US 2010O286160A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0286160 A1 Gilbert et al. (43) Pub. Date: Nov. 11, 2010

(54) SUBSTITUTED PIPERAZINES AS CB1 Related U.S. Application Data ANTAGONSTS (60) Provisional application No. 60/946,896, filed on Jun. (75) Inventors: Eric J. Gilbert, Scotch Plains, NJ 28, 2007. (US); William J. Greenlee, Teaneck, NJ (US); Sarah Wei Li, Publication Classification Belle Mead, NJ (US); Michael W. (51) Int. Cl. Miller, Scotch Plains, NJ (US); A 6LX 3L/2197 (2006.01) Jack D. Scott, Scotch Plains, NJ C07D 24I/04 (2006.01) (US); Adrew Stamford, Chatham C07D 403/2 (2006.01) Township, NJ (US); Chander C07D 24I/02 (2006.01) Shekher Celly, Colonia, NJ (US) C07D 40/12 (2006.01) C07D 40/4 (2006.01) Correspondence Address: A6IP 9/00 (2006.01) MERCK PATENT DEPARTMENT (K-6-1, 1990) (52) U.S. Cl...... 514/252.11:544/400: 544/372: 2000 GALLOPNGHILL ROAD 544/370; 544/357: 514/254.01: 514/254.05; KENILWORTH, NJ 07033-0530 (US) 514/252.12:544/360; 514/253.13:544/364; 514/253.09 (73) Assignee: Intervet Inc. (57) ABSTRACT (21) Appl. No.: 12/665,253 Compounds of Formula (I): or pharmaceutically acceptable (22) PCT Fled: Jun. 25, 2008 salts, Solvates, oresters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic (86) PCT NO.: PCT/US08/07917 syndrome and obesity, neuroinflammatory disorders, cogni tive disorders and psychosis, addiction (e.g., Smoking cessa S371 (c)(1), tion), gastrointestinal disorders, and cardiovascular condi (2), (4) Date: Jun. 14, 2010 tions. US 2010/0286160 A1 Nov. 11, 2010

SUBSTITUTED PPERAZINES AS CB1 0006 CB (CB-/-) and CB (CB-/-) receptor knockout ANTAGONSTS mice have been used to elucidate the specific role of the two cannabinoid receptor Subtypes. Furthermore, for ligands Such PRIORAPPLICATIONS as delta-9-THC which act as agonists at both receptors, these mice have allowed identification of which receptor subtype is 0001. This application claims the benefit of priority to mediating specific physiological effects. CB-/-, but not Application No. 60/946,896, filed Jun. 28, 2007, which is CB-/-, mice are resistant to the behavioural effects of ago incorporated in its entirety by reference. nists such as delta-9-THC. CB-/- animals have also been shown to be resistant to both the body weight gain associated BACKGROUND OF THE INVENTION with chronic high fat diet exposure, and the appetite-stimu lating effects of acute food deprivation. 0002 The CB receptor is one of the most abundant neu 0007. These findings suggest a clear role for both endog romodulatory receptors in the brain, and is expressed at high enous and exogenous cannabinoid receptor agonists in levels in the hippocampus, cortex, cerebellum, and basal gan increasing food intake and body weight via selective activa glia (e.g., Wilson et al., Science, 2002, vol. 296, 678-682). tion of the CB receptor subtype. Selective CB receptor antagonists, for example pyrazole 0008. The therapeutic potential for cannabinoid receptor derivatives such as rimonabant (e.g., U.S. Pat. No. 6,432, ligands has been extensively reviewed (Exp. Opin. Ther. Pat. 984), can be used to treat various conditions, such as obesity and metabolic syndrome (e.g., Bensaid et al., Molecular 1998, 8,301-313; Exp. Opin. Ther. Pat. 2000, 10, 1529-1538; Pharmacology, 2003 vol. 63, no. 4, pp. 908-914: Trillou et al., Trends in Pharm. Sci. 2000, 21, 218-224: Exp. Opin. Ther. Am. J. Physiol. Regul. Integr: Comp. Physiol. 2002 vol. 284, Pat. 2002, 12(10), 1475-1489). R345-R353; Kirkham, Am. J. Physiol. Regul. Integr: Comp. 0009. At least one compound (SR-14171 6A: Rimona Physiol. 2002 vol. 284, R343-R344), neuroinflammatory dis bant) characterised as a CB receptor antagonist/inverse ago orders (e.g., Adam, et al., Expert Opin. Ther. Patents, 2002, nist is known to be in clinical trials for the treatment of vol. 12, no. 10, 1475-1489; U.S. Pat. No. 6,642,258), cogni obesity. tive disorders and psychosis (e.g., Adam et al., Expert Opin. 0010 Clinical trials with the CB receptor antagonist Ther. Pat., 2002, vol. 12, pp. 1475-1489), addiction (e.g., rimonabant have also observed an antidiabetic action that smoking cessation; U.S. Patent Publ. 2003/0087933), gas exceeds that accounted for by weight loss alone (Scheen A.J., trointestinal disorders (e.g., Lange et al., J. Med. Chem. 2004, et al., Lancet, 2006 in press). CB receptor mRNA is located vol. 47, 627-643) and cardiovascular conditions (e.g., Porter on C- and B-cells in the Islets of Langerhans and it has been et al., Pharmacology and Therapeutics, 2001 Vol. 90, 45-60; reported that CB receptor agonists reduce insulin release Sanofi-Aventis Publication, Bear Stearns Conference, New from pancreatic beta cells in vitro in response to a glucose York, Sep. 14, 2004, pages 19-24). There now exists extensive load (Juan-Pico et al. Cell Calcium, 39, (2006), 155-162). pre-clinical and clinical data Supporting the use of CB1 recep Consistent with this, Bermudez-Siva et al., (Eur J. Pharma tor antagonists/inverse agonists for the treatment of obesity. col., 531 (2006), 282-284) have reported that CB receptor 0003 Preparations of marijuana (Cannabis sativa) have agonists increase glucose intolerance following ip injection been used for over 5000 years for both medicinal and recre of a glucose load to rats. This effect was reversed by a CB ational purposes. The major psychoactive ingredient of mari receptorantagonist that increased glucose tolerance in the test juana has been identified as delta-9-tetrahydrocannabinol when given alone. Thus, the action of rimonabant may be due (delta-9-THC), one of a member of over 60 related cannab to a direct action on the pancreas. It is also possible that CB inoid compounds isolated from this plant. It has been dem receptor antagonists affect insulin sensitivity indirectly via an onstrated that delta-9-THC exerts its effects via agonist inter action on adiponectin (Chandran et al., Diabetes care, 26. action with cannabinoid (CB) receptors. So far, two (2003), 2442-2450) which is elevated by CB receptor cannabinoid receptor subtypes have been characterised (CB antagonists (Cota et al., J. Clin Invest., 112 (2003), 423-431; and CB). The CB receptor subtype is found predominantly Bensaid et al., Mol. Pharmacol., 63 (2003, 908-914). Indeed, in the central nervous system, and to a lesser extent in the it has been reported that endocannabinoid levels are enhanced peripheral nervous system and various peripheral organs. The in the pancreas and adipose tissue of obese and diabetic mice CB receptor Subtype is found predominantly in lymphoid and in the plasma and adipose tissue of obese or type 2 tissues and cells. To date, three endogenous agonists (en diabetic patients (Matias et al., JClin Endocrinol and Metab., docannabinoids) have been identified which interact with 91 (2006), 3171-3180) suggesting a possible causal role of both CB and CB receptors (anandamide, 2-arachidonyl elevated cannabinoid tone in the onset of type 2 diabetes. glycerol and noladin ether). 0011. However, there is still a need for improved cannab 0004 Genetically obese rats and mice exhibit markedly inoid agents, particularly selective CB receptor antagonists, elevated endocannabinoid levels in brain regions associated with fewer side-effects and improved efficacy. with ingestive behaviour (DiMarzo et al. 2001 Nature 410: 0012 WO95/25443, U.S. Pat. No. 5,464,788, and U.S. 822-825). Furthermore, increased levels of endocannab Pat. No. 5,756,504 describe N-arylpiperazine compounds inoids are observed upon the fasting of normal, lean animals useful for treating preterm labor, stopping labor, and dysmen (Kirkham et al., British Journal of Pharmacology 2002, 136 orrhea. However, none of the N-aryl piperazines exemplified (4) 550-557). therein have an aryland/or heteroaryl substituent at both the 0005 Exogenous application of endocannabinoids leads 1- and 2-positions of the piperazine ring. to the same physiological effects observed with delta-9-THC (0013 WO 01/02372 and U.S. Published Application No. treatment, including appetite stimulation (Jamshida et al., 2003/0186960 describe cyclized amino acid derivatives for British Journal of Pharmacology 2001, 134: 1151-1 154), treating or preventing neuronal damage associated with neu analgesia, hypolocomotion, hypothermia, and catalepsy. rological diseases. However, none of the 3-aryl piperazine US 2010/0286160 A1 Nov. 11, 2010

2-ones exemplified therein have an aryl and/or heteroaryl compounds disclosed have a Substituted aryl and/or het substituent at both the 1- and 2-positions of the piperazine eroaryl Substituent at both the 1- and 2-positions of a pipera ring. Zine ring. 0014 WO 96/01656 describes radiolabelled substituted (0024 WO 2007/020502 describes pyrrolidone com piperazines useful in pharmacological screening procedures, pounds as cannabinoid receptor ligands, in particular CB1 receptor ligands, and their use intreating diseases, conditions, including labeled N-aryl piperazines. However, none of the and/or disorders modulated by cannabinoid receptor antago N-aryl piperazines exemplified therein have an aryl and/or nists. However, none of the compounds disclosed have a heteroaryl substituent at both the 1- and 2-positions of the substituted aryl and/or heteroaryl substituent at both the 1 piperazine ring. and 2-positions of a piperazine ring. 0015 U.S. Pat. No. 5,780,480 describes N-aryl pipera 0025 WO 2007/057687 and WO2006/060461 describe Zines useful as fibrinogen receptor antagonists for inhibiting piperazine derivatives and their use as CB1 antagonists and in the binding offibrinogen to blood platelets, and for inhibiting treating various diseases, conditions, and/or disorders modu the aggregation of blood platelets. However, none of the lated by cannabinoid receptor antagonists. However, there N-aryl piperazines exemplified therein have an aryl and/or remains a need in the art for selective CB1 antagonists having heteroaryl substituent at both the 1- and 2-positions of the a different functional group Substitution pattern around the piperazine ring. piperazine ring. 0016 WO 03/008559 describes choline analogs useful for treating conditions or disorders. However, the only substi BRIEF SUMMARY OF THE INVENTION tuted piperazine derivative exemplified is N-(2-hydroxy 0026. In its many embodiments, the present invention pro ethyl)-N'-(2-pyridylmethyl)-piperazine. vides novel Substituted piperazine compounds as selective 0017 JP3-200758, JP4-26683, and JP 4-364175 describe CB receptor antagonists for treating various conditions N,N'-diarylpiperazines (i.e., 1,4-diarylpiperazines) prepared including, but not limited to metabolic syndrome (e.g., obe by reacting bis(2-hydroxyethyl)arylamines with an amine sity, waist circumference, abdominal girth, lipid profile, and Such as aniline. However, no 1, 2-disubstituted piperazines insulin sensitivity), neuroinflammatory disorders, cognitive are exemplified. disorders, psychosis, addictive behavior, gastrointestinal dis 0018 WO97/22597 describes various 1,2,4-trisubstituted orders, and cardiovascular conditions. piperazine derivatives as tachykinin antagonists for treating 0027. The selective CB receptor antagonists of the tachykinin-mediated diseases such as asthma, bronchitis, present invention are piperazine derivatives having the struc rhinitis, cough, expectoration, etc. However, none of the 1.2, ture of Formula (I): 4-trisubstituted piperazine derivatives exemplified therein have an aryl and/or heteroaryl substituent at both the 1- and 2-positions of the piperazine ring. (I) 0019 EP 0268222, WO 88/01131, U.S. Pat. No. 4,917, X (A) (R'), 896, and U.S. Pat. No. 5,073,544 describe compositions for n-in-1 enhancing the penetration of active agents through the skin, comprising azacyclohexanes, including N-acyl and N,N'-dia n cylpiperazines. However, none of the N-acyl or N,N'-dia cylpiperazines exemplified therein have an aryl and/or het Arl eroaryl substituent at both the 1- and 2-positions of the piperazine ring. ora pharmaceutically acceptable salt, Solvate, isomer, or ester 0020 U.S. Pat. No. 6,528,529 describes compounds, thereof, wherein: including N,N'-disubstituted piperazines, which are selective 10028. Ar' and Arare independently aryl or heteroaryl, for muscarinic acetylcholine receptors and are useful for 0029 wherein each of Ar' and Ar is substituted with treating diseases such as Alzheimer's disease. However, none one or more groups independently selected from Y'; of the N,N'-disubstituted piperazines exemplified therein 10030) with the proviso that when Ar is pyridine or have an aryl and/or heteroaryl substituent at both the 1- and pyrimidine, a nitrogen of said pyridine or pyrimidine 2-positions of the piperazine ring. is not in the para position relative to the point of 0021 NL 6603256 describes various biologically active attachment to the piperazine ring; piperazine derivatives. However, none of the piperazine 0031 in and mare independently 0 or 1: derivatives exemplified therein have a substituted aryland/or 0032 A is selected from the group consisting of heteroaryl substituent at both the 1- and 2-positions of the C(O)—, S(O) , —C(=N-OR)—, and —(C(R) piperazine ring. 2) - wherein q is 1, 2, or 3: 0022 Wikström et al., J. Med. Chem. 2002, 45, 3280 0033 B is selected from the group consisting of 3285, describe the synthesis of 1,2,3,4,10,14b-hexahydro-6- —N(R) , —C(O)—, and —(C(R).), whereinris 1 or methoxy-2-methyldibnzoc,fpyrazine 1,2-aaZepin. How 2. ever, none of the piperazine intermediates described therein 0034 with the proviso that when B is —C(O)—, then A have a substituted aryl and/or heteroaryl substituent at both is —C(O)—or —(C(R).) ; the 1- and 2-positions of the piperazine ring. 0035 X is selected from the group consisting of: 0023 WO 2007/018460 and WO 2007/018459 describe 0036) –C(O)N(R), C(O)-cycloalkyl, -C(O)— tricyclic piperidines and piperazine containing compounds, heterocycloalkyl, aryl substituted with one or more compositions, and methods for their use in treating obesity, groups independently selected from C(O)N(R), het psychiatric and neurological disorders. However, none of the eroaryl Substituted with one or more groups indepen US 2010/0286160 A1 Nov. 11, 2010

dently selected from C(O)N(R), and benzo-fused 0049 wherein each of said aryl, each -alkylene-aryl, cycloalkyl-, wherein the cycloalkyl portion of said each heteroaryl, each aryl portion of said —O-aryl, each benzo-fused cycloalkyl- is substituted with at least one heteroaryl portion of said —O-heteroaryl, each aryl por —OH group, and wherein the aryl portion of said benzo tion of said —S-aryl, each heteroaryl portion of said fused cycloalkyl-is unsubstituted or substituted with one —S-heteroaryl, each aryl portion of said —S(O)-aryl, or more groups independently selected from Z. each heteroaryl portion of said —S(O)-heteroaryl, each 0037 with the proviso that, when X is C(O)N(R), aryl portion of said —C(O)-aryl, each heteroaryl portion —C(O)-cycloalkyl, or —C(O)-heterocycloalkyl, then of said —C(O)-heteroaryl, each aryl portion of said n=1 and B is NR ; I0038 each R' is independently selected from the group —C(O)C-aryl, and each heteroaryl portion of said consisting of alkyl, haloalkyl, -alkylene-NRR, -alkylene —C(O)C-heteroaryl of Y is unsubstituted or substi OR, alkylene-N-alkylene-CN, and alkylene-O-S(O)- tuted with one or more groups Z; or alkyl; or 0050 two groups Y' form a -O-CH2-O-group; 0039 two R' groups attached to the same ring carbonatom I0051) each R is independently selected from the group form a carbonyl group; consisting of H, alkyl, haloalkyl, alkoxy, cycloalkyl, 0040 p is 0, 1, 2, 3, or 4: heterocycloalkyl, unsubstituted aryl, aryl substituted 0041 each R is independently H, alkyl, aryl, heteroaryl, with one or more groups independently selected from Z. cycloalkyl, or heterocycloalkyl, unsubstituted heteroaryl, heteroaryl substituted with one 0042 wherein each of said aryl heteroaryl, cycloalkyl, or more groups independently selected from Z. and heterocycloalkylof R is unsubstituted or optionally cycloalkyl, -alkylene-OH, -alkylene-O-alkyl, -alkylene Substituted with one or more groups independently O-aryl, -alkylene-OC(O)-alkyl, -alkylene-OC(O)-aryl, selected from Y'; -alkylene-OC(O)-heteroaryl, and alkylene-NR'R'', or I0043 each R is independently selected from the group 0.052 two R groups, together with the nitrogen to consisting of H, alkyl, unsubstituted aryl, aryl Substituted with one or more Y' groups, OR, -alkylene-O-alkyl, which they are attached, form a heteroaryl, heterocy and -alkylene-OH: cloalkyl, heterocycloalkenyl, or a benzo-fused hetero 0044 each R is independently selected from the group cycloalkyl group; and consisting of H, alkyl, aryl, —C(O)—O-alkyl, —C(O)- 0053 each Z is independently selected from the group alkyl, -C(O)-aryl, -C(O)-heteroaryl, -S(O), alkyl, consisting of alkyl, halo, haloalkyl, -OH, -O-alkyl, and —S(O)aryl, - S(O) heteroaryl, and —S(O) heterocy CN: cloalkyl, 0.054 with the proviso that when A is —C(O) , then 0045 wherein each of said aryl, the aryl portion of said eachY' on Ar" is independently selected from the group —C(O)-aryl, the aryl portion of said S(O)aryl of R, consisting of cycloalkyl, benzyl, aryl, -O-haloalkyl, and the heteroaryl portion of said —C(O)-heteroaryl, —O-aryl, —O-cycloalkyl, -S-aryl. —S-haloalkyl, and —S(O) heteroaryl, is unsubstituted or substituted —S-cycloalkyl, - S(O)-alkyl, —S(O)-cycloalkyl, with one or more groups independently selected from —S(O)-aryl, -alkylene-CN. —C(O)-aryl, —C(O)-ha Yl. loalkyl, —C(O)— cycloalkyl, —C(O)C-aryl, —C(O) I0046) each R is independently selected from the group O-haloalkyl, —C(O)O-heteroaryl, —C(O)O- consisting of H, alkyl, aryl. —S(O)-alkyl, - SCO)-cy cycloalkyl, —C(O)O-heterocycloalkyl, -alkylene-C cloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-het erocycloalkyl, —C(O) N(R), —C(O)-alkyl, -C(O)- (O)—O-alkyl, and —O-alkylene-aryl, wherein each cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)- benzyland eacharyl portion of Y', and eacharyl portion heterocycloalkyl, and -alkylene-OH, and each heteroaryl portion of said —O-aryl, said —S- 0047 wherein each of said aryl, the aryl portions of said aryl, said —S(O)-aryl, said —C(O)-aryl, said —C(O) —S(O)-aryl and —C(O)-aryl, and the heteroaryl por O-aryl, —C(O)O-heteroaryl, —C(O)O-heterocy tions of said —S(O)-heteroaryl and said —C(O)-het cloalkyl, and—O-alkylene-aryl of Y', are unsubstituted eroaryl of R is unsubstituted or substituted with one or or Substituted with one or more groups independently more Z groups; selected from Z: or two groups Y' forma—O—CH2— 0048 each Y is independently selected from the group O— group. consisting of halo. —CN, alkyl, haloalkyl, cycloalkyl, het 0055. In another embodiment, the present invention also erocycloalkyl, heterocycloalkenyl, aryl, -alkylene-aryl, provides for compositions comprising at least one selective heteroaryl, —O-alkyl, —O-haloalkyl, —O-aryl, —O-het CB receptor antagonist compound of Formula (I), above, or eroaryl, —O-cycloalkyl, -O-heterocycloalkyl. —S-aryl, its various embodiments as described herein, or a pharmaceu —S-alkyl, - S-haloalkyl, - S-heteroaryl. —S-cycloalkyl, tically acceptable salt, Solvate, isomer, or ester thereof, and a —S-heterocycloalkyl, —S(O)-alkyl, - S(O)-cy pharmaceutically acceptable carrier. cloalkyl, —S(O)-heterocycloalkyl, —S(O)-aryl, —S(O) 0056. In another embodiment, the present invention also -heteroaryl, -alkylene-CN. —C(O)-alkyl, —C(O)-aryl, provides for compositions comprising at least on selective —C(O)-haloalkyl, —C(O)-heteroaryl, —C(O)— CB receptor antagonist compound of Formula (I), or its cycloalkyl, —C(O)-heterocycloalkyl, —C(O)O-alkyl, various embodiments as described herein, or a pharmaceuti —C(O)O-aryl, —C(O)O-haloalkyl, —C(O)O-heteroaryl, cally acceptable salt, Solvate, isomer, or ester thereof, incom —C(O)3-cycloalkyl, —C(O)C-heterocycloalkyl, bination with at least one cholesterol lowering compound or - N(R)C(O)-alkyl, - N(R)C(O) N(R) -OH, other pharmaceutically active agent, as described herein. -alkylene-OH, -alkylene-C(O)—O-alkyl, —O-alkylene 0057. In yet another embodiment, the present invention aryl, and - NRR, also provides for a method of treating, reducing, or amelio US 2010/0286160 A1 Nov. 11, 2010

rating metabolic syndrome, obesity, waist circumference, 0064. In another embodiment, the present invention abdominal girth, lipid profile, insulin sensitivity, neuroin relates to a compound of Formula (I), or a pharmaceutically flammatory disorders, cognitive disorders, psychosis, addic acceptable salt, Solvate, isomer, or ester thereof, wherein: tive behavior, gastrointestinal disorders, and cardiovascular I0065 Ar" and Arare independently (C-C)aryl or (C- conditions by administering an effective amount of at least Co)heteroaryl, one compound of Formula (I) or its various embodiments as 0.066 wherein each of Ar" and Ar is substituted with described herein, or a pharmaceutically acceptable salt, Sol one or more groups independently selected from Y'; Vate, isomer, or ester thereof, to a patient in need thereof. I0067 with the proviso that when Ar is pyridine or 0058. In yet another embodiment, the present invention pyrimidine, a nitrogen of said pyridine or pyrimidine also provides for a method of treating vascular conditions, is not in the para position relative to the point of hyperlipidaemia, atherosclerosis, hypercholesterolemia, attachment to the piperazine ring; sitosterolemia, Vascular inflammation, metabolic syndrome, 0068 n and mare independently 0 or 1: stroke, diabetes, obesity and/or reducing the level of sterol(s) 0069 A is selected from the group consisting of in a host in need thereof by administering an effective amount C(O) , S(O) , —C(=N-OR)—, and —(C(R) of a composition comprising a combination of at least one 2) - wherein q is 1, 2, or 3: compound of Formula (I) or its various embodiments as 0070 B is selected from the group consisting of described herein, or a pharmaceutically acceptable salt, Sol —N(R) , —C(O)—, and —(C(R).), whereinris 1 or Vate, isomer, or ester thereof, and at least one cholesterol 2. lowering compound. 0071 with the proviso that when B is —C(O)—, then A is —C(O)—or —(C(R).) ; 0072 X is selected from the group consisting of: DETAILED DESCRIPTION OF THE INVENTION 0.073 –C(O)N(R), —C(O)–(C-C)cycloalkyl, —C(O)—(C-C)heterocycloalkyl, (C-C)aryl Sub 0059. The selective CB receptor antagonist compounds stituted with one or more groups independently selected of the present invention are selective CB receptor antago from C(O)N(R), (C-Co)heteroaryl substituted nists of mammalian CB receptors, preferably human CB with one or more groups independently selected from receptors, and variants thereof. Mammalian CB receptors —C(O)N(R), and benzo-fused (Cs-Co)cycloalkyl-, also include CB receptors found in rodents, primates, and wherein the cycloalkyl portion of said benzo-fused (C- other mammalian species. Co)cycloalkyl- is substituted with at least one —OH 0060. In one embodiment, the selective CB receptor group, and wherein the aryl portion of said benzo-fused antagonist compounds of the present invention are selective (C-Co)cycloalkyl- is unsubstituted or Substituted with CB receptor antagonists that bind to a CB receptor with a one or more groups independently selected from Z. binding affinity (Kai, measured as described herein) of 0074 with the proviso that, when X is –C(O)N(R), about 2 uM or less, or about 1 uM or less, or about 400 nM or —C(O)—(C-C)cycloalkyl, or —C(O)—(C-Co)het less, or about 200 nMorless, or about 100 nMorless, or about erocycloalkyl, then n=1 and B is NR : 10 nM or less. These ranges are inclusive of all values and I0075 each R" is independently selected from the group Subranges therebetween. consisting of (C-C)alkyl, (C-C)haloalkyl, —(C-C) 0061. In one embodiment, the selective CB receptor alkylene-NRR. —(C-C)alkylene-OR. —(C-C) antagonist compounds of the present invention are selective alkylene-N, —(C-C)alkylene-CN, and (C-C)alky CB receptor antagonists that have a ratio of CB receptor lene-O-S(O) (C-C)alkyl; or affinity to CB2 receptor affinity (Kai):Kcal measured as (0076) two R' groups attached to the same ring carbonatom described herein) of about 1:2 or better, or about 1:10 or form a carbonyl group; better, or about 1:25 or better, or about 1:50 or better, or about (0077 p is 0, 1, 2, 3, or 4: 1:75 or better, or about 1:90 or better. These ranges are inclu (0078 each R is independently H, (C-C)alkyl, (Co-Co) sive of all values and subranges therebetween. aryl, (C-Co)heteroaryl, (C-C)cycloalkyl, or (C-C) 0062. Thus, in one embodiment, a selective CB receptor heterocycloalkyl, antagonist of the present invention has an affinity for the CB 0079 wherein each of said aryl, heteroaryl, cycloalkyl, receptor, measured as described herein, of at least 400 nM or and heterocycloalkyl of R is unsubstituted or optionally less, and a ratio of CB, to CB2 receptor affinity (i.e., (Kai): Substituted with one or more groups independently Kai) of at least 1:2 or better. In another embodiment the selected from Y'; CB1 receptor affinity is about 200 nMorless, and the (Kai): 0080 each R is independently selected from the group Kai is about 1:10 or better. In another embodiment the consisting of H. (C-C)alkyl, unsubstituted (C-C)aryl, CB affinity is about 100 nM or less, and the (KaiKai, (Co-Co.)aryl Substituted with one or more Y' groups, is about 1:25 or better. In another embodiment the CB affin —OR. -(C-C)alkylene-O-(C-C)alkyl, and —(C- ity is about 10 nM or less, and the (KaiKai is about C.)alkylene-OH: 1:75 or better. In another embodiment the CB affinity is I0081) each R" is independently selected from the group about 10 nM or less, and the (KaiKai is about 1:90 or consisting of H., (C-C)alkyl, (C-C)aryl, —C(O)— better. These ranges are inclusive of all values and Subranges O—(C-C)alkyl, -C(O)—(C-C)alkyl, —C(O)—(C- therebetween. Co)aryl, —C(O)—(C-Co)heteroaryl, - S(O) (C-C) 0063. In one embodiment, the present invention provides alkyl. —S(O)(C-C)aryl, -SO)(C-C)heteroaryl, for a selective CB receptor antagonist compound of Formula and —S(O)(C-Co)heterocycloalkyl, (I), or a pharmaceutically acceptable salt, Solvate, isomer, or 0082 wherein each of said (C-C)aryl, the aryl por ester thereof, wherein the various Substituent groups (i.e., X, tion of said —C(O)—(C-Co)aryl, the aryl portion of Ar", Ari, etc.) are as defined hereinabove. said—S(O) (Co-Co)aryl of R', and the heteroaryl por

