US00885.3252B2

(12) United States Patent (10) Patent No.: US 8,853,252 B2 McElroy et al. (45) Date of Patent: *Oct. 7, 2014

(54) CANNABINOID RECEPTOR 7,482.470 B2 1/2009 McElroy et al. ANTAGONSTS/INVERSEAGONSTS 2006. R 539 SE et al. al USEFUL FOR TREATING METABOLC cElroy et al. DISORDERS,DABETES INCLUDING OBESITY AND FOREIGN PATENT DOCUMENTS

- EP 1429761 B2 11/2006 (75) Inventors: John F. McElroy, Wilmington, DE (US); Robert J. Chorvat, West Chester, OTHER PUBLICATIONS PA (US (US) Cavallo-Perin, P. Mechanism of Insulin Resistance in Human Liver (73) Assignee: Jenrin Discovery, Inc., Wilmington, DE Cirrhosis. J. Clin. Invest. 75, (1985), 1659-1665.* (US) PCT/US2008/082173. International Search Report and Written Opin ion of the corresponding parent application, Oct. 4, 2010. (*) Notice: Subject to any disclaimer, the term of this Lange, J.H.M. et al., Synthesis, Biological Properties and Molecular patent is extended or adjusted under 35 Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selec U.S.C. 154(b) by 225 days tive CB1 Cannabinoid Receptor Antagonists; J. Med. Chem. 2004, M YW- 47,627-643. This patent is Subject to a terminal dis- Remington, et al. The Science and Practice of Pharmacy, 2000, Lip claimer. pincott Williams and Wilkins, 20th Edition, pp. 218-220. Wierzbicki, A.S., Rimonabant: endocannabinoid inhibition for the (21) Appl. No.: 13/414,586 metabolic syndrome, Drug Focus 2006, 60(12), 1697-1706. Pi-Sunyer, F.X., Effect of Rimonabant, a Cannabinoid-1 Receptor (22) Filed: Mar. 7, 2012 Blocker, on Weight and Cardiometabolic Risk Factors in Overweight or Obese Patients, JAMA 2006, 297-(7), 761-775. (65) Prior Publication Data Solvay's SLV319 Obesity Candidate Treatment Advances in Phase II Clinical Trials, Solvay Press Release, Dec. 8, 2006. US 2012/O264797 A1 Oct. 18, 2012 STRADIVARIUS (Strategy to Reduce Althersclerosis Development Related U.S. Application D Involving Administration of Rimonabant—the Intravascular elated U.S. Application Data Ultrasound Study), Clinical Trials.gov, http://clinicaltrials.gov/ct2/ (63) Continuation of application No. 127650.947, filed on show? study/NCT00 124332, Jul. 26, 2005. Dec. 31, 2009, now Pat. No. 8,138,216, which is a EP 08844826.1 Extended European Search Report dated Oct. 4. continuation of application No. 12/262.765, filed on 2010. Oct. 31, 2008, now Pat. No. 7,655,685. Sep. 11, 2013 translation of Office Action in patent application in Israel National Phase of PCT/US2008/082173. (60) Provisional application No. 60/984,760, filed on Nov. Aug. 13, 2013 translation of Office Action in JP Application No. 2, 2007. 2010-532311. Jun. 25, 2013 exam report in AU 2008/318409. (51) Int. Cl. Dec. 18, 2013 office action in CA 2,702.755. A6 IK3 L/45 (2006.01) CO7D 23/06 (2006.01) * cited by examiner (52) U.S. Cl. CPC ...... C07D 231/06 (2013.01) Primary Examiner — Samantha Shterengarts USPC ...... 514/403; 548/379.1: 548/379.4: (74) Attorney, Agent, or Firm — Vance Intellectual Property, 548/379.7 PC (58) Field of Classification Search USPC ...... 514/403: 548/379. 1,379.4, 379.7 (57) ABSTRACT See application file for complete search history. The present invention provides novel pyrazoles that are useful (56) Ref Cited as cannabinoid receptorantagonists and pharmaceutical com eerees e positions thereof and methods of using the same for treating U.S. PATENT DOCUMENTS obesity, diabetes, hepatic disorders, and/or cardiometabolic disorders. 6,476,060 B2 11/2002 Lange et al. 6,974,810 B2 12/2005 Lange et al. 29 Claims, No Drawings US 8,853,252 B2 1. 2 CANNABINOID RECEPTOR ing body weight secondary to reducing the amount of calories ANTAGONSTS/INVERSEAGONSTS that reach the systemic circulation. Unfortunately, these indi USEFUL FOR TREATING METABOLC rect therapies produce only a modest initial weight loss (ap DISORDERS, INCLUDING OBESITY AND proximately 5% compared to placebo) that is usually not DABETES maintained. After one or two years of treatment, most patients return to or exceed their starting weight. In addition, most CROSS-REFERENCE TO RELATED approved anti-obesity therapeutics produce undesirable and APPLICATIONS often dangerous side effects that can complicate treatment and interfere with a patient’s quality of life. The present application claims priority benefit under 35 10 The lack of therapeutic effectiveness, coupled with the U.S.C. S119(e) of U.S. Provisional Patent Application Ser. spiraling obesity epidemic, positions the treatment of obe No. 60/984,760 filed Nov. 2, 2007. The disclosure this appli sity as one of the largest and most urgent unmet medical cation is incorporated herein by reference. needs. There is, therefore, a real and continuing need for the development of improved medications that treat or prevent FIELD OF THE INVENTION 15 obesity. The present invention provides cannabinoid receptor The endocanabinoid system, comprised of the canabinoid antagonists/inverse agonists and pharmaceutical composi receptors (CB1 and CB2) and their endogenous ligands (e.g., tions thereof and methods of using the same for treating anandamide, 2-AG), plays a prominent role in the control of obesity, diabetes, hepatic disorders, and/or cardiometabolic food intake and energy metabolism. CB1 receptors are widely disorders. The present invention also relates to a novel expressed in the brain, including cortex, hippocampus, method for treating obesity, diabetes, hepatic disorders, and/ amygdala, pituitary and hypothalamus. CB1 receptors have or cardiometabolic disorders using a pyrazoline. also been identified in numerous peripheral organs and tis Sues, including thyroid gland, adrenal gland, reproductive BACKGROUND OF THE INVENTION 25 organs, adipose tissue, liver, muscle, pancreas, and gas trointestinal tract. CB2 receptors are localized almost exclu Obesity is associated with an increase in the overall amount sively in immune and blood cells Endocrine Reviews 2006, of adipose tissue (i.e., body fat), especially adipose tissue 27, 73. localized in the abdominal area. Obesity has reached epi The plant-derived cannabinoid agonist A-tetrahydrocan demic proportions in the United States. The prevalence of 30 nabinol (A-THC), the main psychoactive component of obesity has steadily increased over the years among all racial marijuana, binds to both CB1 and CB2 receptors. A-THC is and ethnic groups. The most recent data from the Centers for widely reported to increase appetite and food intake (hyper Disease Control and Prevention, and the National Center for phagia) in humans and in animals. This hyperphagic effect is Health Statistics report 66% of the adult population over largely blocked by pretreatment with selective CB1 receptor weight (BMI, 25.0-29.9), 31% obese (BMI,30-39.9), and 5% 35 blockers (i.e., CB1 blockers) (e.g., rimonabant (SR141716A, extremely obese (BMI, 40.0). Among children aged 6 AcompliaR)), strongly supporting the belief that CB1 recep through 19 years, 32% were overweight and 17% were obese. tor activation mediates the hyperphagic effect of A-THC, This translates to 124 million Americans medically over Endocrine Reviews 2006, 27, 73. weight, and 44 million of these deemed obese. Obesity is In humans, rimonabant produces a clinically meaningful responsible for more than 300,000 deaths annually, and will 40 weight loss in obese patients. Obese patients also experience Soon overtake tobacco usage as the primary cause of prevent improvements in diabetic and cardiometabolic risk factors able death in the United States. Obesity is a chronic disease associated with obesity, including an increase in the level of that contributes directly to numerous dangerous co-morbidi high density lipoprotein cholesterol (HDL), and decreases in ties, including type 2 diabetes, cardiometabolic diseases, triglycerides, glucose, and hemoglobin Alc (HbAlc, a hepatic disorders, cardiovascular disease, inflammatory dis 45 marker of cumulative exposure to glucose) levels. Rimona eases, premature aging, and some forms of cancer. Type 2 bant also produces greater reductions in abdominal fat depos diabetes, a serious and life-threatening disorder with growing its, which are a known risk factor for diabetes and heart prevalence in both adult and childhood populations, is cur disease Science 2006, 311, 323. Taken together, these rently the 7" leading cause of death in the United States. improvements in adiposity and cardiometabolic risk factors Since more than 80% of patients with type 2 diabetes are 50 produce an overall decrease in the prevalence of the metabolic overweight, obesity is the greatest risk factor for developing syndrome Lancet 2005, 365, 1389 and NEJM 2005, 353, type 2 diabetes. Increasing clinical evidence indicates that the 2121. best way to control type 2 diabetes is to reduce weight. In patients with type 2 diabetes not currently treated with The most popular over-the counter drugs for the treatment other anti-diabetic medications, rimonabant was shown to of obesity, phenylpropanolamine and ephedrine, and the most 55 significantly improve blood Sugar control and weight, as well popular prescription drug, fenfluramine, were removed from as other risk factors such as HDL and triglycerides, when the marketplace as a result of safety concerns. Drugs cur compared to placebo (International Diabetes Federation rently approved for the long-term treatment of obesity fall World Diabetes Congress, Cape Town, South Africa, 2006). into two categories: (a) CNS appetite Suppressants such as After six months of treatment, HbA1c levels were signifi Sibutramine and rimonabant, and (b) gut lipase inhibitors 60 cantly lowered by 0.8% from a baseline value of 7.9 as com Such as orlistat. CNS appetite Suppressants reduce eating pared to a reduction of 0.3% in the placebo group. These behavior through activation of the satiety center in the brain results are consistent with preclinical studies that demon and/or by inhibition of the hunger center in the brain. Gut strate improved glycemic and lipid control in diabetic and lipase inhibitors reduce the absorption of dietary fat from the dyslipedemic mice, rats, and dogs (Pharmacology Biochem gastrointestinal (GI) tract. Although appetite Suppressants 65 istry & Behavior; 2006, 84,353 American Journal of Physi and gut lipase inhibitors work through very different mecha ology, 2003, 284, R345, American Diabetes Association nisms, they share in common the same overall goal of reduc Annual Meeting, 2007: Abstract Number 0372-OR). US 8,853,252 B2 3 4 The beneficial effects of rimonabant on diabetic and car the prevention or treatment of obesity, diabetes, dyslipidemia, diometabolic risk factors such as high blood pressure, insulin cardiovascular disorders, and/or hepatic disorders. resistance, and elevated triglycerides cannot be explained by diet-related weight loss alone. For example, in patients SUMMARY OF THE INVENTION receiving 20 mg of rimonabant, only approximately 50% of 5 the beneficial effects on triglycerides, fasting insulin, and Accordingly, in an aspect, the present invention provides insulin resistance can be accounted for by weight loss sec novel pyrazolines or pharmaceutically acceptable salts ondary to reduced food intake. These results suggest a direct thereof that are CB1 receptor antagonists/inverse agonists. pharmacological effect of CB1 antagonists on glucose and In another aspect, the present invention provides novel lipid metabolism, in addition to indirect effects on metabo 10 pharmaceutical compositions, comprising: a pharmaceuti lism secondary to hypophagia-mediated weight loss Science cally acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present inven 2006, 311, 323 and JAMA 2006, 311, 323). Taken together, tion or a pharmaceutically acceptable salt form thereof. these results suggest that CB1 antagonists might be effective In another aspect, the present invention provides novel in the treatment of diabetes, dyslipidemia, cardiovascular 15 methods for treating obesity, diabetes (e.g., insulin resistance, disorders (e.g., atherosclerosis, hypertension), and hepatic inadequate glucose tolerance, Type I diabetes, and Type II disorders (e.g., cirrhosis, fatty liver diseases), even in patients diabetes), dyslipidemia (e.g., elevated triglycerides and low that are not clinically overweight or obese. HDL), cardiovascular disorders (e.g., atherosclerosis and The CB1 receptor is one of the most abundant and widely hypertension), and/or hepatic disorders (e.g., cirrhosis and distributed G protein-coupled receptors in the mammalian fatty liver disease), comprising: administering to a mammal brain. It is believed that the appetite-suppressant properties of in need of such treatment a therapeutically effective amount CB1 antagonists are mediated through an interaction with of at least one of the compounds of the present invention or a CB1 receptors in the hypothalamus (regulation of food pharmaceutically acceptable salt form thereof. intake), and in the mesolimbic region (rewarding properties In another aspect, the present invention provides processes of food). However, CB1 receptors are far more broadly dis 25 for preparing novel compounds. tributed in brain (e.g., neocortex, hippocampus, thalamus, In another aspect, the present invention provides novel cerebellum, and pituitary), and while interacting with tar compounds or pharmaceutically acceptable salts for use in geted CB1 receptors in hypothalamus and mesolimbic therapy. regions to Suppress appetite, CB1 antagonists have equal In another aspect, the present invention provides the use of access to non-targeted CB1 receptors that have little if any 30 novel compounds for the manufacture of a medicament for role inappetite control. Binding to non-targeted receptors can the treatment of