrogenation with Raney-nickel affords the aniline The final coupling of these aniline intermediates with 4-chlorophenyl isocyanate gave 71. Purification afforded the final compounds 63, 65, 68 and 72. [ka] Scheme 2. Reagents and Conditions: (a) 1-Bromo-3-nitrobenzene, Pd(PPh 3) 4, DME, NaHCO3, reflux, 16 hours (b) Hydrazine hydrate, Raney Ni, ethanol, 50°C , 2 hours (c) 4-chlorophenyl isocyanate, chloroform, 50℃, 16 hours (d) 5% KO H2O, reflux, 4 hours (e) 3-iodoaniline, AcOK, Pd(OAc)2, AcNMe2, sealed tube, 150°C , 20 hours (f) (i) NaOMe, MeOH, room temperature, 5 hours (ii) (MeO)2CHCH2NH2, AcOH, 70°C, 1 hour (iii) 6N HCl aqueous solution, MeOH, 70°C, 3 hours.

[0069] Compounds 76-86, 90, 91 and 95 were prepared according to Scheme 3. 1-Bromo-3-nitrobenzene Buchwald-Hartwig coupling of 73 with the corresponding amine gave intermediates 74a-j. Nitrogen was obtained by transfer hydrogenation using hydrazine hydrate and Raney nickel in ethanol. Reduction of the aryl group gave the 3-substituted anilines 75a-j in good yields. ) with pyrrolidine N2 substitution to give intermediate 88, which is reduced to the corresponding aniline 89 by hydrogenation. 3-Nitrophenol (92) was subjected to the Mitsunobu reaction to give intermediate 93, which was then subjected to the Raney–Nitrogen reaction. These anilines were then reduced to anilines 94 by transfer hydrogenation catalyzed by HCl. The reaction of anilines (75a-j, 89, and 94) with 4-chlorophenyl isocyanate gave the final The novel diaryl ureas 76-86, 90, 91, and 95 were obtained. [ka] Scheme 3. Reagents and Conditions: (a) Amine, Pd(OAc)2, Cs2CO3, XantPhos, 1,4-Dioxa (b) Hydrazine hydrate, Raney Ni, ethanol, 50°C, 2 hours (c) 4- Chlorophenyl isocyanate, chloroform, 50°C, 16 hours (d) Pyrrolidine, Et3N, T HF, 60°C, 2 hours (f) Cyclopentanol, DIAD, PPh3, THF, 0°C to room temperature, 4 hours. [Example]

[0070] General Method A. A mixture of aryl bromides or aryl iodides (1 equivalent) is treated with dimethoxyphenyl Boronic acid (1.1 equiv.) in ethane (0.1 M) was added, followed by 1 M aqueous NaHCO3 (3 equiv.), followed by Pd( Ph3)4 (0.075 equiv.) was added. The reaction mixture was refluxed overnight under nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. The combined organic layers were The filtrate was concentrated in vacuo and the residue was purified by column chromatography. Purification by chromatography (SiO2, ethyl acetate / hexanes) gave the desired product.

[0071] 2-Methoxy-6-(3-nitrophenyl)pyridine (11a) was reacted with 2-bromo-6-methoxypyridine (0. 12 ml, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol), Prepared according to Method A as a white solid (0.12 g, 50%). 1 H NMR (300 MHz, CDCl3) δ 8.89 (t, J = 1.98 Hz, 1H), 8.01 (dd, J = 0.57, 7.35 Hz, 1H), 7.64 - 7.74 (m, 2H ), 7.41 (d, J = 7.35 Hz, 1H), 6.72 - 6.80 (m, 2H), 4.04 (s, 3H). MS (ESI) m / z fo r C 12 H 10 N2O3[M+H] + : Calculated value: 231.1; Measured value: 231.4.

[0072] 4-Methyl-2-(3-nitrophenyl)pyridine (11b) was dissolved in 2-bromo-4-methylpyridine (0.11 m l, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) by general method A as a white solid (0.16 g, 73%). 1 H NMR (300 MHz, CDCl3) δ 8 .84 (t, J = 1.98 Hz, 1H), 8.58 (d, J = 4.90 Hz, 1H), 8.34 - 8.39 (m, 1H), 8.23 ​​- 8.27 (m, 1H), 7.60 - 7.67 (m, 2H), 7.15 (dd, J = 0.66, 4.99 Hz, 1H), 2.46 (s, 3 H). MS (ESI) m / z for C 12 H 10 N2O2[M+H] +: Calculated value: 214.1; Measured value: 214.4.

[0073] 2-Methoxy-4-(3-nitrophenyl)pyridine (11c) was reacted with 2-methoxy-5-bromopyridine (0. 21 ml, 1.60 mmol) and 3-nitrophenylboronic acid (0.29 g, 1.76 mmol) were prepared by the usual method. Prepared according to A as a white solid (0.34 g, 85%). 1 H NMR (300 MHz, CDCl3) δ 8 .36 - 8.46 (m, 2H), 8.17 - 8.25 (m, 1H), 7.79 - 7.88 (m, 2H), 7.58 - 7.66 (m, 1H) ), 6.88 (d, J = 8.48 Hz, 1H), 4.00 (s, 3H). MS (ESI) m / z for C 12 H 10 N2O3[M+H] + : Calculated value: 231.1; Measured value: 231.5.

[0074] 2-(3-Nitrophenyl)pyridine (11d) was reacted with 2-bromopyridine (1.00 g, 6.33 mmol) and 3 -nitrophenylboronic acid (1.16 g, 6.96 mmol) according to general procedure A to give orange Prepared as a colored solid (0.85 g, 67%). 1 H NMR (300 MHz, CDCl3) δ 8.86 (t, J = 1 .88 Hz, 1H), 8.75 (td, J = 1.20, 4.94 Hz, 1H), 8.37 (td, J = 1.39, 7.77 Hz, 1H), 8.27 (ddd, J = 0.94, 2.21, 8.15 Hz, 1H), 7.85 (d, J = 1.70 Hz, 2H), 7.66 (t, J = 8.01 Hz, 10H), 7.62 - 7.70 (m, 1H), 7.34 (ddd, J = 2.45, 4.76, 6.17 Hz, 1H). S (ESI) m / z for C 11 H8N2O2[M+H] + : Calculated value: 201.1; Measured value: 201.4.

[0075] 4-(3-nitrophenyl)pyridine (11e) was dissolved in 4-bromopyridine hydrochloride (0.19 g, 1.0 mmol). and 3-nitrophenylboronic acid (0.18 g, 1.1 mmol) according to general procedure A to give brown was prepared as a solid (0.13 g, 67%). 1 H NMR (300 MHz, CDCl3) δ 8.73 - 8.78 (m, 7.62 - 7.74 (m, 3H), 7.51 - 7.59 (m, 2H), 7.43 - 7.50 (m, 2H). for C 11 H8N2O2[M+H] + : Calculated value: 201.1; Measured value: 201.4.

[0076] 5-(3-Nitrophenyl)pyrimidine (11f) was dissolved in 5-bromopyrimidine (0.16 g, 1.0 mmol) and and 3-nitrophenylboronic acid (0.18 g, 1.1 mmol) according to general procedure A to give a pale yellow was prepared as a solid (0.10 g, 52%). 1 H NMR (300 MHz, CDCl3) δ 9.29 - 9.32 (m, 1H), 9.03 (s, 2H), 8.48 (t, J = 1.98 Hz, 1H), 8.33 - 8.38 (m, 1H), 7.94 (qd, J = 0.93, 7.75 Hz, 1H), 7.71 - 7.79 (m, 1H). MS (ESI) m / z for C10 H7N3O2[M+H] + : total Calculated value: 202.1; Measured value: 202.4.

[0077] 1-(3-Methoxyphenyl)-3-nitrobenzene (11g) was dissolved in 2-bromo-3-methoxybenzene (0 from 3-nitrophenylboronic acid (0.30 g, 1.6 mmol) and 3-nitrophenylboronic acid (0.29 g, 1.8 mmol) using the general procedure Prepared according to A as a white solid (0.24 g, 65%). 1 H NMR (300 MHz, CDCl3) δ 8 .33 - 8.40 (m, 1H), 8.13 (td, J = 1.06, 8.24 Hz, 1H), 7.80 - 7.88 (m, 1H), 7.54 (t, J = 8.01 Hz, 1H), 7.29 - 7.41 (m, 1H), 7.13 (dd, J= 0.85, 7.63 Hz, 1H), 7.04 - 7.09 (m, 1H), 6.86 - 6.94 (m, 1H), 3.82 (s, 3H).

[0078] 1-(3-hydroxyphenyl)-3-nitrobenzene (11h) was reacted with 2-bromo-3-hydroxybenzene The general procedure was carried out from boronic acid (0.30 g, 1.7 mmol) and 3-nitrophenylboronic acid (0.32 g, 1.9 mmol). Prepared according to Method A as a white solid (0.24 g, 64%). 1 H NMR (300 MHz, CDCl3) δ 8.44 (d, J = 1.70 Hz, 1H), 8.16 - 8.25 (m, 1H), 7.85 - 7.95 (m, 1H), 7.56 - 7 .65 (m, 1H), 7.33 - 7.40 (m, 1H), 7.20 (br. s., 1H), 7.13 (br. s., 1H), 6.88 - 7 .00 (m, 1H), 5.42 (br. s., 1H).

[0079] 1-(3-nitrophenyl)-3-(propan-2-yloxy)benzene (11i) was reacted with 1-bromo-3-(propan-2-yloxy)benzene (11i) (propan-2-yloxy)benzene (0.30 g, 1.7 mmol) and 3-nitrophenylboronic acid (0.28 g, 1.7 mmol) according to general procedure A as a yellow liquid (0.30 g, 84%). 1 H NMR (300 MHz, CDCl3) δ 8.44 (t, J = 1.98 Hz, 1H), 8.15 - 8.24 (m, 1H), 7.90 (td, J= 1.25, 7.86 Hz, 1H), 7.54 - 7.65 (m, 1H), 7.33 - 7.44 (m, 1H), 7.10 - 7.2 0 (m, 2H), 6.95 (dd, J = 1.88, 8.10 Hz, 1H), 4.64 (spt, J = 6.06 Hz, 1H), 1.34 - 1.43 (m, 6H).

[0080] 1-(4-chlorophenyl)-3-nitrobenzene (11j) was dissolved in 1-iodo-4-chlorobenzene (0.30 g , 1.25 mmol) and 3-nitrophenylboronic acid (0.23 g, 1.38 mmol) according to general method A. It was thus prepared as a white solid (0.24 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 8.37 - 8.43 (m, 1H), 8.21 (ddd, J = 1.04, 2.26, 8.19 Hz, 1H), 7.88 (ddd, J = 1.04, 1 .74, 7.77 Hz, 1H), 7.62 (t, J = 8.01 Hz, 1H), 7.51 - 7.58 (m, 2H), 7.41 - 7.50 ( m, 2H).

[0081] 1,3-Dichloro-4-(3-nitrophenyl)benzene (11k) was reacted with 1-bromo-3,5-dichlorobenzene The general procedure was carried out from boronic acid (0.30 g, 1.32 mmol) and 3-nitrophenylboronic acid (0.24 g, 1.46 mmol). Prepared according to Method A as a white solid (0.29 g, 82%). 1 H NMR (300 MHz, CDCl ) δ 8.41 (t, J = 1.79 Hz, 1H), 8.27 (dd, J = 1.22, 8.19 Hz, 1H), 7.87 (d, J = 7 .72 Hz, 1H), 7.62 - 7.70 (m, 1H), 7.50 (d, J = 1.70 Hz, 2H), 7.43 (t, J = 1.70 H z, 1H).

[0082] 1,2-Dichloro-4-(3-nitrophenyl)benzene (11l) was treated with 1-iodo-3,4-dichlorobenzene The general procedure was carried out from boronic acid (0.30 g, 1.10 mmol) and 3-nitrophenylboronic acid (0.20 g, 1.21 mmol). Prepared according to Method A as a white solid (0.19 g, 65%). 1 H NMR (300 MHz, CDCl ) δ 8.40 (t, J = 1.98 Hz, 1H), 8.21 - 8.27 (m, 1H), 7.87 (td, J= 1.25, 7.68 Hz, 1H), 7.71 (d, J = 2.07 Hz, 1H), 7.64 (t, J = 8.01 Hz, 1H), 7.55 - 7.59 (m, 1H), 7.46 (dd, J = 2.17, 8.38 Hz, 1H).

[0083] 1,3-Dichloro-2-(3-nitrophenyl)benzene (11m) was reacted with 2-bromo-1,3-dichlorobenzene The general procedure was carried out from boronic acid (0.30 g, 1.32 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol). Prepared according to Method A as a yellow solid (0.23 g, 65%). 1 H NMR (300 MHz, CDCl ) δ 8.26 - 8.34 (m, 1H), 8.18 (d, J = 1.70 Hz, 1H), 7.59 - 7.68 (m, 2H), 7.41 - 7.49 (m, 2H), 7.29 - 7.35 (m, 1H).

[0084] 1-(4-Fluorophenyl)-3-nitrobenzene (11n) was reacted with 1-bromo-4-fluorobenzene (0. 30 g, 1.71 mmol) and 3-nitrophenylboronic acid (0.31 g, 1.88 mmol), Prepared according to Method A as a white solid (0.35 g, 93%). 1 H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 8.19 (d, J = 7.54 Hz, 1H), 7.86 (d, J = 7.72 Hz, 1H), 7.57 - 7.62 (m, 2H), 7.18 (t, J = 8.57 Hz, 2H).

[0085] 1-(2,4-Difluorophenyl)-3-nitrobenzene (11o) was reacted with 1-bromo-2,4-difluorophenyl Benzene (0.19 g, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) were used to Prepared according to general method A as a white solid (0.17 g, 71%). 1 H NMR (300 MHz, C DCl3) δ 8.37 (s, 1H), 8.23 ​​(td, J = 1.08, 8.19 Hz, 1H), 7.85 (dd, J= 1.13, 7.72 Hz, 1H), 7.59 - 7.67 (m, 1H), 7.46 (dt, J = 6.31, 8.62 Hz, 1H), 6.92 - 7.06 (m, 2H).

[0086] 1-(4-tert-butylphenyl)-3-nitrobenzene (11p) was reacted with 1-bromo-4-tert-butylphenyl From benzene (0.30 g, 1.41 mmol) and 3-nitrophenylboronic acid (0.26 g, 1.55 mmol), Prepared according to typical method A as a colorless liquid (0.15 g, 42%). 1 H NMR (300 MHz, CDCl ) δ 8.43 (t, J = 1.88 Hz, 1H), 8.12 - 8.18 (m, 1H), 7.87 - 7.92 (m, 1H), 7.48 - 7.60 (m, 5H), 1.37 (s, 9H).

[0087] 1,3-Di-tert-butyl-5-(3-nitrophenyl)benzene (11q) was reacted with 1-bromo-3,5-di-tert- Butylbenzene (0.30 g, 1.1 mmol) and 3-nitrophenylboronic acid (0.20 g, 1.2 mmol) et al., according to general procedure A as a colorless liquid (0.22 g, 63%). 1 H NMR (300 M H z, CDCl3) δ 8.41 - 8.44 (m, 1H), 8.19 (td, J = 1.08, 8.19 Hz, 1H), 7.91 (dd, J= 0.47, 7.82 Hz, 1H), 7.59 - 7.63 (m, 1H), 7.52 (t, J = 1.51 Hz, 1H), 7.42 (d, J = 1.70 Hz, 2H), 1.40 (s, 21H).

[0088] 1-(3-nitrophenyl)-3-phenylbenzene (11r) was reacted with 1-bromo-3-phenylbenzene (0. from 17 ml of 1-nitrophenylboronic acid (0.17 g, 1.0 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.1 mmol) using the general method Prepared according to A as a colorless liquid (0.27 g, 98%). 1 H NMR (300 MHz, CDCl) δ 8.5 2 (t, J = 1.98 Hz, 1H), 8.21 - 8.26 (m, 1H), 7.98 (td, J= 1.27, 7.82 Hz, 1H), 7. 81 - 7.84 (m, 1H), 7.63 - 7.69 (m, 4H), 7.59 - 7.63 (m, 2H), 7.45 - 7.50 (m, 2H) , 7.39 - 7.43 (m, 1H).

[0089] 1-(4-phenylphenyl)-3-nitrobenzene (11s) was reacted with 1-bromo-4-phenylbenzene (0. 30 g, 1.29 mmol) and 3-nitrophenylboronic acid (0.24 g, 1.42 mmol), Prepared according to Method A as a white solid (0.21 g, 58%). 1 H NMR (300 MHz, CDCl3) δ 8.50 (t, J = 1.98 Hz, 1H), 8.20 (ddd, J = 0.75, 2.12, 8.24 Hz, 1H), 7.95 (td, J = 1.18, 7.82 Hz, 1H), 7.71 (d, J = 0.94 Hz, 4H), 7.62 - 7.66 (m, 3H), 7.44 - 7. 51 (m, 2H), 7.37 - 7.42 (m, 1H).

[0090] [4-(3-nitrophenyl)phenyl](phenyl)methanone (11t) was reacted with (4-iodophenyl)(phenyl)methanone (11t) to form (phenyl)methanone (0.31 g, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) l) according to general method A as a brown solid (0.18 g, 60%). 1 H NMR ( 300 MHz, CDCl3) δ 8.49 - 8.55 (m, 1H), 8.28 (dd, J = 1.79, 7.63 Hz, 1H), 7.91 - 8.01 (m, 3H), 7.81 - 7.87 (m, 2H), 7.73 - 7.78 (m, 2H), 7.60 - 7.71 (m, 2H), 7. 49 - 7.56 (m, 2H).

[0091] 5-(3-nitrophenyl)-1-benzofuran (11u) was dissolved in 5-bromo-1-benzofuran (0.13 ml, 1 0.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A. This was prepared as a white solid (0.20 g, 84%). 1 H NMR (300 MHz, CDCl3) δ 8.47 ( t, J = 1.98 Hz, 1H), 8.18 (ddd, J = 1.04, 2.21, 8.24 Hz, 1H), 7.90 - 7.96 (m, 1H) ), 7.81 - 7.85 (m, 1H), 7.68 - 7.71 (m, 1H), 7.58 - 7.64 (m, 2H), 7.51 - 7.56 (m , 1H), 6.85 (dd, J = 0.85, 2.17 Hz, 1H).

[0092] 2-(3-nitrophenyl)naphthalene (11v) was dissolved in 2-bromonaphthalene (0.41 g, 2.00 mmol) and and 3-nitrophenylboronic acid (0.37 g, 2.20 mmol) according to general procedure A to obtain a white Prepared as a solid (0.37 g, 74%). 1 H NMR (300 MHz, CDCl3) δ 8.57 (t, J = 1.98 Hz, 1H), 8.22 (ddd, J = 0.94, 2.17, 8.19 Hz, 1H), 8.08 (d, J = 1.51 Hz, 1H), 8.0 1 - 8.06 (m, 1H), 7.96 (d, J= 8.48 Hz, 1H), 7.86 - 7.93 (m, 2H), 7.74 (dd, J = 1 .88, 8.48 Hz, 1H), 7.64 (t, J = 8.01 Hz, 1H), 7.52 - 7.57 (m, 2H).