US 2010/0286160 A1 Nov. 11, 2010

0100. In another embodiment, in Formula (I), X is

O N-C-,

whereint-0, 1, 2, or 3. In one such embodiment, t—1. whereint-0, 1, 2, or 3. In one such embodiment, t—1. 0112. In another embodiment, in Formula (I), X is het eroaryl Substituted with one or more groups independently 0101. In another embodiment, in Formula (I), X is selected from —C(O)N(R). In one such embodiment, at least one R is H. In another such embodiment, at least one R' is alkyl. In another such embodiment, at least one R is -alky /N lene-OH. In another such embodiment, at least one R is HN C-, -alkylene-O-alkyl. In another such embodiment two R groups, together with the nitrogen to which they are attached, N form a heteroaryl, heterocycloalkyl, heterocycloalkenyl, or a benzo-fused heterocycloalkyl group. whereint-0, 1, 2, or 3. In one such embodiment, t—1. 0113. In another embodiment, in Formula (I), X is het 0102. In another embodiment, in Formula (I), X is eroaryl substituted with at least one group —C(O)NH2. —C(O)-cycloalkyl. In one such embodiment, said cycloalkyl 0114. In another embodiment, in Formula (I), X is het of X is unsubstituted. In another such embodiment, said eroaryl Substituted with at least one group independently cycloalkyl of X is substituted with one or more groups inde selected from —C(O)N(alkyl). pendently selected from Z. In one such embodiment, X is 0.115. In another embodiment, in Formula (I), X is het —C(O)-cyclopropyl. In another Such embodiment, X is eroaryl Substituted with at least one group independently —C(O)-cyclobutyl. In another such embodiment, X is selected from —C(O)NH(alkyl). —C(O)-cyclopentyl. In another such embodiment, X is 0116. In another embodiment, in Formula (I), X is het —C(O)-cyclohexyl. eroaryl Substituted with at least one group independently (0103) In another embodiment, in Formula (I), X is aryl selected from C(O)NH(alkylene-OH). Substituted with one or more groups independently selected 0117. In another embodiment, in Formula (I), X is het from C(O)N(R). In one such embodiment, said aryl of X eroaryl Substituted with at least one group independently is phenyl. In one Such embodiment, said aryl of X is naphthyl. selected from —C(O)N(alkylene-OH). In another such embodiment, at least one R is H. In another 0118. In another embodiment, in Formula (I), X is het such embodiment, at least one R is alkyl. In another such eroaryl Substituted with at least one group independently embodiment, at least one R is -alkylene-OH. In another such selected from —C(O)NH(alkylene-Oalkyl). embodiment, at least one R is -alkylene-O-alkyl. In another 0119. In another embodiment, in Formula (I), X is het Such embodiment two R groups, together with the nitrogen eroaryl substituted with at least one group selected from to which they are attached, form a heteroaryl, heterocy —C(O)N(alkylene-Oalkyl). cloalkyl, heterocycloalkenyl, or a benzo-fused heterocy I0120 In another embodiment, in Formula (I), X is het cloalkyl group. eroaryl Substituted with at least one group independently 0104. In another embodiment, in Formula (I), X is aryl selected from substituted with at least one group —C(O)NH2. 0105. In another embodiment, in Formula (I), X is aryl Substituted with at least one group independently selected from —C(O)N(alkyl). 0106. In another embodiment, in Formula (I), X is aryl Substituted with at least one group independently selected from C(O)NH(alkyl). whereint-0, 1, 2, or 3. In one such embodiment, t—1. 0107. In another embodiment, in Formula (I), X is aryl I0121. In another embodiment, in Formula (I), X is het Substituted with at least one group independently selected eroaryl Substituted with at least one group independently from C(O)NH(alkylene-OH). selected from 0108. In another embodiment, in Formula (I), X is aryl Substituted with at least one group independently selected from —C(O)N(alkylene-OH). 0109. In another embodiment, in Formula (I), X is aryl HN Substituted with at least one group independently selected C-, from —C(O)NH(alkylene-Oalkyl). N 0110. In another embodiment, in Formula (I), X is aryl substituted with at least one group selected from —C(O)N whereint-0, 1, 2, or 3. In one such embodiment, t—1. (alkylene-Oalkyl). I0122. In another embodiment, in Formula (I), X is benzo 0111. In another embodiment, in Formula (I), X is aryl fused cycloalkyl-, wherein the cycloalkyl portion of said Substituted with at least one group independently selected benzo-fused cycloalkyl- is substituted with at least one —OH from groups, and wherein said aryl portion of said benzo-fused US 2010/0286160 A1 Nov. 11, 2010 cycloalkyl- is unsubstituted. In one such embodiment, said I0138. In another embodiment, in Formula (I), Ar' is cycloalkyl portion of said benzo-fused cycloalkyl- is Substi pyridyl and Art is phenyl. tuted with two —OH groups. I0139. In another embodiment, in Formula (I), Ar' and Ar 0123. In another embodiment, in Formula (I), X is benzo are heteroaryl. fused cycloalkyl-, wherein the cycloalkyl portion of said I0140. In another embodiment, in Formula (I), Ar' is benzo-fused cycloalkyl- is substituted with at least one —OH pyridyl. group, and wherein said aryl portion of said benzo-fused I0141. In another embodiment, in Formula (I), Ar° is cycloalkyl- is Substituted with one or more groups indepen pyridyl. dently selected from halo and CN. In one such embodiment, I0142. In another embodiment, in Formula (I), both Ar' and said cycloalkyl portion of said benzo-fused cycloalkyl- is Ari are pyridyl. substituted with two —OH groups. In one such embodiment, I0143. In another embodiment, in Formula (I), Ar is Z is fluoro or chloro. In another such embodiment, Z is CN. pyridyl substituted with two groups independently selected 0.124. In another embodiment, in Formula (I), at least one from Y'. Y' is alkyl. In one such embodiment, at least oneY' is (C-C) 10144) In another embodiment, in Formula (I), Ar is alkyl. pyridyl substituted with one Y' group in the 2-position and 0.125. In another embodiment, in Formula (I), at least one one Y' group in the 4-position, relative to the point of attach Y' is halo. In one such embodiment, at least one Y is chloro. ment to the piperazine ring, whichY' groups may be the same In one such embodiment, at least one Y is fluoro. or different. 0126. In another embodiment, in Formula (I), at least one (0145. In another embodiment, in Formula (I), Ari is: Y is CN. 0127. In another embodiment, in Formula (I), at least one Y is OH. Yl I0128. In another embodiment, in Formula (I), Ar' and Ar are aryl. I0129. In another embodiment, in Formula (I), Ar' is phe / \ . nyl. NF 0130. In another embodiment, in Formula (I), Ar is phe nyl. I0146) wherein each Y is independently as defined herein. 0131 Inanother embodiment, in Formula (I), both Art and I0147 In another embodiment, in Formula (I), Art is sub Arare phenyl. stituted with two groups, each independently selected from (0132) In another embodiment, in Formula (I), Ar is phe Y1. nyl substituted with two groups independently selected from I0148. In another embodiment, in Formula (I), Art is sub Yl. stituted with three groups, each independently selected from I0133. In another embodiment, in Formula (I), Ar is phe Y1. nyl substituted with one Y' group in the 4-position and oneY' 10149. In another embodiment, in Formula (I), Ar is sub group in the 2-position, relative to the point of attachment to stituted with four groups, each independently selected from the piperazine ring, which two Y' groups may be the same or Y1. different, as represented by the moiety below: I0150. In another embodiment, in Formula (I), Ar is sub stituted with five groups, each independently selected from Yl Yl. 0151. In another embodiment, in Formula (I), m=0 and n=0. 0152. In another embodiment, in Formula (I), m=0, n=1, and B is —(C(R)), . In one such embodiment, r-1. In another such embodiment each R is independently selected from Hand-alkylene-OH. In another such embodiment, each I0134) In another embodiment, in Formula (I), Ar' is phe R is independently selected from H and —(CH) OH. In nyl substituted with one group Y' in the 4-position, relative to another such embodiment, each R is independently selected the point of attachment to the piperazine ring, as represented from H and —(CH), OH. In another such embodiment, by the moiety below: each R is independently selected from H and —(CH), OH. 0153. In another embodiment, in Formula (I), m=0, n=1, and B is —(C(R).), , wherein r-1, and each R is indepen dently selected from H and -alkyl. In another such embodi ment, each R is independently selected from Hand methyl. In another such embodiment, each R is independently selected from H and ethyl. I0135) In another embodiment, in Formula (I), Ar' is aryl 0154) In another embodiment, in Formula (I), m=1, n=0, and Aris heteroaryl. and A is —(C(R).) . In one such embodiment, each R is I0136. In another embodiment, in Formula (I), Ar' is phe independently selected from H or alkyl. In another such nyl and Ar’ is pyridyl. embodiment, q is 1 and each R is H. In another such embodi 0137 In another embodiment, in Formula (I), Ar" is het ment, q is 2 and each R is independently selected from Hand eroaryland Ar is aryl. alkyl. US 2010/0286160 A1 Nov. 11, 2010

0155. In another embodiment, in Formula (I), m=1, n=0, and A is —C(O)—. (IB) 0156. In another embodiment, in Formula (I), m=1, n=0, (R') and A is —S(O) . Xn - (in p 0157. In another embodiment, in Formula (I), m=1, n=1, (B), 1 and A is —(C(R).) - and B is —(C(R).)-. In one such embodiment, q=1 and each R is H. In one such embodiment, N NA2 s r=1. In another such embodiment, each R is independently selected from alkyland—OR, wherein each R is indepen i. dently selected from Horalkyl. In another such embodiment, m=1, n=1, and A is —CH2—, and B is —C(CH)(OH)—. In wherein the variables of the formula (e.g., X, B, A, R', Ar", another such embodiment, m=1, n=1, and A is —CH2—, and Ar, n, m, and p) are as defined in Formula (I) above. 0169. In another embodiment of the compounds of For B is CH(OH)—. mula (I) of the present invention relates to compounds, phar 0158. In another embodiment, in Formula (I), m=1, n=1, maceutically acceptable salts, Solvates, esters, or isomers of and A is C(=N-OR)—. In one such embodiment, R is the following Formula (IC): H 0159. In another embodiment, in Formula (I), m=1, n=1, A is —(C(R).) - and B is —C(O)-. In one such embodi (IC) ment, q is 1. In another such embodiment, q is 1 and R is H. X (A)m 0160. In another embodiment, in Formula (I), m=1, n=1, A is —C(O)—, and B is —(C(R)), . In one such embodi NB1 O ment, each R is independently selected from H. -OH, and n alkyl. In one such embodiment, ris 1. In another such embodi i. ment, r is 1 and each R is a group independently selected from Hand alkyl. In another such embodiment, r1 and B is wherein the variables of the formula (e.g., X, B, A, R', Ar", selected from —C(OH)(CHCH)—.—C(OH)(CH)—, and Ar, n, m, and p) are as defined in Formula (I) above. —C(OH)H-. (0170. In embodiments where n=1 and m=1, then X is 0161 In another embodiment, in Formula (I), m=1, n=1, A attached to B, B is attached to A, and A is attached to the is —C(O)—, and B is N(R)-. In one such embodiment, nitrogen of the piperazine ring as shown in the following R is H. formula: 0162. In another embodiment, in Formula (I), m=1, n=1, A is —(C(R).) , and B is —NR -. In one such embodi ment, q is 1 or 2. In another such embodiment, H, alkyl, halo, X A (R) p aryl, and aryl substituted with one or more halo. n1B n1/ 0163. In another embodiment, in Formula (I), p=0. (0164. In another embodiment, in Formula (I), p=1, and R' N YA2 is alkyl. (0165. In another embodiment, in Formula (I), p=1, and R' Arl is methyl. 0166 In another embodiment, in Formula (I), p=2. In one (0171 In embodiments where n=0 and m=1, then X is Such embodiment, two groups R' are taken together to form a attached directly to A and A is attached to the nitrogen of the carbonyl group. piperazine ring as shown in the following formula: 0167. In another embodiment, in Formula (I), the present invention relates to compounds, pharmaceutically acceptable A (R') salts, Solvates, esters, or isomers of the following Formula Y n1 (IA): N YA2 (IA) (R') Arl X n-in-1(A), p 0.172. In embodiments where n=1 and m=0, then X is attached to B and B is attached directly to the nitrogen of the n piperazine ring as shown in the following formula: Arl (R') wherein the variables of the formula (e.g., X, B, A, R', Ar", - B“N-1 Ar, n, m, and p) are as defined in Formula (I) above. 0.168. In another embodiment of the compounds of For N YA2 mula (I) of the present invention relates to compounds, phar maceutically acceptable salts, Solvates, esters, or isomers of Arl the following Formula (IB): US 2010/0286160 A1 Nov. 11, 2010

0173. In embodiments where both n and m=0, then X is 0187. In another embodiment, in Formula (I-D), X is -Ph attached directly to the nitrogen of the piperazine ring as C(O)N(alkylene-OH). shown in the following formula: 0188 In another embodiment, in Formula (I-D), X is -Ph C(O)NH(alkylene-Oalkyl). 0189 In another embodiment, in Formula (I-D), X is -Ph X (RI)p C(O)N(alkylene-Oalkyl). n1/ 0190. In another embodiment, in Formula (I-D), X is

n O

Arl N-C-Ph

0.174. In another embodiment of the compounds of the present invention, or pharmaceutically acceptable salts, Sol whereint-0, 1, 2, or 3. In one such embodiment, t—1. Vates, esters, or isomers thereof, is a compound of the For 0191 In another embodiment, in Formula (I-D), X is mula (I-D):

(I-D) HNAN C-Ph x1 BNNN -/ Yl Nu whereint-0, 1, 2, or 3. In one such embodiment, t—1. 0.192 In another embodiment, in Formula (I-D), at least o Yl, one Y is alkyl. In one such embodiment, at least one Y is (C-C) alkyl. 0193 In another embodiment, in Formula (I-D), at least one Y is halo. In one such embodiment, at least one Y is Yl chloro. In one such embodiment, at least one Y is fluoro. 0194 In another embodiment, in Formula (I-D), at least one Y is –CN. (0175 wherein: 0.195. In another embodiment, in Formula (I-D), at least (0176) B is —(C(R).), , wherein r is 1 or 2: one Y is –OH. (0177 each R is independently selected from H, alkyl, 0196. In another embodiment of the compounds of the OH, unsubstituted phenyl, and phenyl substituted with one or present invention, or pharmaceutically acceptable salts, Sol more groups selected from alkyl, OH, CN, and haloalkyl: Vates, esters, or isomers thereof, is a compound of the For (0178 each R" is independently selected from alkyl and mula (I-E): —C(O)—: (0179 p is 0, 1, or 2: 0180 X is aryl substituted with one or more groups inde (I-E) pendently selected from —C(O)N(R); and Y and Rare as BN - defined above. x1 NN 7. Yl 0181. In another embodiment, in Formula (I-D), X is phe nyl Substituted with one or more groups independently selected from —C(O)N(R). In one such embodiment, at least one R is H. In another such embodiment, at least one R o Yl, is alkyl. In another such embodiment, at least one R is -alky lene-OH. In another such embodiment, at least one R is -alkylene-O-alkyl. In another such embodiment two R groups, together with the nitrogen to which they are attached, Yl form a heteroaryl, heterocycloalkyl, heterocycloalkenyl, or a benzo-fused heterocycloalkyl group. 0.197 wherein: 0182. In another embodiment, in Formula (I-D), X is phe (0198 B is —(C(R).) , wherein r is 1 or 2: nyl substituted with one group —C(O)N(R). (0199 each R is independently selected from H, alkyl, 0183 In another embodiment, in Formula (I-D), X is -Ph OH, unsubstituted phenyl, and phenyl substituted with one or C(O)NH. more groups selected from alkyl, OH, CN, and haloalkyl: 0184. In another embodiment, in Formula (I-D), X is -Ph (0200 each R' is independently selected from alkyl and C(O)N(alkyl). —C(O)—: 0185. In another embodiment, in Formula (I-D), X is -Ph 0201 p is 0, 1, or 2: C(O)NH(alkyl). 0202 X is heteroaryl substituted with one or more groups 0186. In another embodiment, in Formula (I-D), X is -Ph independently selected from C(O)N(R); and Y and R' C(O)NH(alkylene-OH). are as defined above. US 2010/0286160 A1 Nov. 11, 2010

0203. In another embodiment, in Formula (I-E), said het 0224. In another embodiment, in Formula (I-E), at least eroaryl of X is pyridinyl. one Y is-OH. 0204. In another embodiment, in Formula (I-E), said het 0225. In another embodiment of the compounds of the eroaryl of X is pyrimidinyl. present invention, or pharmaceutically acceptable salts, Sol 0205. In another embodiment, in Formula (I-E), said het eroaryl of X is pyrrolyl. Vates, esters, or isomers thereof, is a compound of the For 0206. In another embodiment, in Formula (I-E), said het mula (I-F): eroaryl of X is imidazolyl. 0207. In another embodiment, in Formula (I-E), at least (I-F) one R is H. (R') 0208. In another embodiment, in Formula (I-E), at least one R is alkyl. (B), 1 Yl 0209. In another embodiment, in Formula (I-E), at least one R is -alkylene-OH. 0210. In another embodiment, in Formula (I-E), at least one R is -alkylene-O-alkyl. o Yl, 0211. In another embodiment, in Formula (I-E), two R groups, together with the nitrogen to which they are attached, form a heteroaryl, heterocycloalkyl, heterocycloalkenyl, or a benzo-fused heterocycloalkyl group. Yl 0212. In another embodiment, in Formula (I-E), said at least one-C(O)N(R), of X is –C(O)NH. 0213. In another embodiment, in Formula (I-E), said at 0226 wherein: least one —C(O)N(R) of X is —C(O)N(alkyl). 0227 m=n=1: 0214. In another embodiment, in Formula (I-E), said at least one-C(O)N(R) of X is –C(O)NH(alkyl). (0228) A is (C(R).), wherein q is 1 or 2; 0215. In another embodiment, in Formula (I-E), said at 0229 B is N(R) ; least one-C(O)N(R) of X is –C(O)NH(alkylene-OH). 0230 each R is independently selected from H, alkyl, 0216. In another embodiment, in Formula (I-E), said at cycloalkyl, unsubstituted aryl, aryl substituted with CN, halo, least one —C(O)N(R) of X is —C(O)N(alkylene-OH). OH, alkyl, or haloalkyl: 0217. In another embodiment, in Formula (I-E), said at 0231 each R" is independently selected from alkyl and least one –C(O)N(R) of X is C(O)NH(alkylene Oalkyl). —C(O)—: 0218. In another embodiment, in Formula (I-E), said at 0232 p is 0, 1, or 2: least one —C(O)N(R) of X is —C(O)N(alkylene-Oalkyl). 0233 each Y is independently selected from alkyl, halo, 0219. In another embodiment, in Formula (I-E), said at CN, and OH: least one-C(O)N(R) of X is 0234 X is –C(O)N(R); and Rare as defined above. 0235. In another embodiment, in Formula (I-F), X is —C(O)N(R), wherein at least one R is H. In another such embodiment, at least one R is alkyl. In another such embodi ment, at least one R is -alkylene-OH. In another such embodiment, at least one R is -alkylene-O-alkyl. In another Such embodiment two R groups, together with the nitrogen whereint-0, 1, 2, or 3. In one such embodiment, t—1. to which they are attached, form a heteroaryl, heterocy 0220. In another embodiment, in Formula (I-E), said at cloalkyl, heterocycloalkenyl, or a benzo-fused heterocy least one-C(O)N(R), of X is cloalkyl group. 0236. In another embodiment, in Formula (I-F), X is O —C(O)NH. 0237. In another embodiment, in Formula (I-F), X is n^n - —C(O)N(alkyl). Y 0238. In another embodiment, in Formula (I-F), X is - C(O)NH(alkyl). whereint-0, 1, 2, or 3. In one such embodiment, t—1. 0239. In another embodiment, in Formula (I-F), X is 0221. In another embodiment, in Formula (I-E), at least - C(O)NH(alkylene-OH). one Y is alkyl. In one such embodiment, at least one Y is 0240. In another embodiment, in Formula (I-F), X is (C-C) alkyl. —C(O)N(alkylene-OH). 0222. In another embodiment, in Formula (I-E), at least one Y is halo. In one such embodiment, at least one Y is 0241. In another embodiment, in Formula (I-F), X is chloro. In one such embodiment, at least one Y is fluoro. - C(O)NH(alkylene-Oalkyl). 0223) In another embodiment, in Formula (I-E), at least 0242. In another embodiment, in Formula (I-F), X is one Y is –CN. —C(O)N(alkylene-Oalkyl). US 2010/0286160 A1 Nov. 11, 2010 11

0243 In another embodiment, in Formula (I-F), X is (I-H) X (R') p Sr. Yl whereint-0, 1, 2, or 3. In one such embodiment, t—1. 0244. In another embodiment, in Formula (I-F), X is r Yl,

O Yl

0260 wherein: whereint-0, 1, 2, or 3. In one such embodiment, t—1. 10261) each R' is independently selected from alkyl and 0245. In another embodiment of the compounds of the —C(O)—: present invention, or pharmaceutically acceptable salts, Sol 0262 p is 0, 1, or 2: Vates, esters, or isomers thereof, is a compound of the For 10263 each Y is independently selected from alkyl, halo, mula (I-G): CN, and OH; and 0264 X is benzo-fused cycloalkyl-, wherein the cycloalkyl portion of said benzo-fused cycloalkyl- is Substi (I-G) tuted with at least one —OH group, and wherein said aryl X (A), (R') portion of said benzo-fused cycloalkyl- is unsubstituted. n1(B), a. N 1.y Yl 0265. In another embodiment, in Formula (I-H), said benzo-fused cycloalkyl of X is substituted with from one to three —OH groups. 0266. In another embodiment, in Formula (I-H), X is an r) Yl, indanol. 0267 In another embodiment, in Formula (I-H), X is an indandiol. 0268. In another embodiment of the compounds of the Y1 present invention, or pharmaceutically acceptable salts, Sol Vates, esters, or isomers thereof, is a compound of the For mula (I-I): 0246 wherein: 0247 m=n=1: 10248) A is (C(R).), wherein q is 1 or 2; (I-I) 0249 B is N(R) ; (R') (0250 each R is independently selected from H. alkyl, X n1/. p cycloalkyl, unsubstituted aryl, aryl substituted with CN, halo, OH, alkyl, or haloalkyl: 0251 each R" is independently selected from alkyl and —C(O)—: 0252 p is 0, 1, or 2: o Yl (0253) each Y is independently selected from alkyl, halo, CN, and OH; and 0254 X is —C(O)-cycloalkyl, wherein said cycloalkyl of X is unsubstituted or substituted with one or more groups Yl independently selected from Z., wherein Z is as defined above. 0255. In another embodiment, in Formula (I-G), X is —C(O)-cyclopropyl. 0269 wherein: 0256 In another embodiment, in Formula (I-G), X is (0270 each R' is independently selected from alkyl and —C(O)-cyclobutyl. —C(O)—: 0257. In another embodiment, in Formula (I-G), X is (0271 p is 0, 1, or 2: —C(O)-cyclopentyl. (0272 each Y is independently selected from alkyl, halo, 0258. In another embodiment, in Formula (I-G), X is CN, and OH; and —C(O)-cyclohexyl. 0273 X is benzo-fused cycloalkyl-, wherein the 0259. In another embodiment of the compounds of the cycloalkyl portion of said benzo-fused cycloalkyl- is Substi present invention, or pharmaceutically acceptable salts, Sol tuted with at least one —OH group, and wherein said aryl Vates, esters, or isomers thereof, is a compound of the For portion of said benzo-fused cycloalkyl- is substituted with mula (I-H): halo or —CN. US 2010/0286160 A1 Nov. 11, 2010

0274. In another embodiment, in Formula (I-I), said butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl, benzo-fused cycloalkyl of X is substituted with from one to etc. Non-limiting examples of R when R is aryl include any three —OH groups. of the examples for aryl described herein, including phenyl, 0275. In another embodiment, in Formula (I-I), X is an naphthyl, etc. When R is aryl substituted with one or more indanol, wherein the aryl portion of said indanol is substituted (e.g., 1, 2, 3, or 4 or more)Y' groups, each Y may be inde with from one to three groups independently selected from pendently selected from any of the non-limiting examples for halo. Y' described above. When R is -alkylene-OH, -alkylene-O- 0276. In another embodiment, in Formula (I-I), X is an alkyl, -alkylene-O-aryl, -alkylene-OC(O)-alkyl, -alkylene indandiol, wherein the aryl portion of said indandiol is sub OC(O)-aryl, -alkylene-OC(O)-heteroaryl, and alkylene-N stituted with from one to three groups independently selected (R), non-limiting examples of alkylene and heteroaryl from halo. groups include any of those such groups described above. (0277. In one embodiment, Ar" and Art are independently When two R' groups, together with the nitrogen to which they aryl or heteroaryl, wherein each of Ar' and Ari is substituted are attached, form a heteroaryl, heterocycloalkyl, heterocy with one or more groups independently selected from Y'. cloalkenyl, or a benzo-fused heterocycloalkyl group, non Non-limiting examples of said aryl and heteroaryl of Ar" limiting examples of Such heteroaryl, heterocycloalkyl, het and/or Ar include, for example, phenyl, naphthyl, pyridyl erocycloalkenyl, and benzo-fused heterocycloalkyl groups (e.g., 2-, 3-, and 4-pyridyl), pyrimidinyl, quinolyl, thienyl, include any of those such groups described above. imidazolyl, furanyl, etc. Substituted with one or more (e.g., 1, 0281. In one embodiment, X is —C(O)-cycloalkyl or 2, 3, or 4)Y' groups as defined herein. —C(O)-heterocycloalkyl. Non-limiting examples of X when 0278. In one embodiment, A is selected from —C(O)—, X is —C(O)-cycloalkyl include —C(O)-cyclopropyl, S(O) , —C(=N-OR)—, and —(C(R).) — wherein —C(O)-cyclobutyl, —C(O)-cyclopentyl, —C(O)-cyclo q is 1, 2, or 3. Non-limiting examples of A when A is —(C hexyl, —C(O)-cycloheptyl, —C(O)-adamantyl, —C(O)-(bi (R).) — include, for example, —CH2—, —CH2CH2 , cyclo2.1.1 hexanyl), —C(O)-(bicyclo[2.2.1]heptenyl), —CH(CH)— —C(CH) , —CH2CH2CH2—, —CH —C(O)-(bicyclo[3.1.1 heptenyl), —C(O)-(bicyclo[2.2.2 (CH)CH , —CHCH(CH)— —CH(CH)—(CH) , octenyl), C(O)-(bicyclo[3.2.1]octenyl), etc. Non-limiting —(CH2). CH(CH)—, —CH(phenyl)-CH2—, —CH2— examples of X when X is —C(O)-heterocycloalkyl include CH(phenyl)-, —CH(phenyl)-, etc. Non-limiting examples of any heterocycloalkyl groups of —C(O)-heterocycloalkyl A when A is C(=N-OR)—include —C(=N-OH) , described herein. —C(=N OCH) , —C(=N OCHCH) , 0282. In one embodiment, X is aryl substituted with one or —C(=N OCH(CH))— —C(=N OC(CH))—, more groups independently selected from C(O)N(R). —C(=N-O-phenyl), etc. Non-limiting examples include -phenyl-C(O)N(R), -naph (0279. In one embodiment, B is selected from N(R) , thyl C(O)N(R), etc., wherein –C(O)N(R) is as —C(O)—, and —(C(R).), wherein r is 1, 2, or 3. Non described herein. limiting examples of B when B is —(C(R).), , include, for 0283. In one embodiment, X is heteroaryl substituted with one or more groups independently selected from —C(O)N example, CH2—, CHCH . CH(CH) , (R). Non-limiting examples include heteroaryl include -py —C(CH) , —CH(CH(CH))—, —CH(CHCHCCH) ridyl-C(O)N(R), -azaindolyl-C(O)N(R), -benzimida )— —CH2CHCH , —CH(CH)CH , —CHCH zolyl-C(O)N(R) -benzofuranyl-C(O)N(R), -furanyl-C (O)N(R), -indolyl-C(O)N(R), etc., wherein –C(O)N (R) is as described herein. CHCH(OH) , -CH(OH)CHCH(CH) , -CH(CH 0284. In one embodiment, X is benzo-fused cycloalkyl-, (OH)(CH)) , —CH(CH)CHCH(OH) , —CH wherein the cycloalkylportion of the benzo-fused cycloalkyl (CHOH) , —CH(OCH) , —CH(OCH)CH , is substituted with at least one —OH group, and wherein the —CH-CH(OCH) , —CH(OCH)CH-CH(CH) , —CH aryl portion of said benzo-fused cycloalkyl- is unsubstituted (CH)CHCH(OCH) , —CH(CHOCH) , —CH or Substituted with one or more groups independently (OCH) , —CH(OCHCH)CH , CHCH selected from Z. Non-limiting examples of benzo-fused (OCHCH) , —CH(OCHCH)CHCH(CH) , —CH cycloalkyl include 1.2.3,4-tetrahydronaphthyl, indanyl, bicy (CH)CH-CH(OCHCH) , —CH(CHOCHCH) , etc. cloak.2.0 octa-1,3,5-trienyl, etc. Non-limiting examples of B when B is N(R)— include 0285) In one embodiment, each R" is independently —NH —N(alkyl)-, - N(aryl)-, wherein the terms “alkyl selected from alkyl, haloalkyl, -alkylene-NRR, -alkylene and “aryl' are as defined herein. OR, alkylene-N, and alkylene-O-S(O)-alkyl. Non-limit (0280. In one embodiment, X is C(O)N(R). Non-lim ing examples of R' when R' is alkyl include methyl, ethyl, iting examples of R when X is C(O)N(R), include the n-propyl, iso-propyl. n-butyl, iso-butyl, sec-butyl, tert-butyl, following. Non-limiting examples of R' when R is alkyl n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl, etc. Non include any of the examples for alkyl described herein, limiting examples of R' when R' is haloalkyl include —CF, including methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso —CHF, —CHF, —CHCF. —CFCF —CHBr, butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, —CHCl, —CCls, etc. When R' is alkylene-N, or alkylene n-hexyl, iso-hexyl, etc. Non-limiting examples of R when R O S(O)-alkyl, the alkylene portion thereof can include any is halo alkyl include any of the examples for alkyl described of the alkylene groups described herein (e.g., —CH2—, herein, including —CF, —CHF, —CHF, —CHCF, —CHCH , —CH(CH) , —CHCHCH , —CH —CFCF, —CHBr, —CHCl, —CC1, etc. The “alkyl (CH)CHCH , etc. Similarly, the “alkyl portion of alky portion of R' when R is alkoxy includes any alkyl group lene-O-S(O)-alkyl can include any alkyl group described described herein. Non-limiting examples include methyl, herein (e.g., methyl, ethyl, propyl, butyl, pentyl, etc.) Non ethyl, n-propyl, iso-propyl. n-butyl, iso-butyl, Sec-butyl, tert limiting examples of R' when R' is -alkylene-NR'R' include US 2010/0286160 A1 Nov. 11, 2010

CH NRR, -CH(CH) NRR, CHCH with one or more Y' groups, OR, -alkylene-O-alkyl, and NRR5, CHCHCH NRR, —CH(CH) -alkylene-OH. Non-limiting examples of R when R is alkyl CHCH NNRR, etc., wherein each R and each R is include methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-bu independently defined as described herein. For example, the tyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, “ NR'R' portion of -alkylene-N NRR of R' can be n-hexyl, iso-hexyl, etc. Non-limiting examples of R when R —NH, N(CH), —NH(CH), NH(phenyl), —N(phe is aryl include phenyl, naphthyl, etc., wherein said aryl may nyl), —NH S(O), CH, -NH S(O)-cyclopropyl, be unsubstituted or substituted with one or more groups NH C(O) NH, -NH C(O) N(CH), -NH C selected from Y' groups as defined herein. Non-limiting (O) CH, -NH CHCH-OH, etc. Non-limiting examples of R when R is —OR include -OH, OCH, examples of R' when R' is -alkylene-OR include —CH2— —OCHCH, OCH(CH), —O-phenyl, etc. Non-limiting OR, CH(CH) OR, CHCH, OR, CH(OR) examples of R when R is -alkylene-O-alkyl include CHCH(CH), —CH(CH)CHCH, OR, wherein R is —O CH, O CH, —O CHCH O—C(CH), defined as described herein. For example, the “ OR” por —O—CH(CH)—O CH, —O CHCH O CH, tion of said -alkylene-OR of R' can be -OH, OCHs. —O CHCH-O-CHCH, -O-CH(OCH)CHCH —OCHCH —OCH(CH), —O-phenyl. Alternatively, (CH3)2. -O-CH(CH)CHCH-O CH, two R' groups attached to the same ring carbonatom can form —O—CH2CH2—O—CHCH, etc. Non-limiting examples a carbonyl group, for example as shown below: of R when R is -alkylene-OH include —CH-OH, - CHCH-OH, -CHCHCH-OH, -CH(OH)CH, —CHCH(OH)CH, etc. 0288. In one embodiment, each R is independently selected from H. alkyl, aryl, —C(O)—O-alkyl, —C(O)- X Nb1"SN(A), alkyl, —C(O)-aryl, —C(O)-heteroaryl, - S(O)alkyl, —S(O)aryl, - S(O) heteroaryl, and —S(O) heterocy cloalkyl. Non-limiting examples of R' when R is alkyl include methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-bu tyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, X (A)m O n-hexyl, iso-hexyl, etc. Non-limiting examples of R' when R' is aryl include phenyl, naphthyl, etc., wherein said aryl may NB1 s^ be unsubstituted or substituted with one or more Y' groups as N YAP, o defined herein. Non-limiting examples of R' when R is —C(O)—O-alkyl include —C(O)—O CH, —C(O)— Arl O CHCH. —C(O)—O CHCHCH. —C(O)—O— X NB1 (A), r CH(CH), —C(O)—O CHCHCHCH. —C(O)—O— N O YA2. Arl CHCHCHCHCHCH —C(O)-O-CH(CH) CHCHCHCH - C(O) O CHCH(CH) (0286. In one embodiment, each R is independently CHCHCH, C(O) O CHCH-CH(CH)CHCH selected from H. alkyl, aryl, heteroaryl, cycloalkyl, and het —C(O)—O CHCHCH-CH(CH), etc. Non-limiting erocycloalkyl. Non-limiting examples of R when R is alkyl examples of R' when R is C(O)-alkyl include —C(O)— include methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-bu CH, —C(O)—CHCH —C(O)—CHCHCH tyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, —C(O)—CH(CH), - C(O). CHCHCHCH n-hexyl, iso-hexyl, etc. Non-limiting examples of R when R —C(O)—CH2CH(CH), - C(O)-CH(CH)CHCH is aryl include phenyl, naphthyl, etc. Non-limiting examples —C(O)—C(CH), —C(O). CHCHCHCHCH of R when R is heteroaryl include heteroaryl include azain - C(O). CHCH(CH)CHCH –C(O). CHCHCH dolyl, benzimidazolyl, benzofuranyl, furanyl, 2-pyridinyl, (CH), C(O). CHCHCHCHCHCH-C(O)-CH 3-pyridinyl, 4-pyridinyl, furazanyl, indolyl, quinolyl, iso (CH)CHCHCHCH —C(O). CHCH(CH) quinolyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrimidyl, CHCHCH, —C(O). CHCH-CH(CH)CHCH pyrrolyl, quinoxalinyl, thiophenyl, isoxazolyl, triazolyl, thia - C(O). CHCHCH-CH(CH), etc. Non-limiting Zolyl, indazolyl, thiadiazolyl, imidazolyl, benzobthiophe examples of R' when R is —C(O)-aryl include —C(O)- nyl, tetrazolyl, pyrazolyl, etc. Non-limiting examples of R phenyl, —C(O)-naphthyl, etc., optionally substituted with when R is cycloalkyl include cycloalkyl include cyclopro one or more groups selected from Y'. Non-limiting examples pyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, nor of R' when R is S(O)aryl include —S(O)-phenyl, bornyl, etc. Non-limiting examples of R when R is hetero —S(O)-naphthyl, etc., optionally Substituted with one or cycloalkyl include heterocycloalkyl include morpholinyl, more groups selected from Y'. piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tet 0289. In one embodiment, each R is independently rahydrothiophenyl, tetrahydropyranyl, aZetidinyl, etc., selected from H. alkyl, aryl. —S(O)-alkyl, - S(O)-cy wherein each said aryl, heteroaryl, cycloalkyl, and heterocy cloalkyl, - SCO)-aryl, -S(O)-heteroaryl, -S(O)-hetero cloalkyl may be unsubstituted or substituted with one or more cycloalkyl, -C(O) N(R), —C(O)-alkyl, -C(O)-cy groups independently selected from Y', as defined herein. cloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)- 0287. In one embodiment, each R is independently heterocycloalkyl, and -alkylene-OH. Non-limiting examples selected from H. alkyl, unsubstituted aryl, aryl substituted of R when R is alkyl include methyl, ethyl, n-propyl, iso