obesity, diabetes, dyslipidemia, cardiovascu often lead to unwanted side effects of CNS drugs Endocrine lar disorders, and/or hepatic disorders. Reviews 2006, 27: 73. The CB1 blockers rimonabant and These and other objects, which will become apparent dur taranabant produce psychiatric and neurological side effects. ing the following detailed description, have been achieved by These include depressed mood, anxiety, irritability, insomnia, 35 the inventors discovery that the presently claimed com dizziness, headache, seizures, and Suicidality. pounds or pharmaceutically acceptable salt forms thereofare These side effects are dose-related and appear pronounced expected to be effective CB1 receptor blockers. at the most efficacious weight-reducing doses of rimonabant and taranabant (JAMA 2006, 311, 323, Cell Metabolism DETAILED DESCRIPTION OF THE INVENTION 2008, 7.68). The occurrence of therapeutic efficacy (appetite 40 Suppression) and side effects over the same dose range All references cited herein are hereby incorporated in their strongly suggest that both effects are mediated through con entirety herein by reference. current antagonism of CB1 receptors in both targeted and A CB1 blocker is a neutral CB1 receptor antagonist and/or non-targeted brain regions. Brain-penetrant CB1 blockers a CB1 receptor inverse agonist. do not selectively target CB1 receptors in efficacy brain 45 The present invention is based on the finding that a CB1 regions, while ignoring CB1 receptors in side effect brain receptor blocker has beneficial effects on cardiometabolic regions. disorders including obesity, diabetes, and dyslipidemia that The beneficial effects of the CB1 antagonistrimonabant on cannot be explained by weight loss derived from CNS-medi body weight, adiposity, and diabetic and cardiometabolic risk ated appetite Suppression alone, and that this effect is medi factors such as high blood pressure, insulin resistance and 50 ated, at least in part, through interaction at peripheral CB1 blood lipids cannot be explained by weight loss derived from receptors. To this end, the present invention provides com CNS-mediated appetite suppression alone JAMA 2006, 311, pounds that are designed to preferentially target CB1 recep 323. Approximately 50% of the benefit is likely derived from tors in peripheral tissues (e.g., adipose tissue, liver, muscle, an interaction with CB1 receptors in peripheral tissues known pancreas, and gastrointestinal tract), while sparing CB1 to play an active role in metabolism. These include adipose 55 receptors in brain. With these types of compounds, peripher tissue, liver, muscle, pancreas, and gastrointestinal tract. ally-mediated beneficial effects of CB1 blockers should be In view of the above, it is highly desirable to find effective maintained, whereas CNS side effects should be reduced or and highly selective CB1 receptor blockers with limited or no eliminated. CNS adverse side effects, including mood disorders. Particu The compounds of the present invention have been larly, it is desirable to find compounds that preferentially 60 designed to have reduced CNS exposure by virtue of their target CB1 receptors in peripheral tissues (e.g., adipose tis inability or limited ability to penetrate the blood-brain barrier Sue, liver, muscle, pancreas, and gastrointestinal tract), while (BBB), or by their participation in active transport systems, sparing CB1 receptors in brain. In this way, peripherally thus reducing centrally mediated side-effects, a potential mediated beneficial effects of CB1 blockers should be main problem with many anti-obesity agents. It is expected that the tained, whereas CNS side effects should be reduced or elimi 65 peripherally restricted compounds of the present invention nated. This should provide a novel opportunity to develop will have no or very limited CNS effects, including mood safer alternatives to highly brain penetrant CB1 blockers for disorders, seizures, and Suicidality. Thus, their peripherally US 8,853,252 B2 5 6 mediated CB1 antaonistic properties should provide thera OCH-CH=CHCONR, O(CH)-phenyl-(CH2)COR, peutic agents with greater safety. and O(CH)-phenyl-(CH)-tetrazole; Moreover, if the maximum dosage of a drug used in the Z is selected from H, COR, and CONR; treatment of obesity, diabetes, dyslipidemia, cardiovascular Q is selected from: (CH), CHA(CH),C(O)NR, disorders, and/or hepatic disorders is limited as a result of 5 (CH),CAA" (CH),C(O)NR2 (CH2)CHA(CH2)COR, CNS side effects (e.g., seizures, depression, anxiety, Suicid (CH),CAA" (CH),CO.R., (CH), CHA(CH), SONR, ality, movement disorders, and hyperactivity), incorporation (CH2)CHA(CH), SOR, (CH), CHA(CH),C(NH)NH2, of a peripherally restricting group in Such a drug would lower (CH), CHA(CH),C(NOH)NH2, (CH2)CHA the brain concentration of the drug relative to the concentra (CH),CONHCHA(CH),COR, (CH),CAA" 10 (CH),CONHCHA(CH),COR, (CH2)CHA tion in the systemic circulation, thereby affording the oppor (CH),CONHCHA(CH),CONHCHA(CH),COR, tunity to increase the dosage employed to treat the peripheral (CH), CHA(CH),CONHCHA(CH2)CONR (CH), disorder (e.g., obesity, diabetes, dyslipidemia, cardiovascular CAA"(CH),CONHCHA(CH2)CONR (CH), CHA disorders, and/or hepatic disorders). The increased dosage (CH),CONHCHA(CH),CONHCHA(CH),CONR, may provide greater therapeutic efficacy, as well as a more 15 C-C-cyclic amino-(CH2)COR, C-C-cyclic amino rapid onset of therapeutic action. (CH),CONR, C-C-cycloalkylene-(CH2)COR, and 1 In another embodiment, the present invention provides C-C-cycloalkylene-(CH2)CONR; novel compound of Formula I or a stereoisomer or pharma provided that when Q is (CH),CAA"(CH),C(O)NR or ceutically acceptable salt thereof: (CH),CAA" (CH2)COR, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b): A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, OH, CHOH, CH(CH)OH, C(CH),OH, (CH),COR, (CH),C(O)NR', and (CH)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H. C. alkyl, halo 25 gen, CFO C. alkyl, and NO; alternatively, Q is CHA(CH),C(O)NR or CHA (CH),CO.R., and (a) A is selected from OH, (CH),CO.R. and (CH),C(O)NR'; (b) Ris (CH2)(CHR), (CH), OH or CH(CHOH); or (c) both (a) and (b): 30 A" is C alkyl: M is C=O or SO; R is independently selected from H. (CH,), (CHR), (CH), OH, CH(CHOH), C alkyl, Calkenyl, and C alkynyl: 35 R" is independently selected from H. (CH), (CHR), (CH2), OH, C alkyl, C2-alkenyl, and C2-alkynyl, R’ is independently selected from H. C. alkyl, Calk enyl, and C2-alkynyl: p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12: wherein: 40 m is selected from 0, 1, 2, 3, and 4; and, X,Y,X,Y,X", andY" are independently selected from: H, n is selected from 1, 2, 3, and 4. C. alkyl, halogen, CF. O—C alkyl, NO, NR, In another embodiment, the present invention provides O(CH),COR, O(CH),CN, OCH-CH=CHCOR, CHO novel compounds wherein: (CH),CO.R, CHOCH-CH=CHCOR, O(CH), PO M is SO. (OR), CHO(CH), PO(OR), NR(CH), COR, NR 45 2 In another embodiment, the present invention provides (CH), PO(OR), NRCH-CH=CHCOR, NRSOR, novel compounds of formula Ia or a stereoisomer or pharma NRCO(CH),COR, NRCO(CH),CONR, ceutically acceptable salt thereof, O(CH2)CHCOR, O(CH2)CH (CH), COR, CHO (CH), CHCOR, O(CH),CHCONR, O(CH), C.H. (CH2)CONR, O(CH2)CH-tetrazole, CH 50 Ia O(CH),CHCONR, CHO(CH2)CH-tetrazole, O(CH2)CH (CH2)-tetrazole, NR(CH2)CHCOR, CHNR(CH2)CHCOR, NR(CH2)CH(CH2)COR, NR(CH), CHCONR, CHNR(CH),CHCONR, NR(CH2)CH (CH),CONR, NR(CH2)CH-tetra 55 zole, CHNR(CH),CH-tetrazole, NR(CH), CH, (CH4)-tetrazole, CONHOH, C(NH)NR' (CH),C(NH) NR, O(CH),CONR, O(CH),C(NH)NR's O(CH),C (NOH)NR, CHO(CH),CONR, NR(CH),CONR, OCHCH-CHCONR, CHOCHCH-CHCONR, 60 NRCH-CH=CHCONR, (CH)-tetrazole, O(CH)-tet razole, O(CHCHO).R., NR(CHCHO),R, and SONHCH: Z is selected from: H, C alkyl, OH, O C alkyl, O(CH2CH2O).R., OC(O) C, alkyl, O(CH2)CO.R. 65 OCH-CH=CHCOR, O(CH), PO(OR), O(CH), CONR, O(CH),C(NH)NH, O(CH),C(NOH)NR, US 8,853,252 B2 7 8 3. In another embodiment, the present invention provides Zis selected from: H. C. alkyl, OH, O Calkyl, acety novel compounds of formula Ib or a stereoisomer or pharma loxy, and propionyloxy; ceutically acceptable salt thereof, Q is selected from: (CH),CHA(CH),C(O)NR, (CH),CAA" (CH),C(O)NR2 (CH2)CHA(CH2)COR, (CH),CAA" (CH),CO.R., (CH), CHA(CH), SONR, Ib (CH), CHA(CH),CONHCHA(CH2)COR, X (CH),CAA"(CH),CONHCHA(CH),COR, (CH), CHA(CH2)CONHCHA(CH),CONHCHA(CH2)COR, (CH), CHA(CH),CONHCHA(CH),CONR, (CH), O. O. 10 CAA"(CH),CONHCHA(CH2)CONR (CH), CHA (CH),CONHCHA(CH),CONHCHA(CH),CONR, C-C-cyclic amino-(CH2)COR, C-C-cyclic amino (CH2)CONR, C-C-cycloalkylene-(CH2)COR, and C-C-cycloalkylene-(CH),CONR; 15 provided that when Q is (CH2)CAA"(CH),C(O)NR or (CH),CAA"(CH),COR, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b): A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, OH, CHOH, CH(CH)OH, C(CH),OH, (CH),COR, 2O (CH),C(O)NR', and (CH)-phenyl, wherein the phenyl is Yi. substituted with 0-3 groups selected from H. C. alkyl, halo gen, CFO C. alkyl, and NO; 4. In another embodiment, the present invention provides alternatively, Q is CHA(CH),C(O)NR or CHA(CH), novel compounds of formula Ic or a stereoisomer or pharma COR, and A is OH or (CH),CO.R or R is (CH), (CHR), ceutically acceptable salt thereof, 25 (CH), OH or CH(CHOH): Ic R is independently selected from H. C. alkyl, Calk enyl, and C2-alkynyl: R’ is independently selected from H. C. alkyl, Calk enyl, and C2-alkynyl: O O 30 p is selected from 2, 3, 4, 5, 6, 7, and 8: m is independently selected from 0, 1, 2, and 3; and, n is independently selected from 1, 2, and 3. 5. In another embodiment, the present invention provides novel compounds of formula Ia or a stereoisomer or pharma 1. 35 ceutically acceptable salt thereof, wherein: n Q is selected from: (CH),CHA(CH),C(O)NR, (CH),CAA" (CH),C(O)NR2 (CH2)CHA(CH), SO OS X" NR, (CH2)CHA(CH),CONHCHA(CH),CONR, (CH),CAA"(CH2)CONHCHA(CH2)CONR", (CH), 40 CHA(CH),CONHCHA(CH),CONHCHA(CH), Yi. CONR, C-C-cyclic amino-(CH2)COR, C-C-cyclic amino-(CH2)CONR, and C-C-cycloalkylene-(CH), 5. In another embodiment, the present invention provides CONR; novel compounds of formula Ia or a stereoisomer or pharma provided that when Q is (CH2)CAA"(CH),C(O)NR ceutically acceptable salt thereof, 45 then (a) m is other than 0, (b) A is other than H, or (c) both (a) Ia and (b): alternatively, Q is CHA(CH),C(O)NR and A is OH or (CH),CO.R or R is (CH), (CHR), (CH), OH or CH(CHOH): 50 M is SO; R is independently selected from H and C alkyl: R’ is independently selected from Hand C alkyl: m is independently selected from 0, 1, and 2; and, n is independently selected from 1 and 2. 55 In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharma ceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharma ceutically acceptable salt form thereof. 60 In another embodiment, the present invention provides a novel method of modulating the activity of CB1 receptors (e.g., periperhal CB1 receptors) in a patient, comprising: administering to a patient in need thereof a therapeutically wherein: effective amount of a compound of the present invention or a X, Y, X, Y, X", and Y" are individually selected from the 65 pharmaceutically acceptable salt form thereof. following: H. C. alkyl, halogen, CF. O—C alkyl, NO, In another embodiment, the present invention provides a O(CHCHO),R, NR"(CHCHO).R., and NR; novel method of treating a disease characterized by an inap US 8,853,252 B2 10 propriate activation of peripheral CB1 receptors, comprising: and all embodiments of the present invention may be taken in administering to a patient in need thereof a therapeutically conjunction with any other embodiment or embodiments to effective amount of a compound of the present invention or a describe additional embodiments. It is also to be understood pharmaceutically acceptable salt form thereof. that each individual element of the embodiments is intended In another embodiment, the present invention provides a to be taken individually as its own independent embodiment. novel method for treating a disease mediated by the CB Furthermore, any element of an embodiment is meant to be receptor in a patient, comprising: administering to a patient in combined with any and all other elements from any embodi need thereof a therapeutically effective amount of a com pound of the present invention or a pharmaceutically accept ment to describe an additional embodiment. Definitions able salt form thereof. In an example, the disease is mediated 10 by peripheral CB receptors. In another example, the CB The examples provided in the definitions present in this receptors that are blocked are peripheral CB receptors. application are non-inclusive unless otherwise stated. They In another embodiment, the present invention provides a include but are not limited to the recited examples. novel method for treating a disease, comprising: administer The compounds herein described may have asymmetric ing to a patient in need thereof a therapeutically effective 15 amount of a compound of the present invention or a pharma centers, geometric centers (e.g., double bond), or both. All ceutically acceptable salt form thereof, wherein the disease is chiral, diastereomeric, racemic forms and all geometric iso selected from obesity, diabetes, dyslipidemia, cardiovascular meric forms of a structure are intended, unless the specific disorders, hepatic disorders, and a combination thereof. Stereochemistry or isomeric form is specifically indicated. In another embodiment, the diabetes disorder is selected Compounds of the present invention containing an asym from Type 1 diabetes, Type 2 diabetes, inadequate glucose metrically substituted atom may be isolated in optically active tolerance, and insulin resistance. or racemic forms. It is well known in the art how to prepare In another