[0093] 2-(3-nitrophenyl)quinoline (11w) was reacted with 2-bromoquinoline (0.18 g, 0.84 mmol) and 3- From nitrophenylboronic acid (0.15 g, 0.93 mmol), a white solid was obtained according to general procedure A. Prepared as a product (0.02 g, 11%). 1 H NMR (300 MHz, CDCl3) δ 9.05 (t, J = 1.88 Hz, 1H), 8.53 - 8.58 (m, 1H), 8.28 - 8.34 (m, 2H), 8.20 (d, J = 8.48 Hz, 1H), 7.94 ( d, J = 8.67 Hz, 1H), 7.88 (d, J = 8.10 Hz, 1H), 7.75 - 7.82 (m, 1H), 7.70 (t, J = 8.01 Hz, 1H), 7.55 - 7.63 (m, 1H).

[0094] 3-(3-nitrophenyl)quinoline (11x) was dissolved in 3-bromoquinoline (0.14 ml, 1.00 mmol) and 3 -nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A to obtain a white solid It was prepared as a solid (0.08 g, 33%). 1 H NMR (300 MHz, CDCl3) δ 9.19 (d, J = 2.26 Hz , 1H), 8.55 - 8.60 (m, 1H), 8.38 (d, J = 2.26 Hz, 1H), 8.29 (dd, J = 1.41, 8.19 Hz, 1H), 8.17 (d, J = 8.48 Hz, 1H), 8.05 (d, J = 7.91 Hz, 1H), 7.93 (d, J = 8.10 Hz, 1H), 7.79 (dt, J = 1.32, 7.72 Hz, 1H), 7.72 (t, J = 8.01 Hz, 1H), 7.60 - 7. 67 (m, 1H).

[0095] 2-(3-nitrophenyl)-9H-fluorene (11y) was dissolved in 2-bromo-9H-fluorene (0.25 ml, 1.0 0 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A. This was prepared as a yellow solid (0.07 g, 26%). 1 H NMR (300 MHz, CDCl3) δ 8.51 (t, J = 1.98 Hz, 1H), 8.19 (ddd, J = 0.94, 2.26, 8.10 Hz, 1H), 7.97 (qd, J = 0.94, 7.72 Hz, 1H), 7.84 - 7.91 (m, 2H), 7.81 (d, J = 4.71 Hz, 2H), 7.62 - 7.67 (m, 1H ), 7.56 - 7.60 (m, 1H), 7.40 (d, J= 6.97 Hz, 1H), 7.36 (dd, J = 1.32, 7.35 Hz, 1 H), 3.99 (s, 2H).

[0096] 2-(3-nitrophenyl)thiophene (11z) was dissolved in 2-bromothiophene (0.10 ml, 1.00 mmol). and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A to give yellow methyl boronic acid (3-nitrophenylboronic acid, 0.18 g, 1.10 mmol). was prepared as a solid (0.18 g, 92%). 1 H NMR (300 MHz, CDCl3) δ 8.42 (t, J = 1.8 8 Hz, 1H), 8.06 - 8.13 (m, 1H), 7.89 (d, J = 7.72 Hz, 1H), 7.53 (t, J = 8.01 Hz, 1H), 7.42 (dd, J = 0.85, 3.67 Hz, 1H), 7.37 (dd, J = 0.75, 5.09 Hz, 1H), 7.12 ( dd, J = 3.77, 5.09 Hz, 1H).

[0097] 2-Methyl-4-(3-nitrophenyl)thiophene (11aa) was converted to 4-bromo-2-methylthiophene (0 0.10 ml, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) to give the general Prepared according to Method A as a yellow solid (0.09 g, 42%). 1 H NMR (300 MHz, CDCl3) δ 8.37 (t, J = 1.88 Hz, 1H), 8.09 (td, J = 1.06, 8.24 Hz, 1H), 7.85 (d, J = 7.7 2 Hz, 1H), 7.52 (t, J = 8.01 Hz, 1H), 7.32 (d, J= 1.51 Hz, 1H), 7.08 (s, 1H), 2. 54 (s, 1H).

[0098] 2-Methyl-5-(3-nitrophenyl)thiophene (11ab) was reacted with 4-bromo-2-methylthiophene (0 0.10 ml, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) to give the general Prepared according to Method A as a yellow solid (0.09 g, 42%). 1 H NMR (300 MHz, CDCl3) δ 8.36 (t, J = 1.98 Hz, 1H), 8.05 (ddd, J = 0.94, 2.12, 8.24 Hz, 1H), 7.79 - 7. 84 (m, 1H), 7.50 (t, J = 8.01 Hz, 1H), 7.22 (d, J= 3.58 Hz, 1H), 6.75 - 6.79 (m, 1H), 2.50 - 2.56 (m, 3H).

[0099] 5-(3-nitrophenyl)-1,3-thiazole (11ac) was dissolved in 5-bromo-1,3-thiazole (0.09 ml, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A. This was prepared as a yellow solid (0.10 g, 46%). 1 H NMR (300 MHz, CDCl3) δ 8.86 ( s, 1H), 8.43 (t, J = 1.88 Hz, 1H), 8.17 - 8.24 (m, 2H), 7.88 - 7.94 (m, 1H), 7.5 8 - 7.66 (m, 1H).

[0100] 4-(3-nitrophenyl)-1,3-thiazole (11ad) was dissolved in 4-bromo-1,3-thiazole (0.09 ml, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A. This was prepared as a yellow solid (0.12 g, 58%).1 H NMR (300 MHz, CDCl3) δ 8.93 ( d, J = 1.88 Hz, 1H), 8.78 (t, J = 1.98 Hz, 1H), 8.26 - 8.31 (m, 1H), 8.17 - 8.22 (m, 1H), 7.72 (d, J = 2.07 Hz, 1H), 7.62 (t, J= 8.01 Hz, 1H).

[0101] 2-(3-nitrophenyl)-1,3-thiazole (11ae) was dissolved in 4-bromo-1,3-thiazole (0.09 ml, 1.00 mmol) and 3-nitrophenylboronic acid (0.18 g, 1.10 mmol) according to general procedure A. This was prepared as a yellow solid (0.08 g, 37%). 1 H NMR (300 MHz, CDCl3) δ 8.80 ( t, J = 1.88 Hz, 1H), 8.24 - 8.32 (m, 1H), 7.87 - 7.96 (m, 2H), 7.43 - 7.47 (m, 2 H).

[0102] 3-(Pyridin-3-yl)aniline (14a) was dissolved in 3-bromoaniline (0.11 ml, 1.00 mmol) and 3- Pyridinylboronic acid (0.18 g, 1.10 mmol) was used to obtain a white solid, (0.10 g, 59%) 1 H NMR (300 MHz, CDCl3) δ 8.81 (d, J = 1.70 Hz, 1H), 8.56 (dd, J = 1.41, 4.80 Hz, 1H), 7.77 - 7.85 (m, 1H), 7.31 (dd, J = 4.71, 7.91 Hz, 1H), 7.24 (t, J= 7.72 Hz, 1H), 6.91 - 6.98 (m, 1H), 6.83 - 6.88 (m, 1H), 6. 71 (td, J = 1.11, 7.96 Hz, 1H), 3.83 (br. s., 2H). MS (ESI) m / zfor C 11 H 10 N2[M+H ] + : Calculated value: 171.1; Measured value: 171.0.

[0103] 3-(2H-1,3-benzodioxol-5-yl)aniline (14b) was dissolved in 3-bromoaniline (0.19 ml , 1.74 mmol) and (2H-1,3-benzodioxol-5-yl)boronic acid (0.32 g, 2.08 mmol) et al., following general procedure A as a yellow liquid (0.08 g, 60%). 1 H NMR (300 M H z, CDCl3) δ 6.95 - 7.04 (m, 2H), 6.81 - 6.90 (m, 4H), 6.61 - 6.66 (m, 1H), 6.55 - 6.61 (m, 2H), 6.41 (d, J = 2.64 Hz, 1H), 6.24 (dd, J = 2.54, 8.38 Hz, 1H), 5. 89 (s, 2H), 3.73 (br. s., 2H). MS (ESI) m / z for C 13 H 11 NO2[M+H] + : Calculated value:213.1; Actual value: 213.2.

[0104] 3-(3-methylphenyl)aniline (14c) was dissolved in 3-bromoaniline (0.11 ml, 1.00 mmol) and 3 -methylphenylboronic acid (0.16 g, 1.10 mmol) according to general procedure A to obtain a yellow liquid The compound was prepared as is (0.12 g, 66%). 1 H NMR (300 MHz, CDCl3) δ 7.29 - 7.39 (m, 3H), 7 .12 - 7.22 (m, 2H), 6.96 - 7.00 (m, 1H), 6.90 (t, J= 1.98 Hz, 1H), 6.67 (ddd, J = 0.94, 2.26, 7.91 Hz, 1H), 3.73 (br. s., 2H), 2.41 (s, 3H).

[0105] 3-(2-Methylphenyl)aniline (14d) was dissolved in 3-bromoaniline (0.11 ml, 1.00 mmol) and 2 From 2-methylphenylboronic acid (0.15 g, 1.10 mmol), Prepared according to general method A as a yellow liquid (0.15 g, 82%). 1 H NMR (300 MHz, C DCl3) δ 7.20 - 7.29 (m, 5H), 6.61 - 6.74 (m, 3H), 3.69 (br. s., 2H), 2.28 (s, 3 H). MS (ESI) m / z for C 13 H 13 N [M+H] + : Calculated value: 184.1; Measured value: 184.2.

[0106] 3-(3-nitrophenyl)aniline (14e) was dissolved in 3-bromoaniline (0.19 ml, 1.74 mmol) and 3 -nitrophenylboronic acid (0.32 g, 1.91 mmol) according to general procedure A to obtain a white solid It was prepared as a solid (0.08 g, 21%). 1 H NMR (300 MHz, CDCl3) δ 8.37 - 8.45 (m, 1H), 8.17 (ddd, J = 0.94, 2.26, 8.10 Hz, 1H), 7.83 - 7.92 (m, 1H), 7.57 (t, J = 7.91 Hz, 1H), 7.21 - 7.28 (m, 1H), 6.96 - 7.03 (m, 1H), 6.92 (t, J = 1.88 Hz, 1H), 6 .72 - 6.78 (m, 1H), 3.82 (br. s., 2H). MS (ESI) m / z for C 12 H 10 N2O2[M+H] + : Calculated value :215.1; Actual value:215.0.

[0107] 3-(furan-3-yl)aniline (14f) was dissolved in 3-bromoaniline (0.19 ml, 1.74 mmol) and (furan-3-yl)aniline (14f). A white solid was obtained from (3-amino-3-yl)boronic acid (0.21 g, 1.91 mmol) according to general procedure A. Prepared as a product (0.09 g, 32%). 1 H NMR (300 MHz, CDCl3) δ 7.66 - 7.71 (m, 1H), 7 .45 (t, J = 1.70 Hz, 1H), 7.12 - 7.20 (m, 1H), 6.90 (td, J = 1.30, 7.58 Hz, 1H), 6.81 (t, J = 1.88 Hz, 1H), 6.66 (d, J = 1.13 Hz, 1H), 6.60 (ddd, J = 0.94, 2.45 , 7.91 Hz, 1H), 3.69 (br. s., 2H). MS (ESI) m / z for C 10 H9NO [M+H] + : Calculated value: 160. 1; Actual value: 160.1.

[0108] 3-(Thiophen-3-yl)aniline (14 g) was dissolved in 3-bromoaniline (0.19 ml, 1.74 mmol) and From (thiophen-3-yl)boronic acid (0.25 g, 1.91 mmol), white HCl was obtained according to general procedure A. was prepared as a solid (0.03 g, 10%). 1 H NMR (300 MHz, CDCl3) δ 7.38 - 7.42 (m, 1H), 7.32 - 7.37 (m, 2H), 7.15 - 7.22 (m, 1H), 7.00 (td, J= 1.25, 7.68 Hz, 1H), 6.92 (t, J = 1.88 Hz, 1H), 6.63 (ddd, J = 0.94, 2.26, 7.91 Hz, 1H), 3.71 (br. s. , 2H). MS (ESI) m / z for C 10 H9NS [M+H] + : Calculated value: 176.1; Measured value: 176.3.

[0109] 2-(4-nitrophenyl)-6-(pyrrolidin-1-yl)pyridine (55) was reacted with 2-bromo-6-(pyrrolidine) (phenyl-1-yl)pyridine (0.30 g, 1.32 mmol) and 4-nitrophenylboronic acid (0.24 g, 1.45 mmol) mol) according to general procedure A as an orange solid (0.28 g, 80%). MS (ESI) m / z for C 15 H 15 N3O2[M+H] + : Calculated value: 270.1; Measured value: 270.3.

[0110] tert-Butyl 2-(3-nitrophenyl)-1H-pyrrole-1-carboxylate (61) is a 1-bromo Mono-3-nitrobenzene (0.20 g, 1 mmol) and N-Boc-2-pyrroleboronic acid (0.23 g, 1.1 mmol) ) as a yellow solid (0.15 g, 51%) according to general method A. 1 H NMR (3 00 MHz, CDCl3) δ 8.12 - 8.28 (m, 2H), 7.69 (d, J = 6.22 Hz, 1H), 7.47 - 7.58 (m , 1H), 7.36 - 7.44 (m, 1H), 6.22 - 6.35 (m, 2H), 1.40 (s, 9H).

[0111] General Method D. 1-Bromo-3-nitrobenzene (1 equiv.) in 1,4-dioxane (0.45 M) , the corresponding amine (1.4 equivalents), palladium(II) acetate (0.12 equivalents), cesium carbonate (2 equivalents), and XantPhos (0.12 equiv.) was added and the reaction mixture was heated at 80° C. under nitrogen for 8 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed twice with water and then with brine. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, ethyl acetate / hexane) afforded the desired product. Got it.

[0112] 1-(3-nitrophenyl)piperidine (74a) was dissolved in 1-bromo-3-nitrobenzene (0.40 g, 2 mm ol) and piperidine (0.28 ml, 2.8 mmol) according to general method D to give a red liquid. (0.24 g, 58%). 1 H NMR (300 MHz, CDCl3) δ 7.71 (t, J = 2.26 Hz, 1H), 7 .60 (dd, J = 1.32, 8.10 Hz, 1H), 7.34 (t, J = 8.19 Hz, 1H), 7.18 (dd, J = 1.98, 8.38 Hz, 1H), 3.23-3.31 (m, 4H), 1.67-1.77 (m, 4H), 1.59-1.67 (m, 2H).MS (ESI) m / z for C 11 H 14 N2O2[M+H] + : Calculated value: 207.3; Measured value: 207.5.

[0113] 4-(3-nitrophenyl)morpholine (74b) was dissolved in 1-bromo-3-nitrobenzene (0.20 g, 1 mm ol) and piperidine (0.09 ml, 1.4 mmol) according to general procedure D to give a yellow solid (0.05 g, 22%) 1 H NMR (300 MHz, CDCl3) δ 7.65 - 7.73 (m, 2H), 7.40 (t, J = 8.10 Hz, 1H), 7.18 (dd, J= 1.70, 8.29 Hz, 1H), 3.88 (t, J = 4.90 Hz, 4H) , 3.25 (t, J = 4.90 Hz, 4H). MS (ESI) m / z for C 10 H 12 N2O3[M+H] + : Calculated value:208.1; Actual measurement: 208.3.

[0114] 4-(3-nitrophenyl)pyrrolidine (74c) was dissolved in 1-bromo-3-nitrobenzene (0.20 g, 1 mm ol) and piperidine (0.08 ml, 1.4 mmol) according to general procedure D to obtain an orange solid It was prepared as a solid (0.13 g, 69%). 1 H NMR (300 MHz, CDCl3) δ 7.45 (dd, J = 1.51, 7.91 Hz, 1H), 7.29 - 7.34 (m, 2H), 6.79 (dd, J= 1.98, 8.19 Hz, 1H), 3.33 (t, J = 6.59 Hz, 4H), 2.05 (td, J=3.46, 6.45 Hz, 4H).MS (ESI) m / z for C 10 H 12 N2O2[M+H ] + : Calculated value: 193.1; Measured value: 193.3.

[0115] 1-Methyl-4-(3-nitrophenyl)piperazine (74d) was dissolved in 1-bromo-3-nitrobenzene (0.2 from 1-methylpiperazine (0.0 g, 1 mmol) and 1-methylpiperazine (0.11 ml, 1.4 mmol) according to general method D , prepared as a yellow liquid (0.18 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.71 (t, J = 2.26 Hz, 1H), 7.64 (dd, J = 1.32, 8.10 Hz, 1H), 7.37 (t, J = 8.19 Hz, 1H), 7.19 (dd, J = 1.88, 8.29 Hz, 1H), 3.30 (t, J = 5.10 Hz, 4H), 2.58 (t, J = 5.30 Hz, 4 H), 2.36 (s, 3H). MS (ESI) m / z for C 11 H 15 N3O2[M+H] + : Calculated value: 222.1; Measured value: 222. 4.

[0116] 1-(3-nitrophenyl)azetidine (74e) was dissolved in 1-bromo-3-nitrobenzene (0.20 g, 1 mm ol) and azetidine (0.14 ml, 2 mmol) according to general procedure D to obtain a red solid. (0.16 g, 87%). 1 H NMR (300 MHz, CDCl3) δ 7.52 (ddd, J = 0.75, 2.07, 8 .10 Hz, 1H), 7.30 (t, J = 8.10 Hz, 1H), 7.19 (t, J = 2.26 Hz, 1H), 6.67 (ddd, J = 0.75, 2.26, 8.10 Hz, 1H), 3.96 (t, J = 7.35 Hz, 4H), 2.43 (quin, J = 7.30 Hz, 2H). MS (ESI) m / z for C9H 10 N2O2[M+H] + : Calculated value: 179.1; Measured value: 179.4.

[0117] 4,4-Difluoro-1-(3-nitrophenyl)piperidine (74f) was treated with 1-bromo-3-nitrobenzene The general formula was prepared from 4,4-difluoropiperidine (0.10 g, 0.5 mmol) and 4,4-difluoropiperidine (0.17 g, 0.7 mmol). Prepared according to Method D as a yellow solid (0.16 g, 87%). 1 H NMR (300 MHz, CDCl3) δ 7.74 (t, J = 2.35 Hz, 1H), 7.66 - 7.72 (m, 1H), 7.40 (t, J = 8.19 Hz, 1H), 7. 18 - 7.24 (m, 1H), 3.46 (t, J = 5.70 Hz, 4H), 2.04 - 2.20 (m, 4H). MS (ESI) m / z for C 11 H 12 F2N2O2[M+H] + : Calculated value: 242.1; Measured value: 242.2.

[0118] (1S,4S)-7-(3-nitrophenyl)-7-azabicyclo[2.2.1]heptane (74 g) was treated with 1-bromo-3 -nitrobenzene (0.10 g, 0.5 mmol) and 7-azabicyclo[2.2.1]heptane (0.14 g, 0.7 mmol) mol) according to general method D as a yellow liquid (0.16 g, 87%). 1 H NMR ( 300 MHz, CDCl3) δ 7.67 (t, J = 2.26 Hz, 1H), 7.60 (dd, J = 1.41, 8.01 Hz, 1H), 7.31 (t, J = 8.10 Hz, 1H), 7.14 (dd, J = 1.98, 8.19 Hz, 1H), 4.24 (td, J = 2.52, 1.75 - 1.85 (m, 4H), 1.45 - 1.54 (m, 4H). MS (ESI) m / z for C 12 H 14 N2O2[M+H] + : Calculated value: 219.1; Measured value: 219.2.