US 2010/0286160 A1 Nov. 11, 2010

CH, CHCH(OH)CH, etc. Non-limiting examples of Y (O)OCH)CHCH(CH), O CH(CH)CHCH C(O) when Y is C(O)-aryl include —C(O)-phenyl, -C(O)- O CH, etc. Non-limiting examples of Y" when Y is naphthyl, etc. Non-limiting examples of Y" when Y is —O-alkylene-aryl include —O—CH2-phenyl, —C(O)-haloalkyl include —C(O)—CF, —C(O)—CHF, —O CHCH-phenyl, —O CH(CH)-phenyl, —C(O)—CHF, —C(O)—CHCF, —C(O)—CFCF, —O CHCH(CH)-phenyl, —OC(CH)-phenyl, —C(O)—CHBr, —C(O)—CHCl, —C(O)—CC1, etc. —O CH(CHCH)-phenyl, etc. Non-limiting examples of Non-limiting examples of Y' when Y is —C(O)O-alkyl Y' when Y is N(R), include -NH2, N(CH), -NH include —C(O)—O CH, —C(O) O CHCH (CH), —NH(phenyl), —N(phenyl), —NH S(O), CH, —C(O)—O CHCHCH —C(O)—O—CH(CH), —NH S(O)-cyclopropyl, - NH C(O) NH, -NH —C(O)—O CHCHCHCH —C(O)—O CHCH C(O) N(CH), -NH C(O)-CH, -NH-CHCH (CH), —C(O)—O CH(CH)CHCH. —C(O)—O C OH, etc. (CH), —C(O)—O CHCHCHCHCH. —C(O)— 0292. In some embodiments, the aryl or heteroaryl por O CH-CH(CH)CHCH, —C(O)—O CHCHCH tions of any of the groups of Y may be unsubstituted or (CH3)2. - C(O) O CHCHCHCHCHCH Substituted with one or more Z groups as defined herein. —C(O) O CH(CH)CHCHCHCH, C(O) O 0293. In embodiments where Z is present, each Z is inde CHCH(CH)CHCHCH - C(O) O CHCHCH pendently selected from the group consisting of alkyl, halo, (CH)CHCH. —C(O) O CHCHCH-CH(CH), etc. haloalkyl, —OH, -O-alkyl, and —CN. The terms “alkyl, Non-limiting examples ofY' when Y is N(R)C(O)-alkyl “halo', aloalkyl, and “—O-alkyl are as defined herein. include —NH CO)-alkyl, - N(alkyl)-C(O)-alkyl, and 0294 Also included within the scope of the invention are —N(aryl)-C(O)-alkyl wherein the terms “alkyl and “aryl metabolites of compounds of Formula (I) or its various areas defined above. Non-limiting examples ofY' whenY' is embodiments described herein, that is, compounds formed in -N(R)C(O) N(R) include -NHC(O) NH, -NHC Vivo upon administration. Some examples of metablites (O) N(alkyl), -NHC(O) N(aryl), -NHC(O) NH include: alkyl, -NHC(O) NH-aryl, - N(alkyl)C(O) NH-alkyl, 0295 (i) where a compound of the invention contains a - N(alkyl)C(O) NH-aryl, - N(aryl)C(O) NH-aryl, methyl group, an hydroxymethyl derivative thereof (e.g., —N(aryl)C(O) NH-aryl, etc. Non-limiting examples of Y —CH->OHor—C(R)H-> C(R),OH, wherein each Ris, when Y is O-alkyl include —O CH, O CHCH independently, any corresponding Substituent in Formula (I)); —O CHCHCH —O—CH(CH), 0296 (ii) where a compound of the invention contains an —O CHCHCHCH - O CHCH(CH) - O CH alkoxy group, anhydroxyl derivative thereof (-OR->—OH, (CH)CHCH, —O—C(CH), wherein R is any corresponding Substituent in Formula (I)); —O CHCHCHCHCH —O CHCH(CH) 0297 (iii) where a compound of the invention contains a CHCH, —O CHCH-CH(CH), tertiary amino agroup, a secondary amino derivative thereof —O CHCHCHCHCHCH, -O-CH(CH) ( N(R)--> NHR, wherein each R is, independently, any CHCHCHCH —O CHCH(CH)CHCHCH corresponding secondary or tertiary amino Substitutent in —O CHCH-CH(CH)CHCH - O CHCHCHCH Formula (I)); (CH4), etc. Non-limiting examples of Y" when Y is —O- 0298 (iv) where a compound of the invention contains a haloalkyl include —O CF, —O CHF - O CHF, secondary amino group, a primary derivative thereof —O CHCF, —O CFCF, —O CHBr, ( NHR-> NH, wherein R is any corresponding second —O CHCl, O CC1, etc. Non-limiting examples of Y' ary amino or primary amino Substituent of Formula (I); when Y is —O-alkylene-C(O)CH include —O CH, C 0299 (v) where a compound of the invention contains a (O)OH, - O CHCH C(O)OH, -CHCHCHC(O) phenyl moiety, a phenol derivative thereof (-Ph->-PhOH): OH, O CH(CH) C(O)CH, O CH(C(O)OH) 0300 (vi) where a compound of the invention contains an CHCH(CH), O CH(CH)CHCH C(O)OH, etc. amide group, a carboxylic acid derivative thereof Non-limiting examples of Y" when Y is S-alkyl include ( CONH-> COOH). —S CH, S CHCH. —S CHCHCH. —S CH 0301 As used throughout the specification, the following (CH), —S CHCHCHCH. —S CHCH(CH), terms, unless otherwise indicated, shall be understood to have —S CH(CH)CHCH —S-C(CH), the following meanings: —S CHCHCHCHCH, -S CHCH(CH)CHCH 0302. The term “Patient” includes humans and/or other —S CHCH-CH(CH), animals. Animals include mammals and non-mammalianani —S CHCHCHCHCHCH —S CH(CH) mals. Mammals include humans and other mammalian ani CHCHCHCH —S CHCH(CH)CHCHCH mals. In some embodiments, the patient is a human. In other —S CHCH-CH(CH)CHCH, -S CHCHCHCH embodiments, the patient is non-human. In some embodi (CH), etc. Non-limiting examples of Y' when Y is S ments, non-human animals include companion animals. haloalkyl include —S CF – S CHF, S CHF, Examples of companion animals include house cats (feline), —S CHCF. —S CFCF —S CHBr, —S CHCl, dogs (canine), rabbits, horses (equine), guinea pigs, rodents —S CC1s, etc. Non-limiting examples of Y' when Y is (e.g., rats, mice, gerbils, or hamsters), primates (e.g., mon -alkylene-OH include —CH2—OH, -CHCH, OH, keys), and avians (e.g., pigeons, doves, parrots, parakeets, —CHCHCH-OH, -CH(OH)CH, -CHCH(OH) macaws, or canaries). In some embodiments, the animals are CH, etc. Non-limiting examples ofY' when Y is -alkylene felines (e.g., house cats). In some embodiments, the animals C(O) O-alkyl include —O CH, C(O)O CH, are canines. Canines include, for example, wild and Zoo —O CH-C(O)O CHCH - O CHCH C(O) canines, such as wolves, coyotes, and foxes. Canines also O CHCH —O CHCHCH C(O)O CH, include dogs, particularly domestic dogs, such as, for —O CHCH C(O)O—C(CH), —O CH(CH)—C example, pure-bred and/or mongrel companion dogs, show (O)O CH, - O CHCH C(O)O CH, - O -CH(C dogs, working dogs, herding dogs, hunting dogs, guard dogs, US 2010/0286160 A1 Nov. 11, 2010 police dogs, racing dogs, and/or laboratory dogs. In some embodiments, non-human animals include wild animals; -continued livestock animals (e.g., animals raised for food and/or other products, such as, for example, meat, poultry, fish, milk, Score Description butter, eggs, fur, leather, feathers, and/or wool); beasts of 4 Underweight. Ribs easily palpable with minimal fat covering. Waist easily noted from above. Abdominal burden; research animals; companion animals; and animals tuck evident. raised fortin Zoos, wild habitats, and/or circuses. In other 5 deal. Ribs palpable without excess fat covering. embodiments, non-human animals include primates. Such as Waist observed behind ribs when viewed from above. Abdomentucked when viewed from the side. monkeys and great apes. In other embodiments, animals 6 Overweight. Ribs palpable with slight excess fat include bovine (e.g., cattle or dairy cows), porcine (e.g., hogs covering. Waist is discernable viewed from above, or pigs). Ovine (e.g., goats or sheep), equine (e.g., horses). but is not prominent. Abdominal tuck apparent. canine (e.g., dogs), feline (e.g., house cats), camels, deer, 7 Heavy. Ribs palpable with difficulty, heavy fat cover. Noticeable fat deposits over lumbar area and base of antelope, rabbits, guinea pigs, rodents (e.g., Squirrels, rats, ail. Waist absent or barely visible. Abdominal tuck mice, gerbils, or hamsters), cetaceans (e.g., whales, dolphins, may be present. or porpoises), pinnipeds (e.g., seals or walruses). In other 8 Obese. Ribs not palpable under very heavy fat cover, or palpable only with significant pressure. embodiments, animals include avians. Avians include birds Heavy fat deposits over lumbar area and base of tail. associated with either commercial or noncommercial avicul Waist absent. NO abdominal tuck. Obvious ture. These include, for example, Anatidae. Such as Swans, abdominal distension may be present. geese, and ducks; Columbidae, such as doves and pigeons (e.g., Such as domestic pigeons); Phasianidae. Such as par 0304 Alkyl means an aliphatic hydrocarbon group tridges, grouse and turkeys; Thesienidae, Such as domestic which may be straight or branched and comprising about 1 to chickens: Psittacines, such as parakeets, macaws, and parrots about 20 carbonatoms in the chain. In one embodiment alkyl (e.g., parakeets, macaws, and parrots raised for pets or col groups contain about 1 to about 12 carbonatoms in the chain. lector markets; game birds; and ratites, such as ostriches. In In another embodiment alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more other embodiments, animals include fish. Fish include, for lower alkyl groups such as methyl, ethyl or propyl, are example, the Teleosti grouping of fish (i.e., teleosts). Such as, attached to a linear alkyl chain. "Lower alkyl means a group for example, the Salmoniformes order (which includes the having about 1 to about 6 carbon atoms in the chain which Salmonidae family) and the Perciformes order (which may be straight or branched. Non-limiting examples of suit includes the Centrarchidae family). Examples of fish include able alkyl groups include methyl, ethyl, n-propyl, isopropyl. the Salmonidae family, the Serranidae family, the Sparidae n-butyl, t-butyl, n-pentyl, heptyl, nonyl, or decyl. family, the Cichlidae family, the Centrarchidae family, the 0305 Alkylene' means a divalent group obtained by three-Line Grunt (Parapristipoma trilineatum), and the Blue removal of a hydrogen atom from an alkyl group that is Eyed Plecostomus (Plecostomus spp). Additional examples defined above. Non-limiting examples of alkylene include of fish include, for example, catfish, sea bass, tuna, halibut, methylene, ethylene and propylene. In one embodiment, arctic charr, Sturgeon, turbot, flounder, Sole, carp, tilapia, alkylene groups have about 1-18 carbon atoms in the chain, striped bass, eel, sea bream, yellowtail, amberjack, grouper, which may be straight or branched. In another embodiment, and milkfish. In other embodiments, animals include marsu alkylene groups have about 1-12 carbon atoms in the chain, pials (e.g., kangaroos), reptiles (e.g., farmed turtles), amphib which may be straight or branched. In another embodiment, ians (e.g., farmed frogs), crustaceans (e.g., lobsters, crabs, alkylene groups may be lower alkylenes. “Lower alkylene’ shrimp, or prawns), mollusks (e.g., Octopus and shellfish), means an alkylene having about 1 to 6 carbon atoms in the chain, which may be straight or branched. and other economically-important animals. 0306 “Alkenyl' means an aliphatic hydrocarbon group 0303 "Body Condition Score” refers to an assessment of containing at least one carbon-carbon double bond and which an animal's weight forage and weight for height ratios, and its may be straight or branched and comprising about 2 to about relative proportions of muscle and fat. The assessment is 15 carbon atoms in the chain. In one embodiment alkenyl made by eye, on the basis of amount of tissue cover between groups have about 2 to about 12 carbon atoms in the chain. In the various points of reference. The grading may be expressed another embodiment alkenyl groups have about 2 to about 6 as a score ranging from 1 to 8. As used herein, Body Condi carbon atoms in the chain. Branched means that one or more tion Scores of 1 to 8 are described as follows: lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl' means about 2 to about 6 carbon atoms in the chain which may be straight or branched. The term “substituted alkenyl' means Score Description that the alkenyl group may be substituted by one or more 1 Emaciated. Ribs, lumbar vertebrae, pelvic bones substituents which may be the same or different, each sub and all bony prominences evident from a distance. stituent being independently selected from the group consist No discernable body fat. Obvious loss of muscle ing of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and 3.SS. 2 Very thin. Ribs, lumbar vertebrae and pelvic bond —S(alkyl). Non-limiting examples of Suitable alkenyl groups easily visible. No palpable fat. Some evidence of include ethenyl, propenyl. n-butenyl, 3-methylbut-2-enyl, other bony prominence. Minimal loss of muscle n-pentenyl, octenyl and decenyl. 3.SS. 0307 “Alkenylene' means a divalent group obtained by 3 Thin. Ribs easily palpated and may be visible with no palpable fat. Tops of lumbar vertebrae visible. removal of a hydrogen atom from an alkenyl group that is Pelvic bones becoming prominent. Obvious waist defined above. and lack of abdominal tuck. 0308 “Alkynyl' means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which US 2010/0286160 A1 Nov. 11, 2010 may be straight or branched and comprising about 2 to about 0314 “Cycloalkylene' means a divalent cycloalkyl group 15 carbon atoms in the chain. In one embodiment alkynyl obtained by the removal of a hydrogenatom from a cycloalkyl groups have about 2 to about 12 carbon atoms in the chain. In group as defined above. Non-limiting examples of cycloalky another embodiment alkynyl groups have about 2 to about 4 lenes include: carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl' means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alky nyl groups include ethynyl, propynyl, 2-butynyl, 3-methyl butynyl, n-pentynyl, and decynyl. The term “substituted alky nyl' means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each Substituent being independently selected from the group con sisting of alkyl, aryland cycloalkyl. 0309 "Aryl (sometimes abbreviated “ar” or “Ar) means an aromatic monocyclic or multicyclic ring system compris ing about 6 to about 14 carbon atoms, or about 6 to about 10 carbon atoms. The aryl group can be optionally Substituted with one or more “ring system substituents’ which may be the same or different, and are as defined herein. Non-limiting examples of Suitable aryl groups include phenyl, naphthyl, and biphenyl. 0310 Aryloxy' means a —O-aryl group, wherein aryl is defined as above. the aryloxy group is attached to the parent moiety through the ether oxygen. 0311 "Arylene' means a divalent aryl group obtained by the removal of a hydrogenatom from an aryl group as defined above. Non-limiting examples of arylenes include, for example, 1.2-phenylene, 1.3-phenylene, or 1.4-phenylene. 0312 “Heteroaryl' means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, or about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or Sulfur, alone or in combination. In one embodiment heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl' can be optionally substituted by one or more “ring system substituents' which may be the same or different, and areas defined herein. The prefix aza, oxa orthia 0315 “Alkylene containing one or more cycloalkylene before the heteroaryl root name means that at least a nitrogen, groups' means an alkylene group is bound to one or both of oxygen or Sulfur atom respectively, is present as a ring atom. the open Valancies of a cycloalkylene group. Similarly, “alk A nitrogenatom of a heteroaryl can be optionally oxidized to enylene (or alkynylene) containing one or more cycloalky the corresponding N-oxide. Non-limiting examples of Suit lene groups' means an alkenylene (or alkynylene) group able heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, bound to one or both of the open valancies of a cycloalkylene pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, group. pyrazolyl, furazanyl, pyrrolyl pyrazolyl, triazolyl, 1,2,4-thia diazolyl pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, 0316 “Heterocycloalkyl means a non-aromatic saturated imidazol-2-alpyridinyl, imidazo[2.1-bithiazolyl, benzo monocyclic or multicyclic ring system comprising about 3 to furazanyl, indolyl azaindolyl, benzimidazolylbenzothienyl, about 10 ring atoms, or about 5 to about 10 ring atoms, in quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, which one or more of the atoms in the ring system is an thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinoli element other than carbon, for example nitrogen, oxygen or nyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the Sulfur, alone or in combination. There are no adjacent oxygen like. and/or Sulfur atoms present in the ring system. In one embodi 0313 “Cycloalkyl means a non-aromatic mono- or mul ment heterocycloalkyls contain about 5 to about 6 ring atoms. ticyclic ring system comprising about 3 to about 13 carbon The prefix aza, oxa or thia before the heterocycloalkyl root atoms, or about 5 to about 10 carbon atoms. Preferred name means that at least a nitrogen, oxygen or Sulfur atom cycloalkyl rings contain about 5 to about 7 ring atoms. The respectively is present as a ring atom. The heterocycloalkyl cycloalkyl can be optionally substituted with one or more “ring system substituents’ which may be the same or differ can be optionally Substituted by one or more “ring system ent, and are as defined above. Non-limiting examples of Suit substituents” which may be the same or different, and are as able monocyclic cycloalkyls include cyclopropyl, cyclopen defined herein. The nitrogen or sulfur atom of the heterocy tyl, cyclohexyl, cycloheptyl and the like. Non-limiting cloalkyl can be optionally oxidized to the corresponding examples of Suitable multicyclic cycloalkyls include 1-deca N-oxide, S-oxide or S.S.-dioxide. Non-limiting examples of lin, norbornyl, adamanty1 and the like. Suitable monocyclic heterocycloalkyl rings include piperidyl, US 2010/0286160 A1 Nov. 11, 2010 pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and non-limiting examples of a dibenzo-fused cycloalkyls are thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydro-pyra fluorenyl: nyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothi opyranyl, and the like. 0317 “Heterocycloalkenyl' means a non-aromatic unsat urated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, or about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system CS) and is an element other than carbon, for example nitrogen, oxygen or Sulfur, alone or in combination. There are no adjacent oxygen and/or Sulfur atoms present in the ring system. Het erocycloalkenyls have at least one double bond, wherein said acenaphthenyl: double bond may be between two ring carbonatoms, between a ring carbonatomandaring heteroatom (e.g., between a ring carbon atom and a ring nitrogen atom), or between two ring heteroatoms (e.g., between two ring nitrogenatoms). If more than one double bond is present in the ring, each double bond is independently defined as described herein. In another embodiment heterocycloalkenyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocy cloalkenyl root name means that at least a nitrogen, oxygen or Sulfur atom respectively is present as a ring atom. The het 0320 “Benzo-fused heterocycloalkyl means a heterocy erocycloalkenyl can be optionally substituted by one or more cloalkyl, as defined above, to which one or more phenyl rings “ring system substituents’ which may be the same or differ has been fused, so that each phenyl ring shares two ring ent, and are as defined herein. The nitrogen or Sulfur atom of carbon atoms with the heterocycloalkyl ring. In one embodi the heterocycloalkenyl can be optionally oxidized to the cor ment, the benzo-fused heterocycloalkyl group is attached to responding N-oxide, S-oxide or S.S.-dioxide. Non-limiting the rest of the molecule through the heterocycloalkenyl examples of Suitable monocyclic heterocycloalkenyl rings group. In another embodiment, the benzo-fused heterocy include thiazolinyl, 2,3-dihydro-1H-pyrrolyl. 2,5-dihydro cloalkyl group is attached to the rest of the molecule through 1H-pyrrolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-furan, the benzyl group. A non-limiting example of a benzo-fused 2,5-dihydro-furan, etc. heterocycloalkyls is 2,3-dihydro-benzo 1.4 dioxinyl. 0321) “Cycloalkenyl' means a non-aromatic mono or 0318 “Benzo-fused heterocycloalkenyl' means a hetero multicyclic ring system comprising about 3 to about 10 car cycloalkenyl, as defined above, to which one or more phenyl bon atoms, or about 5 to about 10 carbon atoms, which con rings has been fused, so that each phenyl ring shares two ring tains at least one carbon-carbon double bond. In one embodi carbon atoms with the cycloalkyl ring. In one embodiment, ment cycloalkenyl rings containabout 5 to about 7 ring atoms. the benzo-fused heterocycloalkenyl group is attached to the The cycloalkenyl can be optionally substituted with one or rest of the molecule through the heterocycloalkenyl group. In more “ring system substituents' which may be the same or another embodiment, the benzo-fused heterocycloalkenyl different, and are as defined above. Non-limiting examples of group is attached to the rest of the molecule through the Suitable monocyclic cycloalkenyls include cyclopentenyl, benzyl group. Non-limiting examples of benzo-fused cyclohexenyl, cycloheptenyl, and the like. Non-limiting cycloalkyls are 4H-chromene, chromene-4-one, 1H-isoch example of a suitable multicyclic cycloalkenyl is norbornyle romene, etc. nyl. 0319 “Benzo-fused cycloalkyl means a cycloalkyl, as 0322 "Halo' (or “halogeno” or “halogen) means fluoro, defined above, to which one or more phenyl rings has been chloro, bromo, or iodo groups. Preferred are fluoro, chloro or fused, so that each phenyl ring shares two ring carbon atoms bromo, and more preferred are fluoro and chloro. with the cycloalkyl ring. In one embodiment, the benzo-fused 0323 "Haloalkyl means an alkyl as defined above cycloalkenyl group is attached to the rest of the molecule wherein one or more hydrogen atoms on the alkyl are through the cycloalkenyl group. In another embodiment, the replaced by a halo group as defined above. benzo-fused cycloalkenyl group is attached to the rest of the 0324 “Ring system substituent’ means a substituent molecule through the benzyl group. Non-limiting examples attached to an aromatic or non-aromatic ring system which, of benzo-fused cycloalkyls are indanyl and tetradehy for example, replaces an available hydrogen on the ring sys dronaphthyl: tem. Ring system Substituents may be the same or different, and are defined as described herein. 0325 "Alkoxy' means an —O-alkyl group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen. 0326. With reference to the number of moieties (e.g., sub stituents, groups or rings) in a compound, unless otherwise defined, the phrases “one or more' and “at least one' mean US 2010/0286160 A1 Nov. 11, 2010 19 that there can be as many moieties as chemically permitted, 0331 Lines drawn into the ring systems, such as, for and the determination of the maximum number of Such moi example: eties is well within the knowledge of those skilled in the art. 0327. When used herein, the term “independently, in ref erence to the substitution of a parent moiety with one or more Substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible Sub C stituents may be used. As a non-limiting example, a phenyl independently substituted with one or more alkyl or halo indicate that the indicated line (bond) may be attached to any Substituents can include, chlorophenyl, dichlorophenyl, of the Substitutable ring carbon atoms. Hetero-atom contain trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, 2.3- ing ring systems, when present in a compound according to dichloro-4-methylphenyl, etc. the invention, can be optionally Substituted with a ring system Substitutent at an available ring carbonatom, an available ring 0328. As used herein, the term “composition' is intended heteroatom, or both, where allowed by appropriate valency to encompass a product comprising the specified ingredients rules. in the specified amounts, as well as any product which results, 0332. As well known in the art, a bond drawn from a directly or indirectly, from combination of the specified particular atom wherein no moiety is depicted at the terminal ingredients in the specified amounts. end of the bond indicates a methyl group bound through that 0329. The wavy line as a bond generally indicates a bond to the atom, unless stated otherwise. For example: mixture of, or either of the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example,

H "N-QNH cr"N H represents means containing both CH

H H N CH N wCH3 - NH "N-Q CrN - ON CH3. H H 0333. It should also be noted that any carbon or heteroa 0330 Moreover, when the stereochemistry of a chiral cen tom with unsatisfied Valences in the text, schemes, examples, ter (or stereogenic center) is not expressly indicated, a mix structural formulae, and any Tables herein is assumed to have ture of or any of the individual possible isomers are contem the hydrogen atom or atoms to satisfy the Valences. plated. Thus, for example, 0334. The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's H normal valency under the existing circumstances is not exceeded, and that the Substitution results in a stable com pound. Combinations of substituents and/or variables are per cr"N missible only if such combinations result in stable com H pounds. By “stable compound or “stable structure' is meant a compound that is Sufficiently robust to Survive isolation to a useful degree of purity from a reaction mixture, and formu means containing lation into an efficacious therapeutic agent. 0335 The term “optionally substituted” means optional H H Substitution with the specified groups, radicals or moieties. N CH3 Na yCH3 0336. The term “isolated or “in isolated form for a com pound refers to the physical State of said compound after C r and/or C D being isolated from a synthetic process or natural source or N N combination thereof. The term “purified’ or “in purified H H form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled arti US 2010/0286160 A1 Nov. 11, 2010 20 san, in sufficient purity to be characterizable by standard moiety, Such as, but not limited to a carboxylic acid, Zwitte analytical techniques described herein or well known to the rions (“inner salts') may be formed and are included within skilled artisan. the term "salt(s) as used herein. Pharmaceutically accept 0337. When a functional group in a compound is termed able (i.e., non-toxic, physiologically acceptable) salts are pre “protected’, this means that the group is in modified form to ferred, although other salts are also useful. Salts of the com preclude undesired side reactions at the protected site when pounds of the Formula (I) may be formed, for example, by the compound is subjected to a reaction. Suitable protecting reacting a compound of Formula (I) with an amount of acid or groups will be recognized by those with ordinary skill in the base. Such as an equivalent amount, in a medium such as one art as well as by reference to standard textbooks such as, for in which the salt precipitates or in an aqueous medium fol example, T. W. Greene et al. Protective Groups in Organic lowed by lyophilization. Acids (and bases) which are gener Synthesis (1991), Wiley, New York. ally considered suitable for the formation of pharmaceuti 0338. When any variable (e.g., aryl, heterocycle, R, etc.) cally useful salts from basic (or acidic) pharmaceutical occurs more than one time in any constituent or in any For compounds are discussed, for example, by S. Berge et al. mula (e.g., Formula I), its definition on each occurrence is Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. independent of its definition at every other occurrence. Gould, International.J. of Pharmaceutics (1986) 33 201-217: 0339 Prodrugs and solvates of the compounds of the Anderson et al. The Practice of Medicinal Chemistry (1996), invention are also contemplated herein. The term “prodrug’. Academic Press, New York; in The Orange Book (Food & as employed herein, denotes a compound that is a drug pre Drug Administration, Washington, D.C. on their website); cursor which, upon administration to a Subject, undergoes and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook chemical conversion by metabolic or chemical processes to of Pharmaceutical Salts: Properties, Selection, and Use, yield a compound of formula I or a salt and/or solvate thereof. (2002) Intl Union of Pure and Applied Chemistry, pp. 330 A discussion of prodrugs is provided in T. Higuchi and V. 331. These disclosures are incorporated herein by reference Stella, Pro-drugs as Novel Delivery Systems (1987) Volume thereto. 14 of the A.C.S. Symposium Series, and in Bioreversible 0343 Exemplary acid addition salts include acetates, adi Carriers in Drug Design, (1987) Edward B. Roche, ed., pates, alginates, ascorbates, aspartates, benzoates, benzene American Pharmaceutical Association and Pergamon Press, Sulfonates, bisulfates, borates, butyrates, citrates, camphor both of which are incorporated herein by reference thereto. ates, camphorsulfonates, cyclopentanepropionates, 0340 “Solvate” means a physical association of a com digluconates, dodecylsulfates, ethanesulfonates, fumarates, pound of this invention with one or more solvent molecules. glucoheptanoates, glycerophosphates, hemisulfates, hep This physical association involves varying degrees of ionic tanoates, hexanoates, hydrochlorides, hydrobromides, and covalent bonding, including hydrogenbonding. In certain hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, instances the solvate will be capable of isolation, for example methanesulfonates, methyl sulfates, 2-naphthalene when one or more solvent molecules are incorporated in the Sulfonates, nicotinates, nitrates, oxalates, pamoates, pecti crystal lattice of the crystalline solid. “Solvate” encompasses nates, persulfates, 3-phenylpropionates, phosphates, picrates, both solution-phase and isolatable solvates. Non-limiting pivalates, propionates, salicylates, succinates, Sulfates, Sul examples of Suitable Solvates include ethanolates, methano fonates (such as those mentioned herein), tartarates, thiocy lates, and the like. “Hydrate' is a solvate wherein the solvent anates, toluenesulfonates (also known as tosylates.) unde molecule is H.O. canoates, and the like. 0341 One or more compounds of the present invention 0344 Exemplary basic salts include ammonium salts, may also exist as, or optionally be converted to a solvate. The alkali metal salts such as sodium, lithium, and potassium preparation of Solvates is generally known. Thus, for salts, alkaline earth metal salts such as calcium and magne example, M. Caira et al., J. Pharmaceutical Sci., 93 (3), 601 sium salts, aluminum salts, Zinc salts, salts with organic bases 611 (2004) describe the preparation of the solvates of the (for example, organic amines) such as benzathines, diethy antifungal fluconazole in ethyl acetate as well as from water. lamine, dicyclohexylamines, hydrabamines (formed with Similar preparations of Solvates, hemisolvate, hydrates and N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D- the like are described by E. C. van Tonder etal, AAPS Pharm glucamines, N-methyl-D-glucamides, t-butylamines, pipera SciTech., 5(1), article 12 (2004); and A. L. Bingham et al. Zine, phenylcyclohexylamine, choline, tromethamine, and Chem. Commun., 603-604 (2001). A typical, non-limiting, salts with amino acids such as arginine, lysine and the like. process involves dissolving the inventive compound in Basic nitrogen-containing groups may be quarternized with desired amounts of the desired solvent (organic or water or agents such as lower alkylhalides (e.g. methyl, ethyl, propyl. mixtures thereof) at a higher than ambient temperature, and and butyl chlorides, bromides and iodides), dialkyl sulfates cooling the Solution at a rate Sufficient to form crystals which (e.g. dimethyl, diethyl, dibutyl, and diamyl Sulfates), long are then isolated by standard methods. Analytical techniques chain halides (e.g. decyl, lauryl, myristyl and Stearyl chlo Such as, for example I.R. spectroscopy, show the presence of rides, bromides and iodides), aralkylhalides (e.g. benzyl and the solvent (or water) in the crystals as a solvate (or hydrate). phenethyl bromides), and others. 0342. The compounds of Formula (I) form salts that are (0345 All such acid salts and base salts are intended to be also within the scope of this invention. Reference to a com pharmaceutically acceptable salts within the scope of the pound of Formula (I) herein is understood to include refer invention and all acid and base salts are considered equivalent ence to salts thereof, unless otherwise indicated. The term to the free forms of the corresponding compounds for pur 'salt(s)', as employed herein, denotes acidic salts formed poses of the invention. with inorganic and/or organic acids, as well as basic salts 0346. The compounds of the present invention may con formed with inorganic and/or organic bases. In addition, tain asymmetric or chiral centers, and, therefore, exist in when a compound of Formula (I) contains both a basic moi different stereoisomeric forms. It is intended that all stereoi ety, such as, but not limited to a piperazine, and an acidic Someric forms of the compounds of the invention as well as US 2010/0286160 A1 Nov. 11, 2010

