US008853205 B2

(12) United States Patent (10) Patent No.: US 8,853,205 B2 Makriyannis et al. (45) Date of Patent: *Oct. 7, 2014

(54) HETEROPYRROLE ANALOGSACTING ON 5,462,960 A * 10/1995 Barth et al...... 514,406 RECEPTORS 6.432,984 B1 8, 2002 Barth et al. 6,509,367 B1 1/2003 Martin et al. 7,119, 108 B1 10/2006 Makriyannis et al. (75) Inventors: Alexandros Makriyannis, Watertown, 7,393,842 B2 7/2008 Makriyannis et al. MA (US); Venkata Kiran Vemuri, 7,745.440 B2 6/2010 Makriyannis et al. Boston, MA (US) 7,872,006 B2 1/2011 Moritani et al. 8,084,451 B2 * 12/2011 Makriyannis et al...... 514,241 (73) Assignee: University of Connecticut, Farmington, 2004/0192667 A1 9/2004 Makriyannis et al. CT (US) 2004/0248956 Al 12/2004 Hagmann et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS past is tituted under 35 EP O576,357 A1 12/1993 .S.C. 154(b) by ayS. EP O656354 A1 6, 1995 This patent is Subject to a terminal disis- FREP 2758.723O658546 A1 6,T 19951998 Ca10. FR 2856683 A1 12/2004 WO 9719063 A1 5, 1997 (21) Appl. No.: 13/202,499 WO 972.1682 A1 6, 1997 WO 2005OOO820 1, 2005 (22) PCT Filed: Feb. 19, 2009 WO 2006067443 6, 2006 WO 2006O74445 A2 T 2006 (86). PCT No.: PCT/US2O09/OO 1054 WO 2007061948 A2 5, 2007 S371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Nov. 11, 2011 Fan, H. et al., “Analogs of JHU75528, a PET for imaging of (87) PCT Pub. No.: WO2010/104488 cerebral cannabinoid receptors (CB1): Development of ligands with PCT Pub. Date: Sep. 16, 2010 optimized lipophilicity and binding affinity.” European Journal of Medicinal Chemistry, 44, pp. 593-609, 2009. (65) Prior Publication Data European Search Report dated Jun. 28, 2012. Notification of Transmittal, the International Search Report and Writ US 2012/OO46280 A1 Feb. 23, 2012 ten Opinion of the International Searching Authority for PCT/ US2009/001054 dated Sep. 14, 2009. Related U.S. Application Data International Preliminary Report on Patentability for PCT/US2009/ (63) Continuation-in-part of application No. 1 1/813.546, 001054 dated Aug. 23, 2011. filed as application No. PCT/US2006/000720 on Jan Howlett A.C. et al. "Azido- and isothiocyanato-substituted aryl 10, 2006, now Pat No. 8 O84,451 pyrazoles bind covalently to the CB1 cannabinoid and impair signal transduction'. Journal of Neurochemistry, Wiley (60) Provisional application No. 60/642.544, filed on Jan. Interscience, New York, NY, US, vol. 74, No. 5, Jan. 1, 2000, 2174 10, 2005. 2181. (51) Int. Cl. (Continued) CO7D 231/4 (2006.01) C T E. 3:08: Primary Examiner — Kamal Saeed CO7D 405/2 (2006.01) (74) Attorney, Agent, or Firm — Alix, Yale & Ristas, LLP CO7D 40/0 (2006.01) (52) U.S. Cl. CPC ...... C07D 231/14 (2013.01); Co7D401/10 (7) ABSTRACT 405/12(2013.01); (2013.01); C07D 409/04 C07D 233/90(2013.01); (2013.01) C07D Disclosed are biologically- active hetero pyrrole analogs such USPC ...... 27.28.23 as imidazoles, thiazoles, oxazoles and pyrazoles capable of 514/318: 514/326 514,406. 544/139. 544/140. interacting with the CB1 and/or CB2 cannabinoid receptors. 544/406. 546/1 87; 546/21 1; 548/365.7 Aspects disclose hetero pyrrole analogs acting as CB1 and/or (58) Field of Classification Search CB1 receptor antagonists, having selectivity for the CB1 or None CB2 receptor, acting as neutral antagonists, acting preferen See application file for complete search history. tially on CB1 receptors located in the peripheral nervous system, and/or acting as nitric oxide donors. Pharmaceutical (56) References Cited preparations employing the disclosed analogs and methods of administering therapeutically effective amounts of the dis U.S. PATENT DOCUMENTS closed analogs to provide a physiological effect are also dis 4,256,727 A 3/1981 Triplett et al. closed. 4,732,900 A 3, 1988 Weber et al. 5,155,124 A 10, 1992 Kimata et al. 5,208,231 A 5, 1993 Kimata et al. 20 Claims, 2 Drawing Sheets US 8,853.205 B2 Page 2