[0119] 1-(3-nitrophenyl)azepane (74h) was dissolved in 1-bromo-3-nitrobenzene (0.20 g, 1 mmol ) and hexamethyleneimine (0.16 ml, 1.4 mmol) according to general method D to obtain orange It was prepared as a colored liquid (0.11 g, 48%). 1 H NMR (300 MHz, CDCl3) δ 7.40 - 7.48 (m, 2H), 7.25 - 7.29 (m, 1H), 6.90 - 6.95 (m, 1H), 3.49 (t, J= 5.80 Hz, 4H), 1.81 (d d, J = 4.05, 5.18 Hz, 4H), 1.52 - 1.58 (m, 4H). MS (ESI) m / z for C 12 H 16 N2O2[M+H] + : Calculated value: 221.1; Measured value: 221.2.

[0120] 6-(3-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (74i) was reacted with 1-bromo-3-nitrophenyl A mixture of 2-oxa-6-azaspiro[3.3]heptane hemioxalate (0.20 g, 1 mmol) and 2-oxa-6-azaspiro[3.3]heptane hemioxalate was (0.40 g, 1.4 mmol) according to general procedure D as a yellow solid (0.07 g, 33%). 1 H NMR (300 MHz, CDCl3) δ 7.57 (ddd, J = 0.75, 2.07, 8.10 Hz, 1H), 7. 32 (t, J = 8.19 Hz, 1H), 7.21 (t, J = 2.26 Hz, 1H), 6.69 (ddd, J = 0.75, 2.26, 8 .10 Hz, 1H), 4.86 (s, 4H), 4.11 (s, 4H). MS (ESI) m / zfor C 11 H 12 N2O3[M+H] + : calculation Value: 221.1; Measured: 221.2.

[0121] N,N-Diethyl-3-nitroaniline (74j) was dissolved in 1-bromo-3-nitrobenzene (0.20 g, 1 mmol ) and diethylamine (0.2 ml, 2 mmol) as a red liquid according to general method D Prepared (0.14 g, 74%). 1 H NMR (300 MHz, CDCl3) δ 7.42 - 7.46 (m, 2H), 7.29 (s, 1H), 6.92 (s, 1H), 3.41 (q, J = 7.16 Hz, 4H), 1.20 (t, J = 7.06 Hz, 6H). ) m / zfor C 10 H 14 N2O2[M+H] + : Calculated value: 195.1; Measured value: 195.4.

[0122] 1-(Cyclopentyloxy)-3-nitrobenzene (93). 3-Nitrophenol (0.14 g, 1 A solution of 1.2 mmol of cyclohexanediaminetetraacetic acid (2.2 mmol) in THF (5 ml) was added under nitrogen to triphenylphosphine (0.29 g, 1.1 mmol), Cyclopentasiloxane (0.29 g, 1.1 mmol), 0.1 ml (1.1 mmol) of diisopropyl alcohol was added. The reaction was cooled in an ice-water bath and diisopropyl alcohol was added. Propyl azodicarboxylate (0.22 ml, 1.1 ml) was added slowly over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. After removing the solvent, the mixture was concentrated under reduced pressure and subjected to column chromatography. Purification by column chromatography (SiO2, ethyl acetate / hexanes) gave the desired product as a white solid. (0.14 g, 70%). 1H NMR (300 MHz, CDCl3) δ 7.77 (ddd, J = 0.94, 2.07, 8.10 Hz, 1H), 7.69 (t, J = 2.35 Hz, 1H), 7.40 (t, J = 8.19 Hz, 1H), 7.18 (ddd, J = 0.75, 2.45, 8.29 Hz, 1H), 4.83 (tt, J = 2.61, 5.58 Hz, 1H), 1.76 - 2.03 (m, 6H), 1.61 - 1.72 (m, 2H). MS (ESI) m / z for C 11 H 13 NO3[M+H]+: Calculated: 208.1; Found: 208.2.

[0123] 2-(3-Nitrophenyl)-1H-imidazole (70). 3-Nitrobenzonitrile (0.50 g, 3. To a solution of 17 ml of anhydrous methanol (37 mmol), sodium methoxide (0.18 g, 3.37 mmol) was added. The reaction mixture was stirred for 5 hours at room temperature. Then, acetic acid (0.39 ml, 6.82 mmol) and Add aminoacetaldehyde dimethyl acetal (0.37 ml, 3.37 mmol) and stir. The mixture was heated at 70°C for 1 hour. After cooling to room temperature, methanol (2.25 ml) and 6N aqueous HCl (1.7 ml) was added to the reaction mixture. The mixture was then heated to 70°C for 1 hour. After cooling to room temperature, the solution was The solvent was removed under reduced pressure. Saturated aqueous potassium carbonate was added slowly until the pH reached 8-10. The product precipitated and was collected by filtration as a white solid (0.39 g, 61%). 1 H NMR (3 00 MHz, CD3OD) δ 7.21 - 7.27 (m, 1H), 6.66 - 6.77 (m, 2H), 6.13 - 6.24 (m, 1H), 5.64 - 5.73 (m, 2H). MS (ESI) m / z for C9H7N3O2[M+H] + : Calculated value: 190.1; Measured value: 19 0.3.

[0124] General Method B. Add 1 equivalent of nitrobenzene derivative to a 0.1 M ethanol solution of hydrazine. hydrate (15 eq.) was added. The reaction was stirred at 50° C. for 15 min and an excess of Raney nickel suspension was added. After 1 hour, the bubbling stopped and the mixture was cooled to room temperature and The filtrate was concentrated under reduced pressure, and the residue was used in the next step without further purification. or purified by column chromatography (SiO2, ethyl acetate / hexane). to give the desired product.

[0125] 3-(6-Methoxypyridin-2-yl)aniline (12a) was prepared from 11a (0.23 g, 1.00 mmol) by the general procedure: Prepared according to typical method B as a colorless liquid (0.20 g, quantitative yield). 1H NMR (300 MHz, CDCl3) δ 7.54 (dd, J = 7.54, 8.10 Hz, 1H), 7.36 - 7.41 (m, 2H), 7.17 - 7.27 (m, MS (ESI) m / z for C 12 H 12 NO [M+H] + : Calculated value: 201.1; Measured value: 201.1.

[0126] 3-(4-Methylpyridin-2-yl)aniline (12b) was prepared from 11b (0.16 g, 0.73 mmol) by the general procedure Prepared according to Method B as a yellow solid (0.10 g, 76%). 1 H NMR (300 MHz, CDCl ) δ 8.52 (d, J = 3.96 Hz, 1H), 7.51 (s, 1H), 7.27 (d, J = 5.09 Hz, 3H), 7.04 (d , J = 3.58 Hz, 1H), 6.65 (br. s., 1H), 3.63 (br. s, 2H), 2.39 (s, 3H). MS (ESI) m / z for C 12 H 12 N2[M+H] + : Calculated value: 184.1; Measured value: 184.4.

[0127] 3-(2-Methoxypyridin-4-yl)aniline (12c) was prepared from 11c (0.30 g, 1.30 mmol) using the general procedure Prepared according to typical method B as a colorless liquid (0.17 g, 65%). 1 H NMR (300 MHz, CDCl ) δ 8.35 (d, J = 2.07 Hz, 1H), 7.71 - 7.78 (m, 1H), 7.18 - 7.28 (m, 1H), 6.91 ( td, J = 1.25, 7.68 Hz, 1H), 6.76 - 6.85 (m, 2H), 6.67 (ddd, J= 0.75, 2.26, 7.91 Hz, 1H), 3.97 (s, 3H), 3.34 (br. s., 2H). MS (ESI) m / z for C 12 H 12 NO [M+H] + : total Calculated value: 201.1; Measured value: 201.2.

[0128] 3-(Pyridin-2-yl)aniline (12d) was prepared from 11d (0.85 g, 4.24 mmol) using general procedure B. The crude product was used in the next step without purification.

[0129] 3-(Pyridin-4-yl)aniline (12e) was prepared from 11e (0.13 g, 0.65 mmol) using general procedure B as a white solid (0.07 g, 65%) according to 1 H NMR (300 MHz, CDCl3) δ 8. 61 - 8.66 (m, 1H), 7.63 - 7.72 (m, 3H), 7.52 - 7.56 (m, 1H), 7.45 - 7.50 (m, 3H) MS (ESI) m / z for C 11 H 10 N2[M+H] + : Calculated value: 171.1; Measured value: 171.0.

[0130] 3-(Pyrimidin-5-yl)aniline (12f) was prepared from 11f (0.10 g, 0.52 mmol) by the general procedure Prepared according to B as a white solid (0.09 g, quantitative). 1H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H), 8.90 - 8.94 (m, 2H), 7.26 - 7.33 (m, 1H), 6.95 (dd, J= 0.85, 7.63 Hz, 1H), 6.86 (t, J = 1.88 Hz, 1H), 6.78 (td, J = 1.13, 8.10 Hz, 1H), 3.85 (br. s., 2H). MS (ESI) m / z for C 10 H9N3[M+H] + : Calculated value: 172.1; Measured value: 172.5.

[0131] 3-(3-methoxyphenyl)aniline (12 g) was prepared from 11 g (0.21 g, 0.92 mmol) of Prepared according to method B as a colorless liquid (0.15 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.28 - 7.35 (m, 1H), 7.17 - 7.23 (m, 1H), 7.14 (d, J = 7.72 Hz, 1H), 7.09 (d, J = 2.26 Hz, 1H), 6.97 (d, J = 7.54 Hz, 1H), 6.84 - 6.90 (m, 2H), 6.65 (dd, J = 1. 51, 7.91 Hz, 1H), 3.83 (s, 3H), 3.70 (br. s., 2H). MS (ESI) m / z for C 13 H 13 NO [M+ H] + : Calculated value: 200.1; Measured value: 200.2.

[0132] 3-(3-Hydroxyphenyl)aniline (12h) was prepared from 11h (0.24 g, 1.12 mmol) using the general procedure Prepared according to Method B as a white solid (0.11 g, 54%). 1H NMR (300 MHz, CDCl3) δ 7.21 - 7.29 (m, 1H), 7.13 - 7.19 (m, 1H), 7.07 (d, J = 7.16 Hz, 1H), 7.02 (s, 1H), 6.91 (d, J = 6.78 Hz, 1H), 6.82 (d, J = 1.51 Hz, 2H), 6.60 (d, J = 5.46 Hz , 1H), 3.65 (br. s., 2H). MS (ESI) m / z for C 12 H 11 NO [M+H] + : Calculated value: 185.1; Actual value Value: 185.9.

[0133] 3-[3-(propan-2-yloxy)phenyl]aniline (12i) was prepared from 11i (0.30 g, 1.16 mmol) According to general procedure B from HCl and the crude product was used in the next step without purification.

[0134] 3-(4-Chlorophenyl)aniline (12j) was prepared from 11j (0.22 g, 0.94 mmol) using general procedure B. as a yellow solid (0.18 g, 94%) according to 1 H NMR (300 MHz, CDCl3) δ 7. 41 (d, J = 8.29 Hz, 2H), 7.24 - 7.35 (m, 3H), 7.14 (d, J = 7.91 Hz, 1H), 6.85 - 6.94 (m, 1H), 6.62 (dd, J = 1.41, 8.01 Hz, 1H), 3.66 (br. s, 2H). MS (ESI) m / zf or C 12 H 10 ClN [M+H] + : Calculated value: 204.1; Measured value: 204.4.

[0135] 3-(3,5-Dichlorophenyl)aniline (12k) was synthesized from 11k (0.29 g, 1.09 mmol) using the general procedure Prepared according to Method B as a colorless liquid (0.21 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 1.88 Hz, 2H), 7.31 (t, J = 1.88 Hz, 1H), 7.19 - 7.23 (m, 1H), 6.89 - 6.94 (m, 1H), 6.81 - 6.84 (m, 1H), 6.68 - 6.74 (m, 1H), 3.76 (br. s., 2H). MS (ESI) m / z for C 12 H9Cl2N [M+H] + : Calculated value: 238.0; Measured value: 238.3.

[0136] 3-(3,4-Dichlorophenyl)aniline (12l) was prepared from 11l (0.18 g, 0.67 mmol) using the general procedure Prepared according to Method B as a colorless liquid (0.14 g, 88%). 1 H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 1.70 Hz, 1H), 7.44 - 7.50 (m, 1H), 7.34 - 7.40 (m, 1H), 7.18 - 7.2 4 (m, 1H), 6.92 (d, J = 7.72 Hz, 1H), 6.83 (s, 1H), 6.70 (dd, J = 1.22, 7.82 Hz, 1H), 3.76 (br. s., 2H). MS (ESI) m / zfor C 12 H9Cl2N [M+H] + : Calculated value: 238.0; Measured value :238.3.

[0137] 3-(2,6-dichlorophenyl)aniline (12m) can be prepared from 11m (0.26 g, 0.97 mmol) by conventional methods. Prepared according to Method B as a yellow solid (0.23 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 8.10 Hz, 2H), 7.24 (d, J = 7.91 Hz, 2H), 6.69 - 6.78 (m, 1H), 6. 64 (d, J = 6.97 Hz, 1H), 6.57 (s, 1H), 3.72 (br. s., 2H). MS (ESI) m / z for C 12 H9 ClN [M+H] + : Calculated value: 238.0; Measured value: 238.1.

[0138] 3-(4-Fluorophenyl)aniline (12n) was prepared from 11n (0.32 g, 1.47 mmol) by conventional methods. Prepared according to Method B as a yellow liquid (0.22 g, 80%). 1 H NMR (300 MHz, CDCl) δ 7.2 1 - 7.54 (m, 3H), 7.09 (d, J = 7.35 Hz, 1H), 6.99 (t, J = 7.91 Hz, 1H), 6.82 (d, MS (ESI) m / z for C 12 H 10 FN [M+H] + : Calculated value: 188.1; Measured value: 188.1.

[0139] 3-(2,4-Difluorophenyl)aniline (12o) was prepared from 11o (0.17 g, 0.71 mmol) using the general procedure Prepared according to method B as a colorless liquid (0.15 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.30 - 7.41 (m, 1H), 7.16 - 7.25 (m, 1H), 6.75 - 6.95 (m, 4H), 6.67 (d, J= 7 .72 Hz, 1H), 3.69 (br. s., 2H). MS (ESI) m / z for C 12 H9F2N [M+H] + : Calculated value:206.1; Actual value: 206.2.

[0140] 3-(4-tert-butylphenyl)aniline (12p) was synthesized from 11p (0.15 g, 0.53 mmol) using the general procedure Prepared according to Method B as a yellow liquid (0.14 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.40 - 7.46 (m, 2H), 7.33 - 7.39 (m, 2H), 7.14 (t, J = 7.82 Hz, 1H), 6.92 (d, J = 7.72 Hz, 1H), 6.83 (s, 1H), 6.59 (dd, J = 1.41, 7.82 Hz, 1H), 3.64 (br. s., 2H) ), 1.28 (s, 10H). MS (ESI) m / zfor C 16 H 19 N [M+H] + : Calculated value: 226.2; Measured value: 226.2.

[0141] 3-(3,5-Di-tert-butylphenyl)aniline (12q) was prepared from 11q (0.22 g, 0.71 mmol) in a single reaction. Prepared according to general method B as a yellow oil (0.18 g, 91%). 1 H NMR (300 MHz, C DCl3) δ 7.35 - 7.43 (m, 3H), 7.18 - 7.23 (m, 1H), 6.99 (d, J = 7.72 Hz, 1H), 6. 90 (s, 1H), 6.67 (dd, J = 1.32, 7.91 Hz, 1H), 3.26 - 4.11 (m, 2H), 1.37 (s, 18H) MS (ESI) m / z for C 20 H 27 N [M+H] + : Calculated value: 282.2; Measured value: 282.4.

[0142] 3-(3-phenylphenyl)aniline (12r) was prepared from 11r (0.27 g, 0.98 mmol) by conventional methods. Prepared according to Method B as a colorless liquid (0.18 g, 73%). MS (ESI) m / z for C 18 H 15 N [M+ H] + : Calculated value: 246.1; Measured value: 246.3.

[0143] 3-(4-phenylphenyl)aniline (12s) was prepared from 11s (0.20 g, 0.73 mmol) by conventional methods. Prepared according to Method B as a yellow solid (0.18 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.61 - 7.68 (m, 6H), 7.45 (t, J = 7.44 Hz, 2H), 7.36 (d, J = 7.16 Hz, 1H), 7. 21 - 7.28 (m, 1H), 7.04 (d, J = 7.72 Hz, 1H), 6.95 (d, J= 1.88 Hz, 1H), 6.68 (dd , J = 1.32, 7.91 Hz, 1H), 3.72 (br. s., 2H). MS (ESI) m / z for C 18 H 15 N [M+H] + : total Calculated value: 246.1; Measured value: 246.2.

[0144] 3-(4-Benzoylphenyl)aniline (12t) was synthesized from 11t (0.18 g, 0.59 mmol) using the general procedure Prepared according to Method B as a yellow solid (0.14 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.72 - 7.83 (m, 4H), 7.59 (d, J = 8.29 Hz, 2H), 7.51 (d, J = 7.35 Hz, 1H), 7 .43 (d, J = 7.54 Hz, 2H), 7.14 - 7.20 (m, 1H), 6.96 (d, J= 7.72 Hz, 1H), 6.85 - 6.89 (m, 1H), 6.62 - 6.69 (m, 1H), 3.65 (br. s., 2H). MS (ESI) m / z for C 19 H 15 NO [M+H] + : Calculated value: 274.1; Measured value: 274.2.

[0145] 3-(1-benzofuran-5-yl)aniline (12u) was synthesized from 11u (0.20 g, 0.84 mmol) using the general procedure Prepared according to Method B as a white solid (0.12 g, 66%). 1 H NMR (300 MHz, CDCl3) δ 7.75 (d, J = 1.32 Hz, 1H), 7.63 (d, J = 2.07 Hz, 1H), 7.45 - 7.55 (m, 2H), 7. 18 - 7.26 (m, 1H), 6.98 - 7.03 (m, 1H), 6.91 (t, J = 1.98 Hz, 1H), 6.78 (dd, J = 0.66, 2.17 Hz, 1H), 6.66 (ddd, J = 0.94, 2.31, 7.86 Hz, 1H), 3.71 (br. s., 2H). MS (ESI) m / z for C 14 H 11NO [M+H] + : Calculated value: 210.1; Measured value: 210.2.

[0146] 3-(Naphthalen-2-yl)aniline (12v) was prepared from 11v (0.26 g, 1.05 mmol) using the general procedure Prepared according to B as a white solid (0.11 g, 46%). 1 H NMR (300 MHz, CDCl3) δ 8 .00 (s, 1H), 7.84 - 7.91 (m, 3H), 7.71 (dd, J = 1.60, 8.57 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.26 (d, J = 2.83 Hz, 1H), 7.12 (d, J = 7.16 Hz, 1H), 7.04 (s, 1H), 6.7 1 (d, J = 7.16 Hz, 1H). MS (ESI) m / z for C 16 H 13 N [M+H] + : Calculated value: 220.1; Measured value: 220.2.

[0147] 3-(Quinolin-2-yl)aniline (12w) was prepared from 11w (0.02 g, 0.10 mmol) using general procedure B as a yellow solid (0.02 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 8 .21 (dd, J = 5.84, 8.48 Hz, 2H), 7.80 - 7.87 (m, 2H), 7.73 (ddd, J= 1.41, 6.97, 8.38 Hz, 1H), 7.58 (t, J = 1.98 Hz, 1H), 7.52 - 7.56 (m, 1H), 7.45 - 7.51 (m, 1H) ), 7.31 (t, J = 7.82 Hz, 1H), 6.77 - 6.82 (m, 1H), 3.46 (br. s., 2H). MS (ESI) m / z for C 15 H 12 N2[M+H] + : Calculated value: 221.1; Measured value: 221.2.