mixtures thereof, including racemic mixtures, form part of life or reduced dosage requirements) and hence may be pre the present invention. In addition, the present invention ferred in some circumstances. Isotopically labelled com embraces all geometric and positional isomers. For example, pounds of Formula (I can generally be prepared by following ifa compound of the invention incorporates a double bond or procedures analogous to those disclosed in the Schemes and/ a fused ring, both the cis- and trans-forms, as well as mixtures, or in the Examples hereinbelow, by Substituting an appropri are embraced within the scope of the invention. ate isotopically labelled reagent for a non-isotopically 0347 Diastereomeric mixtures can be separated into their labelled reagent. individual diastereomers on the basis of their physical chemi 0352 Polymorphic forms of the compounds of Formula cal differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or frac (I), and of the salts, Solvates and prodrugs of the compounds tional crystallization. Enantiomers can be separated by con of Formula (I), are intended to be included in the present Verting the enantiomeric mixture into a diastereomeric mix invention. ture by reaction with an appropriate optically active 0353. In still another embodiment, the present invention compound (e.g., chiral auxiliary Such as a chiral alcohol or provides a composition comprising at least one compound of Mosher's acid chloride), separating the diastereomers and Formula (I), or a pharmaceutically acceptable salt, Solvate, converting (e.g., hydrolyzing) the individual diastereomers to isomer, or ester thereof, and a pharmaceutically acceptable the corresponding pure enantiomers. Also, those of ordinary carrier. skill in the art will recognize any compounds of the present 0354. The term “pharmaceutical composition' is also invention that may be atropisomers (e.g., Substituted biaryls). intended to encompass both the bulk composition and indi Such atropisomers are considered as part of this invention. vidual dosage units comprised of more than one (e.g., two, Enantiomers can also be separated by use of chiral HPLC three, four, or more) pharmaceutically active agents such as, column. for example, a compound of the present invention and an 0348 Compounds of Formula (I), and salts, solvates and additional agent selected from the lists of the additional prodrugs thereof, may exist in their tautomeric form (for agents described herein, along with any pharmaceutically example, as an amide or imino ether). All Such tautomeric inactive excipients. The bulk composition and each indi forms are contemplated herein as part of the present inven vidual dosage unit can contain fixed amounts of the afore-Said tion. “more than one pharmaceutically active agents’. The bulk 0349 All stereoisomers (for example, geometric isomers, composition is material that has not yet been formed into optical isomers and the like) of the present compounds (in individual dosage units. An illustrative dosage unit is an oral cluding those of the salts, Solvates and prodrugs of the com dosage unit Such as tablets, pills and the like. Similarly, the pounds as well as the salts and Solvates of the prodrugs). Such herein-described method of treating a patient by administer as those which may exist due to asymmetric carbons on ing a pharmaceutical composition of the present invention is various Substituents, including enantiomeric forms (which also intended to encompass the administration of the afore may exist even in the absence of asymmetric carbons), rota said bulk composition and individual dosage units. meric forms, atropisomers, and diastereomeric forms, are 0355 Unit dosage forms, without limitation, can include contemplated within the scope of this invention. Individual tablets, pills, capsules, Sustained release pills, Sustained Stereoisomers of the compounds of the invention may, for release tablets, Sustained release capsules, powders, granules, example, be substantially free of other isomers, or may be or in the form of solutions or mixtures (i.e., elixirs, tinctures, admixed, for example, as racemates or with all other, or other syrups, emulsions, Suspensions). For example, one or more selected, stereoisomers. The chiral centers of the present compounds of Formula (I), or salts or Solvates thereof, may be invention can have the S or R configuration as defined by the combined, without limitation, with one or more pharmaceu IUPAC 1974 Recommendations. The use of the terms “salt”, tically acceptable liquid carriers such as ethanol, glycerol, or “solvate” “prodrug and the like, is intended to equally apply water, and/or one or more Solid binders such as, for example, to the salt, Solvate and prodrug ofenantiomers, Stereoisomers, Starch, gelatin, natural Sugars (e.g., glucose or f3-lactose), rotamers, tautomers, racemates or prodrugs of the inventive and/or natural or synthetic gums (e.g., acacia, tragacanth, or compounds. Sodium alginate), carboxymethylcellulose, polyethylene gly 0350. The present invention also embraces isotopically col, waxes and the like, and/or disintegrants, buffers, preser labelled compounds of the present invention which are iden Vatives, anti-oxidants, lubricants, flavorings, thickeners, col tical to those recited herein, but for the fact that one or more oring agents, emulsifiers and the like. In addition, the unit atoms are replaced by anatom having an atomic mass or mass dosage forms can include, without limitation, pharmaceuti number different from the atomic mass or mass number usu cally acceptable lubricants (e.g., sodium oleate, Sodium Stear ally found in nature. Examples of isotopes that can be incor ate, magnesium Stearate, Sodium benzoate, Sodium acetate, porated into compounds of the invention include isotopes of and sodium chloride) and disintegrators (e.g., starch, methyl hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine cellulose, agar, bentonite, and Xanthan gum). The amount of and chlorine, such as H, H, C, C, N, O, 7.O.P. P. excipient or additive can range from about 0.1 to about 90% S, F, and C1, respectively. by weight of the total weight of the treatment composition. 0351 Certain isotopically-labelled compounds of For One skilled in the art understands that the amount of carrier mula I (e.g., those labeled with H and ''C) are useful in (S), excipients, and additives (if present) can vary. compound and/or Substrate tissue distribution assays. Triti 0356. In another embodiment, the present invention pro ated (i.e., H) and carbon-14 (i.e., ''C) isotopes are particu vides a method of treating, reducing, or ameliorating hepatic larly preferred for their ease of preparation and detectability. lipidosis and/or fatty liver disease (including but not limited Further, substitution with heavier isotopes such as deuterium to non-alcoholic fatty liver disease) in a patient in need (i.e., H) may afford certain therapeutic advantages resulting thereof, comprising administering to said patient an effective from greater metabolic stability (e.g., increased in vivo half amount of a composition comprising at least one compound US 2010/0286160 A1 Nov. 11, 2010 22 of Formula (I), or a pharmaceutically acceptable salt, Solvate, imer's disease, eating disorders, diabetes type II or non insu or ester thereof and a pharmaceutically acceptable carrier. lin dependent diabetes (NIDD), gastrointestinal diseases, 0357. In another embodiment, the present invention pro Vomiting, diarrhea, urinary disorders, infertility disorders, vides a method of reducing body condition score (BCS) in a inflammations, infections, cancer, neuroinflammation, in par patient in need thereof, comprising administering to said ticular in atherosclerosis, or the Guillain-Barr syndrome, patient an effective amount of a composition comprising at viral encephalitis, cerebral vascular incidents and cranial least one compound of Formula (I), or a pharmaceutically trauma. acceptable salt, Solvate, or ester thereof (optionally together 0362. In yet another embodiment, the present invention with at least one additional active agent) and one or more provides a method of treating, reducing, or ameliorating obe pharmaceutically acceptable carriers. In one embodiment, the sity, in a patient in need thereof, comprising administering to patient is a non-human animal. In one embodiment, the said patient an effective amount of at least one compound of patient is a companion animal. In one embodiment, BCS is Formula (I), or a pharmaceutically acceptable salt, Solvate, reduced from obese to ideal. In another embodiment, BCS is isomer, or ester thereof. reduced from obese to heavy, overweight, or ideal. In another 0363. In yet other embodiments, the present invention pro embodiment, BCS is reduced from obese to heavy. In another vides a method of treating, reducing, or ameliorating meta embodiment, BCS is reduced from obese to overweight. In bolic syndrome, obesity, waist circumference, abdominal another embodiment, BCS is reduced from heavy to over girth, lipid profile, insulin sensitivity, neuroinflammatory dis weight or ideal. In another embodiment, BCS is reduced from orders, cognitive disorders, psychosis, addictive behavior, heavy to ideal. In another embodiment, BCS is reduced from gastrointestinal disorders, and cardiovascular conditions, in a overweight to ideal. patient in need thereof, comprising administering to said 0358. In other embodiments, the present invention pro patient an effective amount of a composition comprising at vides a method of reducing the abdominal girth in a patient in least one compound of Formula (I), or a pharmaceutically need thereof. The method comprises administering an effec acceptable salt, Solvate, isomer, or ester thereof and a phar tive amount of a composition comprising at least one com maceutically acceptable carrier. pound of Formula (I), or a pharmaceutically acceptable salt, 0364. In yet another embodiment, the present invention solvate, or ester thereof (optionally together with at least one provides a method of treating, reducing, or ameliorating obe additional active agent) and one or more pharmaceutically sity, in a patient in need thereof, comprising administering to acceptable carriers. In some embodiments, the patient is a said patient an effective amount of a composition comprising non-human animal. In some such embodiments, for example, at least one compound of Formula (I), or a pharmaceutically the patient may be a companion mammal. Such as a dog, cat, acceptable salt, Solvate, isomer, or ester thereof and a phar or horse. Girth measurements are taken at the widest point maceutically acceptable carrier. behind the last rib and in front of the pelvis. 0365. The compounds of Formula (I) can be useful as CB 0359. In other embodiments, the present invention pro receptor antagonists for treating, reducing, or ameliorating vides a method of repartitioning, wherein energy of an animal metabolic syndrome, obesity, waist circumference, abdomi is partitioned away from fat deposition toward protein accre nal girth, lipid profile, insulin sensitivity, neuroinflammatory tion. The method comprising administering to said patient an disorders, cognitive disorders, psychosis, addictive behavior effective amount of a composition comprising at least one (e.g., Smoking cessation), gastrointestinal disorders, and car compound of Formula (I), or a pharmaceutically acceptable diovascular conditions (e.g., elevated cholesterol and triglyc salt, solvate, or ester thereof (optionally together with at least eride levels). It is contemplated that the compounds of For one additional active agent) and one or more pharmaceuti mula (I) of the present invention, or pharmaceutically cally acceptable carriers. In some embodiments, the patient is acceptable salts, Solvates, or esters thereof, can be useful in a non-human animal. In some such embodiments, for treating one or more the conditions or diseases listed above. In example, the patient may be a food animal. Such as a bovine particular, the compounds of Formula (I) of the present inven animal, Swine animal, sheep, goat, or poultry animal tion are useful in treating obesity. (chicken, turkey, etc.). In other embodiments, the animal is an 0366 “Effective amount” or “therapeutically effective equine animal. amount' is meant to describe an amount of compound or a 0360. In other embodiments, the present invention pro composition of the present invention effective in antagoniz vides a method of treating, reducing, or ameliorating a dis ing a CB receptor and thus producing the desired therapeutic ease or condition selected from the group consisting of meta effect in a suitable patient. bolic syndrome, obesity, waist circumference, abdominal 0367 The selective CB receptor antagonist compound of girth, lipid profile, insulin sensitivity, neuroinflammatory dis Formula (I), or a pharmaceutically acceptable salt, Solvate, orders, cognitive disorders, psychosis, addictive behavior, isomer, or ester thereof, can be administered in a therapeuti gastrointestinal disorders, and cardiovascular conditions, in a cally effective amount and manner to treat the specified con patient in need thereof, comprising administering to said dition. The daily dose of the selective CB receptor antagonist patient an effective amount of at least one compound of of Formula (I) (or pharmaceutically acceptable salts, Solvates, Formula (I), or a pharmaceutically acceptable salt, Solvate, or esters thereof) administered to a mammalian patient or isomer, or ester thereof. Subject can range from about 1 mg/kg to about 50 mg/kg 0361. In another embodiment, the present invention pro (where the units mg/kg refer to the amount of selective CB vides a method of treating, reducing, or ameliorating a dis receptor antagonist compound of Formula (I) per kg body ease or condition selected from psychic disorders, anxiety, weight of the patient), or about 1 mg/kg to about 25 mg/kg, or Schizophrenia, depression, abuse of psychotropes, abuse and/ about 1 mg/kg to about 10 mg/kg. or dependence of a Substance, alcohol dependency, nicotine 0368. Alternatively, the daily dose can range from about 1 dependency, neuropathies, migraine, stress, epilepsy, dyski mg to about 50 mg, or about 1 mg to about 25 mg. or about 5 nesias, Parkinson's disease, amnesia, senile dementia, Alzhe mg to about 20 mg. In one embodiment, the daily dose can US 2010/0286160 A1 Nov. 11, 2010 range from about 0.01 mg/kg to about 1 mg/kg. In another use, to liquid form preparations for either oral or parenteral embodiment, the daily dose can range from about 1 mg/kg to administration. Such liquid forms include solutions, Suspen about 10 mg/kg. In another embodiment, the daily dose can sions, and emulsions. range from about 1 mg/kg to about 25 mg/kg. Although a 0376. In some embodiments, the compounds of this inven single administration of the selective CB receptor antagonist tion are formulated for transdermal delivery. Transdermal compound of Formula (I), or salts, Solvates, or esters thereof, compositions may be, for example, creams, lotions, aerosols, can be efficacious, multiple dosages can also be administered. and/or emulsions, and can be included in a transdermal patch The exact dose, however, can readily be determined by the of the matrix or reservoir type as are conventional in the art for attending clinician and will depend on Such factors as the this purpose. potency of the compound administered, the age, weight, con 0377. It is contemplated that the active can be incorporated dition and response of the patient. into animal feed. A suitable amount of compound of the 0369. The treatment compositions of the present invention present invention can be placed into a commercially available can be administered in any conventional dosage form, pref feed product to achieve desired dosing levels. The amount of erably an oral dosage form such as a capsule, tablet, powder, compound of the present invention incorporated into the feed cachet, Suspension, or solution. The formulations and phar will depend on the rate at which the animals are fed. Com maceutical compositions can be prepared using conventional pounds or compositions of the present invention can be incor pharmaceutically acceptable and conventional techniques. porated into feed mixtures before pelleting. Alternatively, the 0370. In the veterinary context, in particular, the com medicated feed is formed by coating feed pellets with a com pounds of this invention can be administered to an animal pound(s) or compositions of the present invention. patient in one or more of a variety of routes. For example, the 0378. In some embodiments, the present invention pro compounds may be administered orally via, for example, a vides a method of treating fish for an indication described capsule, bolus, tablet (e.g., a chewable treat), powder, drench, herein. Such methods include administering an effective elixir, cachet, Solution, paste, Suspension, or drink (e.g., in the amount of an inventive compound (or compounds) of the drinking water or as a buccal or Sublingual formulation). The invention (optionally together with one or more additional compounds may alternatively (or additionally) be adminis active agents as described herein) to a fish or a fish population. tered via a medicated feed (e.g., when administered to a Administration generally is achieved by either feeding the non-human animal) by, for example, being dispersed in the fish an effective amount of the inventive compound or by feed or used as a top dressing or in the form of pellets or liquid immersing the fish in a solution that contains an effective which is added to the finished feed or fed separately. The compounds also may be administered (alternatively or addi amount of the inventive compound. It is to be further under tionally) parenterally via, for example, an implant or an stood that the inventive compound can be administered by intraruminal, intramuscular, intravascular, intratracheal, or application of the inventive compound(s) to a pool or other Subcutaneous injection. It is contemplated that other admin water-holding area containing the animal, and allowing the istration routes (e.g., topical, intranasal, rectal, etc.) may be fish to absorb the compound through its gills, or otherwise used as well. Formulations for any such administration routes allowing the dosage of the inventive compound to be takenin. can be prepared using, for example, various conventional For individual treatment of specific animals, such as a par techniques known in the art. In some embodiments, from ticular fish (e.g., in a veterinary or aquarium setting), direct about 5 to about 70% by weight of the veterinary formulation injection or injection of osmotic release devices comprising (e.g., a powder or tablet) comprises active ingredient. the inventive compound, alone or in combination with other 0371 Suitable solid carriers are known in the art, and agents, is an optional method of administering the inventive include, for example, magnesium carbonate, magnesium compound. Suitable routes of administration include, for Stearate, talc, Sugar, and lactose. Tablets, powders, cachets, example, intravenous, Subcutaneous, intramuscular, spray and capsules can be used as Solid dosage forms suitable for ing, dipping, or adding the compound directly into the water oral administration. in a holding Volume. 0372 To prepare suppositories, the active ingredient may 0379. In other embodiments, the present invention pro be dispersed homogeneously into a melted wax that melts at vides a composition comprising: (a) at least one compound of low temperatures (e.g., a mixture of fatty acid glycerides or Formula (I), or a pharmaceutically acceptable salt, Solvate, cocoa butter). Such dispersion may be achieved by, for isomer or ester thereof, and (b) at least one additional active example, stirring. The molten homogeneous mixture may be ingredient. Thus, it is contemplated that any of the indications poured into convenient-sized molds, allowed to cool, and, suitable for treatment by at least one compound of Formula (I) thereby, solidify. may be treated using at least one compound of Formula (I) together with at least one additional active ingredient. Such 0373) Liquid form preparations include solutions, suspen additional active ingredient(s) may be combined with one or sions, and emulsions. In some embodiments, for example, more compounds of the invention to form a single composi water or water-propylene glycol solutions are used for tion for use or the active ingredients may be formulated for parenteral injection. Liquid form preparations also may separate (simultaneous or sequential) administration. Such include Solutions for intranasal administration. additional active ingredients are described herein or are know 0374) Aerosol preparations suitable for inhalation may to those of ordinary skill in the art. Non-limiting examples include solutions and Solids in powder form, which may be include centrally acting agents and peripherally acting combined with a pharmaceutically acceptable carrier, Such as agents. Non-limiting examples of centrally acting agents an inert compressed gas. include histamine-3 receptor antagonists such as those dis 0375 Solid form preparations also include, for example, closed in U.S. Pat. No. 6,720,328 (incorporated herein by preparations that are intended to be converted, shortly before reference). Non-limiting examples of such histamine H-3 US 2010/0286160 A1 Nov. 11, 2010 24 receptor antagonists include the compound having a structure 0381. Therapeutic combinations also are provided com (as well as salts, Solvates, isomers, esters, prodrugs, etc. prising: (a) a first amount of at least one selective CB recep thereof): tor antagonist, or a pharmaceutically acceptable salt, Solvate, isomer or ester, thereof, and (b) a second amount of at least one cholesterol lowering compound, wherein the first amount and the second amount together comprise a therapeutically

effective amount for the treatment or prevention of a vascular condition, diabetes, obesity, hyperlipidemia, metabolic Syn drome, or lowering a concentration of a sterol in the plasma of a Subject. 0382 Pharmaceutical compositions for the treatment or prevention of a vascular condition, diabetes, obesity, hyper lipidemia, metabolic syndrome, or lowering a concentration of a sterol in the plasma of a Subject comprising a therapeu CH tically effective amount of the above compositions or thera peutic combinations and a pharmaceutically acceptable car Other non-limiting examples of histamine-3 receptor antago rier also are provided. nists include those disclosed in U.S. Pat. No. 7,105,505 (in 0383. In still yet another embodiment, the compositions corporated herein by reference). Non-limiting examples of and combinations of the present invention comprise at least Such histamine H-3 receptor antagonists include the com one compound of Formula (I), or a pharmaceutically accept pound having a structure (as well as salts, Solvates, isomers, able salt, Solvate, isomer, or ester thereof, and one or more esters, prodrugs, etc. thereof): anti-diabetic drugs. Non-limiting examples of anti-diabetic drugs include Suliffonyl ureas, meglitinides, biguanides, thia Zolidinediones, alpha glucosidase inhibitors, incretin mietics, o O NH2 DPP-IV (dipeptidyl peptidase-4 or DPP-4) inhibitors, amylin F analogues, insulin (including insulin by mouth), and herbal eXtractS. 0384. Non-limiting examples of sulfonylureas include \ /^ N CoucN S CH3. tolbutamide (Orinase.R.), acetohexamide (Dymelor(R), tolazamide (Tolinase(R), chlorpropamide (Diabinese(R), glip e izide (Glucotrol(RO), glyburide (Diabeta(R), Micronase(R), N and Glynase(R), glimepiride (Amaryl(R), and gliclaZide (Diamicron(R). N-l 0385. Non-limiting examples of meglitinides include repaglinide (Prandinr), and mateglinide (Starlix(R). Additional non-limiting examples of centrally acting agents 0386 Non-limiting examples of biguanides include met include neuropeptide Y5 (NPY5) antagonists such as those formin (Glucophage(R). disclosed in U.S. Pat. No. 6,982.267 (incorporated herein by 0387 Non-limiting examples of thaizolidinediones, also reference). Non-limiting examples of such histamine NPY5 known as glitazines, include rosiglitaZone (AVandia.(R), receptor antagonists include the compound having a structure pioglitaZone (ActoS(R), and troglitazine (ReZulin(R). (and salts, Solvates, isomers, esters, prodrugs, etc. thereof): 0388. Non-limiting examples of gludosidase inhibitors include miglitol (Glyset(R) and acarbose (Precose/Gluco bay(R). CH3 0389. Non-limiting examples of incretin mimetics include H N N N GLP agonists such as exenatide and exendin-4, marketed as Byetta R (Amylin Pharmaceuticals, Inc. and Eli Lilly and Company.) F 2 O N CH3. 0390 Non-limiting examples of Amylin analogues N r include pramlintide acetate (Symlin R. Amylin Pharmaceuti O cals, Inc.). 0391) Non-limiting examples of DPP4 inhibitors and other anti-diabetic drugs include the following: Sitagliptin (marketed as Januvia(R), available from Merck, pyrazine based DPP-IV derivatives such as those disclosed in Non-limiting examples of peripherally acting agents include WO-2004085661, bicyclictetrahydropyrazine DPP IV microsomal triglyceride transfer protein (MTP) inhibitors. inhibitors such as those disclosed in WO-03004498, Non-limiting examples of MTP inhibitors include dirlotapide PHX1149 (available from Phenomix, Inc.), ABT-279 and (SlentrolTM, Pfizer). Additional non-limiting examples of ABT-341 (available from Abbott, see WO-2005023762 and additional active ingredients are described herein. WO-2004026822), ALS-2-0426 (available Alantos and 0380. In another embodiment, the present invention pro Servier), AR12243 (available from Arisaph Pharmaceuticals vides a composition comprising: (a) at least one compound of Inc., U.S. Pat. No. 06,803.357 and U.S. Pat. No. 06,890,898), Formula (I), or a pharmaceutically acceptable salt, Solvate, boronic acid DPP-IV inhibitors such as those described in US isomer or ester thereof, and (b) at least one cholesterol low patent application Ser. No. 06/303,661, BI-A and BI-B (avail ering compound. able from Boehringer Ingelheim), xanthine-based DPP-IV US 2010/0286160 A1 Nov. 11, 2010

inhibitors such as those described in WO-2004.046148, with the site of action in the body, for example in the plasma, WO-200404 1820, WO-2004018469, WO-2004018468 and liver, Small intestine, or brain (e.g., hippocampus, cortex, WO-2004018467, saxagliptin (Bristol-Meyers Squibb and cerebellum, and basal ganglia) of a patient. Such administra AstraZenica), BioVitrim (developed by Santhera Pharmaceu tion includes co-administration of these therapeutic agents in ticals (formerly Graffinity)), MP-513 (Mitsubishi Pharma), a Substantially simultaneous manner, Such as in a single tablet NVP-DPP-728 (qv) and structurally related 1-((S)-gamma or capsule having a fixed ratio of active ingredients or in Substituted prolyl)-(S)-2-cyanopyrrolidine compounds and multiple, separate capsules for each therapeutic agent. Also, analogs of NVP-DPP-728 (qv), DP-893 (Pfizer), vildagliptin Such administration includes the administration of each type (Novartis Institutes for BioMedical Research Inc), tetrahy of therapeutic agent in a sequential manner. In either case, the droisoquinoline 3-carboxamide derivatives Such as those dis treatment using the combination therapy will provide benefi closed in U.S. patent application Ser. No. 06/172,081, N-sub cial effects in treating the condition. A potential advantage of stituted 2-cyanopyrrolidines, including LAF-237. Such as the combination therapy disclosed herein may be a reduction those disclosed in PCT Publication Nos. WO-00034241, in the required amount of an individual therapeutic compound WO-00152825, WO-02072146 and WO-03080070, or the overall total amount of therapeutic compounds that are WO-09920614, WO-00152825 and WO-02072146, effective in treating the condition. By using a combination of SYR-322 (Takeda), denagliptin, SNT-189546, RO-0730699, therapeutic agents, the side effects of the individual com BMS-2, Aurigene, ABT-341, Dong-A, GSK-2, Han All, pounds can be reduced as compared to a monotherapy, which LC-15-0044, SYR-619, Bexel, alogliptin benzoate, and ALS can improve patient compliance. Also, therapeutic agents can 2-0426. Non-limiting examples of other anti-diabetic drugs be selected to provide a broader range of complimentary include metformin, thiazolidinediones (TZD), and sodium glucose cotransporter-2 inhibitors such as dapagliflozin effects or complimentary modes of action. 0396. As discussed above, the compositions, pharmaceu (Bristol Meyers Squibb) and sergliflozin (GlaxoSmithKline), tical compositions and therapeutic combinations of the and FBPase (fructose 1,6-bisphosphatase) inhibitors. present invention comprise: (a) one or more compounds 0392. In still yet another embodiment, the compositions according to Formula (I) of the present invention, or pharma and combinations of the present invention comprise at least ceutically acceptable salts, Solvates, isomers oresters thereof. one compound of Formula (I), or a pharmaceutically accept and (b) one or more cholesterol lowering agents. A non able salt, Solvate, isomer or ester thereof, and at least one limiting list of cholesterol lowering agents useful in the sterol absorption inhibitor or at least one 5C.-stanol absorption present invention include HMG CoA reductase inhibitor inhibitor. compounds such as lovastatin (for example MEVACORR) 0393 Instill yet another embodiment of the present inven which is available from Merck & Co.), simvastatin (for tion, there is provided a therapeutic combination comprising: example ZOCOR(R) which is available from Merck & Co.), (a) a first amount of at least one compound of Formula (I), or pravastatin (for example PRAVACHOLR) which is available a pharmaceutically acceptable salt, Solvate, isomer or ester from Bristol Meyers Squibb), atorvastatin, fluvastatin (for thereof, and (b) a second amount of at least one cholesterol example LESCOLR), cerivastatin, CI-981, rivastatin (so lowering compound; wherein the first amount and the second dium 7-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymeth amount together comprise a therapeutically effective amount ylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate), rosuvastatin for the treatment or prevention of one or more of a vascular calcium (CRESTORR) from AstraZeneca Pharmaceuticals), condition, diabetes, obesity, metabolic syndrome, or lower Pravastatin (marketed as LIVALOR), cerivastatin, itavastatin ing a concentration of a sterol in the plasma of a Subject. (or pitavastatin, NK-104 of Negma Kowa of Japan); HMG 0394. In still yet another embodiment, the present inven CoA synthetase inhibitors, for example L-659,699 ((E.E)- tion provides for a pharmaceutical composition for the treat 1143'R-(hydroxy-methyl)-4'-oxo-2R-oxetanyl-3,5,7R-tri ment or prevention of one or more of a vascular condition, methyl-2,4-undecadienoic acid); squalene synthesis inhibi diabetes, obesity, metabolic syndrome, or lowering a concen tors, for example squalestatin 1; squalene epoxidase tration of a sterol in the plasma of a subject, comprising a inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dim therapeutically effective amount of a composition or thera ethyl-2-hepten-4-ynyl)-3-(3,3'-bithiophen-5-yl)methoxy peutic combination comprising: (a) at least one compound of benzene-methanamine hydrochloride); Sterol (e.g., choles Formula (I), or a pharmaceutically acceptable salt, Solvate, or terol) biosynthesis inhibitors such as DMP-565; nicotinic isomer ester thereof; (b) a cholesterol lowering compound; acid derivatives (e.g., compounds comprising a pyridine-3- and (c) a pharmaceutically acceptable carrier. carboxylate structure or a pyrazine-2-carboxylate structure, 0395. As used herein, “therapeutic combination' or “com including acid forms, salts, esters, Zwitterions and tautomers) bination therapy” means the administration of two or more Such as niceritrol, nicofuranose and acipimoX (5-methylpyra therapeutic agents, such as a compound according to Formula Zine-2-carboxylic acid 4-oxide), and niacin extended-release (I) of the present invention, and a cholesterol lowering com tablets such as NIASPANR); clofibrate; gemfibrazol; bile acid pound Such as one or more Substituted aZetidinone or one or sequestrants such as cholestyramine (a styrene-divinylben more Substituted B-lactam, to prevent or treat a condition, for Zene copolymer containing quaternary ammonium cationic example a vascular condition, such as hyperlipidaemia (for groups capable of binding bile acids, such as QUESTRANR) example atherosclerosis, hypercholesterolemia or sitoster or QUESTRAN LIGHTR) cholestyramine which are avail olemia), Vascular inflammation, metabolic syndrome, stroke, able from Bristol-Myers Squibb), colestipol (a copolymer of diabetes, obesity and/or reduce the level of sterol(s) (such as diethylenetriamine and 1-chloro-2,3-epoxypropane, such as cholesterol) in the plasma or tissue. As used herein, "vascu COLESTIDR tablets which are available from Pharmacia), lar comprises cardiovascular, cerebrovascular and combina colesevelam hydrochloride (such as WelChol(R) Tablets (poly tions thereof. The compositions, combinations and treat (allylamine hydrochloride) cross-linked with epichlorohy ments of the present invention can be administered by any drin and alkylated with 1-bromodecane and (6-bromohexyl)- Suitable means which produce contact of these compounds trimethylammonium bromide) which are available from US 2010/0286160 A1 Nov. 11, 2010 26