(56) References Cited Cluny N. L.; Vemuri V. K.; Chambers A. P.; Limebeer C. L.; Bedard H.; Wood J. T.; Lutz B.; Zimmer A.; Parker L. A.; Makriyannis A.; OTHER PUBLICATIONS Sharkey K. A. A novel peripherally restricted cannabinoid , AM6545, reduces food intake and body weight, but does Lange J.H.M. et al. “Bioisosteric replacements of the pyrazole moi not cause malaise, in rodents. BrJ Pharmacol. 2010, 161, (3), 629-42. ety of : synthesis, biological properties, and molecular Limebeer C. L.; Vemuri V. K.; Bedard H.; Lang S. T.; Ossenkopp K. modeling investigations of thiazoles, triazoles, and imidazoles as P; Makriyannis A.; Parker L. A. Inverse agonism of cannabinoid CB1 potent and selective CB1 antagonists'. Journal receptors potentiates LiCI-induced nausea in the conditioned gaping of Medicinal Chemistry, American Chemical Society, US, vol. 48, model in rats. Br J Pharmacol. 2010, 161, (2), 336-49. Jan. 1, 2005, 1823-1838. Tam J.; Vemuri V. K. Liu J.; Batkai S.; Mukhopadhyay B.: Jarbe T. U.: Lemay B. J.; Vemuri V. K. Vadivel S. K.; Zvonok A.; Godlewski G.; Osei-Hyiaman D.; Ohnuma S.; Ambudkar S. V.; Makriyannis A. Central mediation and differential blockade by can Pickel J.; Makriyannis A.; Kunos G. Peripheral CB1 cannabinoid nabinergics of the discriminative stimulus effects of the cannabinoid receptor blockade improves cardiometabolic risk in mouse models of CB(1) receptor antagonist rimonabant in rats. Psychopharmacology . J Clin Invest. 2010, 120, (8), 2953-66. (Berl). 2011 DOI 10.1007/s002 13-011-2226-3). Sink K. S.; Segovia K. N.; Collins L. E.; Markus E. J.; Vemuri V. K.; Cluny N. L.; Chambers A. P. Vemuri V. K. Wood J. T.; Eller L. K.; Makriyannis A.; Salamone J. D. The CB1 inverse agonist AM251, but Freni C.; Reimer R. A.; Makriyannis A.; Sharkey K. A. The neutral not the CB1 antagonist AM4113, enhances retention of contextual cannabinoid CB receptor antagonist AM41 13 regulates body weight fear conditioning in rats. Pharmacol Biochem Behav. 2010, 95, (4), through changes in energy intake in the rat. Pharmacol Biochem 479-84. Behav. 2011, 97, (3), 537-43. Sink K. S.; Segovia K. N.; Sink J.; Randall P. A.; Collins L. E.; Correa Randall P. A.; Vemuri V. K.; Segovia K. N.; Torres E. F.; Hosmer S.; M.; Markus E. J.; Vemuri V. K.; Makriyannis A.; Salamone J. D. Nunes E. J.; Santerre J. L.; Makriyannis A. Salamone J. D. The novel Potential anxiogenic effects of cannabinoid CB1 receptor antago cannabinoid CB1 antagonist AM6545 suppresses food intake and nists/inverse agonists in rats: comparisons between AM41 13, food-reinforced behavior. Pharmacol Biochem Behav. 2010, 97. (1), AM251, and the benzodiazepine inverse agonist FG-7142. Eur 179-84. Neuropsychopharmacol. 2010, 20, (2), 112-22. Jarbe T. U.: LeMay B. J.; Olszewska T., Vemuri V. K.; Wood J. T.; Storr M. A.; Bashashati M., Hirota C.; Vemuri V. K.; Keenan C. M.; Makriyannis A. Intrinsic effects of AM41 13, a putative neutral CB1 Duncan M.; Lutz B.; Mackie K.; Makriyannis A.; Macnaughton W. receptor selective antagonist, on open-field behaviors in rats. K.; Sharkey K. A. Differential effects of CB(1) neutral antagonists Pharmacol Biochem Behav. 2008,91, (1), 84-90. and inverse agonists on gastrointestinal motility in mice. Hodge J.; Bow J. P.; Plyler K. S.; Vemuri V. K.; Wisniecki A.; Neurogastroenterol Motil. 2010, 22, (7), 787-96, e223. Salamone J. D.; Makriyannis A.; McLaughlin P. J. The cannabinoid Chambers A. P.; Vemuri V. K.; Peng Y.; Wood J. T.; Olszewska T.; CB1 receptor inverse agonist AM 251 and antagonist AM 4113 Pittman Q. J.; Makriyannis A.; Sharkey K. A.; A neutral CB1 receptor produce similar effects on the behavioral Satiety sequence in rats. antagonist reduces weight gain in rat. Am J Physiol Regul Integr Behav Brain Res. 2008, 193, (2), 298–305. Comp Physiol. 2007, 293, (6), R2185-93. Bergman J.; Delatte M. S.; Paronis C. A.; Vemuri K.; Thakur G. A.; Sink K. S.; McLaughlin P. J.; Wood J. A.; Brown C.; Fan P.; Vemuri Makriyannis A. Some effects of CB1 antagonists with inverse agonist V. K. Peng Y.; Olszewska T.: Thakur G. A.; Makriyannis A.; Parker and neutral biochemical properties. Physiol Behav. 2008, 93, (4-5), L. A.; Salamone J. D. The novel cannabinoid CB1 receptor neutral 666-70. antagonist AM41 13 Suppresses food intake and food-reinforced Sink K. S.; Vemuri V. K. Wood J.; Makriyannis A.; Salamone J. D. behavior but does not induce signs of nausea in rats. Oral bioavailability of the novel cannabinoid CB1 antagonist Neuropsychopharmacology. 2008, 33, (4), 946-55. AM6527: effects on foodreinforced behavior and comparisons with AM4113. Pharmacol Biochem Behav. 2009, 91, (3), 303-6. * cited by examiner U.S. Patent Oct. 7, 2014 Sheet 1 of 2 US 8,853.205 B2