embodiment, the dyslipidemia disorder is optically active forms, such as by resolution of racemic selected from undesirable blood lipid levels, including forms, by Synthesis from optically active starting materials, or elevated LDL and triglyceride levels, and lowered HDL lev 25 through use of chiral auxiliaries. Geometric isomers of ole els. fins, C=N double bonds, or other types of double bonds may In another embodiment, the cardiovascular disorder is be present in the compounds described herein, and all Such selected from atherosclerosis, hypertension, stroke and heart stable isomers are included in the present invention. Specifi attack. cally, cis and transgeometric isomers of the compounds of the In another embodiment, the hepatic disorder is selected 30 present invention may also exist and may be isolated as a from cirrhosis and fatty liver diseases. mixture of isomers or as separated isomeric forms. All pro In another embodiment, the present invention provides a cesses used to prepare compounds of the present invention novel method for treating a co-morbidity of obesity, compris and intermediates made therein are considered to be part of ing: administering to a patient in need thereof a therapeuti the present invention. All tautomers of shown or described cally effective amount of a compound of the present invention 35 compounds are also considered to be part of the present or a pharmaceutically acceptable salt form thereof. invention. In another embodiment, the co-morbidity is selected from Alkyl includes both branched and straight-chain satu diabetes, dyslipidemia, Metabolic Syndrome, dementia, car rated aliphatic hydrocarbon groups having the specified num diovascular, and hepatic disease. ber of carbon atoms. Calkyl, for example, includes C. C. In another embodiment, the co-morbidity is selected from 40 hypertension; gallbladder disease; gastrointestinal disorders; C, C, Cs, and C alkyl groups. Examples of alkyl include menstrual irregularities; degenerative arthritis; venous statis methyl, ethyl, n-propyl, i-propyl. n-butyl, S-butyl, t-butyl, ulcers; pulmonary hypoVentilation syndrome; sleep apnea; n-pentyl, and S-pentyl. Snoring; coronary artery disease; arterial Sclerotic disease; Alkenyl includes the specified number of hydrocarbon pseudotumor cerebri; accident proneness; increased risks 45 atoms in either straight or branched configuration with one or with Surgeries; osteoarthritis; high cholesterol; and, increased more unsaturated carbon-carbon bonds that may occur in any incidence of malignancies of the ovaries, cervix, uterus, stable point along the chain, such as ethenyl and propenyl. breasts, prostrate, and gallbladder. C2-alkenyl includes C2, Cs, Ca, Cs, and Coalkenyl groups. In another embodiment, the present invention also provides Alkynyl includes the specified number of hydrocarbon a method of preventing or reversing the deposition of adipose 50 atoms in either straight or branched configuration with one or tissue in a mammal by the administration of a compound of more triple carbon-carbon bonds that may occur in any stable the present invention. By preventing or reversing the deposi point along the chain, such as ethynyl and propynyl. C tion of adipose tissue, compound of the present invention are Alkynyl includes C, C, C, Cs, and C alkynyl groups. expected to reduce the incidence or severity of obesity, “Cycloalkyl includes the specified number of hydrocar thereby reducing the incidence or severity of associated co 55 bon atoms in a saturated ring. Such as cyclopropyl, cyclobu morbidities. tyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In another embodiment, the present invention provides a compound of the present invention for use in therapy. C-8 cycloalkyl includes C. C. Cs. C. C7, and Cs cycloalkyl In another embodiment, the present invention provides the groups. use of the present invention for the manufacture of a medica 60 “Cyclic amine' is a hydrocarbon ring wherein one carbon ment for the treatment of obesity, diabetes, dyslipidemia, atom of the ring has been replaced by a nitrogen atom. The cardiovascular disorders, hepatic disorders, and a combina cyclic amine can be unsaturated, partially saturated, or fully tion thereof. saturated. The cyclic amine can also be bicyclic, tricyclic, and The present invention may be embodied in other specific polycyclic. Examples of cyclic amine include pyrrolidine and forms without departing from the spirit or essential attributes 65 piperidine. thereof. This invention encompasses all combinations of Halo’ or “halogen' refers to fluoro, chloro, bromo, and aspects of the invention noted herein. It is understood that any iodo. US 8,853,252 B2 11 12 "Counterion' is used to represent a small, negatively to, mineral or organic acid salts of basic residues such as charged species, such as chloride, bromide, hydroxide, amines; alkali or organic salts of acidic residues such as acetate, and Sulfate. carboxylic acids; and the like. The pharmaceutically accept The group "C.H.' represents a phenylene. able salts include the conventional non-toxic salts or the qua “Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 ternary ammonium salts of the parent compound formed, for membered monocyclic, bicyclic, or tricyclic ring, wherein at example, from non-toxic inorganic or organic acids. For least one ring, if more than one is present, is aromatic. example, such conventional non-toxic salts include, but are Examples of aryl include fluorenyl, phenyl, naphthyl, inda not limited to, those derived from inorganic and organic acids nyl, adamantyl, and tetrahydronaphthyl. selected from 1.2-ethanedisulfonic, 2-acetoxybenzoic, 2-hy “Heteroaryl” refers to any stable 5, 6,7,8,9, 10, 11, or 12 10 droxyethanesulfonic, acetic, ascorbic, benzenesulfonic, ben membered monocyclic, bicyclic, ortricyclic heterocyclic ring Zoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, that is aromatic, and which consists of carbon atoms and 1, 2, ethane Sulfonic, fumaric, glucoheptonic, gluconic, glutamic, 3, or 4 heteroatoms independently selected from the group glycolic, glycolyarsanilic, hexylresorcinic, hydrabamic, consisting of N, O, and S. If the heteroaryl group is bicyclic or hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, tricyclic, then at least one of the two or three rings must 15 hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl Sul contain a heteroatom, though both or all three may each fonic, maleic, malic, mandelic, methanesulfonic, napsylic, contain one or more heteroatoms. If the heteroaryl group is nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, bicyclic or tricyclic, then only one of the rings must be aro polygalacturonic, propionic, Salicyclic, Stearic, Subacetic, matic. The Ngroup may be N, NH, or N-substituent, depend Succinic, Sulfamic, Sulfanilic, Sulfuric, tannic, tartaric, and ing on the chosen ring and if Substituents are recited. The toluenesulfonic. nitrogen and Sulfur heteroatoms may optionally be oxidized The pharmaceutically acceptable salts of the present inven (e.g., S. S(O), S(O), and N—O). The heteroaryl ring may be tion can be synthesized from the parent compound that con attached to its pendant group at any heteroatom or carbon tains a basic or acidic moiety by conventional chemical meth atom that results in a stable structure. The heteroaryl rings ods. Generally, such salts can be prepared by reacting the free described herein may be substituted on carbon or on a nitro 25 acid or base forms of these compounds with a stoichiometric gen atom if the resulting compound is stable. amount of the appropriate base or acid in water or in an Examples of heteroaryl includes acridinyl, azocinyl, ben organic solvent, or in a mixture of the two: generally, non Zimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophe aqueous media like ether, ethyl acetate, ethanol, isopropanol, nyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriaz or acetonitrile are useful. Lists of suitable salts are found in olyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, 30 Remington's Pharmaceutical Sciences, 18th ed., Mack Pub benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, lishing Company, Easton, Pa., 1990, p 1445, the disclosure of chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, which is hereby incorporated by reference. 2H,6H-1.5.2-dithiazinyl, dihydrofuro2,3-btetrahydrofu “Therapeutically effective amount” includes an amount of ran, furanyl, furazanyl, imidazolyl, 1H-indazolyl, indolenyl, a compound of the present invention that is effective when indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isoben 35 administered alone or in combination to treat obesity or Zofuranyl, isochromanyl, isolindazolyl, isoindolinyl, isoin another indication listed herein. “Therapeutically effective dolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, amount also includes an amount of the combination of com oxadiazolyl, 1.2.3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxa pounds claimed that is effective to treat the desired indication. diazolyl, 1.3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxin The combination of compounds can be a synergistic combi dolyl pyrimidinyl, phenanthridinyl, phenanthrolinyl, phena 40 nation. Synergy, as described, for example, by Chou and Zinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the phthalazinyl, pteridinyl, pyranyl, pyrazinyl, pyrazolyl, effect of the compounds when administered in combination is pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, greater than the additive effect of the compounds when pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl pyrrolyl, administered alone as a single agent. In general, a synergistic quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, qui 45 effect is most clearly demonstrated at Sub-optimal concentra nuclidinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiaz tions of the compounds. Synergy can be in terms of lower olyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiaz cytotoxicity, increased effect, or some other beneficial effect olyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, of the combination compared with the individual compo thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1.2, nentS. 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, 50 Obesity is defined as having a body mass index (BMI) of 30 and Xanthenyl. or above. The index is a measure of an individual’s body “Mammal’ and “patient cover warm blooded mammals weight relative to height. BMI is calculated by dividing body that are typically under medical care (e.g., humans and weight (in kilograms) by height (in meters) Squared. Normal domesticated animals). Examples include feline, canine, and healthy body weight is defined as having a BMI between equine, bovine, and human, as well as just human. 55 20 and 24.9. Overweight is defined as having a BMI-25. “Treating or “treatment covers the treatment of a dis Obesity has reached epidemic proportions in the U.S., with 44 ease-state in a mammal, and includes: (a) preventing the million obese Americans, and an additional eighty million disease-state from occurring in a mammal, in particular, when deemed medically overweight. Such mammal is predisposed to the disease-state but has not Obesity is a disease characterized as a condition resulting yet been diagnosed as having it; (b) inhibiting the disease 60 from the excess accumulation of adipose tissue, especially state, i.e., arresting it development; and/or (c) relieving the adipose tissue localized in the abdominal area. It is desirable disease-state, i.e., causing regression of the disease state until to treat overweight or obese patients by reducing their amount a desired endpoint is reached. of adipose tissue, and thereby reducing their overall body “Pharmaceutically acceptable salts' refer to derivatives of weight to within the normal range for their sex and height. In the disclosed compounds wherein the parent compound is 65 this way, their risk for co-morbidities such as diabetes and modified by making acid or base salts thereof. Examples of cardiovascular disease will be reduced. It is also desirable to pharmaceutically acceptable salts include, but are not limited prevent normal weight individuals from accumulating addi US 8,853,252 B2 13 14 tional, excess adipose tissue, effectively maintaining their combined hyperlipidemia, characterized by elevated LDL body weights at a BMI<25, and preventing the development and triglycerides. Abnormal decreases in the levels of lipids of co-morbidities. It is also desirable to control obesity, effec and/or lipoproteins in the blood also can occur. These include tively preventing overweight and obese individuals from hypocholesterolemia, characterized by lowered cholesterol accumulating additional, excess adipose tissue, reducing the (usually high density lipoprotein, or HDL); and abetalipopro risk of further exacerbating their co-morbidities. teinemia, characterized by lowered beta lipoproteins. Type 2 Diabetes or Diabetes mellitus type 2 or (formerly Dyslipidemia contributes to the development of athero called non-insulin-dependent diabetes mellitus (NIDDM), or Sclerosis. Causes may be primary (genetic) or secondary. adult-onset diabetes) is a metabolic disorder that is primarily Diagnosis is by measuring plasma levels of total cholesterol, characterized by insulin resistance, relative insulin defi 10 TGs, and individual lipoproteins. Treatment is dietary ciency, and hyperglycemia. The World Health Organization changes, exercise, and lipid-lowering drugs. A linear relation definition of diabetes is for a single raised glucose reading probably exists between lipid levels and cardiovascular risk, with symptoms otherwise raised values on two occasions, of so many people with “normal cholesterol levels benefit from either fasting plasma glucose a 7.0 mmol/l (126 mg/dl) or achieving still lower levels. Normal and abnormal lipid levels with a Glucose tolerance test: two hours after the oral dose a 15 have been defined in the Third Report of the Expert Panel on plasma glucosea 11.1 mmol/l (200 mg/dl). Type 2 Diabetes is Detection, Evaluation, and Treatment of High Blood Choles rapidly increasing in the developed world and there is some terol in Adults. National Institutes of Health, National Heart, evidence that this pattern will be followed in much of the rest Lung, and Blood Institute, 2001. of the world in coming years. CDC has characterized the The treatment of choice for dyslipidemias is lifestyle increase as an epidemic (Diabetes, Atlanta: Centres for Dis change, including diet and exercise. Drugs are the next step ease Control, Atlanta, Report no. 2007-05-24). In addition, when lifestyle changes are not effective. Lipid lowering drugs whereas this disease used to be seen primarily in adults over include statins, nicotinic acid, bile acid sequestrants, fibrates, age 40 (in contrast to Diabetes mellitus type 1), it is now cholesterol absorption inhibitors, and combination treat increasingly seen in children and adolescents, an increase ments (e.g., niacin and a statin). These agents are not without thought to be linked to rising rates of obesity in this age group. 