Sankyo), water soluble derivatives such as 3.3-ioene, N-(cy No. 5,767,115; U.S. Pat. No. 5,846,966; U.S. Pat. No. 5,698, cloalkyl) alkylamines and poliglusam, insoluble quaternized 548; U.S. Pat. No. 5,633,246; U.S. Pat. No. 5,656,624; U.S. polystyrenes, Saponins and mixtures thereof inorganic cho Pat. No. 5,624,920; U.S. Pat. No. 5,688,787; U.S. Pat. No. lesterol sequestrants such as bismuth salicylate plus montmo 5,756,470; US Publication No. 2002/0137689; WO rillonite clay, aluminum hydroxide and calcium carbonate 02/066464; WO95/08522 and WO96/19450. Non-limiting antacids; ileal bile acid transport (“IBAT”) inhibitors (or api examples of cholesterol absorption inhibitors also include cal sodium co-dependent bile acid transport (ASBT) inhibi non-Small molecule agents, microorganisms such as Bifido tors) such as benzothiepines, for example the therapeutic bacterium animalis subsp. animalis YIT 10394, Bifidobacte compounds comprising a 2.3.4.5-tetrahydro-1-benzothiepine rium animalis subsp. lactis JCM 1253, Bifidobacterium ani 1,1-dioxide structure such as are disclosed in PCT Patent malis subsp. lactis JCM 7117 and Bifidobacterium Application WO 00/38727 which is incorporated herein by pseudolongum Subsp. Globosum, which are described, e.g., in reference; Acyl CoA:Cholesterol O-acyltransferase WO2007029773. Each of the aforementioned publications is (ACAT) Inhibitors such as avasimibe (2,4,6-tris(1-meth incorporated by reference. Substituted AZetidinones of For ylethyl)phenyl)acetylsulfamic acid, 2,6-bis(1-methylethyl) mula (II) phenyl ester, formerly known as CI-1011), HL-004, lecimi 0398. In one embodiment, substituted azetidinones useful bide (DuP-128) and CL-277082 (N-(2,4-difluorophenyl)-N- in the compositions, therapeutic combinations and methods 4-(2,2-dimethylpropyl)phenylmethyl-N-heptylurea), and of the present invention are represented by Formula (II) the compounds described in P. Chang et al., “Current, New below: and Future Treatments in Dyslipidaemia and Atherosclero sis, Drugs 2000 July; 60(1):55-93, which is incorporated by reference herein; Cholesteryl Ester Transfer Protein (II) (“CETP) Inhibitors such as those disclosed in PCT Patent Application No. WO 00/38721 and U.S. Pat. No. 6,147,090, which are incorporated herein by reference; probucol or All-x-g-y-g-z, Ar derivatives thereof, such as AGI-1067 and other derivatives RI R3 disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250, herein incorporated by reference; low-density lipoprotein (LDL) O NAr2 receptor activators such as HOE-402, an imidazolidinyl-py rimidine derivative that directly stimulates LDL receptor activity, described in M. Huettinger et al., “Hypolipidemic orpharmaceutically acceptable salts, Solvates, or esters of the activity of HOE-402 is Mediated by Stimulation of the LDL compounds of Formula (II), wherein, in Formula (II) above: Receptor Pathway”, Arterioscler. Thromb. 1993: 13: 1005 0399 Ar' and Arare independently selected from the 12, herein incorporated by reference; fish oils containing group consisting of aryland R-substituted aryl; Omega 3 fatty acids (3-PUFA); natural water soluble fibers, 04.00 Ar is aryl or R-substituted aryl; Such as psyllium, guar, oat and pectin; plant stanols and/or 04.01 X, Y and Z are independently selected from the fatty acid esters of plant stanols, such as sitostanol ester used group consisting of —CH2—, —CH(lower alkyl)- and in BENECOLR) margarine; nicotinic acid receptor agonists —C(lower alkyl)-; (e.g., agonists of the HM74 and HM74A receptor which 0402 RandR are independently selected from the group receptor is described in US 2004/0142377, US 2005/ 00041 78, US 2005/0154029, U.S. Pat. No. 6,902,902, WO consisting of OR, OC(O)R. —OC(O)CR and OC 2004/071378, WO 2004/071394, WO 01/77320, US 2003/ (O)NR'R7; 0139343, WO 01/94385, WO 2004/083388, US 2004/ 0403 R' and Rare independently selected from the group 254224, US 2004/0254224, US 2003/0109673 and WO consisting of hydrogen, lower alkyl and aryl; 98/56820) for example those described in WO 2004/033431, 0404 q is 0 or 1; r is 0 or 1; m, n and pare independently WO 2005/011677, WO 2005/051937, US 2005/0187280, US selected from 0, 1, 2, 3 or 4: provided that at least one of q and 2005/0187263, WO 2005/077950, WO 2005/016867, WO r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and 2005/016870, WO2005061495, WO2006005195, provided that when p is 0 and r is 1, the Sum of m, q and n is WO2007059203, US2007 105961, CA2574987, and 1, 2, 3, 4 or 5: AU2007200621; and the substituted azetidinone or substi (0405) R' is 1-5 substituents independently selected from tuted p-lactamsterol absorption inhibitors discussed in detail the group consisting of lower alkyl, OR, OC(O)R. below. OC(O)OR, –O(CH), OR, OC(O)NR'R'', 0397 As used herein, “sterol absorption inhibitor” means NRR", NRC(O)R7, NRC(O)OR, NRC(O) a compound capable of inhibiting the absorption of one or NR7R, NRSOR, C(O)OR, C(O)NR'R7, C(O) more sterols, including but not limited to cholesterol, phy R. —S(O)NR'R', S(O).R. O(CH), C(O)CR, tosterols (such as sitosterol, campesterol, Stigmasterol and O(CH) CONR'R'', -(lower alkylene)COOR, avenosterol), 5C.-stanols (such as cholestanol, -CH=CH-C(O)CR, CF, CN, NO, and halogen; 5C-campestanol, 5C.-sitostanol), and/or mixtures thereof, (0406 R is 1-5 substituents independently selected from when administered in a therapeutically effective (sterol and/ the group consisting of OR, OC(O)R. OC(O)OR, or 5C-stanol absorption inhibiting) amount to a patient Such O(CH), OR, OC(O)NR'R'', NR'R'', NRC(O) as a mammal or human. Non-limiting examples of stanol R7, NRCC(O)CR, NRC(O)NR7R, NRS(O).R, absorption inhibitors include those compounds that inhibit C(O)OR, C(O)NR'R'', C(O)R, SONR'R', S(O) cholesterol absorption in the small intestine. Such com oR, O(CH)-o C(O)CR, O(CH2)C(O) pounds are well known in the art and are described, for NR'R'', -(lower alkylene)C(O)OR and -CH=CH-C(O) example, in US RE 37,721; U.S. Pat. No. 5,631,356; U.S. Pat. OR; US 2010/0286160 A1 Nov. 11, 2010 27

0407. R. R7 and Rare independently selected from the and wherein m, n and rare each Zero, q is 1 and p is 2, or group consisting of hydrogen, lower alkyl, aryl and aryl wherein p, q and n are each Zero, r is 1 and m is 2 or 3. substituted lower alkyl; and (0408 R is lower alkyl, aryl or aryl-substituted lower Substituted AZetidinones of Formula (III) alkyl. 0418. In a preferred embodiment, a substituted azetidi 04.09 Preferably, R is 1-3 independently selected sub none of Formula (II) useful in the compositions, therapeutic stituents, and R is preferably 1-3 independently selected combinations and methods of the present invention is repre Substituents. sented by Formula (III) (ezetimibe) below: 0410 Certain compounds useful in the therapeutic com positions or combinations of the invention may have at least one asymmetrical carbon atom and therefore all isomers, (III) including enantiomers, diastereomers, Stereoisomers, rotam ers, tautomers and racemates of the compounds of Formula II-XIII (where they exist) are contemplated as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of the Formulae II-XIII. Isomers may also include geometric iso mers, e.g., when a double bond is present. 0411 Those skilled in the art will appreciate that for some of the compounds of the Formulae II-XIII, one isomer may orpharmaceutically acceptable salts, Solvates, or esters of the show greater pharmacological activity than other isomers. compound of Formula (III). The compound of Formula (III) 0412 Preferred compounds of Formula (II) are those in can be in anhydrous or hydrated form. A product containing which Ar' is phenyl or R-substituted phenyl, more prefer eZetimibe compound is commercially available as ZETIAR) ably (4-R)-substituted phenyl. Ar’ is preferably phenyl or eZetimibe formulation from MSP Pharmaceuticals. R-substituted phenyl, more preferably (4-R)-substituted 0419 Compounds of Formula (II) can be prepared by a phenyl. Ar is preferably R-substituted phenyl, more prefer variety of methods well known to those skilled in the art, for ably (4-R)-substituted phenyl. When Ar" is (4-R)-substi example such as are disclosed in U.S. Pat. Nos. 5,631.365, tuted phenyl, R' is preferably ahalogen. When Arand Arare 5,767,115, 5,846,966, 6,207,822, 6,627,757, 6,093,812, R- and R-substituted phenyl, respectively, R is preferably 5,306,817, 5,561,227, 5,688,785, and 5,688,787, each of halogen or OR and R is preferably -OR, wherein R is which is incorporated herein by reference. lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar" and Art is 4-fluorophenyl and Ar is Substituted AZetidinones of Formula (IV) 4-hydroxyphenyl or 4-methoxyphenyl. 0420. Alternative substituted azetidinones useful in the 0413 X,Y and Z are each preferably —CH2—, RandR compositions, therapeutic combinations and methods of the are each preferably hydrogen. RandR are preferably —OR present invention are represented by Formula (IV) below: wherein R is hydrogen, or a group readily metabolizable to a hydroxyl (such as OC(O)R, OC(O)OR and OC(O) (IV) NR'R', defined above). R1 0414. The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3. Preferred are compounds OF Formula (II) All-A-Y.--z, Ar wherein m, n and rare each Zero, q is 1 and p is 2. R2 0415. Also preferred are compounds of Formula (II) in which p, q and n are each Zero, r is 1 and m is 2 or 3. More N preferred are compounds wherein m, n and rare each Zero, q O Ar2 is 1. p is 2, Z is —CH2—and Ris—OR, especially when R is hydrogen. or a pharmaceutically acceptable salt thereof or a solvate 0416. Also more preferred are compounds of Formula (II) thereof, or an ester thereof, wherein, in Formula (IV) above: wherein p, q and n are each Zero, r is 1., m is 2, X is —CH2— 0421 Ar' is R-substituted aryl; and R is —OR, especially when R is hydrogen. 0422 Aris R-substituted aryl; 0417. Another group of preferred compounds of Formula (II) is that in which Ar' is phenylor R-substituted phenyl, Ari 0423 Aris R-substituted aryl; is phenyl or R-substituted phenyl and Aris R-substituted 0424 Y and Z are independently selected from the group phenyl. Also preferred are compounds in which Ar' is phenyl consisting of —CH2—, —CH(lower alkyl)- and —C(lower or R-substituted phenyl, Ar’ is phenyl or R-substituted phe alkyl)-; nyl, Aris R-substituted phenyl, and the sum of m, n, p, qand 0425 A is selected from —O— —S —S(O) or r is 2, 3 or 4, more preferably 3. More preferred are com —S(O) : pounds wherein Ar" is phenylor R-substituted phenyl, Aris 0426) R' is selected from the group consisting of OR, phenylor R-substituted phenyl, Aris R-substituted phenyl, US 2010/0286160 A1 Nov. 11, 2010 28

0427 R’ is selected from the group consisting of hydro 0441 —(CH)-G-(CH), , wherein G is —O—, gen, lower alkyl and aryl; or R' and R together are =O; —C(O) , phenylene, NR or S(O)o ,e is 0-5 0428 q is 1, 2 or 3: and r is 0-5, provided that the sum of e and r is 1-6: 0442 —(C-C alkenylene)-; and 0429 p is 0, 1, 2, 3 or 4: 0443) -(CH2), V-(CH2) , wherein V is C-C, 0430 R is 1-3 substituents independently selected from cycloalkylene, fis 1-5 and g is 0-5, provided that the sum the group consisting of OR, OC(O)R. OC(O)OR, off and g is 1-6. O(CH), OR, OC(O)NR'R'', NR'R'', NRC(O) 0444 R is selected from: R7, NRC(O)OR, NROC(O)NR7R, NRS(O)- lower alkyl, - NRS(O)-aryl, -C(O)NR'R'', -COR, —SONR'R''. S(O)-alkyl, S(O)--aryl, O(CH) C(O)OR, O(CH)-oC(O)NR'R'', o-halogeno, m-halo geno, o-lower alkyl, m-lower alkyl, -(lower alkylene)-C(O) -CH-, -C(C-C alkyl)-, -CF-, OR, and CH=CH-C(O)OR: 0431) R' and Rare independently 1-3 substituents inde -lon- -la-e- -- , or pendently selected from the group consisting of R. hydro gen, p-lower alkyl, aryl, —NO. —CF and p-halogeno; 0432 R. R7 and Rare independently selected from the –p. group consisting of hydrogen, lower alkyl, aryl and aryl substituted lower alkyl; and R is lower alkyl, aryl or aryl 0445) R' and Rare independently selected from the group substituted lower alkyl. consisting of CH2—, —CH(C-C alkyl)-, —C(di-(C-C) 0433 Methods for making compounds of Formula (IV) alkyl), —CH=CH- and —C(C-C alkyl)=CH-, or R are well known to those skilled in the art. Non-limiting together with an adjacent R, or R together with an adjacent examples of suitable methods are disclosed in U.S. Pat. No. R", form a -CH=CH- or a -CH=C(C-C alkyl)- 5,688.990, which is incorporated herein by reference. group; 0446 a and b are independently 0, 1, 2 or 3, provided both Substituted AZetidinones of Formula (V) are not zero: provided that when R is —CH=CH- or —C(C-C alkyl)-CH , a is 1; provided that when R is 0434. In another embodiment, substituted azetidinones —CH=CH or —C(C-C alkyl)-CH , b is 1; provided useful in the compositions, therapeutic combinations and that whena is 2 or 3, the R's can be the same or different; and methods of the present invention are represented by Formula provided that when b is 2 or 3, the R's can be the same or (V): different; 0447 and when Q is a bond, R' also can be selected from: R19 (V) Xyla R10 R12 R10 W -v-y--z- -X,-(C), -Y,-(C), -Z, - or Arl-R1-Q S. r r R10 N -X,-(C)-Y-S(O)-; O Ar2 kn or a pharmaceutically acceptable salt thereof or a solvate thereof, or an ester thereof, wherein, in Formula (V) above: 0448 where Mis—O— —S ,—S(O)—or—S(O) ; 0435 A is selected from the group consisting of R-sub 0449 X, Y and Z are independently selected from the stituted heterocycloalkyl, R-substituted heteroaryl, R-sub group consisting of —CH2—, —CH(C-C alkyl)- and stituted benzo-fused heterocycloalkyl, and R-substituted —C(di-(C-C) alkyl); benzo-fused heteroaryl; 0450 R'' and R'' are independently selected from the group consisting of —OR'', OC(O)R'', OC(O)OR' 0436 Ar' is aryl or R-substituted aryl; and OC(O)NR'R'': 0437 Ar is aryl or R-substituted aryl; 0451) R'' and R' are independently selected from the 0438 Q is a bond or, with the 3-position ring carbon of the group consisting of hydrogen, (C-C)alkyl and aryl; or R' aZetidinone, forms the spiro group and R'' together are =O, or R'' and R' together are =O; 0452 d is 1, 2 or 3: 0453 h is 0, 1, 2, 3 or 4: 0454 s is 0 or 1; t is 0 or 1; m, n and pare independently R-(R); and 0-4; provided that at least one of sandt is 1, and the sum of m, R. - n, p, Sandt is 1-6, provided that when p is 0 and t is 1, the Sum of m, S and n is 1-5; and provided that when p is 0 and S is 1. the Sum of m, t and n is 1-5. 0439 R" is selected from the group consisting of: 0455 v is 0 or 1; 0440 —(CH)2g , wherein qC is 2-6, pprovided that when 0456 and k are independently 1-5, provided that the sum Q forms a spiro ring, q can also be Zero or 1; of j, k and V is 1-5: US 2010/0286160 A1 Nov. 11, 2010 29

0457 R’ is 1-3 substituents on the ring carbon atoms selected from the group consisting of hydrogen, (C-Co) alkyl, (C-Co.)alkenyl, (C-Co.)alkynyl, (C-C)cycloalkyl, (VI) (C-C)cycloalkenyl, R'7-substituted aryl, R'7-substituted R benzyl, R''-substituted benzyloxy, R''-substituted aryloxy, Arn 4. -S(O), Ar halogeno, NR'R'', NR'R' (C-C alkylene)- X, Y, NR'R''C(O)(C-C alkylene)-, - NHC(O)R', OH, C-C, RI alkoxy, —OC(O)R', C(O)R'', hydroxy(C-C)alkyl, N (C-C)alkoxy(C-C)alkyl, NO. —S(O).R', S(O) O YA, NR'R'' and —(C-C alkylene)C(O)OR'': when R is a substituent on a heterocycloalkyl ring, R is as defined, or R or a pharmaceutically acceptable salt thereof or a solvate is =O or thereof, or an ester thereof, wherein, in Formula (VI) above: 0468 Ar" is aryl, R'-substituted aryl or heteroaryl; 0469 Ar is aryl or R-substituted aryl; 0470 Ar is aryl or R-substituted aryl; 0471 X and Y are independently selected from the group N M(CH2)-2: O consisting of —CH2—, —CH(lower alkyl)- and —C(lower alkyl)-; and, where R is a substituent on a substitutable ring nitrogen, 0472 R is OR, OC(O)R, OC(O)OR or OC R is hydrogen, (C-C)alkyl, aryl, (C-C)alkoxy, aryloxy, (O)NR'R'': R' is hydrogen, lower alkyl or aryl; or R and R' (C-C)alkylcarbonyl, arylcarbonyl, hydroxy, —(CH2). together are —O; gCONRR18, 0473 q is 0 or 1: 0474 r is 0, 1 or 2: 0475 m and n are independently 0, 1,2,3,4 or 5; provided that the Sum of m, n and q is 1, 2, 3, 4 or 5: O 0476) R' is 1-5 substituents independently selected from R18 the group consisting of lower alkyl, OR, OC(O)R. J O OC(O)OR, –O(CH), OR, OC(O)NR'R'', M N y NRR", NRC(O)R7, NRC(O)OR, NRC(O) (CH2)0-4 O NR7R, NRS(O).R, C(O)OR, C(O)NR'R7, —C(O)R. —S(O)NR'R', S(O).R. O(CH), C 0458 wherein J is - O -, -NH , – NR' or (O)OR. --O(CH), C(O)NR'R'', -(lower alkylene)C(O) —CH2—, OR and CH=CH-C(O)CR; 0459 RandR are independently selected from the group 0477 R is 1-5 substituents independently selected from consisting of 1-3 Substituents independently selected from the group consisting of OR, OC(O)R. —OC(O)CR, the group consisting of (C-C)alkyl, -OR'', —OC(O)R'', O(CH), OR, OC(O)NR'R'', NR'R'', NRC(O) OC(O)OR, O(CH), OR, OC(O)NR'R'', R7, NRC(O)OR, NRC(O)NR7R, NRS(O).R. NR'R's, NRC(O)R's, NRC(O)OR, NRC C(O)OR, C(O)NR'R'', C(O)R, S(O)NR'R'', (O)NR'R'', NRS(O).R, C(O)OR, C(O) S(O).R. —O(CH), C(O)CR, O(CH), C(O) NR'R'', C(O)R', S(O)NR'R', S(O) R', NR'R''. —CF, CN, NO, halogen, -(lower alkylene)C –O(CH), C(O)OR'', O(CH), C(O)NR'R'', (O)OR and CH=CH-C(O)OR; —(C-C alkylene)-C(O)OR'', -CH=CH-C(O)OR'', 0478. R. R7 and Rare independently selected from the —CF, —CN. —NO and halogen; group consisting of hydrogen, lower alkyl, aryl and aryl 0460 R is hydrogen, (C-C)alkyl, aryl (C-C)alkyl, substituted lower alkyl: C(O)R' or C(O)OR'': 0479 R is lower alkyl, aryl or aryl-substituted lower 0461) R' and R7 are independently 1-3 groups indepen alkyl; and dently selected from the group consisting of hydrogen, (C- 0480) R' is 1-5 substituents independently selected from C.)alkyl, (C-C)alkoxy, C(O)CH, NO, NR'R'', OH the group consisting of lower alkyl, -OR. —OC(O)R. and halogeno; OC(O)OR, –O(CH), OR, OC(O)NR'R7, 0462 R'' and R' are independently selected from the NRR", NRC(O)R7, NRC(O)OR, NRC(O) group consisting of hydrogen, (C-C)alkyl, aryl and aryl NR7R, NRS(O).R, C(O)OR, C(O)NR'R7, substituted (C-C)alkyl: —C(O)R. —S(O)NR'R''. —S(O).R. O(CH), C 0463) R' is (C-C)alkyl, aryl or R'7-substituted aryl; (O)OR. - O(CH), C(O)NR'R''. - CF, CN, NO. 0464) R' is hydrogen or (C-C)alkyl; and and halogen. 0465) R' is hydrogen, hydroxy or (C-C)alkoxy. 0481 Methods for making compounds of Formula (VI) 0466 Methods for making compounds of Formula (V) are are well known to those skilled in the art. Non-limiting well known to those skilled in the art. Non-limiting examples examples of suitable methods are disclosed in U.S. Pat. No. of suitable methods are disclosed in U.S. Pat. No. 5,656,624, 5,624,920, which is incorporated herein by reference. which is incorporated herein by reference. Substituted AZetidinones of Formula (VI) Substituted AZetidinones of Formula (VII) 0467. In another embodiment, substituted azetidinones 0482. In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formula methods of the present invention are represented by Formula (VI): (VII): US 2010/0286160 A1 Nov. 11, 2010 30

0488 B is selected from indanyl, indenyl, naphthyl, tet —N(R)(R), lower alkyl, phenyl or R'-phenyl: rahydronaphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is selected from the group consisting of 0495)N(lower R' alkyl)et-NC(O)R''R. is selected from -O-, -CH-, -NH (YII) pyrrolyl pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imida 0496 R's, Rani Rare indéfendently selected from Zolyl, thiazolyl pyrazolyl, thienyl, oxazolyl and furanyl, and the group consisting S. e groups defined for W: or R' for nitrogen-containing heteroaryls, the N-oxides thereof, or is hydrogen and Rand R'7 , together with adjacent carbon atoms to which they are d, form a dioxolanyl ring; 0497) R' is H. lowcôf alkyl, phenyl or phenyl lower alkyl: R15 and / 7\R. (0498), RandR are independently selected from R W Sigisereof, or an ester thereof, Statisfits:wherein: 0483 R' is: 0489 W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonyla lkoxy, (lower alkoxyimino)-lower alkyl, lower alkanedioyl, -- -C(lower alkyl)-, -- lower alkyl lower alkanedioyl, allyloxy, —CF —OCF, benzyl, R'-benzyl, benzyloxy, R-benzyloxy, phenoxy, R7-phenoxy, dioxolanyl, NO, N(R)(R), N(R)(R)- -C(OH)-, -C(CH3)-, -C(CH-Rs)-, lower alkylene-, N(R)(R)-lower alkylenyloxy-, OH, halo geno, CN, N, NHC(O)OR', NHC(O)R', R'' (O) -- O – SNH , (R'(O)S)N , S(O)NH, S(O).R. tert buyldilethylsilyloxymethyl C(OR', C(O)OR', C(O)N(R (R), - CH=CHC(O)R'', -lower alkylene-C (O)R'', R'C(O)(lower alkylenyloxy)-, N(R)(R)C(O) 0484 RandR are independently selected from the group (lower alkylenyloxy)- and consisting of —CH2—, —CH(lower alkyl)-, —C(lower alkyl)-, -CH=CH- and —C(lower alkyl)-CH ; or R' together with an adjacent R, or R' together with an adjacent R. forma —CH=CH-ora—CH=C(lower alkyl)- group; -CH-N R13 0485 u and v are independently 0, 1, 2 or 3, provided both are not zero: provided that when R is —CH=CH- or —C(lower alkyl)-CH , v is 1: provided that when R is for Substitution on ring carbon atoms, and the Substituents on —CH=CH or —C(lower alkyl)-CH , u is 1: provided the Substituted heteroaryl ring nitrogen atoms, when present, that when v is 2 or 3, each R can be the same or different; and are selected from the group consisting of lower alkyl, lower provided that when u is 2 or 3, each R can be the same or alkoxy, C(O)OR', C(O)R', OH, N(R)(R)-lower different; alkylene-, N(R)(R)-lower alkylenyloxy-, - S(O)NH and 0486) R' is selected from B (CH),C(O)—, wherein m 2-(trimethylsilyl)-ethoxymethyl: 0490 R7 is 1-3 groups independently selected from the is 0,1,2,3,4 or 5: B (CH) , wherein q is 0,1,2,3,4, 5 group consisting of lower alkyl, lower alkoxy, —C(O)OH, or 6: B-(CH2), Z-(CH2), , wherein Z is —O—, NO, N(R)(R), OH, and halogeno; —C(O)—, phenylene, N(R)-or-S(O)2 e is 0,1,2, 0491 R and R are independently selected from H or 3, 4 or 5 and r is 0, 1, 2, 3, 4 or 5, provided that the sum of e lower alkyl and r is 0, 1, 2, 3, 4, 5 or 6: B (C-C alkenylene)-; B-(C- 0492) R' is selected from lower alkyl, phenyl, R'-phenyl, C alkadienylene)-; B-(CH), Z-(C-C alkenylene)- benzyl or R-benzyl: wherein Z is as defined above, and whereint is 0, 1, 2 or 3, 10493, R'' is selected from OH, lower alkyl, phenyl, ben provided that the sum oft and the number of carbon atoms in zyl, R'-phenyl or R-benzyl: the alkenylene chain is 2,3,4,5 or 6: B (CH), V (CH.) 0494 R'' is selected from H, OH, alkoxy, phenoxy, ben , wherein V is C-C cycloalkylene, fis 1,2,3,4 or 5 and Zyloxy, g is 0, 1, 2, 3, 4 or 5, provided that the Sum off and g is 1, 2, 3, 4, 5 or 6: B-(CH2), V—(C-C alkenylene)- or B-(C- Calkenylene)-V—(CH), , wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6: B-(CH2)— Z—(CH), V—(CH) , wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, N(R)(R), lower alkyl, phenyl or R'-phenyl: provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6; or 0495) R' is selected from O-, -CH-, -NH-, T-(CH) , wherein T is a C-C cycloalkyl and S is 0, 1, 2, - N(lower alkyl). or NC(O)R': 3, 4, 5 or 6; or 0496 R', R' and R7 are independently selected from 0487 R and R together form the group the group consisting of Hand the groups defined for W: or R' is hydrogen and R'' and R'7, together with adjacent carbon atoms to which they are attached, form a dioxolanyl ring; 0497) R' is H. lower alkyl, phenyl or phenyl lower alkyl: and B-CH=C-: 0498 R and R' are independently selected from the group consisting of phenyl, W-Substituted phenyl, naphthyl, US 2010/0286160 A1 Nov. 11, 2010

W-substituted naphthyl, indanyl, indenyl, tetrahydronaph 0507 R', R. R. R', R, and R are independently thyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, selected from the group consisting of hydrogen, lower alkyl, benzo-fused heteroaryl, W-substituted benzo-fused het lower alkoxy, carboxy, NO, NH, OH, halogeno, lower alky eroaryl and cyclopropyl, wherein heteroaryl is as defined above. lamino, dilower alkylamino, NHC(O)CR, R(O)SNH 0499 Methods for making compounds of Formula (VII) and —S(O)NH2, are well known to those skilled in the art. Non-limiting 0508 R is examples of suitable methods are disclosed in U.S. Pat. No. 5,698,548, which is incorporated herein by reference. Substituted AZetidinones of Formula (VIII) 0500. In another embodiment, substituted azetidinones useful in the compositions, therapeutic combinations and methods of the present invention are represented by Formulas (VIIIA) and (VIIIB): wherein n is 0, 1, 2 or 3: 0509 R is lower alkyl; and (VIIIA) 0510 R is OH, lower alkyl, phenyl, benzyl or substituted B phenyl wherein the Substituents are 1-3 groups independently selected from the group consisting of lower alkyl, lower R A alkoxy, carboxy, NO, NH, OH, halogeno, lower alkylamino B-D and dillower alkylamino; or a pharmaceutically acceptable N salt, solvate, or ester thereof. N 4 O R and (VIIIB) Sterol Absorption Inhibitors of Formula (IX) 0511. In another embodiment, sterol absorption inhibitors R A useful in the compositions and methods of the present inven E tion are represented by Formula (IX): N O R4 (IX) or a pharmaceutically acceptable salt, Solvate, or ester thereof, wherein: (0501) A is —CH=CH-, -C=C- or -(CH,)— wherein p is 0, 1 or 2: 0502 B is

RI or a pharmaceutically acceptable salt, Solvate, or ester R2 thereof, wherein, in Formula (IX) above, 0512 R is H or OG; R3 0513 G and G' are independently selected from the group consisting of H, 0503 B' is

RI =7AR’X –{ A. (0504) Dis-(CH2),C(O) or -(CH2) wherein m is 1, 2, 3 or 4 and q is 2, 3 or 4: 0505 E is Co to Co alkyl or —C(O) (C. to Co)-alkyl, wherein the alkyl is straight or branched, Saturated or con taining one or more double bonds; 0506 R is hydrogen, C-C alkyl, straight or branched, saturated or containing one or more double bonds, or B—(CH), , wherein r is 0, 1, 2, or 3: US 2010/0286160 A1 Nov. 11, 2010 32 and (0526) R' is selected from the group consisting of 0527 (CH) , wherein q is 2-6, provided that when Q forms a spiro ring, q can also be Zero or 1;

0528) —(CH)-E-(CH), wherein E is —O , —C(O)—, phenylene, - NR— or -S(O)2 e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6: 0529) —(C-C)alkenylene-; and 0530 -(CH2), V (CH2). , wherein V is C-C, cycloalkylene, fis 1-5 and g is 0-5, provided that the sum off and g is 1-6. 0531) R'? is: O CHR provided that when R is H or OH, G is not H: 0514) R, R and R are independently selected from the -CH-, -C(C-C alkyl)-, -CF-, group consisting of H. —OH, halogeno, -NH2, azido, (C- C.)alkoxy(C-C)-alkoxy or - W R': 0515 W is independently selected from the group consist ing of NH CO)— —O—C(O)— —O—C(O)—N -N-, or - NO; (R') , NH C(O) N(R) and —O C(S)- N (R') : 0516 RandR are independently selected from the group consisting of H., (C-C)alkyl, aryland aryl(C-C)alkyl: 0532) R' and R'' are independently selected from the 0517 R. R. R. R7, R and R are independently group consisting of —CH2—, —CH((C-C) alkyl)-. selected from the group consisting of H. (C-C)alkyl, aryl —C((C-C) alkyl), —CH=CH- and —C((C-C) alkyl) (C-C)alkyl, —C(O)(C-C)alkyl and —C(O)aryl; =CH ; or 0518) R' is selected from the group consisting of R 0533 R'' together with an adjacent R', or R' together substituted T, R-substituted-T-(C-C)alkyl, R-substi with an adjacent R'', form a -CH=CH- or a -CH=C tuted-(C-C)alkenyl, (C-C alkyl)- group: R-substituted-(C-C)alkyl, R-substituted-(C-C)cy 0534 a and b are independently 0, 1, 2 or 3, provided both are not Zero; cloalkyl and 0535 provided that when Ris-CH=CH-or-C(C- R*-substituted-(C-C)cycloalkyl (C-C)alkyl: C alkyl)-CH , a is 1: 0519) R' is selected from the group consisting of Hand 0536 provided that when Ris-CH=CH-or-C(C- (C-C)alkyl: C alkyl)-CH , b is 1: 0520 T is selected from the group consisting of phenyl, 0537 provided that when a is 2 or 3, each R' can be the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, same or different; and iosthiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imida 0538 provided that when b is 2 or 3, each R' can be the Zolyl and pyridyl; same or different; and when Q is a bond, R' also can be: 0521) R' is independently selected from 1-3 substituents independently selected from the group consisting of halo geno, (C-C)alkyl, -OH, phenoxy, —CF, —NO, (C-C) alkoxy, methylenedioxy, Oxo, (C-C)alkylsulfanyl, (C-C) alkylsulfinyl, (C-C)alkylsulfonyl, —N(CH), —C(O)— NH(C-C)alkyl, —C(O) N((C-C)alkyl), —C(O)— (C-C)alkyl, —C(O)—(C-C)alkoxy and pyrrolidinylcarbonyl; or R17 0522) R' is a covalent bond and R', the nitrogen to which O it is attached and R form a pyrrolidinyl, piperidinyl, N-me thyl-piperazinyl, indolinyl or morpholinyl group, or a (C- C.)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group; 0523 Ar' is aryl or R'-substituted aryl; 0524) Ar is aryl or R''-substituted aryl; s 0525 Q is a bond or, with the 3-position ring carbon of the aZetidinone, forms the spiro group 0539 M is - O -, - S - S(O) or -S(O) ; 0540 X, Y and Z are independently selected from the group consisting of —CH2—, —CH(C-C)alkyl- and N and (0541) R' and R'' are independently selected from the group consisting of 1-3 Substituents independently selected ke from the group consisting of (C-C)alkyl, -OR', —OC(O) R', OC(O)OR', O(CH), OR, OC(O)NR'R'', NR'R'', NRC(O)R’, NRC(O)OR, NRC US 2010/0286160 A1 Nov. 11, 2010

(O)NR'R'', NR'S(O).R, C(O)OR', C(O) or a pharmaceutically acceptable salt, Solvate, or ester NR'R'', C(O)R', S(O)NR'R'', S(O) R', thereof, wherein in Formula (X): –O(CH), C(O)OR', O(CH2)C(O)NR'R'', 0559) R' is selected from the group consisting of H.G, G, -(C-C alkylene)-C(O)OR', CH-CH C(O)OR', G, SOH and - POH: —CF, CN, NO; and halogen; 0560 G is selected from the group consisting of H, (0542) R' and R'' are independently selected from the group consisting of OR', OC(O)R', OC(O)OR and OC(O)NR'R'': RO OR RO OR (0543 R'' and R' are independently selected from the group consisting of H, (C-C)alkyl and aryl; or R'' and R' together are=O, or R'' and R' together are =O; OR, OR, 0544 d is 1, 2 or 3: O O 0545 h is 0, 1, 2, 3 or 4: 0546 s is 0 or 1; t is 0 or 1; m, n and pare independently C(O)OR2 CHOR6 0-4: OR 0547 provided that at least one of sandt is 1, and the sum O of m, n, p, Sandt is 1-6. 0548 provided that when p is 0 and t is 1, the sum of m, s -HC OR5, and n is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5; 0549 v is 0 or 1; RO OR 0550 and k are independently 1-5, provided that the sum OR3a of j, k and V is 1-5: 0551 and when Q is a bond and R' is RaO R OR3