08), 09), UOenus UIOSISIOO %

’61-IVI,

O O O O O CN O CO Co CN V v S. uOpen US uO)SIO JO % U.S. Patent Oct. 7, 2014 Sheet 2 of 2 US 8,853,205 B2 22 14.

18

15 -O- vehicle 12 -O-20 mg kg ------Fig. 2A O 1 2 3 4. 5

24 922 CD S4 18 S S 15 -O- vehicle 12 -O-20 mg kg

O 1 2 3 4 5

24 92.21 GD Sa 18 g t 9. 15 -O- vehicle 12 -O-20 mg kg -T-T-I-T- Fig. 2C O 1 2 3 4 5 US 8,853,205 B2 1. 2 HETEROPYRROLEANALOGSACTING ON ness, impairment of monoamine oxidase function and impair CANNABINOID RECEPTORS ment of non-receptor mediated brain function. The addictive and psychotropic properties of Some also limit CROSS REFERENCE TO RELATED their therapeutic value. International Publication number WO 03/007887 A2 to APPLICATIONS Finke et al describes imidazole derivatives alleged to have binding affinity for the central cannabinoid receptor. Interna The present application is a continuation-in-part of U.S. tional Publication number WO 03/027076 A2 to Kruse et all patent application Ser. No. 1 1/813,546, filed Sep. 16, 2008, also describes some imidazole derivatives alleged to have which claims the benefit of PCT/US2006/000720, filed Jan. binding affinity for cannabinoid receptors. 10, 2006, which claims the benefit of U.S. Provisional Appli 10 cation No. 60/642,544, filed Jan. 10, 2005, and claims the BRIEF DESCRIPTION OF THE DRAWINGS benefit of PCT/US2009/001054, filed Feb. 19, 2009, the con tents of each of which are incorporated herein by reference in FIGS. 1A-1B are graphs showing cAMP accumulation their entirety. with hCB1-HEK292 cells (Compound 2 and 15); and 15 FIGS. 2A-2C are graphs showing food intake, weigh STATEMENT REGARDING FEDERALLY change and body weight following administration of Com SPONSORED RESEARCH ORDEVELOPMENT pound 15 to rats. This invention was made with Government support under SUMMARY OF THE INVENTION Grant No. DA7215 awarded by the National Institute on Abuse. The Government may have certain rights in the inven Briefly stated, one embodiment of the invention is con tion. cerned with new and improved cannabimimetic (cannabinoid like) imidazole analogs. The inventive cannabimimetic imi FIELD OF THE INVENTION dazole ligands of this embodiment can be represented by 25 general formula I and their enantiomers, diastereomers, geo The present invention relates generally to biologically metric isomers, racemates, tautomers, rotamers, atropiso active hetero pyrrole analogs such as imidazoles, thiazoles, mers, metabolites, in vivo hydrolysable esters, N-oxides, oxazoles and pyrazoles capable of interacting with the CB1 salts, Solvates, hydrates, polymorphic forms (crystalline or and/or the CB2 cannabinoid receptors, including neutral amorphous) or pro-: antagonists, inverse-agonists and partial agonists. Another 30 aspect of the invention is concerned with Such compounds having a range of useful applications including use of certain I neutral antagonists, inverse-agonists and partial agonists to R4 A B treat medical conditions with no or substantially reduced S 4 incidence of side-effects. Other aspects of the invention are 35 (re concerned with new and improved hetero pyrrole analogs - N2 N 6 acting as neutral antagonists, inverse-agonists and partial ar agonists selective for the CB1 and/or the CB2 receptors and R2 use of these new and improved hetero pyrrole analogs as peripherally acting or centrally acting compounds. Also, 40 A comprises a direct bond, O, or —(CH)N(R5) aspects of the invention are concerned with all isotopic varia B comprises a direct bond, O, N(R5), —(CH), or—NH tions of these compounds, combination and