25 adverse effects, including flushing and impaired glucose tol Insulin resistance means that body cells do not respond erance (nicotinic acid), bloating, nausea, cramping, and con appropriately when insulin is present. Unlike insulin-depen stipation (bile acid sequestrants). Bile acid sequestrants may dent diabetes mellitus (Type 1), the insulin resistance is gen also increase TGs, so their use is contraindicated in patients erally “post-receptor, meaning it is a problem with the cells with hypertriglyceridemia. Fibrates potentiate muscle toxic that respond to insulin rather than a problem with insulin 30 ity when used with statins, and may increase LDL in patients production. Type 2 diabetes is presently of unknown etiology with high TGs. (i.e., origin). About 90-95% of all North American cases of Drugs enter the CNS from the systemic circulation by diabetes are type 2, and about 20% of the population over the crossing the blood-brain barrier (BBB). The BBB is a highly age of 65 has diabetes mellitus Type 2 (Nature, 2001, 414, specialized gate-keeper that protects the brain by preventing 6865). Diabetes affects over 150 million people worldwide 35 the entry of many potentially harmful substances into the and this number is expected to double by 2025. About 55 CNS from the systemic circulation. Much is known about the percent of type 2 diabetics are obese-chronic obesity leads to BBB, and of the physical-chemical properties required for increased insulin resistance that can develop into diabetes compounds transported across it. (Morbidity and Mortality Weekly Report 2008, 53, 1066). Drugs that do not cross the BBB into the CNS or that are Type 2 diabetes is often associated with obesity, hyperten 40 readily eliminated through transport mechanisms (J. Clin. Sion, elevated cholesterol (combined hyperlipidemia), and Invest. 1996, 97, 2517) are known in the literature and have with the condition often termed Metabolic syndrome (it is low CNS activity due to their inability to develop brain levels also known as Syndrome X, Reavan's syndrome, or necessary for pharmacological action. The BBB has at least CHAOS). There are several drugs available for Type 2 dia one mechanism to remove drugs prior to their accumulation betics, including metformin, thiazolidinediones, which 45 in the CNS. P-Glycoproteins (P-gp) localized in plasma increase tissue insulin sensitivity, C-glucosidase inhibitors membrane of the BBB can influence the brain penetration and which interfere with absorption of some glucose containing pharmacological activity of many drugs through transloca nutrients, and peptide analogs that must be injected. tion across membranes. The lack of accumulation into the Dyslipidemia is the presence of abnormal levels of lipids brain by some drugs can be explained by their active removal and/or lipoproteins in the blood. Lipids (fatty molecules) are 50 from the brain by P-gp residing in the BBB. For example, the transported in a protein capsule, and the density of the lipids typical opioid drug loperamide, clinically used as an antidi and type of protein determines the fate of the particle and its arrheal, is actively removed from the brain by P-gp, thus influence on metabolism. Lipid and lipoprotein abnormalities explaining its lack of opiate-like CNS effects. Another are extremely common in the general population, and are example is domperidone, a dopamine receptor blocker that regarded as a highly modifiable risk factor for cardiovascular 55 participates in the P-gp transport (J. Clin. Invest. 1996, 97. disease due to the influence of cholesterol, one of the most 2517). Whereas dopamine receptor blockers that cross the clinically relevant lipid Substances, on atherosclerosis. In BBB can be used to treat schizophrenia, the readily-elimi addition, some forms may predispose to acute pancreatitis. nated domperidone can be used to prevent emesis, without the In western Societies, most dyslipidemias are hyperlipi likelihood of producing adverse CNS effects. demias; that is, an elevation of lipids in the blood, often due to 60 In addition to the above compounds, agents possessing diet and lifestyle. The prolonged elevation of insulin levels structural characteristics that retard or prevent BBB penetra can also lead to dyslipidemia. The most prevalent hyperlipi tion or contribute to participation in active elimination pro demias include: hypercholesterolemia, characterized by cesses have been identified in various classes of therapeutics. elevated cholesterol (usually LDL), hypertriglyceridemia, These include antihistamines (Drug Metab. Dispos. 2003, 31, characterized by elevated triglycerides (TGs); hyperlipopro 65 312), beta-adrenergic receptor antagonists (Eur: J. Clin. teinemia, characterized by elevated lipoproteins; hyperchy Pharmacol. 1985, 28, Suppl. 21. Br. J. Clin. Pharmacol., lomicronemia, characterized by elevated chylomicrons; and 1981, 11, 549), non-nucleoside reverse transcriptase inhibi US 8,853,252 B2 15 16 tors (NNRTIs, J. Pharm. Sci., 1999, 88, 950), and opioid In compound AA, one of X, Y, X, Y, X", Y, Z, Z", or Q is a antagonists. This latter group has been tested in relation to group capable of reducing or limiting the CNS activity of their activity in the gastrointestinal tract. These peripherally compound AA. This reduced or limited CNS activity occurs selective opioid antagonists are described in various US pat ents as being useful in the treatment of non-CNS pathologies via at least one of X,Y,X'Y', X".Y. Z, Z, and Q being a group in mammals, in particular those of the gastrointestinal tract that either limits compound AA’s ability to cross the BBB see U.S. Pat. No. 5,260,542; U.S. Pat. No. 5,434,171; U.S. relative to that of SLV319 or enables it to be actively removed Pat. No. 5,159,081; and U.S. Pat. No. 5,270,238. from the brain at a rate greater than that of SLV319. Examples Other types of non-brain penetrant compounds can be pre of the amount of compound AA present in the brain can pared through the creation of a charge within the molecule. include (a) from 50,55, 60, 65,70, 75,80, 85,90,91, 92,93, Thus, the addition of a methyl group to the tertiary amine 10 94, 95, 96, 97,98, 99, to 100% lower than SLV319, (b) from functionality of the drugs scopolamine or atropine, unlike the 90, 91, 92,93, 94, 95, 96, 97,98, 99, to 100% lower than parent molecules, prevents their passage across the BBB SLV319, and (c) from 98, 99, to 100% lower than SLV319, through the presence of a positive charge. However, the new when administered at the same dosage. molecules (methyl-Scopolamine and methyl-atropine) retain The compounds of the present invention are expected to be their full anticholinergic pharmacological properties. As 15 cannabinoid receptor antagonists or inverse agonists (e.g., Such, these drugs can also be used to treat peripheral diseases, have activity at s10 uM). Representative compounds have without the concern of adverse CNS effects. The quaternary been tested and shown to be active (e.g., see Tables A, B, and ammonium compound methylmaltrexone is also used for the C). prevention and/or treatment of opioid-induced gastrointesti An inverse agonist is a compound that not only blocks the nal side effects associated with opioid administration (J. action of the endogenous agonist at the receptor, but also Pharmacol. Exp. Ther: 2002, 300, 118). The discovery that the anti-obesity activity of cannabinoid exhibits its own activity which is usually the opposite of that receptor blockers may in part be mediated by a non-CNS shown by the agonist. Inverse agonists are also effective mechanism could make it beneficial for the compounds of the against certain types of receptors (e.g. certain histamine present invention to be peripherally restricted (i.e., have an receptors/GABA receptors) that have intrinsic activity with inability or limited ability to cross the BBB, or be readily 25 out the interaction of a ligand upon them (also referred to as eliminated from the brain through active transport systems). constitutive activity). It may be desirable for the compounds of the present inven Most methods of treating obesity are dependent on a sig tion to be peripherally restricted, which in turn will result in nificant reduction in energy intake, either by a decrease in no or very limited CNS effects. Compounds that provide food intake (e.g., sibutramine) or by inhibition offat absorp peripherally mediated anti-obesity, anti-diabetic, or anti-dys 30 tion (e.g., orlistat). In the present invention, adipose tissue lipidemic properties should result in therapeutic agents with may be reduced in the absence of a significant reduction in greater safety. It can be desirable that the compounds of the food intake. The weight loss, as a result of the present inven present invention, when administered in a therapeutically tion, comes from the treatment with a compound of the effective amount, have no or very limited CNS effects. It can present invention, largely independent of though not totally also be desirable that the lack of CNS effects is a result of the 35 dissociated from, appetite and food intake. It can be desirable compounds of the present invention having minimal brain that adipose tissue loss occurs while food intake is main concentrations when administered in therapeutically effec tained, increased or (a) about 1,2,3,4,5,6,7,8,9, 10, 11, 12, tive amounts. In this context, minimal brain concentrations means levels that are too low to be therapeutically effective 13, 14, 15, 16, 17, 18, 19, or 20% below the normal range of for the treatment of a CNS indication or too low to cause the subject prior to being treated in accordance with the significant or measurable deleterious or undesired side 40 present invention (i.e., its pre-administration level), (b) about effects, or both. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below its SLV319 (Compound I when X and X" are 4-Cl; X, Y, Y', pre-administration level, (c) about 1, 2, 3, 4, 5, 6, 7, 8, 9, or Y", Z, and Z are H; Q is CH; and M is SO) is a drug that 10% below its pre-administration level, or (d) about 1, 2, 3, 4, crosses the BBB and is indicated for the treatment of obesity. or 5% below its pre-administration level. It is believed that SLV319 works to treat obesity via a CNS 45 In some cases, loss of adipose tissue can be accompanied mechanism. Compounds like SLV319 and compound AA by a concomitant loss of lean muscle mass. This is particu have been described in various publications including.J. Med. larly evident in cancer patients who show a generalized wast Chem. 2004, 47(3), 627 and U.S. Pat. No. 6,476,060. ing of body tissues, including adipose tissue and lean muscle mass. In the present invention, however, it can be desirable for 50 body fat to be significantly reduced in the absence of a sig nificant reduction in lean body mass. Adipose tissue loss comes from treatment with a compound of the present inven tion, independent of a significant change in lean body mass. Thus, adipose tissue loss can occur while lean body mass is 55 maintained, increased, or (a) is no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% below the normal range of the subject prior to being treated in accordance with the present invention (i.e., its pre-administration level), (b) is no 60 more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% below pre-administration levels, (c) is no more than about 1,2,3,4,5,6,7,8,9, or 10% below pre-administration levels, or (d) is no more than about 1, 2, 3, 4, or 5% below pre-administration levels. 