R15 RO O O CHR and —x-i-Y-sous R 16 O CHR O ORS Ar" can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, -HC imidazolyl pyrazolyl, thiazolyl pyrazinyl, pyrimidinyl or pyridazinyl: OR4, 0552) R' and R' are independently selected from the OR3 group consisting of H., (C-C)alkyl, aryland aryl-substituted (Sugar derivatives) (C-C)alkyl, 0561 wherein R, R and R are each independently 0553 R’ is (C-C)alkyl, aryl or R-substituted aryl; selected from the group consisting of H. —OH, halo, -NH2, 0554 R’ is H., (C-C)alkyl, aryl (C-C)alkyl, -C(O) azido, (C-C)alkoxy(C-C)alkoxy or —W R': R' or C(O)OR': 0562 W is independently selected from the group consist 0555 Rand Rare independently 1-3 groups indepen ing of NH CO)— —O C(O)— —O—C(O)—N dently selected from the group consisting of H. (C-C)alkyl, S} s NH C(O) N(R') and —O C(S)-N R") ; (C-C)alkoxy, —C(O)OH, NO, NR'R''. -OH and 0563 Rand Rare each independently selected from the halogeno; and group consisting of H., (C-C)alkyl, acetyl, aryland aryl(C- 0556 R is H, -OH or (C-C)alkoxy. C.)alkyl: 0557 Methods for making compounds of Formula (IX) 0564 R. R. R. R. R. and R“are each independently are well known to those skilled in the art. Non-limiting selected from the group consisting of H., (C-C)alkyl, acetyl, examples of suitable methods are disclosed in U.S. Pat. No. yS.-Calkyl, —C(O)(C-C)alkyl and —C(O)aryl; 5,756,470, which is incorporated herein by reference. 0565 R is independently selected from the group con sisting of R*-substituted T. R*-substituted-T-(C-C)alkyl, Substituted AZetidinones of Formula (X) R-substituted-(C-C)alkenyl, R-substituted-(C-C) 0558. In another embodiment, substituted azetidinones alkyl, R-substituted-(C-C)cycloalkyl and R-substi useful in the compositions and methods of the present inven tuted-(C-C)cycloalkyl(C-C)alkyl; tion are represented by Formula (X) below: 10566) R' is independently selected from the group con sisting of H and (C-C)alkyl: 0567 T is independently selected from the group consist ing of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, (X) thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl pyra Zolyl, imidazolyl and pyridyl; ORI Z AR 0568 R° is independently selected from 1-3 substituents All--- S. which are each independently selected from the group con sisting of H, halo, (C-C)alkyl, -OH, phenoxy, —CF, k —NO, (C-C)alkoxy, methylenedioxy, Oxo, (C-C)alkyl N Sulfanyl. (C-C)alkylsulfinyl, (C-C)alkylsulfonyl, O YA2 —N(CH), —C(O) NH(C-C)alkyl, —C(O)—N(C-C) alkyl). —C(O)—(C-C)alkyl, —C(O)—(C-C)alkoxy and pyrrolidinylcarbonyl; or US 2010/0286160 A1 Nov. 11, 2010 34

0569. R° is a covalent bond and R', the nitrogen to which 0584) i) - SOH; and it is attached and R form a pyrrolidinyl, piperidinyl, N-me 0585 j) - POH: thyl-piperazinyl, indolinyl or morpholinyl group, or a (C- provided that when R' is H, R is not H, -OH, OCH or C.)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, —O-G; N-methylpiperazinyl, indolinyl or morpholinyl group; 0586 Ar' is aryl, R'-substituted aryl, heteroaryl or R'- 0570 G' is represented by the structure: substituted heteroaryl; 0587 Aris aryl, R'-substituted aryl, heteroaryl or R'- substituted heteroaryl; HO 0588 L is selected from the group consisting of: 0589 a) a covalent bond; O O 0590 b)-(CH2) , wherein q is 1-6; C| - Cy C or 0591 c) —(CH)-E-(CH), , wherein E is —O—, N N —C(O)—, phenylene, - NR— or -S(O)2 e is H H 0-5 and r is 0-5, provided that the sum of e and r is 1-6: O 0592 d) —(C-C)alkenylene-: 0593 e) -(CH2), V (CH) , wherein V is R33-CH C-C cycloalkylene, f is 1-5 and g is 0-5, provided that A the Sum off and g is 1-6, and HN 0594 f) wherein R is independently selected from the group con sisting of unsubstituted alkyl, R-substituted alkyl, (R) R15 R17 R 15 (R)alkyl-, -v-y--z- —x-is-y--z- O R 16 R18 R 16 CH2 R15 CH —x-i-Y-so R 16 N HO1 wherein M is —O— —S , —S(O)— or —S(O) ; CH-. CH 0595 X,Y and Zare each independently selected from the group consisting of —CH2—, —CH(C-C)alkyl- and —C((C-C)alkyl)-; N-NH O 0596) R is selected from the group consisting of H and alkyl: 0571) R' is one to three substituents, each Ribeing inde 0597) R' and R'' are each independently selected from pendently selected from the group consisting of HO(O)C the group consisting of 1-3 Substituents which are each inde HO-, HS (CH)S , HN (NH)(NH)C(NH) , pendently selected from the group consisting of (C-C)alkyl, (NH4)C(O) and HO(O)CCH(NH")CHSS : OR', OC(O)R', OC(O)OR', O(CH), OR', 0572 R is independently selected from the group con OC(O)NR'R20, NRR, NRC(O)R2, NRC sisting of H and NH : (O)OR, NRC(O)NR'R'', NR'S(O).R, C(O) 0573 R is independently selected from the group con OR1, C(O)NR'R2, C(O)R', S(O)NR'R'29, S(O) sisting of H, unsubstituted alkyl, R-substituted alkyl, oR', O(CH)-o C(O)CR', O(CH2)C(O) unsubstituted cycloalkyl and R-substituted cycloalkyl; NR'R'', (C-C alkylene)-C(O)OR', -CH=CH-C 0574 G’ is represented by the structure: (O)OR', -CF –CN, NO, and halo: 0598) R' and R7 are each independently selected from the group consisting of —OR', —OC(O)R', —OC(O) OR2, OC(O)NR'R'': 0599 R'' and R' are each independently selected from the group consisting of H. (C-C)alkyl and aryl; or 0600 R'' and R together are =O, or R7 and R' together are —O; wherein R7 and Rare each independently selected from the 0601 d is 1, 2 or 3: group consisting of (C-C)alkyl and aryl; 0602 h is 0, 1, 2, 3 or 4: (0575 R is one to five substituents, each Ribeing inde 0603 s is 0 or 1: pendently selected from the group consisting of 0604 t is 0 or 1: 0576) a) H; 0605 m, nandpare each independently selected from 0-4: (0577 b) OH: 0606 provided that at least one of sandt is 1, and the sum 0578 c) OCH: of m, n, p, Sandt is 1-6, provided that when p is 0 and t is 1. 0579 d) fluorine; the sum of m, n and p is 1-5; and provided that when p is 0 and 0580 e) chlorine: S is 1, the Sum of m, t and n is 1-5; 0581 f). O-G: 0607 v is 0 or 1; 0608 and k are each independently 1-5, provided that the 0583 h). O-G’; Sum of j, k and V is 1-5; US 2010/0286160 A1 Nov. 11, 2010 35

0609 Q is a bond, -(CH2) , wherein q is 1-6, or, with Substituted AZetidinones of Formulae (XI)-(XIII) the 3-position ring carbon of the azetidinone, forms the spiro 0620. An example of a useful substituted azetidinone is group one represented by the Formula (XI):

(XI) R12-(R13): (R),

0610 wherein R' is -- -local- -- -lon wherein R' is defined as above. -la-e- -- O –p. 0621. A more preferred compound is one represented by Formula (XII):

0611) R' and R'' are each independently selected from (XII) the group consisting of —CH2—, —CH(C-C alkyl)-. —C((C-C) alkyl), —CH=CH- and —C(C-C alkyl) =CH-; or R' together with an adjacent R', or R' together with an adjacent R'', form a -CH=CH- or a -CH=C (C-C alkyl)- group: 0612 a and b are each independently 0, 1, 2 or 3, provided both are not zero: provided that when R' is —CH=CH-or —C(C-C alkyl)-CH , a is 1; provided that when R'' is —CH=CH- or —C(C-C alkyl)-CH , b is 1; provided that whenais 2 or 3, each R' can be the same or different; and provided that when b is 2 or 3, each R' can be the same or different; 0613 and when Q is a bond and L is

R 15 0622 Another useful compound is represented by For —x-i-Y-so mula (XIII): R 16 (XIII) O then Ar' can also be pyridyl, isoxazolyl, furanyl pyrrolyl, HO OH thienyl, imidazolyl, pyrazolyl, thiazolyl pyrazinyl, pyrimidi OH nyl or pyridaZinyl: HO 0614) R' and R'' are each independently selected from O the group consisting of H. (C-C)alkyl, aryland aryl-substi OH HO tuted (C-C)alkyl; O 0615I R' is (C-C)alkyl, aryl or R-substituted aryl; 0616) R’ is H., (C-C)alkyl, aryl (C-C)alkyl, -C(O) O OH R' or C(O)OR': 0617 R and Rare each independently selected from N the group consisting of 1-3 Substituents which are each inde pendently selected from the group consisting of H. (C-C) alkyl, (C-C)alkoxy, C(O)OH, NO, NR'R''. -OH F and halo; and 0618. R is H, -OH or (C-C)alkoxy. 0623. Other useful substituted azetidinone compounds include N-sulfonyl-2-azetidinones Such as are disclosed in 0619. Examples of compounds of Formula (X) which are U.S. Pat. No. 4,983,597, ethyl 4-(2-oxoazetidin-4-yl)phe useful in the methods and combinations of the present inven noxy-alkanoates Such as are disclosed in Ram et al., Indian J. tion and methods for making such compounds are disclosed Chem. Sect. B. 29B, 12 (1990), p. 1134-7, diphenyl azetidi in U.S. patent application Ser. No. 10/166,942, filed Jun. 11, nones and derivatives disclosed in U.S. Patent Publication 2002, incorporated herein by reference. Nos. 2002/0039774, 2002/0128252, 2002/0128253 and US 2010/0286160 A1 Nov. 11, 2010 36

2002/0137689, 2004/063929, WO 2002/066464, U.S. Pat. pounds of Formula (I) in combination with one or more Nos. 6,498,156 and 6,703,386, each of which is incorporated cholesterol biosynthesis inhibitors and/or lipid-lowering by reference herein. compounds discussed below. 0624. Other sterol absorption inhibitors useful in the com 0629 Generally, a total daily dosage of cholesterol bio positions, therapeutic combinations and methods of the synthesis inhibitor(s) can range from about 0.1 to about 160 present invention are described in WO 2004/005247, WO mg per day, and preferably about 0.2 to about 80 mg/day in 2004/000803, WO 2004/000804, WO 2004/000805, WO single or 2-3 divided doses. 0250027, U.S. published application 2002/0137689, and the 0630. In another alternative embodiment, the composi compounds described in L. Kvaerne et al., Angew. Chem. Int. tions, therapeutic combinations or methods of the present Ed., 2004, vol. 43, pp. 4653-4656, all of which are incorpo invention can comprise at least one compound of Formula (I), rated herein by reference. An illustrative compound of Kv or pharmaceutically acceptable salts, Solvates, or esters aerne et al. is: thereof, and one or more bile acid sequestrants (insoluble anion exchange resins), co-administered with or in combina tion with the compound of Formula (I), or a pharmaceutically OH acceptable salt, Solvate, isomer, or ester thereof, and a Substi tuted aZetidinone or a substituted B-lactam discussed above. OH 0631 Bile acid sequestrants bind bile acids in the intes tine, interrupting the enterohepatic circulation of bile acids ? and causing an increase in the faecal excretion of steroids. Use of bile acid sequestrants is desirable because of their O N non-systemic mode of action. Bile acid sequestrants can lower intrahepatic cholesterol and promote the synthesis of F Y apo B/E (LDL) receptors that bind LDL from plasma to O further reduce cholesterol levels in the blood. 0632 Generally, a total daily dosage of bile acid seques trant(s) can range from about 1 to about 50 grams per day, and 0625. The compounds of Formulae II-XIII can be pre preferably about 2 to about 16 grams per day in single or 2-4 pared by known methods, including the methods discussed divided doses. above and, for example, in WO 93/02048, U.S. Pat. Nos. 0633. In an alternative embodiment, the compositions or 5,306,817 and 5,561,227, herein incorporated by reference, treatments of the present invention can comprise at least one which describe the preparation of compounds wherein—R'- compound of Formula (I), or pharmaceutically acceptable Q- is alkylene, alkenylene or alkylene interrupted by a hetero salts, solvates, oresters thereof, and one or more IBAT inhibi atom, phenylene or cycloalkylene; WO 94/17038 and U.S. tors. The IBAT inhibitors can inhibit bile acid transport to Pat. No. 5,698,548, herein incorporated by reference, reduce LDL cholesterol levels. Generally, a total daily dosage describe the preparation of compounds wherein Q is a spiro of IBAT inhibitor(s) can range from about 0.01 to about 1000 cyclic group; WO95/08532, U.S. Pat. No. 5,631,365, U.S. mg/day, and preferably about 0.1 to about 50 mg/day in single Pat. No. 5,767,115, U.S. Pat. No. 5,846,966, and U.S. R.E. or 2-4 divided doses. 37,721, herein incorporated by reference, describe the prepa ration of compounds wherein -R-Q- is a hydroxy-substi 0634. In another alternative embodiment, the composi tuted alkylene group: PCT/US95/03196, herein incorporated tions or treatments of the present invention can comprise at by reference, describes compounds wherein -R'-Q- is a least one compound of Formula (I), or pharmaceutically hydroxy-substituted alkylene attached to the Ar" moiety acceptable salts, Solvates, or esters thereof, and nicotinic acid through an —O- or S(O)-group; and U.S. Ser. No. 08/463, (niacin) and/or derivatives thereof. Nicotinic acid and its 619, filed Jun. 5, 1995, herein incorporated by reference, derivatives inhibit hepatic production of VLDL and its describes the preparation of compounds wherein -R-Q- a metabolite LDL and increases HDL and apo A-1 levels. An hydroxy-Substituted alkylene group attached to the azetidi example of a suitable nicotinic acid product is NIASPANR) none ring by a —S(O)o-group. Each of the above patents or (niacin extended-release tablets), which are available from publications are herein incorporated by reference in their Kos entirety. 0635 Generally, a total daily dosage of nicotinic acid or a derivative thereof can range from about 500 to about 10,000 0626. The daily dose of the sterol absorption inhibitor(s) mg/day, preferably about 1000 to about 8000 mg/day, and administered to the subject can range from about 0.1 to about more preferably about 3000 to about 6000 mg/day in single or 1000 mg per day, preferably about 0.25 to about 50 mg/day, divided doses. and more preferably about 10 mg per day, given in a single 0636. In another alternative embodiment, the composi dose or 2-4 divided doses. The exact dose, however, is deter tions or treatments of the present invention can comprise at mined by the attending clinician and is dependent on the least one compound of Formula (I), or pharmaceutically potency of the compound administered, the age, weight, con acceptable salts, Solvates, or estes thereof, and one or more dition and response of the patient. AcylCoA:Cholesterol O-acyltransferase (ACAT) Inhibi 0627. For administration of pharmaceutically acceptable tors, which can reduce LDL and VLDL levels. ACAT is an salts of the above compounds, the weights indicated above enzyme responsible for esterifying excess intracellular cho refer to the weight of the acid equivalent or the base equiva lesterol and may reduce the synthesis of VLDL, which is a lent of the therapeutic compound derived from the salt. product of cholesterol esterification, and overproduction of 0628. In another embodiment of the present invention, the apo B-100-containing lipoproteins. Generally, a total daily compositions or therapeutic combinations described above dosage of ACAT inhibitor(s) can range from about 0.1 to comprise one or more selective CB receptor antagonist com about 1000 mg/day in single or 2-4 divided doses. US 2010/0286160 A1 Nov. 11, 2010 37

0637. In another alternative embodiment, the composi Generally, a total daily dosage of antioxidants or vitamins can tions or treatments of the present invention can comprise at range from about 0.05 to about 10 grams per day in single or least one compound of Formula (I), or pharmaceutically 2-4 divided doses. acceptable salts, Solvates, or esters thereof, and one or more 0647. In another alternative embodiment, the composi Cholesteryl Ester Transfer Protein (“CETP) Inhibitors, such tions or treatments of the present invention can comprise at as torcetrapib. CETP is responsible for the exchange or trans least one compound of Formula (I), or pharmaceutically fer of cholesteryl ester carrying HDL and triglycerides in acceptable salts, Solvates, oresters thereof, and monocyte and VLDL. Pancreatic cholesteryl ester hydrolase (pCEH) inhibi macrophage inhibitors such as polyunsaturated fatty acids tors such as WAY-121898 also can be co-administered with or (PUFA), thyroid hormones including throxine analogues such as CGS-26214 (a thyroxine compound with a fluori in combination. nated ring), gene therapy and use of recombinant proteins 0638 Generally, a total daily dosage of CETP inhibitor(s) Such as recombinantapo E. Generally, a total daily dosage of can range from about 0.01 to about 1000 mg/day, and prefer these agents can range from about 0.01 to about 1000 mg/day ably about 0.5 to about 20 mg/kg body weight/day in single or in single or 2-4 divided doses. divided doses. 0648. Also useful with the present invention are composi 0639. In another alternative embodiment, the composi tions or therapeutic combinations that further comprise hor tions or treatments of the present invention can comprise at mone replacement agents and compositions. Useful hormone least one compound of Formula (I), or pharmaceutically agents and compositions for hormone replacement therapy of acceptable salts, Solvates, or esters thereof, and probucol or the present invention include androgens, estrogens, derivatives thereof, which can reduce LDL levels. progestins, their pharmaceutically acceptable salts and 0640 Generally, a total daily dosage of probucolor deriva derivatives thereof. Combinations of these agents and com tives thereof can range from about 10 to about 2000 mg/day, positions are also useful. and preferably about 500 to about 1500 mg/day in single or 0649. The dosage of androgen and estrogen combinations 2-4 divided doses. vary, desirably from about 1 mg to about 4 mg androgen and from about 1 mg to about 3 mg estrogen. Examples include, 0641. In another alternative embodiment, the composi but are not limited to, androgen and estrogen combinations tions or treatments of the present invention can comprise at Such as the combination of esterified estrogens (sodium least one compound of Formula (I), or pharmaceutically estrone Sulfate and sodium equilin Sulfate) and methyltest acceptable salts, Solvates, or esters thereof, and low-density osterone (17-hydroxy-17-methyl-, (17B)-androst-4-en-3- lipoprotein (LDL) receptor activators. one) available from Solvay Pharmaceuticals, Inc., Marietta, 0642 Generally, a total daily dosage of LDL receptor acti Ga., under the tradename Estratest. vator(s) can range from about 1 to about 1000 mg/day in 0650 Estrogens and estrogen combinations may vary in single or 2-4 divided doses. dosage from about 0.01 mg up to 8 mg, desirably from about 0643. In another alternative embodiment, the composi 0.3 mg to about 3.0 mg. Examples of useful estrogens and tions or treatments of the present invention can comprise at estrogen combinations include: least one compound of Formula (I), or pharmaceutically 0651 (a) the blend of nine (9) synthetic estrogenic sub acceptable salts, Solvates, or esters thereof, and fish oil. Gen stances including sodium estrone sulfate, sodium equilin Sul erally, a total daily dosage of fish oil or Omega 3 fatty acids fate, sodium 17 O-dihydroequilin sulfate, sodium 17 O.-estra can range from about 1 to about 30 grams per day in single or diol sulfate, sodium 17 B-dihydroequilin sulfate, sodium 17 2-4 divided doses. C-dihydroequilenin Sulfate, sodium 17 B-dihydroequilenin 0644. In another alternative embodiment, the composi Sulfate, Sodium equilenin Sulfate and Sodium 17 B-estradiol tions or treatments of the present invention can further com sulfate; available from Duramed Pharmaceuticals, Inc., Cin prise at least one compound of Formula (I), or pharmaceuti cinnati, Ohio, under the tradename Cenestin; cally acceptable salts, Solvates, or esters thereof, and natural 0652 (b) ethinyl estradiol (19-nor-17 C-pregna-1,3,5(10)- water Soluble fibers, such as psyllium, guar, oat and pectin, trien-20-yne-3,17-diol; available by Schering Plough Corpo which can reduce cholesterol levels. Generally, a total daily ration, Kenilworth, N.J., under the tradename Estinyl: dosage of natural water Soluble fibers can range from about 0653 (c) esterified estrogen combinations such as sodium 0.1 to about 10 grams per day in single or 2-4 divided doses. estrone Sulfate and sodium equilin Sulfate; available from 0645. In another alternative embodiment, the composi Solvay under the tradename Estratab and from Monarch tions or treatments of the present invention can comprise at Pharmaceuticals, Bristol, Tenn., under the tradename Men least one compound of Formula (I), or pharmaceutically est; acceptable salts, Solvates, or esters thereof, and plant sterols, 0654 (d) estropipate (piperazine estra-1,3,5(10)-trien-17 plant stanols and/or fatty acid esters of plant stanols, such as one, 3-(sulfooxy)-estrone sulfate); available from Pharmacia sitostanol ester used in BENECOLR) margarine, which can & Upjohn, Peapack, N.J., under the tradename Ogen and reduce cholesterol levels. Generally, a total daily dosage of from Women First Health Care, Inc., San Diego, Calif., under plant sterols, plant stanols and/or fatty acid esters of plant the tradename Ortho-Est; and stanols can range from about 0.5 to about 20grams per day in 0655 (e) conjugated estrogens (17 O.-dihydroequilin, 17 single or 2-4 divided doses. C-estradiol, and 17 B-dihydroequilin); available from Wyeth 0646. In another alternative embodiment, the composi Ayerst Pharmaceuticals, Philadelphia, Pa., under the trade tions or treatments of the present invention can comprise at name Premarin. least one compound of Formula (I), or pharmaceutically 0656 Progestins and estrogens may also be administered acceptable salts, Solvates, or esters thereof, and antioxidants, with a variety of dosages, generally from about 0.05 to about Such as probucol, tocopherol, ascorbic acid, B-carotene and 2.0 mg progestin and about 0.001 mg to about 2 mg estrogen, Selenium, or vitamins such as vitamin B or vitamin B. desirably from about 0.1 mg to about 1 mg progestin and US 2010/0286160 A1 Nov. 11, 2010 about 0.01 mg to about 0.5 mg estrogen. Examples of proges progesterone (pregn-4-ene-320-dione); available from tin and estrogen combinations that may vary in dosage and Solvay under the tradename Prometrium; and medrox regimen include: yprogesterone acetate; available from Pharmacia & Upjohn 0657 (a) the combination of estradiol (estra-1,3,5 (10)- under the tradename Provera. triene-3, 17 B-diol hemihydrate) and norethindrone (17 B-ac 0668. In another alternative embodiment, the composi etoxy-19-nor-17 C-pregn-4-en-20-yn-3-one); which is avail tions, therapeutic combinations or methods of the present able from Pharmacia & Upjohn, Peapack, N.J., under the invention can comprise at least one compound of Formula (I), tradename Activella; or pharmaceutically acceptable salts, Solvates, isomers or 0658 (b) the combination of levonorgestrel (d(-)-13 esters thereof, and one or more obesity control medications. B-ethyl-17 C-ethinyl-17 C.-hydroxygon-4-en-3-one) and ethi Useful obesity control medications include, but are not lim nyl estradial; available from Wyeth-Ayerst under the trade ited to, drugs that reduce energy intake or Suppress appetite, name Alesse, from Watson Laboratories, Inc., Corona, Calif., drugs that increase energy expenditure and nutrient-partition under the tradenames Levora and Trivora, Monarch Pharma ing agents. Suitable obesity control medications include, but ceuticals, under the tradename Nordette, and from Wyeth are not limited to, noradrenergic agents (such as diethylpro Ayerst under the tradename Triphasil; pion, mazindol, phenylpropanolamine, phentermine, phen 0659 (c) the combination of ethynodiol diacetate (19-nor dimetrazine, phendamine tartrate, methamphetamine, phen 17 C-pregn-4-en-20-yne-3 B, 17-diol diacetate) and ethinyl dimetrazine and tartrate); serotonergic agents (such as estradiol; available from G. D. Searle & Co., Chicago, Ill., sibutramine, fenfluramine, dexfenfluramine, fluoxetine, flu under the tradename Demulen and from Watson under the Voxamine and paroxtine); thermogenic agents (such as ephe tradename Zovia: drine, caffeine, theophylline, and selective B3-adrenergic 0660 (d) the combination of desogestrel (13-ethyl-11 agonists); alpha-blocking agents; kainite or AMPA receptor methylene-18,19-dinor-17 C.-pregn-4-en-20-yn-17-ol) and antagonists; leptin-lipolysis stimulated receptors; phosphodi ethinyl estradiol; available from Organon under the trade esterase enzyme inhibitors (such as milrinoone, theophylline, names Desogen and Mircette, and from Ortho-McNeil Phar vinpocetine, EHNA (erythro-9-(2-hydroxy-3-monyl)ad maceutical, Raritan, N.J., under the tradename Ortho-Cept; enine), sildenafil citrate, marketed as VIAGRAR), and tadala 0661 (e) the combination of norethindrone and ethinyl fil, marketed as Clalis(R); compounds having nucleotide estradiol; available from Parke-Davis, Morris Plains, N.J., sequences of the mahogany gene; fibroblast growth factor-10 under the tradenames Estrostep and FemHRT, from Watson polypeptides; monoamine oxidase inhibitors (such as under the tradenames Microgestin, Necon, and Tri-Norinyl, befloxatone, moclobemide, brofaromine, phenoxathine, esu from Ortho-McNeil under the tradenames Modicon and prone, befol, toloxatone, pirlindol, amiflamine, Sercloremine, Ortho-Novum, and from Warner Chilcott Laboratories, baZinaprine, lazabemide, millacemide and caroXaZone); com Rockaway, N.J., under the tradename Ovcon, pounds for increasing lipid metabolism (such as evodiamine 0662 (f) the combination of norgestrel ((+)-13-ethyl-17 compounds); and lipase inhibitors (such as orlistat). Gener hydroxy-18,19-dinor-17 C-preg-4-en-20-yn-3-one) and ethi ally, a total dosage of the above-described obesity control nyl estradiol; available from Wyeth-Ayerst under the trade medications can range from 1 to 3,000 mg/day, desirably names OVral and Lof Ovral, and from Watson under the from about 1 to 1,000 mg/day and more desirably from about tradenames Ogestrel and Low-Ogestrel; 1 to 200 mg/day in single or 2-4 divided doses. 0663 (g) the combination of norethindrone, ethinyl estra 0669. The compositions, therapeutic combinations or diol, and mestranol (3-methoxy-19-nor-17 C-pregna-1,3,5 methods of the present invention can comprise at least one (10)-trien-20-yn-17-ol); available from Watson under the compound of Formula (I), or pharmaceutically acceptable tradenames Brevicon and Norinyl: salts, Solvates, isomers or esters thereof, and one or more 0664 (h) the combination of 17 f-estradiol (estra-1,3,5 blood modifiers which are chemically different from the sub (10)-triene-3,17 B-diol) and micronized norgestimate (17 stituted aZetidinone and Substituted B-lactam compounds C-17-(Acetyloxyl)-13-ethyl-18,19-dinorpregn-4-en-20-yn (such as compounds II-XIII above) and the lipid modulating 3-one3-oxime); available from Ortho-McNeil under the agents discussed above, for example, they contain one or tradename Ortho-Prefest; more different atoms, have a different arrangement of atoms 0665 (i) the combination of norgestimate (18,19-dinor or a different number of one or more atoms than the sterol 17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-, absorption inhibitor(s) or lipid modulating agents discussed oxime, (17(C)-(+)-) and ethinyl estradiol; available from above. Useful blood modifiers include but are not limited to Ortho-McNeil under the tradenames Ortho Cyclen and Ortho anti-coagulants (argatroban, bivalirudin, dalteparin Sodium, Tri-Cyclen; and desirudin, dicumarol, lyapolate Sodium, nafamo.stat mesy 0.666 (j) the combination of conjugated estrogens (sodium late, phenprocoumon, tinzaparin sodium, warfarin Sodium); estrone Sulfate and sodium equilin Sulfate) and medroX antithrombotic (Abcoximab, aspirin, anagrelide hydrochlo yprogesterone acetate (20-dione, 17-(acetyloxy)-6-methyl-, ride, Beraprost, bivalirudin, ciloStaZol, Carbasalate calcium, (6(C))- pregn-4-ene-3); available from Wyeth-Ayerst under Cloricromen, Clopidogrel, dalteparin sodium, danaparoid the tradenames Premphase and Prempro. sodium, dazoxiben hydrochloride, Ditazole, Ditazole, Dipy 0667. In general, a dosage of progestins may vary from ridamole, Eptifibatide, efegatran Sulfate, enoxaparin Sodium, about 0.05 mg to about 10 mg or up to about 200 mg if fluretofen, ifetroban, ifetroban sodium, Indobufen, Iloprost, microsized progesterone is administered. Examples of lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban progestins include norethindrone; available from ESI Led acetate, Picotamide, Prasugrel, Prostacyclin, Treprostinil, erle, Inc., Philadelphia, Pa., under the tradename Aygestin, Ticlopidine, Treprostinil, Triflusal, roxifiban acetate, from Ortho-McNeil under the tradename Micronor, and from Sibrafiban, tinzaparin Sodium, trifenagrel, abciximab, Vita Watson under the tradename Nor-QD; norgestrel; available min Kantagonists, Zolimomab aritox, enzymes such as from Wyeth-Ayerst under the tradename Ovrette; micronized Alteplase, Ancrod, Anistreplase, Brinase, Drotrecogin alfa, US 2010/0286160 A1 Nov. 11, 2010 39