[0148] 3-(Quinolin-3-yl)aniline (12x) was prepared from 11x (0.08 g, 0.33 mmol) using general procedure B as a yellow solid (0.07 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 9 .15 (d, J = 2.26 Hz, 1H), 8.25 (d, J = 2.07 Hz, 1H), 8.13 (d, J = 8.29 Hz, 1H), 7.85 (d, J = 8.10 Hz, 1H), 7.70 (ddd, J= 1.41, 6.92, 8.43 Hz, 1H), 7.52 - 7.59 ( m, 1H), 7.26 - 7.33 (m, 1H), 7.09 (dd, J = 0.94, 7.72 Hz, 1H), 7.00 (t, J = 1.98 MS (ESI) m / zfor C 15 H 12 N2[M+H] + : Calculated value: 221.1; Measured value: 221.2.

[0149] 3-(9H-Fluoren-2-yl)aniline (12y) was prepared from 11y (0.07 g, 0.26 mmol) by the general procedure Prepared according to Method B as a white solid (0.05 g, 71%). 1 H NMR (300 MHz, CDCl3) δ 7.77 - 7.83 (m, 2H), 7.74 (d, J = 0.75 Hz, 1H), 7.52 - 7.60 (m, 2H), 7.35 - 7 .42 (m, 1H), 7.31 (dd, J = 1.22, 7.44 Hz, 1H), 7.20 - 7.28 (m, 2H), 7.03 - 7.07 (m, 1H), 6.97 (t, J = 1.98 Hz, 1H), 6.68 (ddd, J= 0.75, 2.31, 7.86 Hz, 1H), 3.94 (s, 2H), 3.73 (br. s., 2H). MS (ESI) m / z for C 19 H 15 N [M+H] + : Calculated value: 258.1; Actual Measurement: 258.2.

[0150] 3-(Thiophen-2-yl)aniline (12z) was prepared from 11z (0.18 g, 0.89 mmol) using the general procedure Prepared according to B as a yellow solid (0.10 g, 64%). 1 H NMR (300 MHz, CDCl3) δ 7 .20 - 7.29 (m, 2H), 7.10 - 7.18 (m, 1H), 6.98 - 7.08 (m, 2H), 6.92 (s, 1H), 6.59 (dd, J = 2.07, 7.91 Hz, 1H), 3.69 (br. s., 2H). MS (ESI) m / z for C 12 H9Cl2N [M+H ] + : Calculated value: 238.0; Measured value: 238.1.

[0151] 3-(5-methylthiophen-3-yl)aniline (12aa) from 11aa (0.09 g, 0.42 mmol): Prepared according to general method B as a white solid (0.08 g, quantitative). 1 H NMR (300 MHz , CDCl3) δ 7.12 - 7.17 (m, 2H), 6.93 - 7.02 (m, 2H), 6.87 (d, J = 1.88 Hz, 1H), 6.59 (dd, J = 1.51, 7.91 Hz, 1H), 3.68 (br. s., 2H), 2.50 (s, 3H). MS (ESI) m / z for C 11 H 11 NS [M+H] + : Calculated value: 190.1; Measured value: 190.2.

[0152] 3-(5-methylthiophen-2-yl)aniline (12ab) was prepared from 11ab (0.09 g, 0.42 mmol): Prepared according to general method B as a colorless liquid (0.08 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.09 - 7.16 (m, 1H), 7.05 (d, J = 3.39 Hz, 1H), 6.93 - 6.99 (m, 1H), 6 .86 (t, J = 1.88 Hz, 1H), 6.67 - 6.72 (m, 1H), 6.56 (ddd, J= 0.94, 2.26, 7.91 Hz , 1H), 3.65 (br. s., 2H), 2.48 (s, 2H). MS (ESI) m / z for C 11 H 11 NS [M+H] + : Calculated value :190.1; Actual value:190.3.

[0153] 3-(1,3-Thiazol-5-yl)aniline (12ac) was prepared from 11ac (0.09 g, 0.46 mmol) using the general procedure Prepared according to typical method B as a colorless liquid (0.06 g, 73%). 1 H NMR (300 MHz, CDCl ) δ 8.72 (s, 1H), 8.03 (s, 1H), 7.13 - 7.23 (m, 1H), 6.97 (dd, J = 0.94, 7.72 H z, 1H), 6.88 (d, J = 3.77 Hz, 1H), 6.66 (td, J = 1.06, 8.05 Hz, 1H), 3.80 (br. s ., 2H). MS (ESI) m / zfor C9H8N2S [M+H] + : Calculated value: 177.1; Measured value: 177.4.

[0154] 3-(1,3-Thiazol-4-yl)aniline (12ad) was prepared from 11ad (0.12 g, 0.58 mmol) using the general procedure Prepared according to typical method B as a colorless liquid (0.06 g, 61%). 1 H NMR (300 MHz, CDCl ) δ 8.86 (d, J = 1.88 Hz, 1H), 7.48 (d, J = 1.88 Hz, 1H), 7.26 - 7.35 (m, 2H), 6.69 (dd, J = 1.22, 2.35 Hz, 1H), 6.23 (dd, J = 2.26, 7.91 Hz, 1H), 3.71 (br. s. , 2H). MS (ESI) m / zfor C9H8N2S [M+H] + : Calculated value: 177.1; Measured value: 177.5.

[0155] 3-(1,3-Thiazol-2-yl)aniline (12ae) was prepared from 11ae (0.08 g, 0.37 mmol) by the general procedure: Prepared according to method B as a colorless liquid (0.03 g, 46%). 1 H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 3.39 Hz, 1H), 7.29 - 7.35 (m, 3H), 7.22 (t, J = 8.01 Hz, 1H), 6. 72 - 6.77 (m, 1H), 3.80 (br. s., 2H). MS (ESI) m / zfor C9H8N2S [M+H] + : Calculated value: 17 7.1; Actual value: 177.3.

[0156] 4-[6-(pyrrolidin-1-yl)pyridin-2-yl]aniline (56) was dissolved in 55 (0.29 g, 1.06 mmol). Prepared according to general method B from as a colorless liquid (0.18 g, 71%). 1 H NMR (300 MHz, CDCl3) δ 7.84 - 7.95 (m, 2H), 7.44 (t, J = 7.91 Hz, 1H), 6.91 (d, J = 7.3 5 Hz, 1H), 6.68 - 6.78 (m, 2H), 6.22 (d, J= 8.29 Hz, 1H), 3.75 (br. s., 2H), 3.5 3 (t, J = 6.50 Hz, 4H), 1.96 - 2.04 (m, 4H). MS (ESI) m / z for C 15 H 17 N3[M+H] + : total Calculated value: 240.1; Measured value: 240.3.

[0157] tert-Butyl 2-(3-aminophenyl)-1H-pyrrole-1-carboxylate (62) was reacted with 61 (0.14 7 g, 0.51 mmol) as a white solid according to general procedure B. 5%). 1 H NMR (300 MHz, CDCl3) δ 7.21 - 7.37 (m, 1H), 7.06 - 7.18 (m, 1H), 6.70 - 6.78 (m, 1H), 6.57 - 6.68 (m, 2H), 6.18 (d, J = 10.74 Hz, 2H), 3.63 (br. s., 2H ), 1.37 (s, 9H). MS (ESI) m / z for C 15 H 18 N2O2[M+H] + : Calculated value: 259.1; Measured value: 259.5 .

[0158] 3-(1H-imidazol-2-yl)aniline (71) was prepared from 70 (0.30 g, 1.58 mmol) using the general procedure Prepared according to Method B as a white solid (0.25 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.05 - 7.23 (m, 5H), 6.69 (d, J = 8.10 Hz, 1H), 3.74 (br. s., 2H). MS (ESI) m / z for C9H9N3[M+H] + : Calculated value: 160.1; Measured value: 160.2.

[0159] 3-(Piperidin-1-yl)aniline (75a) was prepared from 74a (0.24 g, 1.16 mmol) by the general procedure B as a colorless liquid (0.18 g, 88%). 1 H NMR (300 MHz, CDCl) δ 7.0 0 (t, J = 8.01 Hz, 1H), 6.35 (dd, J = 1.79, 8.19 Hz, 1H), 6.22 (t, J = 2.17 Hz, 1H), 6.11 - 6.16 (m, 1H), 3.55 (br. s., 2H), 3.09 (t, J = 1.00 Hz, 4H), 1.66 (qu in, J = 5.51 Hz, 4H), 1.50 - 1.58 (m, 2H). MS (ESI) m / z for C 11 H 16 N2[M+H] + : calculation Value: 177.1; Actual value: 177.5.

[0160] 3-(morpholin-4-yl)aniline (75b) was prepared from 74b (0.05 g, 0.22 mmol) using the general procedure Prepared as a white solid (0.04 g, 90%) according to B. MS (ESI) m / z for C 11 H 16 N2[M +H] + : Calculated value: 179.1; Measured value: 179.5. 1 H NMR (300 MHz, CDCl3) δ 7.06 (t, J = 8.29 Hz, 1H), 6.35 (dd, J = 1.41, 8.19 Hz, 1H), 6.20 - 6.28 (m, 2H), 3.84 (t, J = 4. 90 Hz, 4H), 3.62 (br. s., 2H), 3.12 (t, J = 4.90 Hz, 4H). 10 H 14 NO [M+H] + : Calculated value: 178.1; Measured value: 178.5.

[0161] 3-(Pyrrolin-1-yl)aniline (75c) was prepared from 74c (0.13 g, 0.68 mmol) using general procedure B as a colorless liquid (0.10 g, 86%) according to 1 H NMR (300 MHz, CDCl3) δ 7.00 (t, J = 8.01 Hz, 1H), 6.03 (dd, J = 2.17, 8.01 Hz, 2H), 5.90 (t, J = 1.98 Hz, 1 H), 3.55 (br. s., 2H), 3.23 (t, J = 6.59 Hz, 4H), 1.96 (td, J = 3.34, 6.50 Hz, 4 H). MS (ESI) m / z for C 10 H 14 N2[M+H] + : Calculated value: 163.1; Measured value: 163.5.

[0162] 3-(4-Methylpiperazin-1-yl)aniline (75d) was prepared from 74d (0.18 g, 0.82 mmol) by the general procedure Prepared according to typical method B as a white solid (0.12 g, 75%). 1 H NMR (300 MHz, CDC l3) δ 7.04 (t, J = 8.01 Hz, 1H), 6.37 (dd, J = 1.88, 8.10 Hz, 1H), 6.25 (t, J = 2.07 Hz, 1H), 6.21 (dd, J = 1.98, 7.82 Hz, 1H), 3.60 (br. s., 2H), 3.18 (t, J = 4.90 Hz, 4H), 2.55 (t, J = 5.10 Hz, 4H), 2.34 (s, 3H). 11 H 17 N 3[M+H] + : Calculated value: 192.1; Measured value: 192.4.

[0163] 3-(Azetidin-1-yl)aniline (75e) was prepared from 74e (0.16 g, 0.87 mmol) using the general procedure B as a colorless liquid (0.10 g, 80%). 1 H NMR (300 MHz, CDCl) δ 6.9 8 (t, J = 7.91 Hz, 7H), 6.07 (ddd, J = 0.75, 2.07, 7.91 Hz, 7H), 5.89 (ddd, J = 0.66, 2.07, 8.01 Hz, 7H), 5.76 (t, J = 2.17 Hz, 7H), 3.82 (t, J = 7.25 Hz, 30H), 3.52 (br. s., 8H), 2.30 (quin, J = 7.21 Hz, 15H). MS (ESI) m / z for C9H 12 N2[M+H] + : Calculated value: 149.1; Measured value: 149.2.

[0164] N1,N1-Diethylbenzene-1,3-diamine (75j) was prepared from 74j (0.16 g, 0.87 mmol) by general HPLC. Prepared according to method B as a colorless liquid (0.10 g, 80%). 1 H NMR (300 MHz, CDCl3) δ 6.99 (t, J = 8.29 Hz, 1H), 6.11 - 6.16 (m, 1H), 6.00 - 6.04 (m, 2H), 3.53 (br .s., 1H), 3.30 (q, J = 6.97 Hz, 4H), 1.14 (t, J = 7.06 Hz, 6H). r C 10 H 16 N2[M+H] + : Calculated value: 165.1; Measured value: 165.2.

[0165] 3-(4,4-Difluoropiperidin-1-yl)aniline (75f) was prepared from 74f (0.07 g, 0.30 mmol) , prepared according to general method B as a colorless liquid (0.07 g, quantitative). 1 H NMR (300 MHz , CDCl3) δ 7.05 (t, J = 7.91 Hz, 1H), 6.36 (td, J = 1.13, 8.29 Hz, 1H), 6.20 - 6.28 (m, 2H), 3.62 (br. s., 2H), 3.64 (br. s, 2H), 3.32 (t, J = 5.50 Hz, 4H), 2. 06 (tt, J = 5.91, 13.78 Hz, 4H). MS (ESI) m / z for C 11 H 16 N2[M+H] + : Calculated value: 177.1 ; Actual value: 177.2.

[0166] 3-[(1S,4S)-7-azabicyclo[2.2.1]heptan-7-yl]aniline (75 g) was dissolved in 74 g (0.02 g, 0 Prepared from 1.001 mmol) according to general method B as a colorless liquid (0.03 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 6.97 (t, J = 8.01 Hz, 1H), 6.31 (td, J = 1.11, 8.15 Hz, 1H), 6.23 (t, J = 2.17 Hz, 1H), 6.15 (ddd, J = 0.66, 2.12, 7.77 Hz, 1H), 4.12 ( td, J = 2.59, 4.62 Hz, 2H), 3.55 (br. s., 2H), 1.75 - 1.83 (m, 4H), 1.36 - 1.44 (m, 4H). MS (ESI) m / z for C 12 H 16 N2[M+H] + : Calculated value: 188.1; Measured value: 188.2.

[0167] 3-(Azepan-1-yl)aniline (75h) was prepared from 74h (0.11 g, 0.46 mmol) using general procedure B as a colorless liquid (0.06 g, 68%) according to 1 H NMR (300 MHz, CDCl3) δ 6.95 - 7.02 (m, 1H), 6.12 - 6.18 (m, 1H), 5.99 - 6.05 (m, 2H), 3.54 (br. s., 2H), 3. 36 - 3.44 (m, 4H), 1.76 (dd, J = 3.96, 5.09 Hz, 4H), 1.50 - 1.56 (m, 4H). MS (ES I) m / z for C 12 H 18 N2[M+H] +: Calculated value: 191.1; Measured value: 191.2.

[0168] 3-{2-oxa-6-azaspiro[3.3]heptan-6-yl}aniline (75i) was dissolved in 74i (0.04 g, 0.16 Prepared from 100 mmol) according to general method B as a white solid (0.04 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 6.99 (t, J = 7.91 Hz, 1H), 6.12 (ddd, J = 0.75, 2.17, 7. 82 Hz, 1H), 5.89 (ddd, J = 0.75, 2.17, 8.01 Hz, 1H), 5.77 (t, J = 2.17 Hz, 1H), 4.81 (s, 4H), 3.97 (s, 4H), 3.61 (br. s., 2H). MS (ESI) m / z for C 11 H 14 NO [M+H] + : Calculated value: 191.1; Measured value: 191.2.

[0169] 1-[(3-nitrophenyl)methyl]pyrrolidine (88). 3-Nitrobenzyl bromide (0.22 g To a solution of 1 mmol) in THF (7.5 ml) was added triethylamine (0.15 ml, 1 mmol) and pyrrolidine (0. 17 ml, 2.05 mmol) was added. The reaction mixture was refluxed for 2 hours. The solvent was evaporated under reduced pressure. The organic layer was removed and the residue was diluted with ethyl acetate and washed with water and brine. Dry over magnesium, filter, and concentrate in vacuo to give the desired product as a yellow liquid. Obtained (0.21 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 8.06 - 8.12 (m, 1H) , 7.69 (d, J = 7.54 Hz, 1H), 7.44 - 7.52 (m, 1H), 3.71 (s, 2H), 2.48 - 2.57 (m, 4H), 1.80 (td, J = 3.23, 6.92 Hz, 4H). MS (ESI) m / z for C 11 H 14 N2O2[M+H] + : Calculated value :207.1; Actual value:207.2.

[0170] 3-(Pyrrolidin-1-ylmethyl)aniline (89). 88 (0.19 g, 0.93 mmol) in ethanol To the solution was added 10% w / w Pd / C (0.012 g). The reaction mixture was heated in a Parr hydrogenator for 50 min. The reaction mixture was then subjected to hydrogenation at psi and room temperature for 1 hour. The reaction mixture was then poured onto a pad of Celite. ad) and concentrated in vacuo to give the desired product as a white solid (0.14 g, 88%). 1 H NMR (300 MHz, CDCl3) δ 7.07 (t, J = 6.88 Hz, 1H), 6.63 - 6.79 (m, 2 H), 6.42 - 6.60 (m, J= 6.78 Hz, 1H), 4.81 (br. s., 2H), 3.58 (s, 2H), 2.40 - 2.7 4 (m, 4H), 1.66 - 1.94 (m, 4H). 13 C NMR (75 MHz, CDCl3) δ 146.6, 139.4, 129.1, 119.2, 115.7, 114.0, 60.3, 53.8, 23.4. MS (ESI) m / z for C 11 H 16 N2[M+H] + : Calculated value: 177.1; Actual value: 177.2.

[0171] 3-(Cyclopentyloxy)aniline (94) was prepared from 93 (0.10 g, 0.5 mmol) by the general procedure Prepared according to B as a white solid (0.05 g, 58%). 1 H NMR (300 MHz, CDCl3) δ 7 .03 (t, J = 8.01 Hz, 1H), 6.23 - 6.32 (m, 2H), 6.20 - 6.23 (m, 1H), 4.67 - 4.74 (m, 1H), 3.62 (br. s., 2H), 1.74 - 1.91 (m, 6H), 1.55 - 1.64 (m, 2H). MS (ESI) m / z for C 11 H 15 NO [M+H] + : Calculated value: 178.1; Measured value: 178.2.

[0172] 3-(1H-Pyrrol-2-yl)aniline (64). 62 (0.06%) in 5% aqueous potassium hydroxide (23 ml). g, 0.23 mmol) was refluxed for 4 hours. After cooling to room temperature, the mixture was poured into water and The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Concentration gave the desired product as a white solid (0.03 g, 78%). 1 H NMR (300 MHz, CDCl 3) δ 8.41 (br. s., 1H), 7.05 - 7.22 (m, 1H), 6.73 - 6.94 (m, 3H), 6.40 - 6.60 ( m, 2H), 6.28 (s, 1H), 3.67 (br. s., 2H). MS (ESI) m / zfor C 10 H 10 N2[M+H] + : Calculated value :159.1; Actual value:159.2

[0173] 3-(1-Methyl-1H-pyrrol-2-yl)aniline (67). 3-Iodoaniline in a sealed tube (0.24 ml, 2 mmol) in N,N-dimethylacetamide (8 ml) was added to N-methylpyrrole (0.36 m l, 8 mmol), potassium acetate (0.39 g, 8 mmol), and palladium(II) acetate (0.005 g, 0.02 m mol) was added. The reaction mixture was stirred at 150° C. for 20 hours. The organic layer was diluted with ethyl acetate and washed three times with water and once with brine. The residue was purified by column chromatography (SiO2, acetic acid). Purification by ethyl acetate / hexanes afforded the desired product as a yellow liquid (0.08 g, 22%). . 1 H NMR (300 MHz, CDCl3) δ 7.17 (t, J = 7.82 Hz, 1H), 6.76 - 6.81 (m, 1H), 6.6 9 (td, J= 2.10, 8.24 Hz, 2H), 6.61 (ddd, J = 0.75, 2.31, 8.05 Hz, 1H), 6.16 - 6. 21 (m, 2H), 3.68 (br. s., 2H), 3.64 (s, 3H). MS (ESI) m / zfor C 11 H 12 N2[M+H] + : total Calculated value: 173.1; Measured value: 173.5.