65 In some cases, loss of adipose tissue can be accompanied by a concomitant loss of water mass. This is particularly evident with diet regimens that promote dehydration. In the US 8,853,252 B2 17 18 present invention, it can be desirable for body fat to be sig thyroid hormone beta. agonists: 35) FAS (fatty acid syn nificantly reduced in the absence of a significant reduction in thase) inhibitors: 37) DGAT2 (diacylglycerol acyltransferase water mass. In other words, adipose tissue loss comes from 2) inhibitors; 38) ACC2 (acetyl-CoA carboxylase-2) inhibi treatment with a compound of the present invention, indepen tors; 39) glucocorticoid antagonists; 40) acyl-estrogens: 41) dent of a significant change in water mass. It can be desirable lipase inhibitors, such as orlistat (Xenical(R): 42) fatty acid that adipose tissue loss occurs while water mass is main transporter inhibitors: 43) dicarboxylate transporter inhibi tained, increased, or (a) is no more than about 1, 2, 3, 4, 5, 6, tors; 44) glucose transporter inhibitors; 45) phosphate trans 7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, porter inhibitors; 46) serotonin reuptake inhibitors: 47) Met 25, 26, 27, 28, 29, or 30% below the normal range of the formin (Glucophage(R): 48) Topiramate (Topimax(R): 49) Subject prior to being treated in accordance with the present 10 opiate antagonists such as naltrexone, 50) the non-selective invention (i.e., its pre-administration level), (b) is no more transport inhibitor bupropion, and/or 51) MAO inhibitors. than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% Examples of MAO inhibitors include Moclobemide: Bro below pre-administration levels, (c) is no more than about 1, faromine; BW A616U; Ro 41-1049; RS-2232; SR 95191, 2, 3, 4, 5, 6, 7, 8, 9, or 10% below pre-administration levels, Harmaline: Harman; Amiflamine; BW 1370U87: FLA 688; or (d) is no more than about 1, 2, 3, 4, or 5% below pre 15 FLA 788: Bifemelane; Clorgyline: LY 51641; MDL 72,394; administration levels. 5-4-Benzyloxyphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadia Sibutramine and orlistat are currently marketed for use in Zol-2-one, 5-(4-Arylmethoxyphenyl)-2-(2-cyanoethyl)tetra the treatment of obesity, albeit weight loss is achieved Zoles; Lazabemide; Ro 16-6491; Almoxatone; XB308; through entirely different mechanism of action. Sibutramine RS-1636; RS-1653; NW-1015; SL 340026; L-selegiline; inhibits the neuronal reuptake of serotonin and noradrenaline, Rasagiline: Pargyline; AGN 1135; MDL 72.974; MDL and orlistat inhibits gut lipase enzymes that are responsible 72,145; MDL 72,638; LY 54761; MD 780236; MD 240931; for breaking down ingested fat. Bifemelane; Toloxatone; Cimoxatone; Iproniazid: Cannabinoid receptor blockers can promote weight loss Phenelzine; Nialamide; Phenylhydrazine: 1-Phenylcyclopro through inhibition of peripheral cannabinoid receptors, a pylamine; Isocarboxazid; and, Tranylcypromine. Additional mechanism entirely different from appetite Suppressants, gut 25 examples of MAO inhibitors can be found in USPA 2007/ lipase inhibitors, and other agents with similar indications 0004683: U.S. application Ser. No. 1 1/445,044: USPA 2007/ (e.g., serotoninagonists, leptin, fatty acid synthase inhibitors, 0015734; and U.S. application Ser. No. 1 1/424,274. and monoamine oxidase (MAO) inhibitors). Co-administra Examples of diabetes disorders include treating Type 1 tion of a cannabinoid receptor blocker together with one or diabetes, Type 2 diabetes, inadequate glucose tolerance, and more other agents that are useful for treating the indications 30 insulin resistance. described above (e.g., obesity, diabetes, dyslipidemia, cardio Examples of second components useful for treating diabe vascular disorders, hepatic disorders, and a combination tes include (a) insulin sensitizers including (i) PPAR-Yago thereof) is expected to be beneficial, by producing, for nists such as the glitaZones (e.g. troglitaZone, pioglitaZone, example, either additive or synergistic effects. Examples of englitaZone, MCC-555, rosiglitaZone), and compounds dis additional agents include an appetite Suppressant, a lipase 35 closed in WO97/27857, 97/28115,97/28137, and 97/27847: inhibitor, and a MAO inhibitor (e.g., MAO-B and a combi and (ii) biguanides Such as metformin and phenformin; (b) nation of MAO-A/B). Therefore, the present invention pro insulin or insulin mimetics; (c) sulfonylureas such as tolbuta vides a method of treating obesity, diabetes, dyslipidemia, mide and glipizide, or related materials; (d) C-glucosidase cardiovascular disorders, and/or hepatic disorders, and a inhibitors (e.g., acarbose); (e) cholesterol lowering agents combination thereof, comprising administering a therapeuti 40 such as (i) HMG-CoA reductase inhibitors (lovastatin, simv cally effective amount of a compound of the present invention astatin, pravastatin, fluvastatin, atorvastatin, rivastatin, and and a second component effective for treating the desired other statins), (ii) sequestrants (e.g., cholestyramine, colesti indication. pol, and dialkylaminoalkyl derivatives of a cross-linked dex Examples of second components include anti-obesity tran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, agents, which include, but are not limited to: 1) growth hor 45 (iv) PPAR-O. agonists (e.g., fenofibric acid derivatives includ mone secretagogues; 2) growth hormone secretagogue recep ing gemfibrozil, clofibrate, fenofibrate, and bezafibrate), (v) tor agonists/antagonists; 3) melanocortin agonists; 4) Mc4r inhibitors of cholesterol absorption (e.g., B-sitosterol) and (melanocortin 4 receptor) agonists; 5).beta.-3 agonists; 7) acyl CoA: cholesterol acyltransferase inhibitors (e.g., meli 5HT2C (serotonin receptor 2C) agonists; 8) orexin antago namide), and (vi) probucol, (f) PPAR-C/Yagonists; (g) anti nists; 9) melanin concentrating hormone antagonists; 10) 50 obesity compounds (described previously): (h)ileal bile acid melanin-concentrating hormone 1 receptor (MCH1R) transporter inhibitors: (i) insulin receptor activators, () antagonists; 11) melanin-concentrating hormone 2 receptor dipeptidyl peptidase IV, or DPP-4 inhibitors (sitagliptin, (MCH2R) agonist/antagonists; 12) galanin antagonists; 13) vildagliptin and other DPP-4 inhibitors (k) exenatide, (1) CCKagonists; 14) CCK-A (cholecystokinin-A) agonists; 16) pramLintide. (m) FBPase inhibitors, (n) glucagon receptor corticotropin-releasing hormone agonists; 17) NPY 5 antago 55 antagonists, (o) glucagon-like peptide-1, and (p) the gluca nists: 18) NPY 1 antagonists; 19) histamine receptor-3 (H3) gon-like peptide-1 analogues (liraglutide, and others). modulators: 20) histamine receptor-3 (H3) blockers: 21) The compounds of the present invention are expected to be B-hydroxy steroid dehydrogenase-1 inhibitors (...beta.-HSD CB1 receptor blockers and are expected to be useful for 1): 22) PDE (phosphodiesterase) inhibitors; 23) phosphodi treating diseases mediated by the CB receptor. The com esterase-3B (PDE3B) inhibitors; 24) NE (norepinephrine) 60 pounds of the present are expected to possess an affinity in transport inhibitors; 25) non-selective serotonin/norepineph vitro for the central and/or peripheral cannabinoid receptors rine transport inhibitors, such as sibutramine, phentermine, or under the experimental conditions described by Devane et al., fenfluramine: 26) ghrelin antagonists; 28) leptin derivatives; Molecular Pharmacology, 1988, 34, 605-613. The com 29) BRS3 (bombesin receptor subtype 3) agonists: 30) CNTF pounds according to the invention are also expected to pos (Ciliary neurotrophic factors); 31) CNTF derivatives, such as 65 sess an affinity for the cannabinoid receptors present on axokine (Regeneron); 32) monoamine reuptake inhibitors; preparations of electrically stimulated isolated organs. These 33) UCP-1 (uncoupling protein-1), 2, or 3 activators; 34) tests can be performed on guinea-pig ileum and on mouse vas US 8,853,252 B2 19 20 deferens according to Roselt et al., Acta Physiologica Scan include from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, dinavia 1975, 94, 142-144, and according to Nicolau et al., 0.08, 0.09, 0.1, 0.2,0.3, 0.4,0.5,0.6,0.7, 0.8, 0.9, 1.0, 2, 3, 4, Arch. Int. Pharmacodyn, 1978,236, 131-136. 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, CB1 receptor affinities can be determined using membrane 76, 80, 85,90, 95, to 100 mg/kg of mammal body weight. The preparations of Chinese hamster ovary (CHO) cells in which 5 compound can be administered in a single dose or in a number the human cannabinoid CB1 receptor is stably transfected of smaller doses over a period of time. The length of time (Biochem J. 1991, 279, 129-134) in conjunction with 3H during which the compound is administered varies on an CP-55,940 as radioligand. After incubation of a freshly pre individual basis, and can continue until the desired results are pared cell membrane preparation with the 3H]-radioligand, achieved (i.e., reduction of body fat, or prevention of again in with or without addition of test compound, separation of 10 body fat). Therapy could, therefore, last from 1 day to weeks, bound and free ligand is performed by filtration over glass months, or even years depending upon the Subject being fiber filters. Radioactivity on the filter is measured by liquid treated, the desired results, and how quickly the Subject Scintillation counting. The ICso values can be determined responds to treatment in accordance with the present inven from at least three independent measurements. tion. Formulations and Dosages 15 In the present invention, the compound(s) of the present A possible example of a tablet of the present invention is as invention can be administered in any convenient manner (e.g., follows. enterally or parenterally). Examples of methods of adminis tration include orally and transdermally. One skilled in this art is aware that the routes of administering the compounds of the Ingredient mg/Tablet present invention may vary significantly. In addition to other Active ingredient 100 oral administrations, Sustained release compositions may be Powdered lactose 95 favored. Other acceptable routes may include injections (e.g., White corn starch 35 Polyvinylpyrrollidone 8 intravenous, intramuscular, Subcutaneous, and intraperito Na carboxymethylstarch 10 neal); Subdermal implants; and, buccal, Sublingual, topical, 25 Magnesium stearate 2 rectal, vaginal, and intranasal administrations. Bioerodible, non-bioerodible, biodegradable, and non-biodegradable sys Tablet weight 250 tems of administration may also be used. Examples of oral formulations include tablets, coated tablets, hard and soft gelatin capsules, Solutions, emulsions, and Suspensions. 30 A possible example of a capsule of the present invention is If a solid composition in the form of tablets is prepared, the as follows. main active ingredient can be mixed with a pharmaceutical vehicle, examples of which include silica, starch, lactose, magnesium Stearate, and talc. The tablets can be coated with Ingredient mg/Tablet Sucrose or another appropriate Substance or they can be 35 Active ingredient 50 Crystalline lactose 60 treated so as to have a Sustained or delayed activity and so as Microcrystalline cellulose 34 to release a predetermined amount of active ingredient con Talc 5 tinuously. Gelatin capsules can be obtained by mixing the Magnesium stearate 1 active ingredient with a diluent and incorporating the result ing mixture into soft or hard gelatin capsules. A syrup or elixir 40 Capsule fill weight 150 can contain the active ingredient in conjunction with a Sweet ener, which is typically calorie-free, an antiseptic (e.g., meth In the above capsule, the active ingredient has a Suitable ylparaben and/or propylparaben), a flavoring, and an appro particle size. The crystalline lactose and the microcrystalline priate color. Water-dispersible powders or granules can cellulose are homogeneously mixed with one another, sieved, contain the active ingredient mixed with dispersants or wet 45 ting agents or with Suspending agents such as polyvinylpyr and thereafter the talc and magnesium Stearate are admixed. rolidone, as well as with Sweeteners or taste correctors. Rectal The final mixture is filled into hard gelatin capsules of suit administration can be effected using Suppositories, which are able size. prepared with binders melting at the rectal temperature (e.g., A possible example of an injection solution of the present cocoa butter and/or polyethylene glycols). Parenteral admin 50 invention is as follows. istration can be effected using aqueous Suspensions, isotonic saline Solutions, or injectable sterile solutions, which contain pharmacologically compatible dispersants and/or wetting Ingredient mg/Tablet agents (e.g., propylene glycol and/or polyethylene glycol). Active Substance 1.0 mg The active ingredient can also be formulated as microcap 55 1NHCI 20.0 ul Sules or microspheres, optionally with one or more carriers or acetic acid 0.5 mg NaCl 8.0 mg additives. The active ingredient can also be presented in the Phenol 10.0 mg form of a complex with a cyclodextrin, for example Cl-, 3-, or 1NNaOH q.S. ad pH 5 Y-cyclodextrin, 2-hydroxypropyl-3-cyclodextrin, and/or HO q.S. ad 1 mL methyl-3-cyclodextrin. 60 The dose of the compound of the present invention admin istered daily will vary on an individual basis and to some Synthesis extent may be determined by the severity of the disease being The compounds of the present invention can be prepared in treated (e.g., obesity, diabetes, and cardiometabolic disor a number of ways known to one skilled in the art of organic ders). The dose of the compound of the present invention will 65 synthesis (e.g., see U.S. Pat. No. 6,476,060 B2, J Med Chem also vary depending on the compound administered. 2004, 47, 627). The compounds of the present invention can Examples of dosages of compounds of the present invention be synthesized using the methods described below, together US 8,853,252 B2 21 22 with synthetic methods known in the art of synthetic organic ing the many alternatives to the trained practitioner is Greene chemistry, or by variations thereon as appreciated by those and Wuts (Protective Groups. In Organic Synthesis, Wiley and skilled in the art. Preferred methods include, but are not Sons, 1991). All references cited herein are hereby incorpo limited to, those described below. The reactions are per rated in their entirety herein by reference.