Fibrinolysin, Protein C. Reteplase, Saruplase, Steptokinase, chloride, cetamolol hydrochloride, cicloprolol hydrochlo Tenecteplase, and Urokinase), otherantithrobotic agents such ride, dexpropranolol hydrochloride, diacetolol hydrochlo as Aragatroban, Bivalirudin, Dabigatran, Desirudin, Jirduin, ride, dilevalol hydrochloride, esmolol hydrochloride, Lepirudin, Melagatran, and Ximelagatran); fibrinogen recep exaprolol hydrochloride, flestolol sulfate, labetalol hydro tor antagonists (roxifiban acetate, fradafiban, orbofiban, chloride, levobetaxolol hydrochloride, levobunolol hydro lotrafiban hydrochloride, tirofiban, xemilofiban, monoclonal chloride, metalol hydrochloride, metoprolol, metoprolol tar antibody 7E3, sibrafiban); platelet inhibitors (cilostazol, clo trate, nadolol, pamatolol Sulfate, penbutolol Sulfate, pidogrel bisulfate (marketed as Plavix.R.), epoprostenol, epo practolol, propranolol hydrochloride, so talol hydrochloride, prostenol sodium, ticlopidine hydrochloride, aspirin, ibupro timolol, timolol maleate, tiprenolol hydrochloride, tolamolol, fen, naproxen, Sulindac, idomethacin, mefenamate, bisoprolol, bisoprolol fumarate, nebivolol); adrenergic droxicam, diclofenac, Sulfinpyrazone, piroxicam, dipy stimulants; angiotensin converting enzyme (ACE) inhibitors ridamole); platelet aggregation inhibitors (acadesine, bera (benazepril hydrochloride (marketed as LOTENSINR), prost, beraprost sodium, ciprostene calcium, itaZigrel, lifariz benazeprilat, captopril (marketed as CAPTOENR), delapril ine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, hydrochloride, fosinopril sodium, libenzapril, moexipril fradafiban, orbofiban, tirofiban, xemilofiban); hemorrheo hydrochloride (marketed as UNIVASCR), pentopril, perin logic agents (pentoxifylline); lipoprotein associated coagula dopril, quinapril hydrochloride (marketed as ACCUPRIL(R), tion inhibitors; Factor VIIa inhibitors (4H-31-benzoxazin-4- quinaprilat, ramipril (marketed as RAMACE(R) and ones, 4H-3,1-benzoxazin-4-thiones, quinazolin-4-ones, ALTACER) (or ACE/NEP inhibitors such as ramipril, mar quinazolin-4-thiones, benzothiazin-4-ones, imidazolyl-bo keted as DELIXR/TRITACE(R), spirapril hydrochloride, ronic acid-derived peptide analogues TFPI-derived peptides, peridopril, (marketed as ACEONR), spiraprilat, trandolapil naphthalene-2-sulfonic acid (1-3-(aminoiminomethyl)- (marketed as MAVIKR), teprotide, enalapril maleate (mar benzyl-2-oxo-pyrrolidin-3-(S)-y1} amide trifluoroacetate, keted as VASOTECR), lisinopril (marketed as ZESTRIL(R), dibenzofuran-2-sulfonic acid 1-3-(aminomethyl)-benzyl Zofenopril calcium, perindopril erbumine); antihypertensive 5-oxo-pyrrolidin-3-yl)-amide, tolulene-4-sulfonic acid {1- agents (althiazide, benzthiazide, captopril, carvedilol, chlo 3-(aminoiminomethyl)-benzyl-2-oxo-pyrrolidin-3-(S)- rothiazide sodium, clonidine hydrochloride, cyclothiazide, y1}-amide trifluoroacetate, 3,4-dihydro-1H-isoquinoline-2- delapril hydrochloride, dilevalol hydrochloride, doxazosin sulfonic acid (1-3-(aminoiminomethyl)-benzyl)-2-oxo mesylate, fosinopril sodium (marketed as MONOPRIL(R), pyrrolin-3-(S)-yl)-amide trifluoroacetate); Factor Xa guanfacine hydrochloride, lomerizine, methyldopa, meto inhibitors (disubstituted pyrazolines, disubstituted triazo prolol succinate, moexipril hydrochloride, monatepil male lines, Substituted n-(aminoiminomethyl)phenyl propyla ate, pelanserin hydrochloride, phenoxybenzamine hydro mides, Substituted n-(aminomethyl)phenyl propylamides, chloride, praZosin hydrochloride, primidolol, quinapril tissue factor pathway inhibitor (TFPI), low molecular weight hydrochloride, quinaprilat, ramipril, teraZosinhydrochloride, heparins (such as dalteparin Sodium, marketed as FRAG candesartan, candesartan cilexetil, telmisartan, amlodipine MIN(R), heparinoids, benzimidazolines, benzoxazolinones, besylate, amlodipine maleate, bevantolol hydrochloride); benzopiperazinones, indanones, dibasic (amidinoaryl) pro angiotensin II receptor antagonists (candesartan, irbesartan, panoic acid derivatives, amidinophenyl-pyrrolidines, amidi losartan potassium, candesartan cilexetil, telmisartan); anti nophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidi anginal agents (amlodipine besylate, amlodipine maleate, noindoles, amidinoazoles, bis-arly Sulfonylaminobenzamide betaxolol hydrochloride, bevantolol hydrochloride, buto derivatives, peptidic Factor Xa inhibitors). prozine hydrochloride, carvedilol, cinepazet maleate, meto 0670. The compositions, therapeutic combinations or prolol Succinate, molsidomine, monatepil maleate, primi methods of the present invention can comprise at least one dolol, ranolazine hydrochloride, tosifen, Verapamil compound of Formula (I), or pharmaceutically acceptable hydrochloride); coronary vasodilators (fostedil, azaclorzine salts, Solvates, isomers or esters thereof, and one or more hydrochloride, chromonar hydrochloride, clonitrate, dilt cardiovascular agents which are chemically different from iazem hydrochloride, dipyridamole, droprenilamine, erythri the Substituted aZetidinone and Substituted B-lactam com tyl tetranitrate, isosorbide dinitrate, isosorbide mononitrate, pounds (such as compounds II-XIII above) and the lipid lidoflazine, mioflazine hydrochloride, mixidine, molsidom modulating agents discussed above, for example, they con ine, nicorandil, nifedipine, nisoldipine, nitroglycerine, Oxpre tain one or more differentatoms, have a different arrangement nolol hydrochloride, pentrinitrol, perhexyline maleate, pre of atoms or a different number of one or more atoms than the nylamine, propatyl nitrate, terodiline hydrochloride, sterol absorption inhibitor(s) or PPAR receptor activators dis tolamolol, Verapamil); diuretics (the combination product of cussed above. Useful cardiovascular agents include but are hydrochlorothiazide and spironolactone and the combination not limited to calcium channel blockers (clentiazem maleate, product of hydrochlorothiazide and triamterene). amlodipine besylate (marketed as NORVASCR) and 0671 The compositions, therapeutic combinations or LOTREL(R), isradipine, nimodipine, felodipine (marketed as methods of the present invention can comprise at least one PLENDIL(R), nilvadipine, nifedipine, teludipine hydrochlo compound of Formula (I), or pharmaceutically acceptable ride, diltiazem hydrochloride (marketed as CARDIZEMR), salts, Solvates, isomers or esters thereof, and one or more belfosdil, Verapamil hydrochloride (marketed as CALANR), antidiabetic medications for reducing blood glucose levels in fostedil), nifedipine (marketed as ADALATR), nicardipine a patient. Useful antidiabetic medications include, but are not (marketed as CARDENER), nisoldipine (marketed as limited to, drugs that reduce energy intake or Suppress appe SULAR(R), bepridil (marketed as VASCORR); adrenergic tite, drugs that increase energy expenditure and nutrient-par blockers (fenspiride hydrochloride, labetalol hydrochloride, titioning agents. Suitable antidiabetic medications include, proroxan, alfuzosin hydrochloride, acebutolol, acebutolol but are not limited to, Sulfonylurea (Such as acetohexamide, hydrochloride, alprenolol hydrochloride, atenolol, bunolol chlorpropamide, gliamilide, gliclazide, glimepiride, glipiz hydrochloride, carteolol hydrochloride, celiprolol hydro ide, glyburide, glibenclamide, tolaZamide, and tolbutamide), US 2010/0286160 A1 Nov. 11, 2010 40 meglitinide (such as repaglinide and nateglinide), biguanide CB receptor antagonist and at least one cholesterollowering (such as metforminand buformin), alpha-glucosidase inhibi compound, for example a sterol absorption inhibitor tor (such as acarbose, miglitol, camiglibose, and Voglibose), described above. The reduction in plasma concentration of certain peptides (such as amlintide, pramlintide, exendin, and sterols or 5C-stanols can range from about 1 to about 70 GLP-1 agonistic peptides), and orally administrable insulin or insulin composition for intestinal delivery thereof. Gener percent, and preferably about 10 to about 50 percent. Meth ally, a total dosage of the above-described antidiabetic medi ods of measuring serum total blood cholesterol and total LDL cations can range from 0.1 to 1,000 mg/day in single or 2-4 cholesterol are well known to those skilled in the art and for divided doses. example include those disclosed in PCT WO 99/38498 at 0672 Mixtures of two, three, four or more of any of the page 11, incorporated by reference herein. Methods of deter pharmacological or therapeutic agents described above can mining levels of other sterols in serum are disclosed in H. be used in the compositions and therapeutic combinations of Gylling et al., "Serum Sterols During Stanol Ester Feeding in the present invention. a Mildly Hypercholesterolemic Population”. J. Lipid Res.40: 0673. Since the present invention relates to treating con 593-600 (1999), incorporated by reference herein. ditions as discussed above, by treatment with a combination 0677. The treatments of the present invention can also of active ingredients wherein the active ingredients may be reduce the size or presence of plaque deposits in vascular administered separately, the invention also relates to combin ing separate pharmaceutical compositions in kit form. That is, vessels. The plaque Volume can be measured using (IVUS), in a kit is contemplated wherein two separate units are com which a tiny ultrasound probe is inserted into an artery to bined: a pharmaceutical composition comprising at least one directly image and measure the size of atherosclerotic selective CB receptor antagonist of Formula (I), or a phar plaques, in a manner well known to those skilled in the art. maceutically acceptable salt, Solvate, isomer, or ester thereof, and a separate pharmaceutical composition comprising at Synthesis least one cholesterol lowering compound as described above. The kit will preferably include directions for the administra tion of the separate components. The kit form is particularly 0678. The following may be referred to herein by the advantageous when the separate components must be admin abbreviations indicated: tetrahydropyran (THP), tetrahydro istered in different dosage forms (e.g., oral and parenteral) or furan (THF), methanesulfonyl chloride (MsCl), 1-chloroet are administered at different dosage intervals. hyl chloroformate (ACECI), ethyl acetate (EtOAc), 1,1'-bis 0674. In yet another embodiment, the present invention (diphenylphosphino) ferrocene (dppf), ethanol (EtOH), N-(3- provides a method of treating, reducing, or ameliorating a dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride disease or condition selected from the group consisting of (EDC), 1-3-(dimethylamino)propyl-3-ethylcarbodiimide metabolic syndrome, obesity, waist circumference, abdomi methiodide (EDCI), 1-hydroxybenzotriazole (HOBT), N,N- nal girth, lipid profile, insulin sensitivity, neuroinflammatory dimethylformamide (DMF), acetonitirile (MeCN), propioni disorders, cognitive disorders, psychosis, addictive behavior, trile (EtON), N-methylmorpholine-N-oxide (NMO), 3-chlo gastrointestinal disorders, vascular conditions, hyperlipi roperoxybenzoic acid (MCPBA), methanol (MeOH), room daemia, atherosclerosis, hypercholesterolemia, sitoster temperature (RT), liquid chromatography mass spectrometry olemia, Vascular inflammation, stroke, diabetes, and cardio (LCMS), high performance liquid chromatography (HPLC), vascular conditions, and/or reduce the level of sterol(s) in a patient in need thereof, comprising administering to said and thin-layer chromatography (TLC). patient an effective amount of at least one compound of 0679 Piperazines g are prepared according the steps out Formula (I), or a pharmaceutically acceptable salt, Solvate, lined in Scheme A. A benzyl protected ethanolamine a can be isomer, or ester thereof, and one or more cholesterollowering heated with an epoxide b to furnish a mixture of the amino compound. alcohols c and d. The alcohols c and d can be converted into 0675. The treatment compositions and therapeutic combi the diaminee via sequential treatment with MsCl followed by nations comprising at least one compound of Formula (I) and Are NH. The diamine e can be converted into the piperazine at least one cholesterol lowering agent can inhibit the intes fvia deprotection of the THP group in e followed by activa tinal absorption of cholesterol in mammals can be useful in the treatment and/or prevention of conditions, for example tion of the alcohol. The benzyl group in f can be removed via vascular conditions, such as atherosclerosis, hypercholester treatment with ACECI followed by basic hydrolysis which olemia and sitosterolemia, stroke, obesity and lowering of provides piperazines g. plasma levels of cholesterol in mammals, in particular in 0680 All LCMS (MH") values reported herein are the mammals. observed values. 0676 In another embodiment of the present invention, the compositions and therapeutic combinations of the present invention can inhibit sterol or 5C.-stanol absorption or reduce Scheme A plasma concentration of at least one sterol selected from the group consisting of phytosterols (such as sitosterol, campes (R') OTHP terol, Stigmasterol and avenosterol) and/or 5C.-Stanol (Such as cholestanol, 5C-campestanol, 5C.-sitostanol), cholesterol and H mixtures thereof. The plasma concentration can be reduced Cr- He by administering to a mammal in need of Such treatment an H8. D& Arl effective amount of at least one treatment composition or b therapeutic combination comprising at least one selective US 2010/0286160 A1 Nov. 11, 2010 41

-continued -continued (R) (R') OTHP 17a-1 N 14 1) ACECI Ho 2) 1 NNaOH/ t -- Ar2 MeOH Arl Arl C f (R) 14n1(R') OTHP HN17 1) MsCl Ho Air 2) ArNH) na OH Arl d 9. (R') N1/n-11/ OTHP 1) TsOH or HCI He 0681 Also, chiral epoxides, such as handi, can be utilized 2) PPhiBr as that described in Scheme A to provide enantiopure pipera nAr2 3) heat zines and k (Scheme B). The chiral epoxides can be prepared either via asymmetric di-hydroxylation of a styrene (e.g. Arl Sharpless AD mix a or p) or chiral reduction of a bromo e ketone (e.g. CBS reduction). These methods allow the prepa ration of either enantiomer of the epoxide, h or i.

Scheme B OH Sharpless AD HO E N-1\,. 1) MsCl O H 21N C. or B O --- aw 2) NaOH 'A OH h

O

O

Br Chiral reduction NaOH S. --- O Ho- DN Air Arl

-Sell-OTHP Steps outlined in Scheme A 8. US 2010/0286160 A1 Nov. 11, 2010 42

0682. Further functionalization of piperazine g into com pounds is illustrated in Scheme C. piperazine g can be trans formed into the alkylated derivatives such as 1 and m via reductive alkylation (Na(AcO)BH/XC(O)R) and/or direct alkylation (base/X(R). Ms) conditions. Also, the piperazine g can be converted into an amide or Sulfonamide using stan dard techniques (e.g. n and o). Hydroxy-ethyl analogs p can be made via reaction of a hydroxy-mesylate or epoxide with piperazine g.

X 1. 1n (R )p x^. R3 R3 (R) Na(AcO)BH HN R OH X 1/. p n O N R3 R3 NA2 R3 OH Arl 9. R3 O

K2CO3 susn B OH X n1 SOCI O EDCHOBT EtN (R)2 O

(R) O O ls 1(R') X Nb1N^ n1/. (R') US 2010/0286160 A1 Nov. 11, 2010 43

0683 Also, the chiral piperazine j can be functionalized according to the transformations outlined in Scheme C to furnish the corresponding chiral derivatives (Scheme D).

Scheme D R2 R3 R3

ls (R') R X R33 R3 X 1. lay OMS (R') Na(AcO)3BH HN R3 OH X 1y. ne O N R3 R3 YA2 R3 OH N Arl X NA2 X R2 Arl i C O Arl R3 l

O K2CO3 X SOCI O XN ul Nb1 2 EtN (R) B, OH EDCHOBT O X OMS O

susYB, C

(R) O O X ls 1/(R') X n-n1N^ -

n n Ar2 RI) Ar2 X -y ri. YB, u N i. US 2010/0286160 A1 Nov. 11, 2010 44

0684. Also, the chiral piperazine k can be functionalized according to the transformations outlined in Scheme C to furnish the corresponding chiral derivatives (Scheme E).

Scheme E R3 R3 R3 (R) X X 1/ p -N'- OMS R3 R3 (R) Na(AcO)BH HN R3 OH X 1/ p

O K2CO3 X SOCI O XN ul NB1 2 EtN (R)2 B, OH EDCHOBT O X OMS

(R) O O ls (R') x Y^ R'), X 1,/ n-n1,7. N O NS NA2 X - Ar2 Arl YB, N 7. Arl W N y YA2 Arl

0685 Certain reagents for functionalization of the pipera Zine core can be prepared in chiral form. These reagents can be prepared by known procedures in the art, and non-limiting examples are illustrated below. 0686. A ketone can be transformed into either enantiomer of the corresponding alcohol by several methods (1.reduction 2. enzymatic resolution or chiral reduction). Activation of the alcohol (MsCl/EtN) provides the either enantiomer of the mesylate which can be coupled to either enantiomer of the piperazine ( or k) which provides access to four possible diastereomers in pure form (e.g. aa, ab, ac, or ad; Scheme F). US 2010/0286160 A1 Nov. 11, 2010

Scheme F R3 X N -:/ N E YA2 i.

88 R3 R3 Rs R 3 2)1) NaBH4Enzymatic x1 yori x1 oMs - -N Resolution O MSC O 1N / O EtN N X O Chiral reduction l l E NA2

X OH X OMs ir ab R3 X -N-N / N YA2 Arl

80

Rs 1N -^ N YA2 Arl ad

0687 Using procedures known in the art, substituted alk enes can be prepared from olefination of ketones (Wittig.) and/or transition metal mediated methods (Pd(0)/metal-alk enyl derivative). These can be transformed into chiral diols via asymmetric methods (e.g. Sharpless AD mixa or 13). The formed chiral diol can be transformed into the corresponding mesylate and/or epoxide. These can be reacted with the chiral piperazines, and k, to provide four possible diastereomers in pure form (e.g. ae,afag, and ah; Scheme G). US 2010/0286160 A1 Nov. 11, 2010 46

HC = PPh

MSC --- O 1. O O EtN O AD mix f.

X-Br, -l or -OTf R3

X (R') 8. N ~ 1n (R'), R3 OH NuE YA2 HN A. i. n 8.

X NCy irl R 3 vs O X (R') NaOH O O O RoH1. ~ N E YA2 ir af

X (R')

Ri (S1,vOH N NA2 Arl ag

X (R'),

RoHx 17,N YA2 Arl ah

0688 Also, the chiral piperazine cores, and k, can be reacted with chiral epoxides to produce chiral piperazine alcohol derivatives ai, aj, ak, and al (Scheme H). The requisite chiral epoxides can be prepared by procedures known in the art (e.g. chiral reduction of a bromo-ketone and/or asymmet ric epoxidation of an alkene). US 2010/0286160 A1 Nov. 11, 2010 47

O X

()e Br O O H OH X 1. (R') X Asymmetric >% HN A. N-4 He-epoxidation H Wy') N NA2 Arl k Base

(R') (R') XS-7, O x -á, O

ai a.

(RI) (R) X X 1 p X AN 1 p Š OH O O N N YA2 NA2 Arl Arl ak al

0689. The following examples were prepared according to procedures known in the art. -continued

ADmix C. O Her Scheme 1 O

HeMeNCH(OtBu)2 > O O

HO

O

O PPh3P-ch > CHSOCI > HeEtN O US 2010/0286160 A1 Nov. 11, 2010 48

-continued -continued >

> O

0692 Methyl triphenylphosphonium bromide (15.3 g) was suspended in THF (100 mL) at 0°C. n-Butyllithium (25.6 mL of a 1.6M solution in hexanes) was added dropwise at 0° C. The yellow solution was stirred at 0°C. (1 h). The ketone (4.7 g. 21.4 mmol) was added, and the resulting slurry was stirred at 25°C. (18h). The mixture was quenched with water, and the mixture was extracted with EtO. The combined EtO Step 1 layers were washed with brine and dried (MgSO). The mix ture was filtered and concentrated. The residue was filtered through a plug of SiO (rinsing with CHCl). The solution was concentrated. The residue was purified via gradient flash O MeNCH(OtBu)2 chromatography (5/1 hexanes/EtOAc, SiO) which furnished HO 2.45 g (52%) of the alkene as a colorless oil.

O Step 3 0693

O

ADmix C. > O

(0690. The carboxylic acid (10 g, 60.9 mmol) and MeNCH(OtBu) (25 g) were heated in toluene (300 mL) for 5 hours (85°C.). More Me NCH(OtBu), (25 g) was added, and the reaction was heated at 85° C. for 14 hours. The solution was partitioned between EtOAc and sat. NaHCO (ag.). The aqueous layer was extracted with EtOAc. The com bined organic layers were washed with brine and dried over MgSO. The solution residue was filtered through a plug of SiO rinsing with CHC1. This afforded 4.7 g (35%) of the tert-butyl ester as a solid. Step 2 0691 0694. The alkene (2.45 g, 11.2 mmol) and AD mixa (17g) were taken up in tert-butanol/water (1/1, 90 mL), and the mixture was stirred at 25° C. (3 days). The mixture was O PPh3P = CH2 cooled to 0°C., and water (150 mL) was added. Solid NaSO -- (17 g) was added slowly to the mixture at 0°C. The solution was stirred at 0°C. (1 h) and then at 25°C. (1 h). The mixture was extracted with EtOAc. The combined organic layers were >ry washed with brine and dried (MgSO). The solution was filtered and concentrated to give the crude diol. The residue was purified via gradient flash chromatography (1/1 hexanes/ EtOAc, SiO) which furnished 1.97g (70%) of the alkene as a colorless oil that slowly solidified. US 2010/0286160 A1 Nov. 11, 2010 49

Step 4 0695

O

HO O MeNCH(OtBu)2 CHSOCI He He EtN

O HePPhP=CH

S. OMS $ Y ADmix C.

(0696. The diol (1.97g, 7.8 mmol) and EtN (1.3 mL) were taken up in CHCl at 0°C. Methanesulfonyl chloride (1.2 mL) in CHCl (20 mL) was added dropwise at 0°C. The CHSOC, solution was stirred at 0°C. for 15 minutes. The solution was OH Et3N washed with sat. NaHCOs. The aqueous layer was

extracted with CHC1. The combined organic layers were dried (MgSO), filtered, and concentrated. The mesylate was used in the next reaction without further purification. 3 NNaOH OMS Step 5

0697

3 NNaOH > O H II

OMS 0699. In an analogous fashion, the 1,3-disubstituted ketone was processed as that described above for the 1,4- disubstituted analog (Scheme 1) which provided the 1,3- disubstituted ester-epoxide II (Scheme 2).

O > Scheme 3 Dimethylformamide s HOC 21 di-tert-butyl acetal S O toluene I s N reflux N Br Step 1

0698. The mesylate from Step 4 was partitioned between toluene and 3 N. NaOH (1/1, 80 ml), and the resulting mixture was stirred at 25°C. for 2 h. The layers were sepa- O rated, and the aqueous layer was extracted with EtOAc. The ! combined organic layers were washed with brine and dried t-BuO 21 KFB (MgSO). Filtration and concentration provided a yellow oil. PdCl2(dppf)2-CH2Cl2 Purification of the residue via gradient flash chromatography s Br EtN, MeOH (0-10% EtOAc/hexanes, SiO) gave the epoxide I as a color- Step 2 less oil. US 2010/0286160 A1 Nov. 11, 2010 50

ously at RT for 48 h. After that time, NaSO (8.0 g) was -continued added and the mixture was stirred at RT for 1 h. The mixture O was then diluted with 2-propanol and stirred for 1 h. The organic layer was separated, dried over NaSO4, filtered and concentrated. The crude product was purified via flash chro t-BuO 21 ---ADMix-C., t-BuOH/H2O matography (SiO: gradient elution, 100:0 to 50:50 hexanes: N Step 3 EtOAc) to afford the diol (1.18 g. 82%) as a clear oil that N crystallized upon standing. Step 4: (0703. To a solution of the diol (1.37 g, 5.4 mmol) in CHCl (30 mL) was added EtN (650 mg. 6.5 mmol) fol lowed by methanesulfonyl chloride (744 mg. 6.5 mmol). The solution was stirred at RT for 3 h. After that time, the solution was diluted with CH2Cl and washed with NaHCO (aq). The aqueous layer was extracted with CHCl (2x). The com bined organic layers were dried over NaSO filtered and concentrated in vacuo. The crude product was purified via flash chromatography (SiO: gradient elution, 100:0 to 50:50 hexanes: EtOAc) to afford the mesylate (1.45 g, 81%) as a clear oil. Scheme 4

MeOC N . Step 1: t l HerPdCl2(dppf)2-CH2Cl2 EtN, MeOH 0700. To a solution of the 6-bromonicotinic acid (2.5 g. N N C Steps 1 12.4 mmol) in toluene (25 mL) was added dimethylforma MeOC N mide di-tert-butylacetal (5.0g, 24.8 mmol). The solution was He then heated to relfux overnight. Additional dimethylforma c t-BuOH/H2OADMix-C, mide di-tert-butylacetal (10.0g, 59.6 mmol) was added in two s Step 2 portions over 24 h with continued stirring at reflux. The solution was stirred at reflux for a total of 72 h then cooled to RT. To the solution was added sat. NaHCO (aq) and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over NaSO, filtered and concentrated. The crude product was purified via flash chromatography (SiO: gradient elution, 100:0 to 92.8 hexanes: EtOAc) to afford the ester (1.68 g. 52%). Step 2: 0701) To a solution of the bromide from step 1 (1.68 g. 6.5 mmol) in MeCH (20 mL) in a pressure tube was added potas sium trifluoro(prop-1-en-2-yl)borate (J. Am. Chem. Soc 2003, 125, 11148-11149) (1.16 g, 7.8 mmol). The resultant slurry was degassed by bubbling N, through the solvent for 10 min. To this slurry was then added PdCl(dppf)..CHCl (159 mg, 0.20 mmol) and EtN (657 mg, 6.5 mmol). The pressure tube was sealed and the mixture was heated to 100° C. with stirring for 3 h. The mixture was then cooled to RT, trans Step 1: ferred to a round bottom flask and concentrated. The crude product was partitioned between water and EtOAc. The aque 0704. The styrene was prepared from methyl 5-chloropy ous layer was extracted with EtOAc (3x). The combined razine-2-carboxylate (Lonza Inc. Allendale, N.J.) using a pro organic layers were dried over Na2SO, filtered and concen cedure similar to that described in Scheme 3 Step 2. trated. The crude product was purified via flash chromatog Step 2: raphy (SiO: gradient elution, 100:0 to 92:8 hexanes: EtOAc) 0705 The diol carboxylic acid was prepared using a pro to afford the styrene (1.24g, 86%) as a clear oil. cedure similar to that described in Scheme 3 Step 3 except the diol from step 1 of this scheme was used. Step 3: Step 3: 0702. To a biphasic mixture of the styrene from Step 2 0706 To a solution of the carboxylic acid from step 2 (ca (1.24 g, 5.7 mmol) in 1:1 tert-butanol/water (60 mL) was 6.5 mmol) in anhydrous EtOH (30 mL) was added a solution added AD mix a (Aldrich) (7.9 g) and methane sulfonamide of hydrogen chloride (4M in dioxane, 5 mL). The solution (492 mg, 5.2 mmol). The resultant mixture was stirred vigor was heated to reflux with stirring for 4 h. After that time, the US 2010/0286160 A1 Nov. 11, 2010 51 solution was allowed to cool to RT. The solution was then followed by methane sulfonamide (825 mg, 7.2 mmol). The concentrated in vacuo and used without further purification. solution was stirred at RT. After the reaction was complete, the solution was diluted with CHCl and washed with Step 4: NaHCO (aq). The organic layer was dried over NaSO, filtered and concentrated. The crude product was purified via (0707 To a solution was the diol from Step 3 (ca 6.5 mmol) flash chromatography (SiO: gradient elution, 100:0 to 50:50 in CHCl (20 mL) was added EtN (1.4g, 14.3 mmol) hexanes: EtOAc) to afford the mesylate (600mg).

Scheme 5

N O

C

Nn C E HCI He

CN

C

Nus C EDCHOBT 1N1 NH2 CN

C US 2010/0286160 A1 Nov. 11, 2010 52

-continued Cl

CN

C Example 1

Step 1 2 mmol) were heated neat at 100° C. for 18 h. The residue was purified via gradient flash chromatography (0-5% EtOAc/ 0708 CHCl, SiO) which gave 570 mg (50%) of the alcohol as a yellow oil. in- C Step 2 Nu 0710

O CN C HCI

CN

I

C C N Nr C CN

C

O CN 0711. The tert-butyl ester (570 mg, 1 mmol) was taken up C in dioxane (2 mL) and 4 M HCl dioxane (5 mL), and the resulting solution was stirred at 25°C. for 18 h. The solution was concentrated which gave ~580 mg (Quant.) of the pip 0709. The piperazine A (for preparation see: erazine-acid HCl salt as a glass. This material was used with WO2006060461) (664 mg, 2 mmol) and epoxide I (464 mg. out further purification. US 2010/0286160 A1 Nov. 11, 2010 53

Step 3 0712

N EDCHOBT He 1N1 NH2 CN

C ON

CN

C Example 1

0713. The piperazine acid (100 mg, 0.18 mmol), EDC (70 mg), HOBT (50mg), and n-propylamine (0.2 mL) were taken up in (3 mL) and stirred at 25°C. for 18 h. The solution was evaporated. The residue was purified via thin-layer prepara tive chromatography (4/1 CH2Cl2/acetone, SiO2) which gave 45 mg (45%) of Example 1 as a colorless oil: LCMS (MH") 551.3. 0714. The epoxide I or II, piperazine A or B (for prepara tion see: WO2006060461), and amine provided additional examples according to the analogous procedures outlined for Example 1 (Table 1). US 2010/0286160 A1 Nov. 11, 2010 54

TABLE 1.

(Procedure outlined in Scheme 5)

LCMS (MH') epoxide piperazine amine Ex. Structure (Observed)

565.3 oN C

CN

C

553.3 oN C

CN

C

S63.3 ON C

CN

C

II 565.3 oN C CN

C US 2010/0286160 A1 Nov. 11, 2010 55

TABLE 1-continued

(Procedure outlined in Scheme 5)

LCMS (MH') epoxide piperazine amine Ex. Structure (Observed)

II NH2 6 553.3 C

C

OH 2. C. CN II S63.3 N1 H 7 C

O CN C C

II NH2 8 551.3 C

C C. CN 2.C C

NH2 9 O 551.3 CN

CN

C

o C 2.C C US 2010/0286160 A1 Nov. 11, 2010 56

TABLE 1-continued

(Procedure outlined in Scheme 5)

LCMS (MH') epoxide piperazine amine Ex. Structure (Observed) I D 565.3 CN

acC O C

NH2 11 O 553.3

OH CN

2.C

II 565.3

CN

2.C

II NH2 13 551.3

CN l C

C 2. C US 2010/0286160 A1 Nov. 11, 2010 57

-continued O N Scheme 6 s HOC N HCI \ EtOH Fy Cu 1 C NH N 7 N NH -- MeOH

EtOC NN NaH BrCH2CH2Cl O C NH C O)-Cl Ns N NaI(K2CO ( S. ECN100° C. HN n-rrNu C EtO.C. \-N in-N C Cl O C C O C Example 14 C C Step 1 0715 N NS to-CN N-1N ~ C HOC ( N) HCI - EtOC (yN N NH NH E LiOH E -e-

07.16 1H-Imidazole-4-carboxylic acid (3.8 g. 33.8 mmol) O C and 4 MHCl in dioxane (20 mL) were taken up in EtOH (100 C mL) and heated at 80°C. for 18 h. The solution was concen trated. The residue was partitioned between EtOAc and water. The mixture was quenched with solid NaHCO until the aqueous layer was no longer acidic. The layers were sepa N rated. The aqueous layer was, extracted with EtOAc. The S combined organic layers were washed with brine and dried to-K N (MgSO). Filtration and concentration of the solution pro n-r^ C vided 2.47 g (52%) of the ethyl ester as a white solid. Nu cyanuric fluoride Step 2

C 0717

NaH C "sy\ NH BrCH2CH2Cl US 2010/0286160 A1 Nov. 11, 2010 58

0720. The chloro-ethyl imidazole (3.6 mmol), piperazine -continued C (for preparation see: WO2006060461) (500 mg, 1.46 N mmol), NaI (220 mg, 1.46 mmol), and KCO (604 mg. 4.4 SS mmol) were taken up in EtCN (3 mL) and heated at 100° C. EtOC N for 50 h. The solution was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The Cl combined organic layers were washed with brine and dried (MgSO). Filtration and concentration gave a brown oil. The residue was purified via gradient flash chromatography (0-5% EtOAc/CHCl, SiO). Further purification via thin layer preparative chromatography (3/1 acetone/CHCl, 0718 The imidazole-ethyl ester (500 mg, 3.6 mmol) was SiO2) gave 380 mg (51%) of the imidazole-piperazine as a suspended in DMF (5 mL) at 25°C. Sodium hydride (170 mg. colorless oil. 60 wt % dispersion in oil) was added at 25° C., and the resulting mixture was stirred at 25° C. for 0.5 h. Bromo Step 4 chloro ethane (0.7 mL, 8.9 mmol) was added, and the solution was stirred at 25° C. for 16h. The solution was partitioned 0721 between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO). Filtration and concentration gave a yellow oil. The residue was purified via gradient flash chro matography (0-5% EtOH/CHCl, SiO) which furnished N 790 mg (Quant.) of the chloro-ethylimidazole as a mixture of regio isomers. to-Cl n-1N C Step 3 ~ LiOH 0719 -e- C

NaI(K2CO3 K ECN100° C. C EtOC C

Cl O O C C C C C C

N C

N to-K n-1N C C 0722. The ethyl ester (339 mg, 0.67 mmol) and LiOH H2O (140 mg, 3.3 mmol) were taken up in MeOH/HO (1/1. 15 mL) and stirred at 25° C. for 18 h. More LiOH HO (3 g) C was added, and the solution was stirred an additional 18 h. The solution was concentrated. The residue was taken up in water and neutralized with 1 M HCl). The solution was C extracted with CHC1. The combined organic layers were dried (MgSO). The solution was filtered and concentrated which gave 259 mg (81%) of the acid as a white solid. US 2010/0286160 A1 Nov. 11, 2010 59

Step 5 Step 6 0725 0723

N-1NN C N-1NN C N N O O cyanuric 7 N NH fluoride -e- MeOH O C O C C C O N O Ns s y Clu HN) (Clus n C F Nur C Nu

C C

C C Example 14 0724. The acid (259 mg, 0.54 mmol) and pyridine (0.15 0726. The acid fluoride (0.1 mmol) was taken up in 7 N mL) were taken up in CHCl and cooled to 0°C. Cyanuric NH in MeOH. The solution was stirred at 25°C. for 18 h. The fluoride (0.15 mL) was added at 0°C., and the resulting solution was concentrated. The residue was purified via thin mixture was stirred at 0°C. for 4.5h. The solution was diluted layer preparative chromatography (12.5/1 CHC1/EtOH, with CHCl2 and washed with sat. NaHCOs. The aqueous SiO) which gave 36 mg (75%) of Example 14 as a colorless layer was extracted with CHCl2. The combined organic lay oil (LCMS (MH)478.3). ers were dried (MgSO). Filtration and concentration fur 0727. The following examples were prepared according to nished 224 mg (86%) of the acid fluoride as a yellow oil. Step 6 of Scheme 6 using the appropriate amine (Table 2).