pharma SO. R5 is hydrogen, OH, alkyl or substituted alkyl and ceutical preparations and compositions employing the inven 1 is an integer from 0 to 3. tive analogs and methods of administering therapeutically In a variation of formula I, R1 and R2 each independently effective amounts of the inventive analogs to provide a physi 45 comprise —(CH2), Z. ological effect. n is an integer from 0 to about 7. Z comprises H, halogen, CF, CFH, N, NCS, CN, NO, BACKGROUND OF THE INVENTION NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO alkyl, SO-alkyl, SC(CH),COOX, OC(CH),COOX, Marijuana ( sativa) and derivatives have been 50 C(CH2)COOXs. Si(alkyl)s. O-aroyl, O(CH2)(OXs. used for medicinal and recreational purposes. The major O(CH.).NXX, alkyl-CN. NH-acyl, NH-aroyl, CHO, active constituent extracted from is the clas C(halogen), COOX, SOH, SONXX, CONXX, NHC sical cannabinoid A- (A-THC). The (O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmer effects of Such cannabinoids are due to an interaction with capto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfo specific high-affinity receptors. Presently, two cannabinoid 55 nyl, CXXX. —CH=CHXs —C=CXs: receptors have been characterized: CB1, a central receptor X and X each independently comprise H or alkyl, or found in the mammalian brain and a number of other sites in X and X together comprise part of a heterocyclic ring peripheral tissues; and CB2, a peripheral receptor found prin having about 4 to about 7 ring members and optionally one cipally in cells related to the immune system. The CB1 recep additional heteroatom selected from O, N or S, or tor is believed to mediate the psychoactive properties associ 60 X and X together comprise part of an imide ring having ated with classical cannabinoids. Characterization of these about 5 to about 6 members, receptors has been made possible by the development of X comprises H, alkyl, aryl, NO, NO, (CH),CN, specific synthetic ligands such as the agonists WIN 55212-2 hydroxyloweralkyl, or alkyl-NXX. and CP 55,940. X, Xs, and X each independently comprise H, alkyl, In addition to acting at the cannabinoid receptors, cannab 65 carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, inoids such as A-THC also affect cellular membranes, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or thereby producing undesirable side effects such as drowsi O-alkyl-X, wherein US 8,853,205 B2 3 4 X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) -continued (OX), S(O)N(alkyl), S(O),Xs, S(O),OX COOXs. CONXs, SOH, COXs, wherein N Ys X Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, / x . x X’s aromatic ring, heteroaromatic ring, or —CX-CHXo 5 - Y, N= NY, \2YN2 wherein X and Xo each independently comprise H or alkyl Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2 10 In a variation of formula I, R1 and R2 each independently X X X comprise —(CH2), Z. MSS MSS x S4 n is an integer from 0 to about 7. Xi Xi r1. Z comprises a carbocyclic ring having about 4 to about 7 \2N \aN N. 2 s 15 ring members, a heterocyclic ring having about 4 to about 7 xe w X xe YS X ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring e %. a 7s members, a bicyclic ring, a heterobicyclic ring, a tricyclic N 2N or N 2 ring, a heterotricyclic ring, a polycyclic ring, a heteropolycy clic ring; or any above group Substituted on at least one N.'s NY. x^-W available ring atom by an alkyl group; or any above group x- X is y \Asy Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl Y X group, a Substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connect 25 wherein X and Y each independently comprise, H., halo ing point between the —(CH2)—group and the Z group can gen, CF, CFH, N, NCS, CN, NO, NXX, OX, SX be any available ring carbon atom or any available ring nitro OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, gen atom. SC(CH),COOX, OC(CH) COOXs. C(CH),COOXs. In a variation of formula I, R1 and R2 each independently Si(alkyl). alkyl-CN, O-aroyl, O(CH),OXs. comprise —(CH), Z. 30 O(CH.)NXX, NH-acyl, NH-aroyl, CHO, C(halogen), n