Scheme 1

O O

N N (a) yA4 yA4 t-BuOC t-BuOC

t-BuO-C-N/ of2 h N of2. t-BuO-C-N/ s f ? N YN (c) - { N ca e H

C

of2. of2. t-BuO-C-N/ s f HOCN/ s h N N ? ? YN (e) YN wns wns leo ca 2 e

C C formed in a solvent appropriate to the reagents and materials 55 Scheme 1 shows how to convert 2-, 3-, or 4'-(carbo-t- employed and suitable for the transformations being effected. butoxymethoxy)-2-phenylacetophenones, prepared from It will be understood by those skilled in the art of organic commercially available 2-, 3- or 4'-methoxy-2-phenylac synthesis that the functionality present on the molecule etophenones via O-demethylation using HBr/HOAc or BBr/ should be consistent with the transformations proposed. This CH2Cl and alkylation of the resultant phenol with t-butyl will sometimes require a judgment to modify the order of the 60 bromoacetate in the presence of base, in 37% aqueous form synthetic steps or to select one particular process Scheme over aldehyde containing piperidine under reflux to the corre another in order to obtain a desired compound of the inven sponding acrylophenones (step a). Treatment of the acry tion. It will also be recognized that another major consider lophenones with hydrazine hydrate in ethanol can produce ation in the planning of any synthetic route in this field is the the 3,4-diarylpyrazolines (step b). The diarylpyrazolines can judicious choice of the protecting group used for protection of 65 be further treated with arylsulfonyldithioimidocarbonic acid the reactive functional groups present in the compounds methyl esters, prepared from the corresponding aryl Sulfona described in this invention. An authoritative account describ mides, CS, and Mel (see J. Med. Chem., 47, 627 (2004); US 8,853,252 B2 23 24 Chem. Ber: 1966, 99,2885), in a solvent (e.g., acetonitrile) in (step a). Treatment of the acrylophenones with hydrazine the presence of triethylamine at reflux to yield the pyrazole- hydrate in ethanol can produce the 3,4-diarylpyrazolines 1-carboximidothioic acid methyl ester (step c). Further expo- (step b). The diarylpyrazolines can be further treated with Sure of these iminothioethers to an aqueous solution of arylsulfonyldithioimidocarbonic acid methyl esters in a sol methylamine and methylene chloride at room temperature 5 vent like acetonitrile in the presence of triethylamine at reflux should afford the pyrazoline-1-carboxamidines (step d). to yield pyrazole-1-carboximidothioic acid methyl esters Hydrolysis of the ester using TFA/CHCl should produce the (stepc). Further exposure of these iminothioethers to an aque carboxylic acid (step e). ous solution of methylamine and methylene chloride at room

Scheme 2

N N (a) -e- y44 y44 t-BuOC t-BuOC o t-BuOC N1Nof2 h

-N N

e N / o2

C

t-BuOC2n-1'N, O e h HOC2n-1'N, O e h

N N N1 (e) N1 wns wns 2 e 2 e

C C

Scheme 2 describes how 2-(2-, 3'- or 4-carbo-t-bu- is temperature should afford the pyrazoline-1-carboxamidines toxymethoxyphenyl)acetophenones (prepared similarly to (step d). Hydrolysis of the ester using TFA/CHCl should scheme 1) should provide the corresponding acrylophenones produce the carboxylic acid (step e).

US 8,853,252 B2 27 28 Scheme 3 shows the conversion of 4'-chloro-2-phenylac taining triethylamine should yield the pyrazoline-esters (step etophenone in 37% aqueous formalin and MeOH containing d). Hydrolysis of the ester using TFA/CHCl should produce piperidine and acetic acid at reflux that should occur affording the carboxylic acid (step e). Treatment of the ester with anhy the acrylophenone (J. Agric. Food Chem. 1979, 27(2), 406) (step a). Treatment of the acrylophenone with hydrazine drous ammonia in methanol at about 0° to room temperature hydrate in ethanol can produce the 3,4-diarylpyrazolines can afford the carboxamido compound (stepf). Alternatively, (step b). The diarylpyrazolines can be further treated with the iminothioethers can be coupled with other amino acid arylsulfonyldithioimidocarbonic acid methyl esters in a sol esters to give adducts (step g) that can be hydrolyzed to the vent like acetonitrile in the presence of triethylamine at reflux carboxylic acids (steph). These acids may be converted to the to yield the pyrazole-1-carboximidothioic acid methyl ester 10 carboxamides using oxalyl chloride in dichloroethane fol (step c). Further exposure of these iminothioethers to beta lowed by anhydrous ammonia, or Boc-O in pyridine/THF alaninet-butyl ester in ethanol and methylene chloride con followed by anhydrous ammonia (step i).

Scheme 4 C

O O (a) (b)

C O C O O NQf OH N H | (c) in C O (d) o,

N -e- N

N(YN \o MeS1 SN \ COEt MeIN11. SN COEt H \ 29 eO COEt o?

(i) US 8,853,252 B2 29 30 -continued C C

YN \ YN \ MeHN11. NN CONH 2 MeHN11. SN COH2 la" la" o2 Ol o2 C C

Scheme 4 illustrates how oxidation of 4'-chloro-2-pheny hioic acid methyl ether (step f). Further exposure of these lacrylophenone in methylene chloride with m-chloroperben iminothioethers to an aqueous solution of methylamine and Zoic acid should provide the epoxide (step a), which upon treatment with hydrazine hydrate in ethanol solution at about methylene chloride at room temperature can afford the pyra 35-40°C. can give the 3,4-diarylpyrazoline alcohol (step b). Zoline-1-carboxamidines (step g), and hydrolysis of the ester The pyrazoline can be protected using di-t-butyl-dicarbonate using LiOH in aqueous THF solution can produce the car (t-Boc anhydride) in the presence of a base to give the N-t- BOC-pyrazoline (step c). The carbamate alcohol can then be boxylic acid (step h). The carbxoamides can be prepared by deprotonated with sodium hydride in a solvent like DMF treatment of the ester with anhydrous ammonia in alcohol at followed by alkylation with ethyl 4-bromocrotonate to yield -20°C. to ambient temperature (step i).

Scheme 5 C C O O (a) O f C) { NYN NH 1s HN NH

C C

? (c) ? YN se- YN es N HN 1. N o2 e ca e

C(NH)NH2. CN the ester (step d). Removal of the t-BOC group can be Scheme 5 shows how heating a solution of the 3,4-dia achieved via treatment with TFA (step e). The pyrazoline can rylpyrazoline and S-methylisothiourea in pyridine can form then be reacted with arylsulfonyldithioimidocarbonic acid 65 the pyrazoline-1-carboxamidine (step a). Treatment of this methyl esters in a solvent like acetonitrile in the presence of amidine with tA-cyanobenzenesulfonyl chloride in acetoni triethylamine at reflux to yield the pyrazole-1-carboximidot trile in the presence of N,N-dimethyl-4-aminopyridine and US 8,853,252 B2 31 32 triethylamine can give the carboxamidine-coupled Sulfona 3,4-diarylpyrazoline stirred in the cold can afford the pyra mide derivative (step b). Conversion of the nitrile to the phe nylcarboxamidine can be accomplished using HCl (gas) in Zoline-adduct (step a). Treatment of this thiocarboxamide MeOH at 0°C. to room temperature, followed by ammonium with amino compounds Such as ethyl beta-alanine in the carbonate or anhydrous ammonia in MeCH at about 0°C. to presence of HgCl2 can produce the benzoyl guanidines (step room temperature (step c). b). Hydrolysis of the ester using LiOH in aqueous THF solu

Scheme 6

C in C

N n N f He- 1. ROC 1. N 2 n-1N n N H H O YN O O C C (b) e C C O O O f N (d) N -a- N HNOC 1. 2 N-1SN n N les-s-s N H H

O O

C C

Scheme 6 describes how the reaction of a freshly prepared tion can produce the carboxylic acid (step c). Further conver anhydrous acetonitrile solution of 4-chlorobenzoylisothiocy sion of the acid to the acid chloride followed by treatment anate, made from 4-chlorobenzoylchloride and ammonium with anhydrous ammonia should afford the carboxamide isocyanate (see J. Heterocycl. Chem. 1991, 28, 1645), and a (step d).