[0174] General Method C. A solution of arylamine (1 equiv.) in anhydrous chloroform (0.04 M) is added with 4-chloro- The reaction mixture was then heated at 60° C. for 16 hours. The precipitated product was filtered and washed thoroughly with dichloromethane.

[0175] 3-(4-chlorophenyl)-1-[3-(6-methoxypyridin-2-yl)phenyl]urea (15) was reacted with 12a 0.08 g, 0.5 mmol) as a white solid according to general procedure C , 82%). 1 H NMR (300 MHz, DMSO-d6) δ 8.86 (d, J = 3.96 Hz, 2H), 8.14 - 8.18 (m, 1H), 7.76 - 7.83 (m, 1H), 7.69 (d, J = 8.10 Hz, 1H), 7.56 (d, J = 9.42 Hz, 1H), 7.48 - 7.54 (m, 3H), 7.41 (d, J = 7.91 Hz, 1H), 7.32 - 7.38 (m, 2H), 6.80 (d, J= 8.29 Hz, 1H), 3.97 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 163.1, 153.6, 152.5, 1 40.0, 139.9, 138.9, 138.7, 129.1, 128.6, 125.3, 120.2, 119.8, 119.0, 116.4, 112. 9, 109.3, 52.8. MS (ESI) m / z for C 19 H 16 ClN3O2[M+H] + : Calculated value: 354.1; Measured value: 354. 3.

[0176] 3-(4-chlorophenyl)-1-[3-(4-methylpyridin-2-yl)phenyl]urea (16) was reacted with 12b (0. 0.09 g, 0.55 mmol) as a white solid according to general procedure C 64%). 1 H NMR (300 MHz, CDCl3) δ 8.50 (d, J = 5.09 Hz, 1H), 7.87 (s, 1H), 7.61 ( d, J = 7.54 Hz, 1H), 7.51 (s, 1H), 7.39 (td, J = 7.91, 15.82 Hz, 2H), 7.20 - 7.2 4 (m, 4H), 7.07 - 7.16 (m, 3H), 2.41 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 157.0, 153.2, 149.1, 148.5, 140.4, 138.7, 136.9, 129.6, 129.0, 128.7, 123.6, 122.5, 122 .1, 121.6, 121.3, 119.4, 21.2. MS (ESI) m / z for C 19 H 17 ClNO [M+H] + : Calculated value: 338. 1; Actual value: 338.5.

[0177] 3-(4-chlorophenyl)-1-[3-(2-methoxypyridin-4-yl)phenyl]urea (17) was reacted with 12c( 0.03 g, 0.15 mmol) as a white solid according to general procedure C , 57%). 1 H NMR (300 MHz, DMSO-d6) δ 9.05 (br. s., 1H), 8.96 (br. s., 1H), 8.43 (s, 1H), 7.69 - 8.04 (m, 2H), 7.20 - 7.61 (m, 7H), 6.92 (d, J = 7.54 Hz, 1H), 3. 90 (br. s., 3H). 13 C NMR (75 MHz, DMSO-d6) δ 163.1, 152.5, 144.5, 140.2, 138.7, 137.6, 137.5, 129.4, 128.5, 125.3, 120.0, 119.8, 117.4, 116.2, 110.6, 53.2. (ESI) m / z for C 19 H 16 ClN3O2[M+H] + : Calculated value: 353.1; Measured value: 353.4.

[0178] 3-(4-chlorophenyl)-1-[3-(pyridin-2-yl)phenyl]urea (18) was dissolved in 12d (0.05 g, 0. 29 mmol) according to general method C as a white solid (0.05 g, 53%). 1 H NMR (300 MHz, DMSO-d6) δ 8.89 - 8.96 (m, 2H), 8.67 (d, J = 4.71 Hz, 1H), 8.25 (d, J = 1.70 Hz, 1H), 7.87 - 7.91 (m, 1H), 7.67 (d, J = 7.72 Hz, 1H), 7.45 - 7.5 5 (m, 4H), 7.30 - 7.38 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 155.9, 152.5, 149.5 , 140.0, 139.3, 138.7, 138.5, 137.2, 129.1, 128.6, 125.3, 122.6, 120.2, 119.8, 1 19.0, 116.5. MS (ESI) m / z for C 18 H 14 ClNO [M+H] + : Calculated value: 324.1; Measured value: 324.2.

[0179] 3-(4-chlorophenyl)-1-[3-(pyridin-3-yl)phenyl]urea (19) was dissolved in 14a (0.05 g, 0. 29 mmol) according to general method C as a white solid (0.05 g, 53%). 1 H NMR (300 MHz, DMSO-d6) δ 8.91 (br. s., 1H), 8.85 (br. s., 2H), 8.59 (d, J = 2. 83 Hz, 1H), 8.02 (d, J = 7.35 Hz, 1H), 7.82 (br. s., 1H), 7.38 - 7.55 (m, 5H), 7 .33 (d, J = 7.35 Hz, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 148.5, 147.5, 140. 3, 138.6, 137.7, 135.7, 134.1, 129.6, 128.6, 125.4, 123.9, 120.6, 119.8, 118.1, 116.7. MS (ESI) m / z for C 18 H 14 ClNO [M+H] + : Calculated value: 324.1; Measured value: 324.3.

[0180] 3-(4-chlorophenyl)-1-[3-(pyridin-4-yl)phenyl]urea (20) was dissolved in 12e (0.03 g, 0. 15 mmol) according to general procedure C as a white solid (0.03 g, 33%). 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.89 (s, 1H), 8.65 (d, J = 5.27 Hz, 2H) , 7.93 (s, 1H), 7.65 (d, J = 5.46 Hz, 2H), 7.46 - 7.54 (m, 3H), 7.43 (d, J = 8.1 0 Hz, 2H), 7.34 (d, J = 8.67 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 150.2, 147.1, 140.4, 138.6, 137.8, 129.7, 128.6, 125.4, 121.2, 120.5, 119.8, 119.1, 11 6.5. MS (ESI) m / z for C 18 H 14 ClNO [M+H] + : Calculated value: 324.1; Measured value: 324.1.

[0181] 3-(4-chlorophenyl)-1-[3-(pyrimidin-5-yl)phenyl]urea (21) was dissolved in 12f (0.03 g, 0.15 mmol) according to general procedure C as a white solid (0.03 g, 33%). 1 H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.09 (s, 2H), 8.95 (d, J = 19.21 Hz, 2H), 7.83 (s, 1H), 7.55 (s, 1H), 7.49 - 7.53 (m, 2H), 7.47 (s, 1H), 7.42 (s, 1H) , 7.34 (d, J = 8.85 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 157.3, 154.6, 152.5, 1 40.4, 138.6, 134.4, 133.4, 129.8, 128.6, 125.5, 120.7, 119.8, 118.9, 116.7. ESI) m / z for C 17 H 13 ClNO [MH] - : Calculated value: 323.1; Measured value: 323.3.

[0182] 3-(4-chlorophenyl)-1-(3-phenylphenyl)urea (22) was dissolved in 3-biphenylamine (0.05 g, 0.29 mmol) as a white solid according to general procedure C. %). 1 H NMR (300 MHz, DMSO-d6) δ 8.91 (br. s., 1H), 8.86 (br. s., 1H), 7.80 (br. s., 1H), 7.62 (d, J= 7.91 Hz, 2H), 7.44 - 7.54 (m, 4H), 7.29 - 7.42 (m, 5H), 7. 27 (td, J = 1.98, 4.33 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 140.8, 140.3 , 140.1, 138.7, 129.3, 128.9, 128.6, 127.5, 126.6, 125.3, 120.4, 119.8, 117.4, 1 16.6. MS (ESI) m / z for C 17 H 13 ClNO [MH] - : Calculated value: 321.1; Measured value: 321.2.

[0183] 3-(4-chlorophenyl)-1-[3-(3-methoxyphenyl)phenyl]urea (23) was added to 12 g (0.02 g , 0.1 mmol) according to general procedure C as a white solid (0.02 g, 57%) . 1 H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.82 (s, 1H), 7.76 (br. s., 1H), 7. 49 (br. s., 2H), 7.22 - 7.44 (m, 6H), 7.16 (d, J = 13.37 Hz, 2H), 6.95 (br. s., 1H), 3.82 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 159.7, 152.5, 141.8, 140.7, 140. 0, 138.7, 130.0, 129.3, 128.6, 125.4, 120.5, 119.8, 119.0, 117.6, 116.7, 113.0, 112.2, 55.1. MS (ESI) m / z for C 20 H 17 ClN2O2[MH] - : Calculated value: 351.1; Measured value: 351.4.

[0184] 3-(4-chlorophenyl)-1-[3-(3-hydroxyphenyl)phenyl]urea (24) was added to the ethanol for 12 h (0.02 g, 0.1 mmol) according to general procedure C as a white solid (0.02 g, 44%) . 1 H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.90 (s, 1H), 7.51 (d, J = 8.29 Hz, 1H), 7.18 - 7.38 (m, 4H), 6.98 - 7.10 (m, 2H), 6.90 - 6.97 (m, 1H), 6.74 (d, J = 18.84 Hz, 2H), 6.54 (d, J = 8.67 Hz, 1H), 5.14 (s, 1H). 13 C NMR (75 MHz, DMSO- d6) δ 157.7, 142.5, 141.6, 140.9, 140.0, 138.7, 129.9, 129.2, 128.6, 119.8, 117 .2, 116.5, 115.1, 114.0, 113.3, 113.1, 112.1. MS (ESI) m / z for C 19 H 15 ClN2O2[MH] - : Calculated value: 337.1; Measured value: 337.5.

[0185] 3-(4-chlorophenyl)-1-[3-(3-isopropylphenyl)phenyl]urea (25) was dissolved in 12 ml of 0.0 mL of 10 ... 3 g, 0.13 mmol) as a white solid according to general procedure C. 0%). 1 H NMR (300 MHz, DMSO-d6) δ 8.90 (br. s., 1H), 8.82 (br. s., 1H), 7.77 (br .s., 1H), 7.46 - 7.54 (m, 2H), 7.29 - 7.43 (m, 5H), 7.26 (d, J = 7.35 Hz, 1H), 7.15 (d, J = 6.78 Hz, 1H), 7.09 (br. s., 1H), 6.93 (d, J = 5.27 Hz, 1H), 4.60 - 4.78 (m, 1H), 1.30 (d, J = 5.84 Hz, 6H). 13 C NMR (75 MHz, DMSO-d6) δ 157.9, 152 .5, 141.8, 140.7, 140.1, 138.7, 130.0, 129.2, 128.5, 125.3, 120.4, 119.8, 118.8, 117.5, 116.7, 114.5, 114.0, 69.2, 21.8. MS (ESI) m / z for C 22 H 21 ClN2O2[MH] - : total Calculated value: 379.1; Measured value: 379.3.

[0186] 1-[3-(2H-1,3-benzodioxol-5-yl)phenyl]-3-(4-chlorophenyl)urea (26) was prepared from 14b (0.09 g, 0.40 mmol) as a white solid according to general procedure C. (0.09 g, 59%). 1 H NMR (300 MHz, DMSO-d6) δ 8.73 - 8.90 (m, 2H), 7.71 (s, 1H), 7.44 - 7.56 (m, 3H), 7.28 - 7.39 (m, 4H), 7.07 - 7.23 (m, 2H), 6.98 - 7.03 (m, 1H), 6.07 (s, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 147.9, 146.8, 140.5, 139. 9, 138.6, 134.6, 129.2, 128.6, 125.3, 120.2, 119.8, 117.1, 116.4, 108.6, 107.0, 101.1. MS (ESI) m / z for C 20 H 15 ClN2O3[M+H] + : Calculated value: 367.1; Measured value: 367.4.

[0187] 3-(4-chlorophenyl)-1-[3-(3-methylphenyl)phenyl]urea (27) was dissolved in 14c (0.13 g, 0 Prepared from 1.0001 methylpropional (0.82 mmol) according to general procedure C as a white solid (0.11 g, 41%). 1 H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.81 (s, 1H), 7.79 (s, 1H), 7.48 - 7.5 3 (m, 2H), 7.43 (s, 1H), 7.31 - 7.40 (m, 6H), 7.23 - 7.27 (m, 1H), 7.19 (d, J = 7.16 Hz, 1H), 2.38 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 140.9, 140.2, 14 0.0, 138.6, 138.0, 129.3, 128.8, 128.6, 128.1, 127.2, 125.4, 123.7, 120.4, 119.8 , 117.4, 116.6, 21.1. MS (ESI) m / z for C 20 H17 ClNO [M+H] + : Calculated value: 337.1; Measured value :337.5.

[0188] 3-(4-chlorophenyl)-1-[3-(2-methylphenyl)phenyl]urea (28) was dissolved in 14d (0.15 g, 0 Prepared from 1.0001 methylpropional (0.82 mmol) according to general procedure C as a white solid (0.11 g, 41%). 1 H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.78 (s, 1H), 7.45 - 7.51 (m, 4H), 7.3 7 (d, J = 3.77 Hz, 1H), 7.27 - 7.36 (m, 5H), 7.20 (d, J = 4.71 Hz, 1H), 6.94 (d, J = 7.16 Hz, 1H), 2.24 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 141.8, 141. 3, 139.3, 138.6, 138.5, 134.6, 130.3, 129.3, 128.6, 127.3, 125.9, 125.5, 125.3, 122.6, 119.8, 119.7, 118.9, 116.9, 20.1. MS (ESI) m / z for C 20 H 17 ClNO [MH] - : total Calculated value: 357.1; Measured value: 335.3.

[0189] 3-(4-chlorophenyl)-1-[3-(3-nitrophenyl)phenyl]urea (29) was dissolved in 14e (0.04 g, 0 Prepared from 1.0001 methylpropional (0.0001 methylpropional) as a white solid (0.06 g, 82%) according to general procedure C. 1 H NMR (300 MHz, DMSO-d6) δ 8.88 (d, J = 1.88 Hz, 2H), 8.37 (s, 1H), 8.22 (dd, J = 1.70, 7.91 Hz, 1H), 8.09 (d, J = 7.91 Hz, 1H), 7.88 (s, 1H), 7.77 (t, J= 8.01 Hz, 1H), 7.43 - 7.50 (m, 4H), 7.36 - 7.42 (m, 1H), 7.33 (d, J = 8.85 Hz, 2H). 1 3 C NMR (75 MHz, DMSO-d6) δ 152.5, 148.4, 141.8, 140.4, 138.6, 138.4, 133.1, 130 .5, 129.7, 128.6, 125.5, 122.2, 120.9, 120.6, 119.8, 118.5, 116.7. MS (ESI) m / z for C 19 H 14 ClN3O3[MH] - : Calculated value: 366.1; Measured value: 366.5.

[0190] 3-(4-chlorophenyl)-1-[3-(4-chlorophenyl)phenyl]urea (30) was dissolved in 12j (0.05 g, 0 Prepared from 1.0001 methylpropional (0.0001 methylpropional) as a white solid (0.08 g, 94%) according to general procedure C. 1 H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.98 (s, 1H), 7.86 (t, J = 1.79 Hz, 1H ), 7.78 (s, 1H), 7.56 - 7.69 (m, 2H), 7.53 (d, J = 2.64 Hz, 1H), 7.50 (d, J = 3. 01 Hz, 1H), 7.45 - 7.48 (m, 1H), 7.41 - 7.45 (m, 1H), 7.35 - 7.40 (m, 1H), 7.32 - 7.35 (m, 1H), 7.31 (d, J = 3.39 Hz, 1H), 7.27 (dd, J = 1.51, 4.52 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 140.2, 139.5, 139.1, 138.6, 132.4, 129.4, 128.8 , 128.6, 128.3, 125.4, 120.3, 119.8, 117.8, 116.5. MS (ESI) m / z for C 19 H 14 Cl2N2O [MH] - : Calculated value: 355.1; Measured value: 355.3.

[0191] 3-(4-chlorophenyl)-1-[3-(3,5-dichlorophenyl)phenyl]urea (31) was dissolved in 12kJ (0.03 g, 0.19 mmol) as a white solid according to general procedure C %). 1 H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.88 (s, 1H), 7.83 (d, J = 2.07 H z, 1H), 7.79 (s, 1H), 7.68 - 7.73 (m, 1H), 7.58 - 7.64 (m, 1H), 7.43 - 7.52 (m, 3H), 7.38 - 7.42 (m, 2H), 7.27 - 7.37 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152. 5, 140.3, 138.6, 137.8, 134.6, 129.6, 128.9, 128.6, 126.9, 126.6, 125.3, 120.6, 119.9, 118.7, 116.8. MS (ESI) m / z for C 19 H 13 Cl3N2O [MH] - : Calculated value: 391.0; Measured value :390.9.

[0192] 3-(4-chlorophenyl)-1-[3-(3,4-dichlorophenyl)phenyl]urea (32) was dissolved in 12 L (0.03 g, 0.13 mmol) as a white solid (0.03 g, 61%) according to general procedure C ). 1 H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.92 (s, 1H), 7.82 - 7.90 (m, 2H), 7.69 - 7.76 (m, 1H), 7.62 (dd, J= 1.88, 8.48 Hz, 1H), 7.53 (s, 2H), 7.48 - 7.56 (m, 2H), 7.38 - 7.46 (m, 2H), 7.29 - 7.37 (m, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 140.9, 140.3, 138.6, 138.1, 131.7, 131.0, 130.2, 129.5, 128.6, 128.3, 12 6.8, 125.4, 120.5, 119.8, 118.3, 116.6. MS (ESI) m / z for C 19 H 13 Cl3N2O [MH] - : total Calculated value: 391.0; Measured value: 390.9.

[0193] 3-(4-chlorophenyl)-1-[3-(2,6-dichlorophenyl)phenyl]urea (33) was dissolved in 12 ml (0.02 g, 0.15 mmol) as a white solid (0.04 g, 69%) according to general procedure C ). 1 H NMR (300 MHz, DMSO-d6) δ 8.86 (br. s., 2H), 7.59 (d, J = 2.64 Hz, 2H), 7. 37 - 7.53 (m, 7H), 7.28 - 7.36 (m, 2H), 6.80 - 6.92 (m, J = 6.97 Hz, 1H). 13 CNM R (75 MHz, DMSO-d6) δ 152.4, 139.6, 138.8, 138.6, 136.9, 133.8, 130.1, 128.9, 1 28.6, 128.4, 125.4, 122.7, 119.8, 118.7, 118.0. MS (ESI) m / z for C 19 H 13 Cl3N2O [M -H] - : Calculated value: 391.0; Measured value: 391.1.

[0194] 3-(4-chlorophenyl)-1-[3-(4-fluorophenyl)phenyl]urea (34) was dissolved in 12 ml of 0.03 g , 0.16 mmol) according to general procedure C as a white solid (0.05 g, 92%) . 1 H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.85 (s, 1H), 7.79 (s, 1H), 7.61 - 7.69 (m, 2H), 7.45 - 7.54 (m, 3H), 7.36 - 7.41 (m, 2H), 7.34 (s, 2H), 7.31 (d, J = 3.01 Hz, 2H), 7.23 - 7.28 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 140.1, 139.8, 138.7, 129.4, 128.9, 128.6, 128.6, 128.5, 126.6, 125.4, 120.4, 119.8, 11 7.4, 116.6, 115.8, 115.5. MS (ESI) m / zfor C 19 H 14 ClFNO [MH] - : Calculated value: 339.1; Actual Measurement: 339.6.