is an integer from 0 to about 7. COOX, SOH, SONXX, CONXX, NHC(O)O-alkyl, Z comprises a 5 member unsaturated ring having 0 to 4 NHSO-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alky independently selected heteroatoms as ring members, a Sub lamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, stituted 5 member unsaturated ring having 0 to 4 indepen CXXX. —CH=CHXs, —C=CXs: dently selected heteroatoms as ring members, a 6 member 35 X and X each independently comprise H or alkyl, or aromatic ring having 0 to 5 independently selected heteroat X and X together comprise part of a heterocyclic ring oms as ring members or a Substituted 6 member aromatic ring having about 4 to about 7 ring members and optionally one having 0 to 5 independently selected heteroatoms; and additional heteroatom selected from O, N or S, or wherein the connecting point between the —(CH), group X and X together comprise part of an imide ring having and the Z group can be any available ring carbonatom or any 40 about 5 to about 6 members, available ring nitrogen atom. X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy In a variation of formula I, R1 and R2 each independently loweralkyl, or alkyl-NXX. comprise —(CH2), Z. X, Xs, and X each independently comprise H, alkyl, n is an integer from 0 to about 7. carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi 45 CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, O-alkyl-X, wherein 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofura X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) nyl; or any above group Substituted on at least one available (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. ring atom by an alkyl group; or any above group Substituted CONXs, SOH, COXs, wherein on at least one available ring nitrogenatom by a benzyl group, 50 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, a Substituted benzyl group, an alkoxybenzyl group, a Substi aromatic ring, heteroaromatic ring, or —CX-CHXo tuted alkoxybenzyl group, a benzhydryl group or a Substi wherein tuted benzhydryl group; and wherein the connecting point X and Xo each independently comprise H or alkyl between the —(CH) group and the Z group can be any Wherein m is an integer from 0 to 7 available ring carbon atom or any available ring nitrogen 55 j is an integer from 0 to about 6, or atOm. W comprises H or alkyl In a variation of formula I, R1 and R2 each independently k is an integer from 0 to about 2 comprise —(CH2), Z. In a variation of formula I, R1 and R2 each independently n is an integer from 0 to about 7. —(CH2), Z. Z comprises 60 n is an integer from 0 to about 7. Z comprises a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocy clic ring having 6 ring atoms fused to a heteroaromatic ring S4 y X x^ x^n, having from 5 to 7 ring atoms, a heterocyclic ring having 6 & SCS X,== |YY X== YY 65 ring atoms fused to a heterocyclic ring having from 5 to 7 ring =N. Y. X s X s atoms, an heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aro US 8,853,205 B2 5 6 matic ring having 6 ring atoms fused to a heterocyclic ring alkyl, SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. having from 5 to 7 ring atoms, an aromatic ring having 6 ring C(CH4),COOXs. Si(alkyl), O-aroyl, O(CH.),OX, atoms fused to a heteroaromatic ring having from 5 to 7 ring O(CH.).NXX, alkyl-CN. NH-acyl, NH-aroyl, CHO, atoms, a heteroaromatic ring having 6 ring atoms fused to a C(halogen), COOX, SOH, SONXX, CONXX, NHC heterocyclic ring having from 5 to 7 ring atoms or a heteroaro (O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmer matic ring having 6 ring atoms fused to a heteroaromatic ring capto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfo having from 5 to 7 ring atoms. nyl, CXXX. —CH=CHX. —C=CXs: In a variation of formula I, R1 and R2 each independently X and X2, each independently comprise H or alkyl, or comprise —(CH), Z: X and X together comprise part of a heterocyclic ring in comprises an integer from 0 to about 7. 