O O (a) -e-

ON ON US 8,853,252 B2 34 -continued

HN ON

-1 N YN (d) N YN

(g) N (f) N YN -e- YN MeS1 SN N SN la" la"

C C MeOSHN MeOSHN

C C

Scheme 7 depicts how condensation of a solution of 4'-ni 55 (step d). Acylation of the aniline with ethyl malonyl chloride tro-2-phenylacetophenone in 37% aqueous formalin and in the presence of base should produce the amide (step e). MeOH containing piperidine and acetic acid should afford Treatment of the amidoester with amines such as methy after heating at reflux, the corresponding acrylophenone (step lamine or anhydrous ammonia in a solvent Such as methanol a). Treatment of the acrylophenone with hydrazine hydrate in 60 or methylene chloride at Zero degrees to room temperature ethanol can produce the 3,4-diarylpyrazoline (step b). The should afford the pyrazole-1-carboxamidines with the termi pyrazoline can then be reacted with arylsulfonyldithioimi nal carboxamido group (step f). Alternatively, the aniline docarbonic acid methyl esters in a solvent like acetonitrile in compound can be treated with methanesulfonyl chloride to the presence of triethylamine at reflux to yield the corre give the Sulfonamide (step g), which upon exposure to an sponding pyrazole-1-carboximidothioic acid methyl ester aqueous solution of methylamine and methylene chloride at (stepc). The nitro group can be reduced using sodium dithion room temperature should afford the pyrazoline-1-carboxam ite in aqueous basic solution to produce the aniline compound idines (Steph). US 8,853,252 B2 35 36

Scheme 8 O. O. C. ?

| (b)

C) PhCNW SN W N NF NF

f f N N N N N H H

PhCN1SNN N1SN \ \ NR NR

O, O ON wnsN wnsYN e e o212 o?2

C

Scheme 8 illustrates how treatment of 4-cyano-2-pheny tion and one equivalent of trityl chloride at room temperature lacrylophenone with hydrazine hydrate in ethanol will pro (step c). Reaction of this adduct with arylsulfonyldithioimi duce the 3,4-diarylpyrazoline (step a). The pyrazoline can 60 docarbonic acid methyl esters in a solvent like acetonitrile in then be reacted with tri-n-butyltin azide, conveniently pre the presence of triethylamine at reflux should yield the pyra pared in situ by the reaction of one equivalent of sodium azide Zole-1-carboximidothioic acid methyl ester (step d). Treat and one equivalent of tri-n-butyltin chloride (see J. Med. ment of the iminothioether with aqueous methylamine and Chem. 1991, 56,2395), in reluxingtoluene or xylene to afford methylene chloride at room temperature should afford the the tri-n-butyltin-tetrazole adduct (stepb). The tri-n-butyltin 65 pyrazole-1-carboxamidines (step e). Removal of the trityl adduct can be converted to the trityl-tetrazole adduct by treat group with aqueous TFA in THF at room temperature should ment with one equivalent of aqueous sodium hydroxide solu yield the unprotected tetrazole (step f). US 8,853,252 B2 37 38

Scheme 9

C

(e) R = TBDMS

C R = Et, TBDMS

Scheme 9 shows how to convert 2-, 3-, or 4-polyethoxy 50 imidothioic acid methyl ester (step c). Further exposure of lated analogs of 2-phenylacetophenones, prepared from com these iminothioethers to an aqueous solution of methylamine mercially available 2-, 3- or 4'-methoxy-2-phenylacetophe and methylene chloride at room temperature should afford the nones via O-demethylation using HBr/HOAc or BBr/ pyrazoline-1-carboxamidines (step d). Removal of the CHCl and alkylation of the resultant phenols with alkyl TBDMS-capping group using anhydrous tetrabutylammo capped or TBDMS-capped halides prepared as described in 55 nium fluoride in THF should produce the hydroxyl-PEG ana Nuclear Medicine and Biology, 32,799 (2005). Treatment of log (step e). these polyether ketones in 37% aqueous formaldehyde con One stereoisomer of a compound of the present invention taining piperidine under reflux should give the corresponding may be a more potent cannabinoid receptorantagonist than its acrylophenones (step a). Treatment of the acrylophenones 60 counterpart(s). Thus, Stereoisomers are included in the with hydrazine hydrate in ethanol can produce the 3,4-dia present invention. When required, separation of the racemic rylpyrazolines (step b). The diarylpyrazolines can be further material can be achieved by HPLC using a chiral column or treated with arylsulfonyldithioimidocarbonic acid methyl by a resolution using a resolving agent Such as described in esters, prepared from the corresponding aryl Sulfonamides, Wilen, S. H. Tables of Resolving Agents and Optical Resolu CS, and Mel (see J. Med. Chem., 47,627 (2004); Chem. Ber: 65 tions 1972, 308 or using enantiomerically pure acids and 1966, 99, 2885), in a solvent (e.g., acetonitrile) in the pres bases. A chiral compound of the present invention may also ence of triethylamine at reflux to yield the pyrazole-1-carbox be directly synthesized using a chiral catalyst or a chiral US 8,853,252 B2 39 40 ligand, e.g., Jacobsen, E. Acc. Chem. Res. 2000, 33, 421-431 -continued or using other enantio- and diastereo-Selective reactions and reagents known to one skilled in the art of asymmetric Syn thesis. Examples of stereoisomers include compounds shown below. 5

10

15

25

30

35

40

45

50

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodi ments that are given for illustration of the invention and are not intended to be limiting thereof.

55 EXAMPLES Tables A, B, and C show a variety of examples of com pounds of the present invention synthesized using the route described below. 60 The following examples are representative of the proce dures used to prepare the preferred compounds in this appli cation. Abbreviations: MeOH-methanol 65 DCM-dichloromethane EtOAc-ethyl acetate HC1-hydrochloric acid US 8,853,252 B2 41 42 PE-petroleum ether EtOAc. The combined extracts were washed with brine, and NMM-N-methylmorpholine then dried over anhydrous NaSO. After solvent removal in IBCF-iso-butylchloroformate vacuo the residue was purified by silica gel column chromato TEA-triethylamine gram (PE/EtOAc: 2/1) to afford the carboxamidine (50-80% The preparation of the diphenyl pyrazolines with optional 5 yields). Substituents on the 3-phenyl group were prepared according to the procedures previously described J. Med. Chem., 47. 627 (2004); J. Agric. Food Chem., 27, 406 (1979). The Example 2 pyrazolines were condensed with Sulfonylated carbamic acid methyl esters obtained from the appropriately substituted 10 Lithium hydroxide monohydrate (10 mmoles) and 5 Sulfonamide and methyl chloroformate as previously mmoles of carboxamidine ester in THF (50 mL) and water described. Chlorination of the product acylsulfonamides with (16 mL) was stirred at room temperature for 5-7 hrs. The pH phosphorus pentachloride in heated cholorbenzene produced of the solution was then adjusted to ~1-2 by the addition of 1N the imidoylchlorides which were readily converted to the HCl solution, and the solvent was removed under reduced various amino ester adducts as previously described J. Med. 1 5 pressure. Water (15 mL) was added to the residue which was Chem., 47. 627 (2004). Conversion of these esters to acids, then extracted with EtOAc. The combined extracts were carboxamides, Substituted carboxamides, or di-amino acid washed with brine and dried over anhydrous NaSO. The variants were carried via conventional methodology, and pro carboxylic acid products (70-95% yields) were obtained by cedures representative of this chemistry are described below. evaporation of the solvent in vacuo.

Scheme 3a Z Z

N N YN (a) A YN c11. NN ROC 1.1.N1 NN e " leo o2 Y ca N X 4\ o Z Z

/ (c) d A YN A y as sis ---, " leo " leo o2 N YY o21 NHY 21 X 21 X

Example 1 Example 3 6 O To 10 mmoles of imidoyl chloride suspended in 20 mL of The carboxylic acids (1 mmol), obtained from the ester by DCM was added dropwise to a cooled solution of 12 mmols the procedure described in Example 2, in 40 mL of dry DCM of glycine methyl ester hydrochloride salt and 25 mmoles of containing NMM (3 mmol) was cooled to about -15°C. with TEA in 50 mL DCM, after the addition, the reaction mixture a salt ice bath. A solution of IBCF (1.1 mmol) in dry DCM (20 was allowed to warm to ambient temperature. After stirring 65 mL) was added dropwise overa 5 min period and after stirring for about one hour, the solvent was removed in vacuo and for 20 mins in an ice-brine bath, dry ammonia/THF solution water (50 mL) was added and the mixture was extracted with was added in one portion, and the reaction mixture was then US 8,853,252 B2 43 44 allowed to slowly warm to rt where it was stirred for 20 mins. tion and 30 mL of brine, and then dried over anhydrous The solvent was removed by evaporation, and the residue was NaSO. After filtration of the solution and removal of the diluted with 20 mL of water and extracted with EtOAc. The Solvent in vacuo, the residue was purified by silica gel chro combined extracts were washed with 15 mL of 1N HCl solu- matography to give the carboxamide adduct (60-80% yields). TABLE A

Number Q y X" X NMR ppm CH(CH)CH-CO-Et 4-CI H C (CDCl3) 1.28, 3H, dd, Me 1.35, 3H, dd, Me 2.65, 2H, dd, CH, 4.13-4.18, 3H, m, CH; OCH, 4.60, 2H, m, CHs 5.20, 1H, m, CH 7.11-7.90, 13H, aromatic Hs CH(CH)CH-CO2H 4-CI H C (CDOD) 1.30.3H, dd, Me 2.60, 2H, brd d, CH, 4.06, 1H, m, CH 4.53, 2H, m, CHs 4.90, 1H, m, CH 7.17-7.90, 13H, aromatic Hs CHCO-Me 4-CI H C (CDCl3) 3.77, 3H, s, OMe 4.11, 1H, m, CH 4.43, 2H, m, CH, 4.53, 1H, t, CH 4.64, 1H, m, CH 7.11-7.90, 13H, aromatic Hs CHCOH 4-CI H C (CDOD) 4.08, 1H, m, CH 4.24, 2H, m, CH2 4.53, 1H, m, CH 4.90, 1H, m, CH 7.11-7.90, 13H, aromatic Hs CH(CH)CO-Me 4-CI H C (CDCl3) 1.55, 3H, dd, Me, 3.71, 3H, s, OMe 4.16, 1H, m, CH 4.61, 2H, m, CHs 4.94, 1H, m, CH 7.09-7.90, 13H, aromatic Hs CH(CHOHCH)CO-Me 4-CI H C (CDCl3) 1.36, 3H, m, Me, 3.73,3H, d, OMe 4.15, 1H, m, CH 4.42, 1H, m, CH 4.60, 2H, m, CHs 4.85, 1H, m, CH 7.09-7.90, 13H, aromatic Hs CH(C(CH))CO-Me 4-CI H C (CDCl3) 1.14, 9H, brds, CH 3.67, 3.69,3H, 2s, OMe 3.90-4.95, 4-H, 4brds, CHs 7.22-7.89, 13H, aromatic Hs 8.30, 1H, brods, NH CHCOMe 4-OMe 3- C (CDC1) OMe 3.77, 3H, s, OMe 3.88, 3.90, 6H, 2s, OMes 4.12, 1H, dd, CH 4.45, 2H, d, CH, 4.53, 1H, t, CH 4.62, 1H, m, CH

US 8,853,252 B2 59 60 TABLE B-continued X

N N

2 O X" Q NN ls N1 S as% H Y it 2

Number Q y X" X NMR ppm 2O CONH2 4-C H Cl 1.97, 1H, bras, CH 2.12, 3H, brods, CHs 2.80, 1H, bras, CH 2.89, 1H, bras, CH 4.08, 1H, brom, CH 4.51, 1H, brom, CH 4.62, 1H, bras, CH 5.51, 1H, bras, NH 6.24, 1H, brods, NH 8.1o, 1H, brods, NH 7.03-7.90, 13H, aromatic Hs 21 CHCHSONH 4-C H Cl (CDCl3) 3.54, 2H, t, CH2 4.03, 1H, dd, CH 4.15, 2H, bras, CH2 4.49, 1H, t, CH 4.68, 2H, CH 5.36, 2H, s, NH 7.63, 1H, bras, NH 7.09-7.84, 13H, aromatic Hs