TABLE 2

LCMS Amine Ex Structure (MH')

NH2 15 O S2O3 r / N-1N C ON

C

C US 2010/0286160 A1 Nov. 11, 2010 60

TABLE 2-continued

LCMS Amine Ex. Structure (MH') NH2 16 O N 524.3 N / NH r C OH HO N- N O C C

S34.3

C ON

C

C

were dried over NaSO filtered and concentrated. The crude product was purified via flash chromatography (SiO: gradi Scheme 7 ent elution, 100:0 to 75:25 hexanes:EtOAc) to afford the O alcohol (ca 0.5 g).

NaBH4, Step 2: EtOH F Step 1 0729. A solution of the alcohol (ca 0.5 g) in 1.5 MHSO OH (15 mL) was heated to reflux for 1 h. The aqueous layer was neutralized with NaOH then extracted with EtOAc. The H2SO4 organic layer was dried over NaSO, filtered and concen -3- Step 2 trated. The crude product was purified via flash chromatog F raphy (SiO: hexanes) to afford the indene (ca 0.5 g). Step 3: 0730. To a solution of the indene from step 2 (ca 0.5 g), O (R,R)-(-)N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo m-CPBA He NMO hexanediaminomanganese(III) chloride (Aldrich) (118 mg, F catalyst F 0.19 mmol) and NMO (2.2g, 18.5 mmol) in CHCl (15 mL) Step 3 at -78°C. was added in two portions m-CPBA (1.69 g, 7.4 mmol). The resultant solution was stirred at that temperature for 2 h. At that time, a solution of dimethyl sulfide (1.04 g. 16.7 mmol) in CHCl (5 mL) at -78°C. was added. The Step 1: solution was allowed to warm to RT and 3 NNaOH (aq.) (60 0728. To a solution of 5-fluoro-2,3-dihydro-1H-inden-1- mL) was added. The aqueous layer was extracted with one (0.66 g, 4.4 mmol) in EtOH (5 mL) was added NaBH CH2Cl and the organic layer was washed with water, dried (216 mg, 5.75 mmol). The mixture was stirred at RT for 1 h. over NaSO filtered and concentrated. The crude product After that time, the mixture was concentrated. The residue was purified via flash chromatography (SiO: gradient elu was partitioned between water and EtOAc. The aqueous layer tion, 100:0 to 80:20 hexanes:EtOAc) to afford the epoxide was extracted with EtOAc (3x). The combined organic layers (major enantiomer pictured above; ca 50% ee). US 2010/0286160 A1 Nov. 11, 2010 61

To a pressure tube containing the epoxide (ca 0.5 g) was added the piperazine C (250 mg. 0.73 mmol). The tube was Scheme 8 sealed and the mixture was heated to 100° C. with stirring. O After 16 h, the residue was cooled to RT was purified via flash -- chromatography (SiO: gradient elution, 100:0 to 80:20 hex anes: EtOAc) to afford Example 18 (106 mg): LCMS (MH") F 491.3, and Example 19 (30 mg): LCMS (MH") 491.3.

HN C Scheme 9

Hip100° C.

C C 2.N C : O 100 C C C

C C

^, r C , N C OH N- N : OH ON O C C

C Example 18 Example 20

F 0731 Example 20 was prepared using a procedure similar to that described in Scheme 8 except (1R,2S)-indene oxide (98% ee) (Tet. Lett. 1995,36,5457-5460) was used instead of 5-fluoroindene oxide: LCMS (MH") 475.3.

^ C

C it O 100° C. -- C ->

C Example 19 C US 2010/0286160 A1 Nov. 11, 2010 62

MeOH (5:2, 7 mL). To the solution was added NaBH (11 mg, -continued 0.30 mmol). The mixture was stirred at RT for 48 h. Water was added and the mixture was extracted with CHC1. The organic layer was dried over Na2SO4, filtered and concen trated. The crude product was purified by preparative TLC (SiO: 1:1 hexanes:EtOAc) followed by separation of the C diastereomers by HPLC (semi prep Chiralcel OD column: 90:10 hexanes:iPrOH) to afford the diastereomers Example 5 H O 22 (2 mg): LCMS (MH") 475.3 and Example 23 (1 mg): LCMS (MH)475.3. C

Scheme 12 NH2 C tBocO, NaOH Example 21 COH - - H2O, MeCN Step 1 Example 21 was prepared using a procedure similar to that C described in Scheme 8 except (1S,2R)-indene oxide (98% ee) NHBOc (Tet. Lett. 1995, 36,5457-5460) was used instead of 5-fluor oindene oxide: LCMS (MH") 475.3. CO2H

C

EDCL, HOBt, iPrNEt He NHBoc

1). K2CO3, DMF C CO2H C 2) NaBH4, MeOH C Step 2

BocN r C N- N 1) TFA, CH2Cl2 --- 2) BH THF Step 3 C C OH O

C HN r C C ENCO Examples 22 and 23 N- o He Et3N, CHCl2 C Step 4 (0732. To a solution of the piperazine C (100 mg, 0.30 mmol) in DMF (5 mL) was added the bromide (63 mg, 0.30 mmol). The solution was stirred at RT for 2 days. The solution was partitioned between water and EtOAc. The organic layer was washed with brine, dried over NaSO, filtered and con centrated. The residue was dissolved in a mixture of THF and US 2010/0286160 A1 Nov. 11, 2010 63

-continued H Scheme 13 EHN N rO N1) O HN C C N N O N-\ C i —- E Cs2CO3 C CN Example 24

C Step 1: A 0733. A solution of (R)-2-amino-2-(4-chlorophenyl)ace O tic acid (1.0g, 5.4 mmol), di-tert-butyl dicarbonate (1.2g, 5.4 mmol) and NaOH (450 mg, 11 mmol) in water and MeCN (4:3) was stirred at RT overnight. The solution was acidified Nn-1a by the addition of 1 NHCl (aq). The solution was extracted ^ C with CHC1. The organic layer was dried over NaSO, filtered and concentrated in vacuo to afford the acid (1.4 g).

Step 2: CN 0734 To a solution of piperazine C (300 mg. 0.88 mmol) in MeCN (1.5 mL) was added EDCI (253 mg, 1.32 mmol), HOBt (178 mg, 1.32 mmol), iPr-NEt (122 mg, 0.96 mmol) and the acid from step 1 (300 mg, 1.1 mmol). The solution C was stirred at RT for 48 h. After that time, the solution was Example 25 (Intermediate) concentrated and purified via flash chromatography (SiO2: gradient elution 100:0 to 85:15 hexanes: EtOAc) to afford the amide (600mg). 0737 To a solution of the bromide (2.7 g. 10.8 mmol) and the piperazine A (3 g, 9.0 mmol) in Mecn in a pressure tube Step 3: was added CsCO (4 g). The pressure tube was sealed and the 0735. To a solution of the amide from step 2 (600mg) in mixture was heated to 80° C. with stirring. After 16 h, the CHCl (10 mL) was added TFA. The solution was stirred at mixture was cooled to RT and concentrated in vacuo. The RT for 1 h. After that time, the solution was basified by the residue was then partitioned between CHCl and water. The addition of excess sat. NaCO (aq). The mixture was aqueous layer was extracted with CHCl (3x). The combined extracted with CHCl2. The organic layer was dried over organic layers were dried over NaSO, filtered and concen NaSO filtered and concentrated. The resultant amido trated. The crude product was purified via flash chromatog amine that was taken up in anhydrous THF (10 mL). To this raphy (SiO: gradient elution 100:0 to 1:1 hexanes:EtOAc) to solution was added borane THF complex (1 M in THF, 3 mL, afford Example 25 (1.42 g) as a light yellow solid: LCMS 3 mmol). The resultant solution was heated to reflux with (MH) 505.3. stirring for 3 h. After the reaction was complete, the solution was cooled to RT and excess hydrochloric acid was added (6 N). The mixture was stirred for 30 min. The mixture was then Scheme 14 basified by the addition of excess sat NaHCO (aq) and the O mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO, filtered and concen trated to afford the amine that was used without further puri NS-1a fication.

MeOH Step 4: Step 1 0736. To a solution of the amine (500.1 mmol) in CHCl, (2 mL) was added ethyl isocyanate (11 mg, 0.15 mmol) and iPrNEt (51 mg, 0.5 mmol). The solution was stirred at RT overnight. The solution was then concentrated and purified via preparative TLC (95:5:0.5 CHCl:MeOH:concentrated C NH-OH (aq) to afford Example 24 (ca 44 mg): LCMS Example 25 (Intermediate) (MH) 567.3. US 2010/0286160 A1 Nov. 11, 2010 64

-continued -continued HN N-1N C H N n-1\, N- N ENCO Her EtN, CHCl2 Step 2 CN CN

C C EHN Example 27 O N- N 0741. To a solution of the amine from Scheme 14 step 1 (50 mg, 0.1 mmol) in CHCl (10 mL) was added Et-N (15 mg, 0.15 mmol) and cyclopropanecarbonyl chloride (13 mg, 0.12 mmol). The resultant solution was heated to reflux with stirring for 16h. After that time, the solution was concentrated O CN and purified via preparative TLC (SiO: 95:5:0.5 CHCl: C MeOH:concNHOH (aq) to afford Example 27 (ca. 32 mg): Example 26 LCMS (MH)443.2.

Step 1: 0738. To a solution of Example 25 (1.4g, 2.81 mmol) in MeOH was added hydrazine (360 mg, 11.2 mmol). The resultant solution was heated to reflux with stirring for 3 hours. After the reaction was determined to be complete, the Solution was concentrated in vacuo. To the residue was added HN N-1\on --O EtOAc, the solids were removed via filtration, and the solvent Et3N, toluene was removed in vacuo. The crude product was purified via Dean-Stark trap flash chromatography SiO: gradient elution 100:0:0:096:4: Step 1 0.2:0.2 CHC1:MeOH:7 N. NH (in MeOH): conc NHOH (aq) to afford the intermediate amine (ca. 700 mg). Step 2:

0739 Example 26 was prepared using a method similar to TfG) that described in Scheme 12 Step 4, except the amine from O He iPrNEt step 1 of this scheme was used: N Step 2 0740 LCMS (MH) 446.2. O Y-\ s OH

H2N-N-1a O C D-coc --- Et3N, CHCl2 O CN N O Y-N s OTf C US 2010/0286160 A1 Nov. 11, 2010

followed by iPr-NEt (0.6 mL). The resultant solution was -continued allowed to slowly warm to RT and stir for 48 h. The solution was then concentrated in vacuo and the residue was parti tioned between water and CHC1. The organic layer was O dried over NaSO filtered and concentrated. The crude product was purified via flash chromatography (SiO. gradi entelution 100:0 to 50:50 hexanes: EtOAc) to afford Example N O 28 (470 mg) as a light yellow solid: LCMS (MH") 519.3. s OTf CN Cs2CO3 Step 3 Scheme 17 O

C N A n-n 1 C O N- N H2N2H2 MeOH Step 1 O

N-1a O CN ^ C C Example 28 (Intermediate) HN N-1a r C CN ENCO s Et3N, CHCl2 t Step 2 CN C Example 28 (Intermediate)

C

EHN r N^^ C Step 1: O E Nu 0742 To a solution of 2-(S)-amino-1-propanol (2.0, 27 mmol) in toluene in a round bottom flask was added EtN (0.37 mL, 2.65 mmol) and phthalic anhydride (3.9 g, 27 mmol). A Dean-Stark trap was attached and the Solution was heated to reflux for 24 h with stirring. After the reaction was determined to be complete, the Solution was concentrated in O CN vacuo and the crude product was purified via flash chroma C tography (SiO: gradient elution 100:0 to 0:100 hexanes: EtOAc) to afford the alcohol (4.9 g) as a white solid. Example 29 Step 2: 0743 To a solution of the alcohol from step 1 (500 mg, 2.4 Step 1: mmol) in CH2Cl at -25°C. was added iPr-NEt (465 mg, 3.6 mmol) followed by trifluoromethanesulfonic anhydride (745 0745. The amine was prepared using a similar method to mg, 2.6 mmol). The resultant solution was stirret at -25°C. that described in Scheme 14 Step 1, but the intermediate of for 1 h. After that time, the solution was concentrated and the Example 28 was used. residue was filtered through a silica gel plug using 1:1 EtOAc: hexanes as the elutant. The solvent was concentrated to afford Step 2: the triflate (ca 300 mg). 0746. Example 29 was prepared using a similar method to Step 3: that described in Scheme 12 step 4, except the amine from 0744. To a solution of the piperazine A (500mg) in DMF Step 1 of this scheme was used: (5 mL) at 0°C. was added the triflate from step 2 (ca 300 mg) 0747 LCMS (MH)460.3. US 2010/0286160 A1 Nov. 11, 2010 66

-continued

HN O Y^^E N C D-coc in- C N He Et3N, CHCl2 N O i OTf CN E Her CN CsCO3 Step 3

C

C N-> C A O

C O CN

N

C Example 30

0748 Example 30 was prepared using a similar method to CN that described in Scheme 15, except the amine from Scheme 17 step 1 was used: LCMS (MH) 457.3. C Example 31 (Intermediate)

0749. Example 31 was prepared using a method similar to HN that described in Scheme 16 except 2-(R)-amino-1-propanol OH — - was used: LCMS (MH) 519.3. Et3N, toluene Dean-Stark trap Step 1

TfG) O Her iPrNEt Step 2 in- C N IY C Cs2CO3

C US 2010/0286160 A1 Nov. 11, 2010 67

RT, transferred to a round bottom flask and concentrated in -continued vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over NaSO filtered and concentrated. The crude product was purified via flash chromatography (SiO: gradient elution, 100:0 to 50:50 hexanes:EtOAc) to afford the ester (580 mg). r C The ester was taken up in a solution of HCl (aq) (4N, 3 mL) and HCl (dioxane) (4 N. 20 mL). The resultant solution was C heated to 70° C. for 2h. The solution was concentrated and the carboxylic acid HCl salt was used without further purifica tion.

C

Example 32 (Intermediate)

0750 Example 32 was prepared using a method similar to that described in Scheme 16 step 3, except piperazine C was used: LCMS (MH) 528.3. EDCL, HOBt iPrNEt MeCN

C

1) Na2CO3, EtOH E His CN 2)) HCl(aq.)HCl(aq), dioxane C

CN

Example 33

0752 To a solution of the carboxylic acid from Scheme 21 CN (120 mg, 0.23 mmol) and iPr-NEt (130 mg. 0.99 mmol) in MeCN (1.5 mL) was added EDCI (97 mg 0.50 mmol), pyr rolidine (50 mg. 0.70 mmol) and HOBt (68 mg, 0.50 mmol). The resultant mixture was stirred at RT for 2.5 days. After that time, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 1 M NaOH (aq.). The (0751) To a solution of the mesylate from Scheme 3 (500 aqueous layer was extracted with EtOAc (3x). The combined mg, 1.50 mmol) and the piperazine A (385 mg, 1.16 mmol) in organic layers were washed with brine, dried over NaSO, EtOH (5 mL) in a pressure tube was added NaCO (160 mg. filtered and concentrated. The crude product was purified via 1.50 mmol). The tube sealed and the mixture was heated to preparative TLC (SiO: 1:1 Acetone: Hexanes) to afford 80°C. with stirring for 16 h. The mixture was then cooled to Example 33 (31 mg): LCMS (MH") 564.3. US 2010/0286160 A1 Nov. 11, 2010 68

TABLE 3

The following examples were prepared using a method similar to that described in Scheme 22.

LCMS Amine Example Structure (MH')

NH2 34 552.3

Nr C

CN

C

NH 35 554.3

OH Nur C

CN

C

1n 36 566.3 NH

r C

CN

C US 2010/0286160 A1 Nov. 11, 2010 69

TABLE 3-continued

The following examples were prepared using a method similar to that described in Scheme 22.

LCMS Amine Example Structure (MH') HO n1n t 37 568.3

Me

(0753. To a solution of the mesylate from Scheme 4 (600 mg, 1.97 mmol) in EtOH (15 mL) in a pressure tube was added the piperazine (545 mg, 1.64 mmol) and NaCO (226 mg, 2.13 mmol). The pressure tube was sealed and the mix ture was heated to 80°C. with stirring. After 16 h, the mixture was cooled to RT and concentrated in vacuo. The residue was then partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over NaSO filtered and concentrated. The crude product was purified via flash chromatography (SiO: gradient elution 100:0 to 30:70 hex in- C anes: EtOAc) to afford the ester (ca 450 mg). N- 0754) To a solution of the ester (450 mg, 0.83 mmol) in MeOH (15 mL) was added a solution of LiOH (aq.) (2M, 2.5 He-1) Na2CO3, EtOH mmol). The resultant mixture was stirred at RT for 2.5 days. CN 2) 1954). The mixture was then concentrated. Water was added and the mixture was adjusted to pH 6 by the addition of 1M HCl (aq). The aqueous layer was then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over C NaSO filtered and concentrated to afford the carboxylic A acid (402 mg) that was used without further purification.

HOC cN N 2. 1. C D-NH. HO Me N- Her EDCL, HOBt iPrNEt CN MeCN

C US 2010/0286160 A1 Nov. 11, 2010 70

(0755. To a solution of the carboxylic acid from Scheme 23 -continued (100 mg 0.20 mmol) in MeCN (1 mL) was added cyclopro O pyl amine (23 mg, 0.40 mmol), EDCI (77 mg, 0.40 mmol), HOBt (54 mg. 0.40 mmol) and iPr-NEt (52 mg, 0.40 mmol). The resultant mixture was stirred at RT overnight. After that C time, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 1 M NaOH (aq.). The N aqueous layer was extracted with EtOAc (3x). The combined C organic layers were washed with brine, dried over NaSO, CN filtered and concentrated. The crude product was purified via preparative TLC (SiO: 1:1 EtOAc: Hexanes) to afford Example 38 (28 mg): LCMS (MH) 551.3.

C Example 38

TABLE 4

The following examples were prepared using a method similar to that described in Scheme 24.

LCMS Amine Example Structure (MH')

NH2 39 553.3

C

CN

NH2 40 555.3 HON/ OH C

CN US 2010/0286160 A1 Nov. 11, 2010 71

TABLE 4-continued

The following examples were prepared using a method similar to that described in Scheme 24.

LCMS Amine Example Structure (MH') 1n 41 O 567.3 NH N /N N 21 2 S. N NN C

CN

C

Examples -continued 0756. The compounds of Formula (I) shown in the follow ing table were prepared according to one or more methods Structure reported above.

Structure

C ic C. C

ic

C

C US 2010/0286160 A1 Nov. 11, 2010 72

-continued

Cl

Cl US 2010/0286160 A1 Nov. 11, 2010 73

-continued -continued

Structure Structure

Ot N C

C

C

A N& . ^ C

C

C

HO -n. C

C

C US 2010/0286160 A1 Nov. 11, 2010 74

-continued -continued

Structure Structure

N C h

h

Y-Cl

O s O o reN - r C

C C US 2010/0286160 A1 Nov. 11, 2010 75

-continued -continued

Structure Structure N-1 r r C O N i r C C H6 2. N C i S C N. Os N-1N C C N- O N 1n 21 a - S. N . n C HC 2. N C i

H nS NS-r C N / NH N C O 2 srO N-1N

CN 3.C O n-1N r D.C.-> .C.CC C US 2010/0286160 A1 Nov. 11, 2010 76

each R' is independently selected from the group consist -continued ing of alkyl, haloalkyl, -alkylene-NRR, -alkylene OR, alkylene-Ns, -alkylene-CN, and alkylene-O-S Structure (O)-alkyl; or two R' groups attached to the same ring carbon atom form a carbonyl group: p is 0, 1, 2, 3, or 4: each R is independently H, alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, CI wherein each of said aryl heteroaryl, cycloalkyl, and heterocycloalkyl of R is unsubstituted or optionally Substituted with one or more groups independently selected from Y'; each R is independently selected from the group consist Š ing of H, alkyl, unsubstituted aryl, aryl substituted with one or more Y' groups, —OR. -alkylene-O-alkyl, and -alkylene-OH: C each R" is independently selected from the group consist ing of H. alkyl, aryl, -C(O)—O-alkyl, -C(O)-alkyl, —C(O)-aryl, -C(O)-heteroaryl, -S(O)alkyl, -S(O) 1. A compound of Formula (I): aryl, -S(O)heteroaryl, and—S(O), heterocycloalkyl, wherein each of said aryl, the aryl portion of said —C(O)-aryl, the aryl portion of said –S(O)aryl of (I) R", and the heteroaryl portion of said –C(O)-het X (A) (R') eroaryl, and —S(O)-heteroaryl, is unsubstituted or Substituted with one or more groups independently n1"n-1/ selected from Y'; N each R is independently selected from the group consist YA2 ing of H, alkyl, aryl. —S(O)-alkyl, -S(O)-cycloalkyl, Arl —S(O)2-aryl, -S(O)-heteroaryl, -S(O)-heterocy cloalkyl, -C(O) N(R), —C(O)-alkyl, -C(O)-cy cloalkyl, -C(O)-aryl, —C(O)-heteroaryl, -C(O)-het or a pharmaceutically acceptable salt, thereof, wherein: erocycloalkyl, and -alkylene-OH, Ar' and Arare independently aryl or heteroaryl, wherein each of said aryl, the aryl portions of said wherein each of Ar' and Ar is substituted with one or —S(O)-aryl and —C(O)-aryl, and the heteroaryl more groups independently selected from Y'; portions of said —S(O)-heteroaryland said–C(O)- with the proviso that when Ari is pyridine or pyrimi heteroaryl of R is unsubstituted or substituted with dine, a nitrogen of said pyridine or pyrimidine is one or more Z groups; not in the para position relative to the point of each Y is independently selected from the group consist attachment to the piperazine ring: ing of halo. —CN, alkyl, haloalkyl, cycloalkyl, hetero n and mare independently 0 or 1: cycloalkyl, heterocycloalkenyl, aryl, -alkylene-aryl, A is selected from the group consisting of -C(O) , heteroaryl, -O-alkyl. —O-haloalkyl, -O-aryl, -O- S(O), , -C(=N-OR)- and —(C(R).), heteroaryl, -O-cycloalkyl, -O-heterocycloalkyl, wherein q is 1, 2, or 3: —S-alkyl, -S-haloalkyl, - S-heteroaryl. —S-cy B is selected from the group consisting of N(R)-, cloalkyl, S-heterocycloalkyl, -S(O)-alkyl, -S(O) —C(O)—, and -(C(R).), wherein r is 1 or 2, 2-cycloalkyl, -S(O)-heterocycloalkyl, -S(O)-aryl, with the proviso that when B is C(O)—, then A is —S(O)-heteroaryl, -alkylene-CN, C(O)-alkyl, —C(O)- or -(C(R).), : —C(O)-aryl, -C(O)-haloalkyl, -C(O)-heteroaryl, X is selected from the group consisting of: —C(O) cycloalkyl, -C(O)-heterocycloalkyl, —C(O)N(R), C(O)-cycloalkyl, -C(O)-heterocy —C(O)C)-alkyl, -C(O)O-aryl, -C(O)O-haloalkyl, cloalkyl, aryl Substituted with one or more groups —C(O)C)-heteroaryl, —C(O)O— cycloalkyl, -C(O) independently selected from —C(O)N(R), het O-heterocycloalkyl, - N(R)C(O)-alkyl, N(R)C eroaryl substituted with one or more groups indepen (O) N(R), OH, -alkylene-OH, -alkylene-C(O)— dently selected from C(O)N(R), and benzo-fused O-alkyl, -O-alkylene-aryl, and NRR cycloalkyl-, wherein the cycloalkyl portion of said wherein each of said aryl, each -alkylene-aryl, each het benzo-fused cycloalkyl- is substituted with at least eroaryl, each aryl portion of said -O-aryl, each het one –OH group, and wherein the aryl portion of said eroaryl portion of said —O-heteroaryl, each aryl por benzo-fused cycloalkyl- is unsubstituted or substi tion of said —S-aryl, each heteroaryl portion of said tuted with one or more groups independently selected —S-heteroaryl, each aryl portion of said S(O)- from Z. aryl, each heteroaryl portion of said - S(O)-het with the proviso that, when X is C(O)N(R). eroaryl, each aryl portion of said C(O)-aryl, each —C(O)-cycloalkyl or —C(O)-heterocycloalkyl, then heteroaryl portion of said —C(O)-heteroaryl, each n=1 and B is NR : aryl portion of said —C(O)O-aryl, and each het US 2010/0286160 A1 Nov. 11, 2010 77

eroaryl portion of said–C(O)O-heteroaryl of Y are unsubstituted or Substituted with one or more groups -continued Z; or two groups Y' form a -O-CH2—O— group; each R is independently selected from the group consist ing of H. alkyl, haloalkyl, alkoxy, cycloalkyl, heterocy cloalkyl, unsubstituted aryl, aryl substituted with one or C more groups independently selected from Z, unsubsti tuted heteroaryl, heteroaryl substituted with one or more groups independently selected from Z, cycloalkyl, -alkylene-OH, -alkylene-O-alkyl, -alkylene-O-aryl, -alkylene-OC(O)-alkyl, -alkylene-OC(O)-aryl, -alky C. lene-OC(O)-heteroaryl, and alkylene-NR'R'', or two R' groups, together with the nitrogen to which they are attached, form a heteroaryl, heterocycloalkyl, heterocy cloalkenyl, or a benzo-fused heterocycloalkyl group; and each Z is independently selected from the group consisting of alkyl, halo, haloalkyl, —OH, —O-alkyl, and —CN: with the proviso that when A is C(O) , then each Y' on Ar' is independently selected from the group con sisting of cycloalkyl, benzyl, aryl, —O-haloalkyl, C —O-aryl, —O-cycloalkyl, - S-aryl, - S-haloalkyl, —S-cycloalkyl, -S(O)-alkyl. —S(O)-cycloalkyl, —S(O)-aryl, -alkylene-CN. —C(O)-aryl, —C(O)- C. -cycloalkyl, —C(O)O-heterocycloalkyl, -alkylene-C (O) O-alkyl, and —O-alkylene-aryl, wherein each benzyl and each aryl portion of Y', and each aryl portion and each heteroaryl portion of said —O-aryl. said —S-aryl, said —S(O)-aryl, said —C(O)-aryl, said —C(O)O-aryl, —C(O)O-heteroaryl, —C(O)O- heterocycloalkyl, and —O-alkylene-aryl of Y', are unsubstituted or Substituted with one or more groups independently selected from Z: or two groups Y' form a —O—CH2—O-group. 2-36. (canceled) 37. A compound, or a pharmaceutically acceptable salt, thereof, selected from:

1. C

C

US 2010/0286160 A1 Nov. 11, 2010 79

-continued -continued

or O

O2 Olus,N C

aC s r C O N HO Do C->Dr. OE Cl, O Cl, US 2010/0286160 A1 Nov. 11, 2010 80

-continued -continued

Cl,

C US 2010/0286160 A1 Nov. 11, 2010 81

-continued -continued

C

38. A composition comprising: at least one compound according to claim 1, or a pharmaceutically acceptable salt, thereof, and at least one pharmaceutically acceptable carrier. 39. A composition comprising: at least one compound claim 1, or a pharmaceutically acceptable salt, thereof: and at least one additional active agent other than a compound of claim 1. 40-46. (canceled) 47. A method of treating, reducing, or ameliorating a con C dition or disease selected from psychic disorders, anxiety, Schizophrenia, depression, abuse of psychotropes, Substance abuse. Substance dependency, alcohol dependency, nicotine dependency, neuropathies, migraine, stress, epilepsy, dyski nesias, Parkinson's disease, amnesia, senile dementia. Alzhe imer's disease, eating disorders, type n diabetes, gastrointes tinal diseases, vomiting, diarrhea, urinary disorders, infertility disorders, inflammation, infection, cancer, neu roinflammation, atherosclerosis, Guillain-Barr syndrome, viral encephalitis, cerebral vascular incidents, and cranial trauma in a patient in need thereof, comprising: administering US 2010/0286160 A1 Nov. 11, 2010

to said patient in need thereof an effective amount of a com to said patient in need thereof an effective amount of a com pound of claim 1, or a pharmaceutically acceptable salt, position according to claim 39. thereof. 52. A method of treating, reducing, or ameliorating a con 48. A method of treating, reducing, or ameliorating a con dition or disease selected from metabolic syndrome, obesity, dition or disease selected from metabolic syndrome, obesity, waist circumference, abdominal girth, type II diabetes, insu lin resistance, hepatic lipidosis, fatty liver disease, neuroin waist circumference, abdominal girth, type II diabetes, insu flammatory disorders, cognitive disorders, psychosis, addic lin resistance, hepatic lipidosis, fatty liver disease, neuroin tive behavior, gastrointestinal disorders, and cardiovascular flammatory disorders, cognitive disorders, psychosis, addic conditions, in a patient in need thereof, comprising: admin tive behavior, gastrointestinal disorders, and cardiovascular istering to a patient in need thereof an effective amount of a conditions, in a patient in need thereof, comprising: admin composition according to claim 39. istering to said patient in need thereof an effective amount of 53. A method of treating, reducing, or ameliorating a con at least one compound according to claim 1, or a pharmaceu dition or disease selected from metabolic syndrome, obesity, tically acceptable salt, thereof. waist circumference, abdominal girth, type II diabetes, 49. The method of claim 48, wherein said condition or hepatic lipidosis, and fatty liver disease, comprising admin disease is selected from metabolic syndrome, obesity, waist istering to a patient in need thereof an effective amount of a circumference, abdominal girth, type II diabetes, hepatic lipi composition of claim 39. dosis, and fatty liver disease. 54. A method of reducing body condition score in a patient 50. A method of reducing body condition score in a patient in need thereof, comprising: administering to said patient in in need thereof, comprising administering to said patient in need thereof an effective amount of a composition according need thereof an effective amount of at least one compound to claim 39. according to claim 1, or a pharmaceutically acceptable salt, 55. A method of partitioning energy of an animal away thereof. from fat deposition toward protein accretion, comprising 51. A method of treating, reducing, or ameliorating a con administering to said animal an effective amount of at least dition or disease selected from psychic disorders, anxiety, one compound according to claim 1, or a pharmaceutically Schizophrenia, depression, abuse of psychotropes, Substance acceptable salt, thereof. abuse, Substance dependency, alcohol dependency, nicotine 56. A method of partitioning energy of an animal away dependency, neuropathies, migraine, stress, epilepsy, dyski from fat deposition toward protein accretion, comprising: nesias, Parkinson's disease, amnesia, senile dementia, Alzhe administering to said animal an effective amount of a com imer's disease, eating disorders, type II diabetes, gastrointes position according to claim 39. tinal diseases, vomiting, diarrhea, urinary disorders, 57. A composition comprising: at least one compound infertility disorders, inflammation, infection, cancer, neu according to claim 37, or a pharmaceutically acceptable salt roinflammation, atherosclerosis, Guillain-Barr syndrome, thereof, and at least one pharmaceutically acceptable carrier. viral encephalitis, cerebral vascular incidents, and cranial trauma in a patient in need thereof, comprising: administering c c c c c