10 having about 4 to about 7 ring members and optionally one Z comprises an unsaturated ring having 5 ring atoms and 0 additional heteroatom selected from O, N or S, or to 2 independently selected heteroatoms as ring members X and X together comprise part of an imide ring having fused to an unsaturated ring having 5 ring atoms and 0 to 4 about 5 to about 6 members, independently selected heteroatoms as ring members, an X comprises H, alkyl, NO, NO, (CH),CN, hydroxylow unsaturated ring having 5 ring atoms and 0 to 2 independently 15 eralkyl, or alkyl-NXX, selected heteroatoms as ring members fused to an unsaturated X, Xs, and X each independently comprise H, alkyl, ring having 6 or 7 ring atoms and 0 to 3 independently carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, selected heteroatoms as ring members or an unsaturated ring CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or having 6 ring atoms and 0 to 4 independently selected het O-alkyl-X, wherein eroatoms as ring members fused to an unsaturated ring having X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) 6 or 7 ring atoms and 0 to 4 independently selected heteroa (OX), S(O)N(alkyl), S(O),Xs, S(O),OX COOXs. toms as ring members. CONXs, SOH, COXs, wherein In a variation of formula I, R1 and R2 each independently Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, comprise —(CH2)-Q-(CH2), Z: aromatic ring, heteroaromatic ring, or —CX=CHXo, Q comprises NH, O, S, —CH=CH-, -C=C , —CO, 25 wherein SO, or OSO: X and Xo each independently comprise H or alkyl, m is an integer from 1 to about 7. m is an integer from 0 to 7: n is an integer from 0 to about 7: j is an integer from 0 to about 6; and Z comprises H. halogen, CF, CFH, N, NCS, CN, NO, k is an integer from 0 to about 2. NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO 30 In a variation of formula I, R1 and R2 each independently alkyl, SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. comprise —(CH2)-Q-(CH2), Z: C(CH4),COOXs. Si(alkyl), O-aroyl, O(CH.),OX, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or O(CH.)NXX, alkyl-CN. NH-acyl, NH-aroyl, CHO, OSO; C(halogen), COOX, SOH, SONXX, CONXX, NHC m is an integer from 1 to about 7; (O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmer 35 n is an integer from 0 to about 7; and capto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfo Z comprises a bicyclic ring, a heterobicyclic ring, a tricy nyl, CXXX. —CH=CHXs —C=CXs: clic ring, a heterotricyclic ring, a polycyclic ring or a het X and X2, each independently comprise H or alkyl, or eropolycyclic ring. X and X together comprise part of a heterocyclic ring In a variation of formula I, R1 and R2 each independently having about 4 to about 7 ring members and optionally one 40 comprise —(CH)-Q-(CH), Z: additional heteroatom selected from O, N or S, or Q comprises NH, O, S, CH=CH, C=C, CO, SO, or X and X together comprise part of an imide ring having OSO; about 5 to about 6 members; m is an integer from 1 to about 7; X comprises H, alkyl, NO, NO, (CH2)CN, hydroxylow n is an integer from 0 to about 7: eralkyl, or alkyl-NXX: 45 Z comprises a carbocyclic ring having about 4 to about 7 X, Xs, and X each independently comprise H, alkyl, ring members, a heterocyclic ring having about 4 to about 7 carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, ring members, an aromatic ring having about 5 to about 7 ring CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or members, a heteroaromatic ring having about 5 to about 7 ring O-alkyl-X, wherein members; a bicyclic ring, a heterobicyclic ring, a tricyclic X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 50 ring, a heterotricyclic ring, a polycyclic ring, a heteropolycy (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. clic ring or any above group Substituted on at least one avail CONXs, SOH, COXs, wherein able ring atom by an alkyl group or any above group Substi Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, tuted on at least one available ring nitrogen atom by a benzyl aromatic ring, heteroaromatic ring, or —CX=CHXo, group, a Substituted