[0195] 3-(4-chlorophenyl)-1-[3-(2,4-difluorophenyl)phenyl]urea (35) was dissolved in 120 ml of 0.0 mL of HCl at 27°C. 4 g, 0.20 mmol) as a white solid according to general procedure C. 6%). 1 H NMR (300 MHz, DMSO-d6) δ 8.95 (d, J = 3.77 Hz, 2H), 7.75 (s, 1H), 7.61 - 7.69 (m, 1H), 7.52 - 7.60 (m, 3H), 7.47 - 7.52 (m, 1H), 7.43 - 7.47 (m, 1H), 7 .37 - 7.42 (m, 2H), 7.23 - 7.32 (m, 1H), 7.20 (d, J = 6.97 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 139.8, 138.6, 134.7, 131.9, 131.8, 131.7, 131.7, 129.1, 128.6, 125.4, 122.4, 119.8, 118.6, 117.8, 112.2, 112.1, 111.9, 111.8, 104.8, 104 .5, 104.1. MS (ESI) m / z for C 19 H 13 ClF2N2O [MH] - : Calculated value: 357.1; Measured value: 357.5.

[0196] 3-(4-chlorophenyl)-1-[3-(4-tert-butylphenyl)phenyl]urea (36) was dissolved in 12p (0.01 g, 0.20 mmol) as a white solid according to general procedure C. %). 1 H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.86 (s, 1H), 7.75 (s, 1H), 7.46 - 7.58 (m, 6H), 7.30 - 7.43 (m, 4H), 7.25 (d, J = 7.35 Hz, 1H), 1.32 (s, 9H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 149.9, 140.7, 140.0, 138.7, 137.4, 129.3, 128. 6, 126.3, 125.7, 125.3, 120.3, 119.8, 117.2, 116.4, 34.2, 31.1. MS (ESI) m / z for C 23 H 23 ClNO [MH] - : Calculated value: 377.2; Measured value: 377.4.

[0197] 3-(4-chlorophenyl)-1-[3-(3,5-di-tert-butylphenyl)phenyl]urea (37) (0.06 g, 0.21 mmol) as a white solid according to general procedure C. g, 54%). 1 H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.82 (s, 1H), 7.61 (br. s., 1H), 7.50 (d, J = 6.78 Hz, 3H), 7.31 - 7.44 (m, 6H), 7.22 - 7.27 (m, 1H), 1.34 ( s, 18H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 142.0, 140.0, 139.8, 138.7, 129.2, 128.6, 126.6, 125.3, 121.1, 120.9, 120.7, 119.7, 117.1, 116.9, 34.6, 31.3. SI) m / z for C 27 H 31 ClNO [MH] - : Calculated value: 433.2; Measured value: 433.6.

[0198] 3-(4-chlorophenyl)-1-[3-(3-phenylphenyl)phenyl]urea (38) was dissolved in 12r (0.11 g , 0.72 mmol) according to general procedure C as a white solid (0.16 g, 56%) . 1 H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.83 (s, 1H), 7.86 (br. s., 2H), 7. 75 (d, J = 7.16 Hz, 2H), 7.61 - 7.69 (m, 2H), 7.58 (d, J = 7.35 Hz, 1H), 7.47 - 7.54 (m, 4H), 7.36 - 7.46 (m, 4H), 7.33 (d, J = 8.85 Hz, 2H). 13 C NMR (75 MHz, D MSO-d6) δ 152.5, 141.0, 140.9, 140.7, 140.1, 140.1, 138.6, 129.6, 129.4, 128.9, 128.6, 127.6, 126.9, 125.9, 125.8, 125.4, 125.0, 120.7, 119.8, 117.6, 116.8. (ESI) m / z for C 25 H 19 ClNO [MH] - : Calculated value: 397.1; Measured value: 397.1.

[0199] 3-(4-chlorophenyl)-1-[3-(4-phenylphenyl)phenyl]urea (39) was dissolved in 12s (0.01 g , 0.20 mmol) according to general procedure C as a white solid (0.01 g, 48%) . 1 H NMR (300 MHz, DMSO-d6) δ 8.93 (br. s., 1H), 8.88 (br. s., 1H), 7.88 (s, 1H ), 7.70 - 7.84 (m, 6H), 7.47 - 7.58 (m, 4H), 7.40 (d, J = 5.09 Hz, 3H), 7.31 - 7 .38 (m, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 140.2, 140.2, 139.6, 139.2, 138 .7, 129.4, 129.0, 128.6, 127.5, 127.2, 127.1, 126.6, 126.5, 125.4, 120.3, 119.8, 117.6, 116.5. MS (ESI) m / z for C 25 H 19 ClNO [MH] - : Calculated value: 397.1; Measured value: 397.0 .

[0200] 3-(4-chlorophenyl)-1-[3-(4-benzoylphenyl)phenyl]urea (40) was added to 12 t (0.03 g, 0.11 mmol) as a white solid (0.04 g, 81%) according to general procedure C ). 1 H NMR (300 MHz, DMSO-d6) δ 8.87 (d, J = 1.88 Hz, 2H), 7.88 (s, 1H), 7.79 - 7.86 (m, 4H), 7.74 - 7.78 (m, 2H), 7.66 - 7.72 (m, 1H), 7.54 - 7.62 (m, 2H), 7.4 6 - 7.51 (m, 2H), 7.43 (d, J = 4.52 Hz, 2H), 7.36 - 7.41 (m, 1H), 7.32 (d, J = 8 .85 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 195.3, 152.5, 144.3, 140.3, 139.6, 138 .6, 137.2, 135.8, 132.6, 130.4, 129.6, 129.5, 128.6, 128.6, 126.7, 125.4, 120.7, 119.8, 118.3, 116.8. MS (ESI) m / z for C 26 H 19 ClN2O2[MH] - : Calculated value: 425.1; Measured value :425.3.

[0201] 1-[3-(1-benzofuran-5-yl)phenyl]-3-(4-chlorophenyl)urea (41) was dissolved in 12 μl (0.09 g, 0.55 mmol) as a white solid according to general procedure C %). 1 H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.82 (s, 1H), 8.05 (d, J = 2.07 H z, 1H), 7.87 (d, J= 5.84 Hz, 2H), 7.66 - 7.71 (m, 1H), 7.47 - 7.60 (m, 3H), 7.27 - 7.40 (m, 5H), 7.04 (d, J = 1.32 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 154.0, 152.5, 146.6, 141.2, 140.0, 138.7, 135.6, 129.3, 128.6, 127.9, 127.2, 125.4, 123 .4, 120.7, 119.8, 119.2, 118.7, 117.0, 117.0, 111.5, 107.0. MS (ESI) m / z for C 21 H 15 ClN2O2[MH] - : Calculated value: 361.1; Measured value: 361.4.

[0202] 3-(4-chlorophenyl)-1-[3-(naphthalen-2-yl)phenyl]urea (42) was dissolved in 12 ml of 12 v (0.11 g, 0.68 mmol) according to general procedure C as a white solid (0.14 g, 55%). 1 H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J = 6.40 Hz, 2H), 8.15 (s, 1H), 7.97 - 8.0 4 (m, 2H), 7.91 - 7.96 (m, 2H), 7.79 (dd, J = 1.51, 8.67 Hz, 1H), 7.46 - 7.56 (m , 4H), 7.42 (s, 3H), 7.32 (d, J = 8.85 Hz, 2H), 7.21 (d, J = 8.85 Hz, 2H). 13 CN MR (75 MHz, DMSO-d6) δ 152.6, 140.6, 140.0, 138.5, 137.5, 133.2, 132.2, 129.5, 128.6, 128.5, 128.1, 127.4, 126.5, 126.2, 125.6, 125.1, 125.0, 120.9, 120.0, 117 .7, 116.9. MS (ESI) m / z for C 23 H 17 ClNO [MH] - : Calculated value: 371.1; Measured value: 371.3.

[0203] 3-(4-chlorophenyl)-1-[3-(quinolin-2-yl)phenyl]urea (43) was dissolved in 12 wt. oz (0.01 g, 0. Prepared from 1000mg DMSO (0.09 mmol) according to general procedure C as a white solid (0.02 g, 59%). 1 H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.87 (s, 1H), 8.46 (d, J = 8.48 Hz, 1H) , 8.32 (s, 1H), 8.04 - 8.09 (m, 1H), 8.00 (d, J = 7.72 Hz, 1H), 7.75 - 7.86 (m, 2H), 7.55 - 7.64 (m, 2H), 7.46 - 7.52 (m, 2H), 7.33 (d, J = 8.85 Hz, 2H). 13 CNM R (75 MHz, DMSO-d6) δ 156.1, 152.6, 147.4, 139.9, 139.3, 138.4, 137.3, 130.1, 1 29.4, 128.9, 128.6, 127.8, 126.9, 126.6, 125.6, 121.2, 120.1, 119.7, 118.8, 117. 2. MS (ESI) m / z for C 22 H 16 ClNO [M+H] + : Calculated value: 374.1; Measured value: 374.0.

[0204] 3-(4-Chlorophenyl)-1-[3-(quinolin-3-yl)phenyl]urea (44) was dissolved in 12x (0.05 g, 0. 33 mmol) according to general method C as a white solid (0.08 g, 63%). 1 H NMR (300 MHz, DMSO-d6) δ 9.21 (d, J = 2.26 Hz, 1H), 8.94 (d, J = 7.54 Hz, 2H), 8.60 (d, J = 2.07 Hz, 1H), 8.04 - 8.13 (m, 2H), 7.98 (s, 1H), 7.79 (dt, J= 1.51 , 7.63 Hz, 1H), 7.63 - 7.70 (m, 1H), 7.46 - 7.55 (m, 5H), 7.36 (s, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 149.4, 146.9, 140.4, 138.6, 137.7, 132.9, 132.8, 129 .7, 129.5, 128.6, 128.6, 128.4, 127.6, 127.0, 125.4, 120.9, 119.8, 118.2, 117.0. MS (ESI) m / z for C 22 H 16 ClNO [M+H] + : Calculated value: 374.1; Measured value: 374.3.

[0205] 3-(4-chlorophenyl)-1-[3-(9H-fluoren-2-yl)phenyl]urea (45) was dissolved in 12 ml of ethyl acetate (0.03 mL) of 100 ml of ethyl acetate (0.03 mL). g, 0.18 mmol) as a white solid (0.05 g, 67%) according to general procedure C ). 1 H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.84 (s, 1H), 7.99 (d, J = 7.91 Hz , 1H), 7.90 - 7.96 (m, 2H), 7.85 (s, 1H), 7.60 - 7.69 (m, 2H), 7.49 - 7.55 (m, 2 H), 7.30 - 7.43 (m, 7H), 4.01 (s, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 143.8 , 143.3, 141.1, 140.7, 140.5, 140.1, 138.9, 138.7, 129.3, 128.6, 126.8, 125.5, 1 25.4, 125.1, 123.3, 120.5, 120.4, 120.1, 119.8, 117.3, 116.6. MS (ESI) m / z for C 26 H 19 ClNO [MH] - : Calculated value: 409.1; Measured value: 409.5.

[0206] 3-(4-chlorophenyl)-1-[3-(furan-3-yl)phenyl]urea (46) was dissolved in 14f (0.03 g, 0.16 Prepared from 100 mmol) according to general procedure C as a white solid (0.05 g, 95%). 1 HN MR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.73 (s, 1H), 8.12 (s, 1H), 7.75 (t, J = 1.70 Hz, 1H), 7.65 (s, 1H), 7.47 - 7.52 (m, 2H), 7.29 - 7.36 (m, 4H), 7.20 - 7.2 8 (m, 1H), 6.88 (d, J= 0.94 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 144.2, 140.0, 139.2, 138.6, 132.4, 129.2, 128.6, 125.9, 125.4, 119.8, 119.5, 117.1, 115 .5, 108.7. MS (ESI) m / z for C 17 H 13 ClN2O2[MH] - : Calculated value: 311.1; Measured value: 311.5.

[0207] 3-(4-chlorophenyl)-1-[3-(thiophen-3-yl)phenyl]urea (47) was dissolved in 14 g (0.03 g, 0. 15 mmol) according to general procedure C as a white solid (0.03 g, 63%). 1 H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.76 (s, 1H), 7.75 - 7.79 (m, 2H), 7.63 (dd, J = 2.92, 4.99 Hz, 1H), 7.45 - 7.51 (m, 3H), 7.30 - 7.36 (m, 5H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 141.5, 140.0, 138.7, 135.7, 129.3, 128.6, 127.1, 126 .1, 125.4, 120.9, 120.0, 119.8, 117.3, 116.0. MS (ESI) m / z for C 17 H 13 ClN2OS [MH ] - : Calculated value: 327.0; Measured value: 327.3.

[0208] 3-(4-chlorophenyl)-1-[3-(thiophen-2-yl)phenyl]urea (48) was dissolved in 12z (0.10 g, 0.67 mmol) according to general method C as a white solid (0.13 g, 57%). 1 H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 2H), 7.82 (s, 1H), 7.55 (d, J = 5.09 Hz, 1 H), 7.50 (d, J= 8.85 Hz, 2H), 7.44 - 7.47 (m, 1H), 7.28 - 7.36 (m, 5H), 7.14 (dd , J = 3.67, 4.99 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 152.4, 143.4, 140.2, 138. 6, 134.2, 129.5, 128.6, 128.4, 125.6, 125.4, 123.6, 119.8, 119.1, 117.5, 115.1. MS (ESI) m / z for C 17 H 13 ClN2OS [MH] - : Calculated value: 327.0; Measured value: 327.4.

[0209] 3-(4-chlorophenyl)-1-[3-(5-methylthiophen-3-yl)phenyl]urea (49) was reacted with 12aa (0.03 g, 0.17 mmol) as a white solid according to general procedure C. g, 70%). 1 H NMR (300 MHz, CD3OD) δ 7.73 (br. s., 1H), 7.61 (d, J = 7.54 Hz, 1H ), 7.39 - 7.48 (m, 4H), 7.32 - 7.38 (m, 2H), 7.24 - 7.31 (m, 4H), 2.51 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 141.1, 140.1, 140.0, 138.7, 135.9, 129.2, 12 8.6, 126.6, 125.4, 124.4, 119.8, 118.6, 117.1, 115.8, 15.0. MS (ESI) m / z for C 18 H 15 ClN2OS [MH] - : Calculated value: 341.1; Measured value: 341.4.

[0210] 3-(4-chlorophenyl)-1-[3-(5-methylthiophen-2-yl)phenyl]urea (50) was reacted with 12ab (0.04 g, 0.19 mmol) as a white solid according to general procedure C g, 77%). 1 H NMR (300 MHz, CD3OD) δ 7.71 (s, 1H), 7.44 (d, J = 8.85 Hz, 2H), 7. 21 - 7.32 (m, 5H), 7.16 (d, J = 3.58 Hz, 1H), 6.74 (d, J = 2.64 Hz, 1H), 2.49 (s , 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 141.0, 140.2, 139.0, 138.6, 134.5, 12 9.4, 128.6, 126.7, 125.4, 123.3, 119.8, 118.6, 117.1, 114.7, 15.0. MS (ESI) m / z for C 18 H 15 ClN2OS [MH] - : Calculated value: 341.1; Measured value: 341.4.

[0211] 3-(4-chlorophenyl)-1-[3-(1,3-thiazol-5-yl)phenyl]urea (51) was reacted with 12ac (0. Prepared as a white solid (0.04 g, 0.16 mmol) according to general procedure C from 1,3-dimethyl-2,4-dichloro-1,4-dichloro-2 ... 66%). 1 H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.88 (s, 2H), 8.26 (s, 1H), 7.8 3 (s, 1H), 7.50 (d, J = 8.85 Hz, 2H), 7.30 - 7.41 (m, 5H). 13 C NMR (75 MHz, DMSO -d6) δ 153.5, 152.4, 140.4, 139.2, 138.7, 138.5, 131.2, 129.7, 128.6, 125.5, 12 0.1, 119.9, 118.3, 116.4. MS (ESI) m / z for C 16 H 12 ClN3OS [MH] - : calculated value:328.0; Actual value: 328.4.

[0212] 3-(4-chlorophenyl)-1-[3-(1,3-thiazol-4-yl)phenyl]urea (52) was added to 12ad (0. 0.03 g, 0.19 mmol) as a white solid according to general procedure C 74%). 1 H NMR (300 MHz, DMSO-d6) δ 9.20 (d, J = 1.88 Hz, 1H), 8.85 (s, 2H), 8.12 - 8.15 (m, 1H), 8.11 (d, J = 1.88 Hz, 1H), 7.59 (d, J = 7.35 Hz, 1H), 7.48 - 7. 53 (m, 2H), 7.31 - 7.45 (m, 5H). 13 C NMR (75 MHz, DMSO-d6) δ 155.0, 154.4, 152. 4, 140.0, 138.7, 134.6, 129.2, 128.6, 125.3, 119.9, 119.8, 118.1, 116.2, 114.2. MS (ESI) m / z for C 16 H 12 ClN3OS [MH] - : Calculated value: 328.0; Measured value: 328.3.

[0213] 3-(4-chlorophenyl)-1-[3-(1,3-thiazol-2-yl)phenyl]urea (53) was reacted with 12ae (0. Prepared as a white solid (0.04 g, 0.16 mmol) according to general procedure C from 1,3-dimethyl-2,4-dichloro-1,4-dichloro-2 ... 72%). 1H NMR (300 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.87 (s, 1H), 8.22 (s, 1H), 7.9 3 (d, J = 3.20 Hz, 1H), 7.80 (d, J = 3.01 Hz, 1H), 7.48 - 7.59 (m, 3H), 7.40 - 7 .47 (m, 2H), 7.30 - 7.39 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 167.1, 152.4, 143 .8, 140.3, 138.5, 133.6, 129.7, 128.6, 125.5, 120.4, 119.9, 119.8, 119.8, 115.7. MS (ESI) m / z for C 16 H 12 ClN3OS [MH] - : Calculated value: 328.0; Measured value: 328.4.

[0214] 3-(4-chlorophenyl)-1-{4-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea ( 57) was prepared from 56 (0.18 g, 0.75 mmol) according to general procedure C to give a pale yellow solid (0.18 g, 6 2%). 1 H NMR (300 MHz, DMSO-d6) δ 8.98 (br. s., 2H), 8.01 (d, J = 7.91 Hz, 2H), 7.44 - 7.65 (m, 5H), 7.34 (d, J = 7.91 Hz, 2H), 7.05 (d, J = 6.97 MS (E), 6.31 (d, J= 8.10 Hz, 1H), 3.44 (br. SI) m / z for C 22 H 21 ClNO [MH] -: Calculated value: 328.1; Measured value: 328.4.

[0215] 3-(4-chlorophenyl)-1-(4-phenylphenyl)urea (59) was dissolved in 58 (0.08 g, 0.5 mmol) et al., following general procedure C as a white solid (0.08 g, 53%). 1 H NMR (300 MHz, DMSO-d6) δ 8.85 (br. s., 2H), 7.55 - 7.69 (m, 3H), 7.47 (d, J = 6.03 Hz, 6 H), 7.25 - 7.37 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 139.8, 139.0, 138.5 , 133.7, 128.8, 128.6, 127.0, 126.1, 125.5, 119.8, 119.7, 118.6. MS (ESI) m / z r C 17 H 13 ClNO [MH] - : Calculated value: 321.1; Measured value: 321.2.