35 TABLE C Numerous modifications and variations of the present invention are possible in light of the above teachings. It is X therefore to be understood that within the scope of the 40 appended claims, the invention may be practiced otherwise that as specifically described herein. What is claimed is: f 1. A method of treating a disease, comprising: administer N ing to a mammal in need thereof a therapeutically effective YN O 45 amount of a compound of Formula I or a stereoisomer or leo X" pharmaceutically acceptable salt thereof, wherein the disease Qa N-S 2 sasy is insulin resistance: N N s H --Y"

2 50 I

Number Q y X" X NMR ppm 1 Me 4-OCH2COEt H Cl 1.29, 3H, t, Me 3.23, 3H, d, NMe 4.10, 1H, m, CH 55 4.26, 2H, q, OCH, 4.52, 1H, m, CH 4.60, 1H, m, CH i 4.62, 2H, s, OCH2COEt N Z 6.89-7.90, m, 13H, aromatic 1. HS n 2 Me 4-CONHOH H Cl (CDOD) 60 QHN N 3.05, 3H, s, NMe 3.95 1H, m, CH M N 4.44, 1H, t, CH 4.90, 1H, m, CH 7.14-7.94, m, 13H, aromatic Q4 HS 65 X"

US 8,853,252 B2 63 64 5. The method of claim 1, wherein the compound is of A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, formula Ic or a stereoisomer or pharmaceutically acceptable OH, CHOH, CH(CH)OH, C(CH),OH, (CH), salt thereof: CO.R., (CH),C(O)NR', and (CH)-phenyl, wherein the phenyl is substituted with 0-3 groups selected from 5 H. C. alkyl, halogen, CF. O—C alkyl, and NO; Ic alternatively, Q is CHA(CH),C(O)NR or CHA (CH),CO.R, and A is OH or (CH),COR or R is (CH), (CHR)(CH), OH or CH(CHOH): R is independently selected from H. C. alkyl, Calk O C) enyl, and C-alkynyl: R’ is independently selected from H. C. alkyl, Calk enyl, and C2-alkynyl: { p is selected from 2, 3, 4, 5, 6, 7, and 8: 15 m is independently selected from 0, 1, 2, and 3; and, n is independently selected from 1, 2, and 3. 1s 7. The method of claim 6, wherein: OS Q is selected from: (CH),CHA(CH),C(O)NR, (CH),CAA"(CH),C(O)NR, (CH), CHA (CH), SONR (CH), CHA(CH),CONHCHA Yi. (CH),CONR' (CH),CAA"(CH),CONHCHA (CH),CONR (CH), CHA(CH),CONHCHA 6. The method of claim 1, wherein the compound is a (CH),CONHCHA(CH),CONR, C-C-cyclic compound of formula Ia or a stereoisomer or pharmaceuti amino-(CH2)COR, C-C-cyclic amino cally acceptable salt thereof, 25 (CH),CONR, and C-C-cycloalkylene (CH),CONR; provided that when Q is (CH),CAA"(CH),C(O)NR

Ia then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b): 30 alternatively, Q is CHA(CH),C(O)NR and A is OH or (CH2)COR” or R is (CH2)(CHR), (CH), OH or CH(CHOH): M is SO; 35 R is independently selected from H and C alkyl: R’ is independently selected from Hand C, alkyl: m is independently selected from 0, 1, and 2; and, n is independently selected from 1 and 2. 8. The method of claim 1, wherein the compound is a 40 compound of formula Ib or a stereoisomer or pharmaceuti cally acceptable salt thereof,

Ib 45 wherein: X, Y, X, Y, X", and Y" are individually selected from the following: H. C. alkyl, halogen, CF. O—C alkyl, NO, O(CH-CHO).R. NR(CHCHO),R, and NR; Zis selected from: H.C. alkyl, OH, O—C alkyl, acety 50 loxy, and propionyloxy; Q is selected from: (CH), CHA(CH),C(O)NR, (CH),CAA" (CH),C(O)NR, (CH2)CHA (CH),COR, (CH),CAA"(CH),COR, (CH2)CHA(CH), SONR, (CH2)CHA(CH), 55 CONHCHA(CH),CO.R., (CH),CAA"(CH),CON HCHA(CH),CO.R., (CH), CHA(CH),CONHCHA (CH),CONHCHA(CH),CO.R., (CH), CHA(CH), CONHCHA(CH),CONR (CH2)CAA"(CH), Y it CONHCHA(CH),CONR, (CH2)CHA(CH), 60 CONHCHA(CH),CONHCHA(CH), CONR, C-C-cyclic amino-(CH2)COR, C-C-cyclic wherein: amino-(CH2)CONR, C-C-cycloalkylene-(CH), X, Y, X, Y, X", and Y" are individually selected from the COR, and C-C-cycloalkylene-(CH2)CONR; following: H. C. alkyl, halogen, CF. O—C alkyl, provided that when Q is (CH2)CAA"(CH),C(O)NR or 65 NO, O(CH-CHO).R. NR(CHCHO),R, and NR; (CH),CAA" (CH2)COR, then (a) m is other than 0. Zis selected from: H. C. alkyl, OH, O Calkyl, acety (b) A is other than H, or (c) both (a) and (b): loxy, and propionyloxy; US 8,853,252 B2 65 66 Q is selected from: (CH), CHA(CH),C(O)NR, TABLE B (CH),CAA" (CH),C(O)NR, (CH2)CHA (CH),CO.R., (CH),CAA"(CH),CO.R. (CH), X CHA(CH), SONR, (CH), CHA(CH),CONH CHA(CH2)COR, (CH),CAA"(CH),CONHCHA (CH),CO.R., (CH), CHA(CH),CONHCHA(CH), CONHCHA(CH),CO.R., (CH), CHA(CH2)CON W HCHA(CH),CONR, (CH),CAA"(CH),CONH N CHA(CH),CONR, (CH), CHA(CH),CONH 10 N N CHA(CH),CONHCHA(CH),CONR, C-C- O cyclic amino-(CH2)COR, C-C-cyclic amino QS N 1s- ga S- X" (CH), CONR, C-C-cycloalkylene-(CH2)COR, H --Y" and C-C-cycloalkylene-(CH2)CONR; 15 21 provided that when Q is (CH2)CAA"(CH),C(O)NR or (CH),CAA" (CH2)COR, then (a) m is other than 0. Number Q y X" X (b) A is other than H, or (c) both (a) and (b): A is selected from H. C. alkyl, (CH2)Cle-cycloalkyl, 1 CHCH-CH(OH)CO-Me 4-CI H C OH, CHOH, CH(CH)OH, C(CH)OH, (CH), 2 CHCH-COtBu)CO-Me 4-CI H C CO.R. (CH),C(O)NR', and (CH)-phenyl, wherein 3 C(CH3)2CO2H 4-CI H C the phenyl is substituted with 0-3 groups selected from 4 C(CH),CONH- 4-CI H C CH(CH)COMe H. C. alkyl, halogen, CF. O—C alkyl, and NO; 25 5 CHCHCCH)2)— 4-OMe H C alternatively, Q is CHA(CH),C(O)NR or CHA(CH), CONHCHCH-OH CO.R., and A is OH or (CH),CO.R or R is (CH), 6 CH-CH(OH)CH-CONH 4-CI H C (CHR), (CH), OH or CH(CHOH): 7 CHCH(CH)2CONH- 4-CI H C R is independently selected from H. C. alkyl, Calk 30 CH(CHOH), enyl, and C2-alkynyl: 8 CHCH-CH(OH)CONH 4-CI H C R’ is independently selected from H, C, alkyl, Calk 9 CHCH(CH)2CONH- 4-OMe H C enyl, and C2-alkynyl: CH(CH-OH), O CH(CH3CONH2)CONH 4-CI H C p is selected from 2, 3, 4, 5, 6, 7, and 8: 35 1 CHCONHCHCONH, 4-CI H C m is independently selected from 0, 1, 2, and 3; and, 2 CHCONHCHCONH, 4-OMe H C n is independently selected from 1, 2, and 3. 3 CHCONH- 4-OMe H C 9. The method of claim 8, wherein: CHCHCHOH)CONH, 40 4 CHCHCONH- 4-C H C Q is selected from: (CH), CHA(CH),C(O)NR, CHCONH2, (CH),CAA"(CH),C(O)NR (CH), CHA(CH), 5 CHCHCONH 4-OMe H C SONR, (CH), CHA(CH),CONHCHA(CH), CHCONH2, CONR, (CH),CAA"(CH2)CONHCHA(CH), 6 CHCH(CH),CONH- 4-C H C CONR, (CH), CHA(CH2)CONHCHA(CH), 45 CHCONH2, CONHCHA(CH2)CONR, C-C-cyclic amino 7 CHCH(CH)2CONH- 4-C H C (CH),CO.R, C-C-cyclic amino-(CH2)CONR', CHCHCONH, and C-C-cycloalkylene-(CH2)CONR; 8 CHCHCONH 4-C H C provided that when Q is (CH),CAA"(CH),C(O)NR 50 CHCH-OHCONH, then (a) m is other than 0, (b) A is other than H, or (c) 9 CHCHCONH- 4-C H C both (a) and (b): CHCHCONH,

alternatively, Q is CHA(CH),C(O)NR and A is OH or 2O v CONH2 4-C H C (CH),COR or R is (CH)(CHR), (CH), OH or 55 CH(CHOH): M is SO:

R is independently selected from H and C alkyl: 21 CHCHSONH 4-CI H. C. R’ is independently selected from Hand C, alkyl: 60 m is independently selected from 0, 1, and 2; and, 11. A method of treating a disease, comprising: adminis n is independently selected from 1 and 2. tering to a mammal in need thereofatherapeutically effective 10. The method of claim 1, wherein the compound is 65 amount of a compound selected from the compounds of Table selected from Table Bora stereoisomer or a pharmaceutically A and C or a stereoisomer or a pharmaceutically acceptable acceptable salt thereof: salt thereof, wherein the disease is insulin resistance:

US 8,853,252 B2 69 70 15. The method of claim 1, wherein the compound is: 18. The method of claim 1, wherein the compound is:

5

C C O O 10 O O f Ho / NN NN O N N O O

HN !-l N lsN Sá 15 HN N lsN 1. ga H H O C C

2O or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. 16. The method of claim 1, wherein the compound is: 19. The method of claim 1, wherein the compound is: 25

C C O 30

? 35 N

O O HN Yls S 2 HN ls S 2 2 H 1s1 k H N1 O 40 O C C or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. 45 thereof. 17. The method of claim 1, wherein the compound is: 20. The method of claim 1, wherein the compound is:

50 C O Cy C O C)

N O HN Sleo 60 HN Sleo N N1 N N1 H H O O OH C C

65 or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof. US 8,853,252 B2 71 72 21. The method of claim 1, wherein the compound is: 24. The method of claim 1, wherein the compound is:

C 5 o, O N O C) 10 O H lsY 29 f HN --- N N N N 1 S N H O OH YN C O HN ls- 15 N N or a stereoisomer or a pharmaceutically acceptable salt O thereof. C 25. The method of claim 1, wherein the compound is: C 2O or a stereoisomer or a pharmaceutically acceptable salt thereof. 22. The method of claim 1, wherein the compound is:

25 N n N

H 2 O C O N lN-S 30 HN N N H

C ? is or a stereoisomer or a pharmaceutically acceptable salt YN O thereof. leO 26. The method of claim 1, wherein the compound is: ls -S 2

or a stereoisomer or a pharmaceutically acceptable salt N N thereof. 45 O N O O 23. The method of claim 1, wherein the compound is: s ls 1 le HN N N H O HO C 50 C or a stereoisomer or a pharmaceutically acceptable salt thereof. 27. The method of claim 1, wherein the compound is: 55 C

N O N O O ls ga O 60 HN r NH N- ?n O HO C Y le HN N lsN 65 H or a stereoisomer or a pharmaceutically acceptable salt O thereof. C US 8,853,252 B2 73 74 or a stereoisomer or a pharmaceutically acceptable salt 29. The method of claim 1, wherein the compound is: thereof. 28. The method of claim 1, wherein the compound is: C o, O 10 YN O OS lsN Sleo 2 O HN1 n-n N1 HN N ls N1 S 15 H C

C or a stereoisomer or a pharmaceutically acceptable salt or a stereoisomer or a pharmaceutically acceptable salt thereof. thereof.