benzyl group, an alkoxybenzyl group, a wherein 55 Substituted alkoxybenzyl group, a benzhydryl group or a Sub X and Xo each independently comprise H or alkyl; stituted benzhydryl group; and wherein the connecting point m is an integer from 0 to 7: between the -(CH2)—group and the Z group can be any j is an integer from 0 to about 6, and available ring carbon atom or any available ring nitrogen k is an integer from 0 to about 2. atOm. In a variation of formula I, R1 and R2 each independently 60 In a variation of formula I, R1 and R2 each independently comprise -Q-(CH), Z: comprise —(CH)-Q-(CH), Z: Q is optionally present and if present comprises —CH2— Q comprises N, O, S, CH=CH, C=C, CO, SO, or OSO; NH, —CH, O, —CH. S. —CH, SO, or —CH m is an integer from 1 to about 7; OSO; n is an integer from 0 to about 7; and n is an integer from 0 to about 7: 65 Z comprises a 5 member unsaturated ring having 0 to 4 Z comprises H. halogen, CF, CFH, N, NCS, CN, NO, independently selected heteroatoms as ring members, a Sub NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO stituted 5 member unsaturated ring having 0 to 4 indepen US 8,853,205 B2 7 8 dently selected heteroatoms as ring members, a 6 member NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alky aromatic ring having 0 to 5 independently selected heteroat lamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, oms as ring members or a Substituted 6 member aromatic ring CXXX. —CH=CHXs, —C=CXs: having 0 to 5 independently selected heteroatoms; and X and X2, each independently comprise H or alkyl, or wherein the connecting point between the -(CH) group 5 X and X together comprise part of a heterocyclic ring and the Z group can be any available ring carbonatom or any having about 4 to about 7 ring members and optionally one available ring nitrogen atom. additional heteroatom selected from O, N or S, or In a variation of formula I R1 and R2 each independently X and X together comprise part of an imide ring having comprise —(CH2)-Q-(CH2), Z: about 5 to about 6 members, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or 10 X comprises H, alkyl, NO, (CH2)CN, hydroxylower OSO; alkyl, or alkyl-NXX. m is an integer from 1 to about 7. X, Xs, and X each independently comprise H, alkyl, n is an integer from 0 to about 7; and carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 15 CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofura O-alkyl-X, wherein nyl; or any above group Substituted on at least one available X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) ring atom by an alkyl group; or any above group Substituted (OX), S(O)N(alkyl), S(O),Xs, S(O),OX COOXs. on at least one available ring nitrogenatom by a benzyl group, CONXs, SOH, COXs, wherein a Substituted benzyl group, an alkoxybenzyl group, a Substi Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, tuted alkoxybenzyl group, a benzhydryl group or a Substi aromatic ring, heteroaromatic ring, or —CX=CHXo, tuted benzhydryl group; and wherein the connecting point wherein between the -(CH2)—group and the Z group can be any X and Xo each independently comprise H or alkyl, available ring carbon atom or any available ring nitrogen m is an integer from 0 to 7: atOm. 25 j is an integer from 0 to about 6: In a variation of formula I R1 and R2 each independently k is an integer from 0 to about 2; and comprise —(CH)-Q-(CH), Z: W comprises H or alkyl Q comprises N, O, S, CH=CH, C=C, CO, SO, or OSO; In a variation of formula I R1 and R2 each independently m is an integer from 1 to about 7. comprise. —(CH)-Q-(CH), Z: n is an integer from 0 to about 7: 30 Q comprises NH, O, S, CH=CH, C=C, CO, SO, or Z comprises OSO; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and Z comprises an unsaturated ring having 5 ring atoms and 0 4 x e^p exy 35 to 2 independently selected heteroatoms as ring members & SCS. S.== S. Y Y V.