[0216] tert-Butyl 2-[3-({1-[(4-chlorophenyl)amino]ethenyl}amino)phenyl]-1H-pi C. The methyl-1-carboxylate (63) was prepared from 62 (0.03 g, 0.10 mmol) according to general procedure C. This was prepared as a white solid (0.04 g, 84%). 1 H NMR (300 MHz, DMSO-d6) δ 8.83 ( s, 1H), 8.75 (s, 1H), 7.46 - 7.51 (m, 2H), 7.31 - 7.39 (m, 3H), 7.23 - 7.30 (m, 1H), 6.94 (d, J = 7.54 Hz, 1H), 6.26 - 6.30 (m, 1H), 6.22 - 6.26 (m, 1H), 1.31 ( s, 9H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 148.8, 138.9, 138.6, 134.4, 134.2, 1 28.6, 128.0, 125.3, 122.5, 119.7, 118.6, 117.0, 114.1, 110.7, 83.5, 27.1. HRMS ( ESI) m / zfor C 22 H 22 ClN3O3[M+H] + : Calculated value: 412.1422; Measured value: 412.1423.

[0217] 3-(4-chlorophenyl)-1-[3-(1H-pyrrol-2-yl)phenyl]urea (65) was dissolved in 64 (0.03 g, 0.18 mmol) according to general procedure C as a white solid (0.05 g, 81%). 1 H NMR (300 MHz, DMSO-d6) δ 11.26 (br. s., 1H), 8.87 (br. s., 1H), 8.67 (br. s. , 1H), 7.67 (s, 1H), 7.47 - 7.56 (m, 2H), 7.30 - 7.39 (m, J = 5.70 Hz, 2H), 7.22 - 7.29 (m, 3H), 6.84 (s, 1H), 6.44 (s, 1H), 6.12 (s, 1H). 13 C NMR (75 MHz, DMSO -d6) δ 152.5, 139.8, 138.7, 133.6, 131.1, 129.0, 128.6, 125.3, 119.7, 119.3, 11 7.5, 115.9, 113.7, 109.0, 105.5. HRMS (ESI) m / zfor C 17 H 14 ClNO [M+H] + : Calculated value: 3 12.0898; Actual value: 312.0894.

[0218] 3-(4-chlorophenyl)-1-[3-(1-methyl-1H-pyrrol-2-yl)phenyl]urea (68) was reacted with 67 (0.08 g, 0.45 mmol) as a white solid (0.14 g, 98%). 1 H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.77 (s, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.85 Hz, 2H), 7.30 - 7.36 (m, 4H), 7.03 - 7.08 (m, 1H), 6.83 (t, J = 2.17 Hz, 1H), 6.15 (dd, J = 1.88, 3.58 Hz, 1H), 6.04 - 6.08 (m, 1H), 3.66 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.5, 139.6, 138.6, 133.4, 128.8, 128.6, 125 .4, 124.3, 121.6, 119.8, 117.8, 116.6, 108.3, 107.3, 34.9. HRMS (ESI) m / zfor C 18 H 16 ClNO [M+H] + : Calculated value: 326.1055; Measured value: 326.1049.

[0219] 3-(4-chlorophenyl)-1-[3-(1H-imidazol-2-yl)phenyl]urea (72) was dissolved in 71 (0.13 g, 0.82 mmol) as a white solid (0.22 g, 86 %). 1H NMR (300 MHz, DMSO-d6) δ 12.52 (br. s., 1H), 8.84 (d, J = 11.30 Hz, 2H), 8.07 (br. s., 1H), 7.52 (br. s., 3H), 7.44 (br. s., 1H), 7.34 (d, J = 7.16 Hz, 3H), 7.03 - 7.20 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 145.5, 139.8, 138. 7, 131.4, 129.1, 128.6, 125.4, 119.7, 118.6, 118.0, 115.1. HRMS (ESI) m / z for C1 6H 13 ClNO [M+H] + : Calculated value: 313.0851; Measured value: 313.0846.

[0220] 3-(4-chlorophenyl)-1-[3-(piperidin-1-yl)phenyl]urea (76) was dissolved in 75a (0.09 g, 0.6 mmol) according to general procedure C as a white solid (0.17 g, 81%). 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.54 (s, 1H), 7.48 (d, J = 8.85 Hz, 2H ), 7.31 (d, J= 8.85 Hz, 2H), 7.14 (s, 1H), 7.08 (t, J = 8.10 Hz, 1H), 6.76 (d, J = 7.91 Hz, 1H), 6.55 (dd, J = 1.60, 8.19 Hz, 1H), 3.10 (t, J = 1.00 Hz, 4H), 1.5 7 - 1.68 (m, J = 4.10 Hz, 4H), 1.54 (t, J = 1.00 Hz, 2H). 13 C NMR (75 MHz, DMSO- d6) δ 152.4, 152.1, 140.1, 138.8, 129.0, 128.5, 125.2, 119.6, 109.9, 108.8, 105 .9, 49.6, 25.2, 23.9. MS (ESI) m / z for C 18 H 20 ClNO [M+H] + : Calculated value: 330.8; Measured value :330.3.

[0221] 1-(4-chlorophenyl)-3-[3-(morpholin-4-yl)phenyl]urea (77) was dissolved in 75b (0.03 g, 0.2 mmol) according to general procedure C as a white solid (0.05 g, 72%). 1 H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.59 (s, 1H), 7.48 (d, J = 9.04 Hz, 2H ), 7.31 (d, J= 8.85 Hz, 2H), 7.15 (s, 1H), 7.08 - 7.13 (m, 1H), 6.82 (d, J = 7.7 2 Hz, 1H), 6.59 (dd, J = 1.60, 8.19 Hz, 1H), 3.74 (t, J = 9.20 Hz, 4H), 3.07 (t, J = 4.70 Hz, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 151.6, 140.2, 138.7, 129. 1, 128.5, 125.2, 119.7, 109.5, 109.3, 105.1, 66.1, 48.5. MS (ESI) m / z for C 17 H 18 ClN3O2[M+H] + : Calculated value: 332.1; Measured value: 332.5.

[0222] 1-(4-chlorophenyl)-3-[3-(pyrrolidin-1-yl)phenyl]urea (78) was dissolved in 75c (0.09 g, 0.58 mmol) according to general procedure C as a white solid (0.16 g, 86%). 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.51 (s, 1H), 7.47 (d, J = 8.85 Hz, 2 H), 7.31 (d, J= 8.85 Hz, 2H), 7.03 (t, J = 8.01 Hz, 1H), 6.74 (s, 1H), 6.64 (d, J= 7.91 Hz, 1H), 6.18 (dd, J = 1.51, 8.10 Hz, 1H), 3.19 (t, J = 6.22 Hz, 4H), 1. 94 (t, J = 6.31 Hz, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.3, 148.2, 140.2, 138.8 , 129.1, 128.5, 125.1, 119.6, 106.0, 105.7, 101.6, 47.2, 24.9. MS (ESI) m / z for C 17 H 18 ClNO [M+H] + : Calculated value: 316.1; Measured value: 316.2.

[0223] 1-(4-chlorophenyl)-3-[3-(4-methylpiperazin-1-yl)phenyl]urea (79) was added to 75d( 0.06 g, 0.36 mmol) as a white solid according to general procedure C , 67%). 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.57 (s, 1H), 7.48 (d, J = 8. 85 Hz, 2H), 7.31 (d, J= 8.85 Hz, 2H), 7.15 (s, 1H), 7.09 (t, J = 8.19 Hz, 1H), 6 .76 - 6.81 (m, 1H), 6.57 (dd, J = 1.79, 8.19 Hz, 1H), 3.11 (t, J = 4.70 Hz, 3H), 2.46 (t, J = 4.70 Hz, 3H), 2.22 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 15 1.5, 140.2, 138.7, 129.1, 128.5, 125.2, 119.7, 109.5, 109.1, 105.4, 54.6, 48.1, 45.7. MS (ESI) m / z for C 18 H 21 ClNO [M+H] + : Calculated value: 345.1; Measured value: 345.0.

[0224] 3-[3-(azetidin-1-yl)phenyl]-1-(4-chlorophenyl)urea (80) was dissolved in 75e (0.10 g, 0.69 mmol) according to general method C as a white solid (0.09 g, 44%). 1 H NMR (300 MHz, DMSO-d6) 8.71 (s, 1H), 8.55 (s, 1H), 7.47 (d, J= 8.85 Hz, 2H) , 7.31 (d, J = 9.04 Hz, 2H), 7.01 - 7.07 (m, 1H), 6.65 (d, J = 1.88 Hz, 1H), 6.6 4 (d, J = 2.26 Hz, 1H), 3.77 (t, J = 7.16 Hz, 4H), 2.29 (quin, J = 7.16 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 152.6, 152.3, 140.1, 138.7, 129.0, 128.5, 125.2, 1 19.6, 107.2, 105.2, 101.0, 51.8, 16.3. MS (ESI) m / z for C 16 H 16 ClNO [M+H] + : calculation Value: 302.1; Measured value: 302.2.

[0225] 3-(4-chlorophenyl)-1-[3-(4,4-difluoropiperidin-1-yl)phenyl]urea (81) , was prepared from 75f (0.04 g, 0.28 mmol) as a white solid according to general procedure C ( 0.08 g, 78%). 1 H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.59 (s, 1H), 7.48 (d, J = 8.85 Hz, 2H), 7.32 (d, J= 8.85 Hz, 2H), 7.21 (s, 1H), 7.12 (t, J = 8.10 Hz, 1H), 6.82 (d, J= 7.91 Hz, 1H), 6.64 (dd, J = 1.88, 8.10 Hz, 1H), 3.26 - 3.33 (m, J= 5.27 Hz, 4H), 1.97 - 2.14 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 150.2 , 140.3, 138.7, 129.3, 128.5, 125.2, 119.7, 110.2, 109.7, 106.2, 45.8, 45.8, 45. 7, 33.1, 32.8, 32.5. MS (ESI) m / zfor C 18 H 18 ClF2N3O [M+H] + : Calculated value: 366.1; Measured value :366.2.

[0226] 3-(4-chlorophenyl)-1-{3-[(1S,4S)-7-azabicyclo[2.2.1]heptan-7-yl]phenyl {Isopropyl}urea (82) was prepared from 75 g (0.02 g, 0.1 mmol) of methyl urea (83) as a white solid according to general procedure C. (0.01 g, 28%) 1 H NMR (300 MHz, CDCl3) δ 7.21 - 7.23 (m, 2H), 7.08 - 7.12 (m, 2H), 6.89 - 6.93 (m, 2H), 6.59 - 6.67 (m, 2H), 4.08 - 4.13 (m, 2H), 1 .71 - 1.79 (m, 4H), 1.40 (d, J = 7.16 Hz, 4H). 13 C NMR (75 MHz, CDCl3) δ 153.5, 149.5, 138.4, 136.8, 130.1, 129.0, 128.7, 121.5, 113.0, 112.4, 109.9, 58.0, 28. 7. MS (ESI) m / z for C 19 H 20 ClNO [M+H] + : Calculated value: 342.1; Measured value: 342.4.

[0227] 1-[3-(azepan-1-yl)phenyl]-3-(4-chlorophenyl)urea (83) was dissolved in 0.05 g of 0. 31 mmol) according to general procedure C as a white solid (0.09 g, 82%). 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (s, 1H), 7.47 (d, J = 8.85 Hz, 2H) , 7.31 (d, J= 8.67 Hz, 2H), 7.01 (t, J = 8.10 Hz, 1H), 6.90 (s, 1H), 6.59 (d, J= 7.91 Hz, 1H), 6.31 (dd, J = 1.79, 8.19 Hz, 1H), 3.41 (t, J = 5.84 Hz, 4H), 1.63 - 1.82 (m, 4H), 1.38 - 1.52 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.4, 148.8, 140.4, 138.8, 129.3, 128.5, 125.1, 119.6, 105.5, 105.3, 101.1, 48.7, 26.9, 26.4 MS (ESI) m / z for C 19 H 22 ClNO [M+H] + : Calculated value: 344.1; Measured value: 344.4.

[0228] 3-(4-chlorophenyl)-1-(3-{2-oxa-6-azaspiro[3.3]heptan-6-yl}phenyl) Urea (84) was prepared from 75i (0.03 g, 0.16 mmol) as a white solid according to general procedure C. (0.04 g, 68%). 1 H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.58 (s, 1H) , 7.47 (d, J = 8.85 Hz, 2H), 7.31 (d, J = 8.85 Hz, 2H), 7.05 (t, J = 8.29 Hz, 1H ), 6.64 - 6.70 (m, 2H), 6.03 - 6.09 (m, 1H), 4.72 (s, 4H), 3.94 (s, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.3, 151.9, 140.1, 138.7, 129.0, 128.5, 125.2, 119.6, 10 7.6, 105.6, 101.4, 79.9, 60.9, 38.4. MS (ESI) m / z for C 18 H 18 ClN3O2[M+H] + : Calculated value :344.1; Actual value:344.2.

[0229] 1-(4-chlorophenyl)-3-[3-(dimethylamino)phenyl]urea (85) was reacted with 3-(N,N-dimethyl From (amino)aniline hydrochloride (0.11 g, 0.5 mmol), a white solid was obtained according to general procedure C. (0.13 g, 92%). 1 H NMR (300 MHz, CDCl3) δ 7.28 - 7.34 (m, 2H), 7.1 8 - 7.24 (m, 2H), 6.76 (s, 1H), 6.70 (t, J = 2.26 Hz, 1H), 6.53 - 6.60 (m, 2H), 6.43 (s, 1H), 2.96 (s, 6H). MS (ESI) m / z for C 15 H 16 ClNO [M+H] + : Calculated value:290.1; Actual value: 290.2.

[0230] 3-(4-chlorophenyl)-1-[3-(diethylamino)phenyl]urea (86) was dissolved in 75 ml (0.03 g, 0.1 8 mmol) according to general method C as a white solid (0.04 g, 69%). 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.49 (s, 1H), 7.47 (d, J = 9.04 Hz, 2H), 7.31 (d, J= 8.85 Hz, 2H), 7.02 (t, J = 8.10 Hz, 1H), 6.86 (t, J = 2.07 Hz, 1H), 6.60 (d, J = 7.91 Hz, 1H), 6.30 (dd, J = 2.26, 8.10 Hz, 1H), 3.25 - 3.32 (m, 4H ), 1.09 (t, J = 6.97 Hz, 6H). MS (ESI) m / zfor C 17 H 20 ClNO [M+H] + : Calculated value:318.1; Actual value: 318.4.

[0231] 3-(4-chlorophenyl)-1-[3-(pyrrolidin-1-ylmethyl)phenyl]urea (90) was dissolved in 89 (0.0 6 g, 0.33 mmol) as a white solid according to general procedure C. 3%). 1 H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 9.01 (s, 1H), 7.67 (s, 1H), 7.48 ( d, J = 8.85 Hz, 2H), 7.35 (d, J= 7.91 Hz, 1H), 7.20 (d, J = 8.67 Hz, 2H), 6.99 - 7.12 (m, 2H), 4.00 (s, 2H), 3.10 - 3.27 (m, 4H), 2.02 - 2.09 (m, 4H). 13 C NMR ( 75 MHz, CDCl3) δ 153.4, 140.6, 137.9, 129.8, 129.6, 128.7, 127.4, 123.7, 120.2, 120.0, 58.8, 53.5, 23.1). MS (ESI) m / z for C 18 H 20 ClNO [M+H] + : Calculated value:330.1; Actual value: 330.4.

[0232] 3-(4-chlorophenyl)-1-(3-methoxyphenyl)urea (91) was dissolved in 3-methoxyaniline (0.16 g, 1 mmol) according to general procedure C as a white solid (0.25 g, 91%) . 1 H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.71 (s, 1H), 7.48 (d, J = 8.85 Hz, 2H), 7.32 (d, J= 8.85 Hz, 1H), 7.14 - 7.22 (m, 2H), 6.93 (dd, J = 1.13, 8.10 Hz , 1H), 6.56 (dd, J = 1.88, 8.10 Hz, 1H), 3.73 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 159.7, 152.3, 140.7, 138.6, 129.5, 128.6, 125.3, 119.7, 110.6, 107.4, 104.1, 54.9. MS (ESI) m / z for C 14 H 13 ClN2O2[M+H] + : Calculated value: 277.1; Measured value: 277.2.

[0233] 3-(4-chlorophenyl)-1-[3-(cyclopentyloxy)phenyl]urea (95) was reacted with 94 (14200- 122) (0.05 g, 0.29 mmol) as a white solid according to general procedure C. .08 g, 84%). 1 H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.67 (s, 1H), 7.48 (d, J = 8.85 Hz, 2H), 7.32 (d, J= 8.85 Hz, 2H), 7.16 (dd, J = 2.92, 4.99 Hz, 2H), 6.8 7 (dd, J = 1.13, 8.10 Hz, 1H), 6.51 (dd, J = 2.07, 8.10 Hz, 1H), 4.75 (t, J= 5.6 5 Hz, 1H), 1.83 - 1.97 (m, 2H), 1.66 - 1.76 (m, 4H), 1.51 - 1.62 (m, 2H). 13 CNM R (75 MHz, DMSO-d6) δ 158.0, 152.3, 140.6, 138.6, 129.4, 128.6, 125.3, 119.7, 1 10.3, 108.9, 105.6, 78.5, 32.3, 23.5. MS (ESI) m / z for C 18 H 19 ClN2O2[M+H] + : calculation Value: 331.1; Measured: 331.2.

[0234] Biological data CB1 calcium mobilization assay CHO-RD-HGA16 cells (Molecular Devices, CA) stably expressing human CB1 receptors were cultured at 100 1 μL of Ham's F12 (10% fetal bovine serum, 100 units of penicillin / streptomycin, and 100 25,000 cells / well were plated in 96-well black-walled assay plates in 100 μg / ml normocin-containing medium. The cells were seeded and incubated overnight at 37°C, 5% CO2. Calcium 5 dye (Molecular Devices, C A) was reconstituted according to the manufacturer's instructions. The reconstituted dye was added to a pre-warmed (37°C) 1:40 in Say buffer (1x HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4, 37 °C) The growth medium was removed and the cells were diluted in 100 μL of pre-warmed (37°C) assay buffer. The cells were gently washed with a buffer. The cells were then resuspended in 200 μL of diluted calcium 5 dye solution. The cells were incubated at 37°C and 5% CO2 for 45 minutes. 50 antagonist to determine the value For the assay, EC 80 CP55,940 at a concentration of 0.25% BSA / 0.5% DMSO / 0.5% EtOH / Prepare 10x the desired final concentration in Say buffer and place in a 96-well polypropylene plate and warmed to 37° C. Serial dilutions of test compounds were made in 2.25% BSA / 4.5% DMSO / 4.5% Prepare the dye-loaded culture in EtOH / assay buffer at 10x the desired final concentration. After this period, the cells were pretreated with 25 μL of serially diluted test compounds and incubated at 37° C. for 15 minutes. After the pre-culture period, the plate was incubated with FLIPR Tetra (Molecular Devices, CA Calcium-mediated fluorescence changes were monitored every second for 90 seconds. At 10 seconds, 25 μL of CP55,940 was added to the EC 80 Using Tetra, adding Relative fluorescence units (RFU) were plotted against the log of compound concentration. The data were fitted to a three-parameter logistic curve to obtain IC 50 value For modulation experiments, the cells were A single concentration of test compound (as desired in 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer) The cells were pretreated with a serial dilution of CP55,940 (prepared at 10 times the concentration of CP55,940 in 0.25% BSA / 0.5% DMSO). While adding 10x the desired concentration of HCl / 0.5% EtOH / assay buffer, The same procedure as above was followed except that Tetra was used. Agonist screening For the assay, the cells were pre-treated with 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer. Treat with 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer to the desired final concentration A single concentration dilution of the test compound prepared 10 times the original concentration was added to Tetra. The RFUs of the test compounds were calculated using the E of CP55,940. max Compared to RFUs By %E max values ​​were calculated.

[0235] CB2 calcium mobilization assay This assay was performed using cells plated at 30,000 cells / well in a 96-well plate. CHO-RD-HGA16 (Molecular Devices, CA) cells stably expressing the human CB2 receptor. The CB1 calcium mobilization assay was performed in a similar manner to that described above, except that calcium 5 Preincubation with the dye and treatment with CP55,940 and test compounds were performed in the CB1 assay. Calcium-mediated fluorescence changes were monitored every 1.52 seconds for 60 seconds. At 19 seconds, 25 μL of CP55,940 was monitored at EC 80 While adding tetrahydrofuran at a concentration The data were collected using a Tetra (excitation / emission: 485 / 525 nm). and treated as described above.

[0236] [ 35 S]GTP-γ-S binding test Cerebellum from adult male CD-1 mice was dissected on ice, flash frozen, and stored for 8 hours until the day of the experiment. The cerebella were then stored at 0°C. The cerebella were then resuspended in membrane buffer (50 mM Tris, 3 mM MgCl, 0.2 mM E) on ice. The cells were homogenized in GTA (100 mM NaCl, pH 7.4) using a Polytron and incubated at 40,000 × g for 10 min at 4°C. The supernatant was discarded, and the pellet was suspended in membrane buffer and homogenized. The pellet was resuspended in membrane buffer and centrifuged again at 40,000 x g for 10 minutes. Protein was quantified by the Radford method. The membrane was resuspended in assay buffer (1 mg / ml bovine serum albumin). 3 units / ml adenosine deaminase (ADDM) in membrane buffer containing serum albumin (BSA) for 10 min. Preincubated with 30 μM GDP and 0.1 nM [ 35 30 with S]GTP-γ-S The mixture was incubated at 5°C for 60 minutes. Nonspecific binding was determined by adding 30 μM unlabeled GTP-γ-S. Serial dilutions of test compounds were performed until the final DMSO concentration in the assay was 0.1%. Inhibition curves for test compounds were performed in the absence of test compounds. Normalized to CP55,940 (100 nM) stimulation in the absence of CP55,940 (i.e., vehicle = 100%) and control. The data were fitted with a three-parameter nonlinear regression with θ and θ constrained to be >0 and =100, respectively. If the 5% confidence intervals did not overlap, pIC 50 Values ​​were considered significantly different.

[0237] Metabolic stability assessment was performed by Paraza Pharma Inc. (Montreal, Canada). Compounds were incubated with rat liver microsomes at 37°C for a total of 45 minutes. The solution was added to a 100 mM potassium phosphate buffer containing 0.5 mg / ml of rat liver microsomal protein. Phase I metabolism was performed in PBS at pH 7.4. NADPH was added to a final concentration of 1 mM and the ATP was added at 0, 5, 15 The samples were collected at 1, 30, and 45 minutes. The cells were then incubated with ice-cold stop solution (1 μM labetalol and 1 μM glyburide in acetonitrile). The resulting mixture was quenched in a 1:1 ratio using HCl and centrifuged to remove precipitated proteins. The supernatant was further diluted 1:4 with acetonitrile:water (1:1). Analyze by calculation of half-life and in vitro clearing using Microsoft Excel (2007) Lance test was carried out.

[0238] Relapse of extinguished cocaine-seeking behavior Animals: Adult male Sprague-Dawley rats weighing 280-300 g (Harlan, Indianapolis, IN) N) were used in this study. Animals had free access to water and food except during experimental sessions. The mice were individually housed under a 12 / 12 hour light / dark cycle (behavioral experiments were conducted during the light period). Institutional Animal Care and Use Committee, University at Buffalo, and 2011 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory A Animal Resources on Life Sciences, National Research Council, National Academy of Sciences, Washington Animals were housed and maintained and experiments were performed according to the instructions of the NIH (DC).

[0239] Drug self-administration, extinction, and relapse: Relapse induction methods have been described in detail elsewhere. 37, 38 Briefly, rats were surgically implanted with a chronic indwelling jugular catheter. After allowing time for recovery from surgery, subjects were given a fixed ratio (FR) of 14-day, 2-hour sessions daily. ] schedule (starting with FR = 1 and increasing to FR 5 within five training sessions). Train rats to use the active lever ( The reinforcer was given by pressing the active lever (left lever). This was done by presenting a stimulus light in the same direction, followed by a 30-second time-out period. In this case, pressing the lever did not result in any programmed consequences. After obtaining the drug, extinction of drug-seeking behavior occurred during a daily 2-hour session. This was done by not producing any consequences for pressing the lever. All other conditions remained unchanged. After 7 days of extinction, all rats reached extinction criterion (during the training session). (less than 20% total response).

[0240] The drug-induced reinstatement test was conducted the day after the last extinction session. A priming injection of cocaine (10 mg / kg, ip) was administered immediately before the start of the study. Minutes before administration, rats were pretreated with vehicle, Compound 2 (15, 30 mg / kg) or 34 (10 mg / kg).

[0241] Data analysis: Data are expressed as mean ± standard error of the mean (SEM). Differences in active lever responses between relapse sessions were evaluated using a paired t-test (within-subject comparisons). The effect of Compound 2 on relapse was assessed by one-way analysis of variance (ANOVA) followed by post hoc analysis. The effects of the compound on recurrence were analyzed by Bonferroni's test (intersubject comparison). The effects of compounds 34 were analyzed by Student's t-test. P < 0.05 was considered statistically significant. .

[0242] Biological evaluation in calcium mobilization assays FLIPR-based calcium mobilization assays were performed on CB1 and CB2 receptors as previously described. It was used as a primary screen to evaluate the efficacy of synthetic diaryl ureas in

[0243] In these assays, the promiscuous Gα16 protein was overexpressed. CHO cells expressing CP55,940 were engineered to stably express either the CB1 or CB2 receptors. Compounds were evaluated for their ability to reduce the mobilization of intracellular calcium levels stimulated by ATP. EC 80 IC of synthetic compounds against CP55,940 (100 nM) 50 The values ​​were measured (Tables 1 and 2).

[0244] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] a EC 80Values ​​are for at least three independent experiments in duplicate. All data are means ± standard error of the mean (SEM). b Agonists are screened at a final concentration of 10,000 nM. Values ​​are calculated from at least two replicates in duplicate. Means ± SD for independent experiments. c Values ​​are expressed as the mean (95% confidence interval) for at least three independent experiments in duplicate. . d ND: Not measured.

[0245] [Table 2] a EC 80 Values ​​are for at least three independent experiments in duplicate. All data are means ± standard error of the mean (SEM). b Agonists are screened at a final concentration of 10,000 nM. Values ​​are calculated from at least two replicates in duplicate. Means ± SD for independent experiments.

[0246] As shown, several compounds showed good efficacy in the calcium mobilization assay. The substance was then used to measure the activity of CB1 receptors in mouse cerebellar membranes when stimulated with an agonist. 35 The CB1 receptor agonist CP55,940 was evaluated for its efficacy in antagonizing the binding of [S]GTP-γ-S. As with PSNCBAM-1 (B), diaryl urea (A) was used as an agonist probe. As expected for a CB1 negative allosteric modulator, 35 S] It reduced GTP-γ-S binding in a dose-dependent manner.

[0247] Metabolic stability of selected diaryl ureas [Table 3] b Values ​​are expressed as the mean ± SEM from two independent experiments.

[0248] Metabolism affects the clearance and duration of action (half-life) of a drug. They must be stable enough to reach the intended site and exert their intended effect. Therefore, the metabolic stability of selected compounds (B, 20, and 34) was evaluated using rat liver microsomes. It was worth it.

[0249] Table 3 shows the half-lives (T 1 / 2 ) and clearance (CL). B is T1 / 2 It was rapidly metabolized in 13.4 minutes, suggesting moderate first-pass metabolic stability. The metabolic stability was increased by about 3-fold for compound 20 (T 1 / 2 = 41.9 minutes). compound 34 showed significant improvement in the metabolic stability, but with a half-life of more than 300 minutes and less than 4.6 μl / min / mg had a clearance of 100 mm.

[0250] Attenuation of cocaine-seeking behavior in rats after an extinction period. Blocking CB1 receptors using antagonist / inverse agonists SR141716A and AM251 These include the consumption of palatable foods, the self-administration of some drugs of abuse, and food and drug requirements. It has been demonstrated to reduce relapse of seeking behavior. Carai, MA; Colombo, G.; Ges sa, GL Rimonabant: the first therapeutically relevant cannabinoid antagonist. Life Sci 2005, 77, 2339-50; De Vries, TJ; Shaham, Y.; Homberg, JR; Cromba g, H.; Schuurman, K.; Dieben, J.; Vanderschuren, LJ; Schoffelmeer, AN A ca Nabinoid mechanism in relapse to cocaine seeking. Nat Med 2001, 7, 1151-4; and Fattore, L.; Spano, S.; Cossu, G.; Deiana, S.; Fadda, P.; Fratta, W. Cannabinoi d CB(1) antagonist SR 141716A attenuates reinstatement of heroin self-administra tion in heroin-abstinent rats. Neuropharmacology 2005, 48, 1097-104 each of which is incorporated herein for such teachings.

[0251] Compounds of the present invention were tested to determine whether they achieved the same effect in vivo. .

[0252] As shown in Figure 2, the cocaine prime eliminated the activity. The break-lever response significantly recurred (t-test: t[7]=16.29, p<0.0001). cocaine-induced relapse of cocaine-seeking behavior was attenuated in a dose-dependent manner (one-way ANOVA). Post-hoc analysis revealed that at the 30 mg / kg dose, B was significantly more sensitive to cocaine-induced stimuli than B. Interestingly, the 10 mg / 34 at 30 mg / kg produced the same degree of attenuation as 30 mg / kg of B (t-test: t

[20] =1.24, p<0.05). 34, like B, exhibited the in vivo antagonistic effects expected of CB1 NAMs. B and 34 showed greater efficacy in calcium mobilization and 35 S]GTP-γ-S binding assay In both cases, in vitro IC 50 In terms of values, they are equivalent, so the in vivo efficacy This difference is likely due to the improved metabolic stability of 34, which This allows higher concentrations to reach the site of action in the central nervous system.

[0253] The endocannabinoid system, particularly the CB1 receptor, is involved in many conditions such as mood disorders and drug addiction. Showing promising potential as a therapeutic target in neuropsychiatric disorders 34 Many CB1 antagonists Although antagonists / inverse agonists have been reported, the harmful effects inherent in these ligands This effect has limited their development into potential drug candidates. This important signaling pathway is essential for the development of orthosteric ligands, while avoiding their side effects. A series of novel diaryl ureas as an alternative approach to manipulate signal transduction pathways Write it down.

[0254] The diaryl ureas of the present invention have the ability to mobilize calcium and 35 In the [S]GTP-γ-S binding assay In particular, compound 34 provides comparable or even greater potency as measured by the same The compounds of the present invention show similar in vitro potency, but with significantly improved microsomal stability. The substance was effective in reducing the tendency of rats to relapse to cocaine use after a period of extinction. In this model, the optimized analog 34 appears to be more potent than the standard compound B. This appeared to be due to its improved metabolic stability.

[0255] The specific pharmacological responses observed may be due to the specific active compound or pharmaceutical carrier selected. whether or not there is a drug present, and the type of formulation and mode of administration used, and may vary depending on the circumstances, and such expected variations or differences in results may be material. Variations are contemplated in accordance with the practice of the present invention.

[0256] Although particular embodiments of the present invention are illustrated and described in detail herein, the present invention is not limited to these. The above detailed description is provided as an example of the present invention and is not intended to be limiting. These modifications should not be construed as constituting any limitation on the scope of the present invention. All modifications which are obvious to those skilled in the art and which do not depart from the spirit of the invention are within the scope of the appended claims. are intended to be included in the scope.

Claims

1. Compounds of formula (I): 【Chemistry 1】 Where: R 1 is O-(C 1-6 alkyl), O-(5- to 13-membered cycloalkyl), N(R 2 ) 2 , (C 1-8 Archi L) x -(5- to 13-membered aryl), (C 1-8 alkyl) x -(5- to 13-membered heteroaryl), Or (C 1-8 alkyl) x -(4- to 13-membered heterocyclyl), wherein each aryl, Each heteroaryl and heterocyclyl is optionally substituted with one or more of the following: It has been: R 2 、 OR 2 、 C(O)R 2 、 C(O)OR 2 、 NO 2 、 halogen, or C 1-6 haloalkyl; R 2 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, or 5- to 13-membered alkenyl It is a reel; R 3 is H, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, halogen, C 1-6 Haloal Kill, No 2 , or CN; each x is independently 0 or 1; and n is 1, 2 or 3; or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein n is 1.

3. R 3 3. The compound of claim 1 or 2, wherein is halogen or cyano.

4. R 3 4. The compound according to claim 1, wherein is Cl.

5. R 1 is 5- to 13-membered aryl, and optionally one or more R 2 Replaced by Item 5. The compound according to any one of items 1 to 4.

6. R 1 is phenyl, and optionally one or more R 2 6. The compound according to claim 1, wherein the compound is substituted with The compound according to any one of claims 1 to 4.

7. R 1 7. The compound of claim 1, wherein is unsubstituted phenyl.

8. R 1 is one R 2 7. The compound of claim 1, wherein the compound is phenyl substituted with thing.

9. R 1 There are two R 2 7. The compound of claim 1, wherein the compound is a phenyl substituted with thing.

10. R 2 10. The compound of any one of claims 1 to 6, 8 and 9, wherein is halogen.

11. R 1 is a 5- to 13-membered heteroaryl, and optionally one or more R 2 is replaced by 5. A compound according to any one of claims 1 to 4.

12. R 1 furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole azole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole azole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isothiazole Soxoquinone, benzofuran, benzoxazole, benzothiophene, indole, indole dazole, benzimidazole, imidazopyridine, pyrazolopyridine and pyrazolopyridine idine, each optionally containing one or more R 2 substituted with 12. The compound according to any one of claims 11 to 11.

13. R 1 is pyridine, and optionally one or more R 2 13. The compound of claim 12, wherein Compound.

14. R 1 is thiophene, and optionally one or more R 2 13. The compound according to claim 12, wherein The compounds listed above.

15. R 1 is azetidine, and optionally one or more R 2 13. The compound according to claim 12, wherein The compounds listed above.

16. 16. The compound of claim 1, wherein x is 0.

17. 17. A method for blocking CB1 receptors comprising administering an effective amount of a compound according to any one of claims 1 to 16. A method for treating a disease in a mammal susceptible to the treatment.

18. The disease is withdrawal, drug dependence, smoking cessation, addiction, opioid dependence, cocaine dependence, Cocaine addiction relapse, tobacco addiction, alcohol addiction, inhibition of angiogenesis, tumor growth Inhibition of cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, Lung cancer, prostate cancer, desmotrophic small round cell tumor cell tumors), and renal cell carcinoma, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain , neuropathic pain, inflammatory pain, infertility, memory loss, cognitive dysfunction, Alzheimer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis Arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia , dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite loss 18. The method of claim 17, wherein the therapeutic effect is exercise or weight loss.

19. 17. A compound according to any one of claims 1 to 16 and one or more pharmaceutically acceptable carriers. A pharmaceutical composition comprising:

20. A disease in a mammal sensitive to CB1 blockade, comprising administering an effective amount of a compound A compound according to any one of claims 1 to 16 for preparing a medicament for the treatment of use.

21. The disease is withdrawal, drug dependence, smoking cessation, addiction, opioid dependence, cocaine dependence, Cocaine addiction relapse, tobacco addiction, alcohol addiction, inhibition of angiogenesis, tumor growth Inhibition of cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, Lung cancer, prostate cancer, desmotrophic small round cell tumor cell tumors), and renal cell carcinoma, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain , neuropathic pain, inflammatory pain, infertility, memory loss, cognitive dysfunction, Alzheimer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis Arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia , dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite loss 21. The use of claim 20, wherein the therapeutic effect is exercise or weight loss.

22. A compound according to any one of claims 1 to 16 for use as an active therapeutic substance. Compound.

23. 17. A compound according to any one of claims 1 to 16 for use in treating a CB1 mediated disease.

3. The compound according to claim 1.

24. The disease is withdrawal, drug dependence, smoking cessation, addiction, opioid dependence, cocaine dependence, Cocaine addiction relapse, tobacco addiction, alcohol addiction, inhibition of angiogenesis, tumor growth Inhibition of cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, Lung cancer, prostate cancer, desmotrophic small round cell tumor cell tumors), and renal cell carcinoma, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain , neuropathic pain, inflammatory pain, infertility, memory loss, cognitive dysfunction, Alzheimer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis Arteriosclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia , dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite loss 24. The compound of claim 23, wherein the compound is a compound selected from the group consisting of steroids, steroids, anti-inflammatory drugs ...

25. withdrawal, comprising administering an effective amount of a compound according to any one of claims 1 to 16; Drug addiction, smoking cessation, addiction, opioid addiction, cocaine addiction, cocaine addiction relapse , tobacco addiction, alcohol addiction, inhibition of angiogenesis, inhibition of tumor growth, cancer, endometrium Cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, Desmotrophic small round cell tumors and kidney Cellular cancer, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammation Sexual pain, infertility, memory loss, cognitive impairment, Alzheimer's disease, Tourette's syndrome, dysplasia dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerosis, Hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia, diabetes , retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite behavior or weight loss A method for treating one or more of the following:

26. and administering an effective amount of said compound to treat withdrawal, drug dependence, smoking cessation, addiction, opioid addiction, Idiopathic addiction, cocaine addiction, cocaine relapse, tobacco addiction, alcohol addiction , inhibition of angiogenesis, inhibition of tumor growth, cancer, endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast Pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, desmotrophic small round cell tumor (desmotrophic small round cell tumors) and renal cell carcinoma, analgesia, pain, chronic pain Pain, acute pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, infertility, memory loss, cognitive function impairment, Alzheimer's disease, Tourette's syndrome, dyskinesia, tardive dyskinesia, muscle Atrophic lateral sclerosis, stroke, atherosclerosis, hypertension, hemorrhagic shock, cardiogenic shock Shock, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders , a pharmaceutical agent for treating one or more of intestinal hypomotility, obesity, appetite behavior, or weight loss 17. Use of a compound according to any one of claims 1 to 16 for the preparation of

27. withdrawal, drug addiction, smoking cessation, addiction, opioid addiction, cocaine addiction, cocaine dependence relapse of disease, tobacco addiction, alcoholism, inhibition of angiogenesis, inhibition of tumor growth, cancer, Endometrial cancer, hepatocellular carcinoma, ovarian cancer, breast cancer, pancreatic cancer, colorectal cancer, lung cancer, prostate cancer Adenocarcinoma, desmotrophic small round cell tumors , and renal cell carcinoma, analgesia, pain, chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain. Pain, inflammatory pain, infertility, memory loss, cognitive impairment, Alzheimer's disease, Tourette's syndrome group, dyskinesia, tardive dyskinesia, amyotrophic lateral sclerosis, stroke, atherosclerotic arteries Sclerosis, hypertension, hemorrhagic shock, cardiogenic shock, hypercholesterolemia, dyslipidemia , diabetes, retinopathy, glaucoma, anxiety, gastrointestinal disorders, decreased intestinal motility, obesity, appetite behavior or weight loss 17. A method according to any one of claims 1 to 16 for use in treating one or more of the following conditions: The compounds listed above.

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