== S. YY fused to an unsaturated ring having 5 ring atoms and 0 to 4 =N. Y. X s X s independently selected heteroatoms as ring members, an X unsaturated ring having 5 ring atoms and 0 to 2 independently 40 selected heteroatoms as ring members fused to an unsaturated ( . . . . ring having 6 or 7 ring atoms and 0 to 4 independently - Y, N= Y, Y2 selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 4 independently selected het s N=VX afs n( N K 3. X s eroatoms as ring members fused to an unsaturated ring having 45 6 or 7 ring atoms and 0 to 4 independently selected heteroa N- 1’& 5s Y, \a N s toms as ring members. X X X In a variation of formula I R1 and R2 each independently comprise —(CH2)-Q-(CH2), Z: Xi Xi, Pors, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or 2N s 2N s N 4 s 50 OSO; X X m is an integer from 1 to about 7; x aS x S4 n is an integer from 0 to about 7; and Z comprises N 2Na or rS. 2 NY.N NS. xy-" 55 x'? X- isy -ASY Y X dy s N N1 N1 60 wherein X and Y each independently comprise, H., halo gen, CF, CFH, N, NCS, CN, NO, NXX, OX, SX OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, SC(CH),COOXs. OC(CH)COOXs. C(CH),COOXs. Si(alkyl). alkyl-CN, O-aroyl, O(CH),OXs. 65 O(CH2).NXX2, NH-acyl, NH-aroyl, CHO, C(halogen), N- -/ COOX, SOH, SONXX, CONXX, NHC(O)O-alkyl, US 8,853,205 B2 10 -continued In a variation of formula I R1 and R2 each independently comprise -T-(CH2), Z: in comprises an integer from 0 to about 7. T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbonatoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri cyclic ring, a heterotricyclic ring, a polycyclic ring or a het 10 eropolycyclic ring; and Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring 15 members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycy clic ring; or any above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl group, a Substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connect ing point between the —(CH) group and the Z group can In a variation of formula I R1 and R2 each independently be any available ring carbon atom or any available ring nitro comprise -T-(CH2), Z: 25 gen atom. in comprises an integer from 0 to about 7. In a variation of formula I R1 and R2 each independently T comprises a carbocyclic ring having 3 to about 8 ring comprise -T-(CH2), Z: members, an unsaturated ring having 3 to about 8 carbon in comprises an integer from 0 to about 7. atoms as ring members, an aromatic ring having 5 to about 8 T comprises a carbocyclic ring having 3 to about 8 ring carbonatoms as ring members, a heterocyclic ring having 3 to 30 members, an unsaturated ring having 3 to about 8 carbon about 8 ring members, a heteroaromatic ring having 5 to about atoms as ring members, an aromatic ring having 5 to about 8 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri carbonatoms as ring members, a heterocyclic ring having 3 to cyclic ring, a heterotricyclic ring, a polycyclic ring or a het about 8 ring members, a heteroaromatic ring having 5 to about eropolycyclic ring; 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri Z comprises H. halogen, CF, CFH, N, NCS, CN, NO, 35 cyclic ring, a heterotricyclic ring, a polycyclic ring or a het NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO eropolycyclic ring; and alkyl, SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi C(CH4),COOXs. Si(alkyl), O-aroyl, O(CH.),OX, nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, O(CH.)NXX, alkyl-CN. NH-acyl, NH-aroyl, CHO, 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofura C(halogen), COOX, SOH, SONXX, CONXX, NHC 40 nyl; or any above group Substituted on at least one available (O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmer ring atom by an alkyl group; or any above group Substituted capto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfo on at least one available ring nitrogenatom by a benzyl group, nyl, CXXX. —CH=CHX. —C=CXs: a Substituted benzyl group, an alkoxybenzyl group, a Substi X and X2, each independently comprise H or alkyl, or tuted alkoxybenzyl group, a benzhydryl group or a Substi 45 tuted benzhydryl group; and wherein the connecting point X and X together comprise part of a heterocyclic ring between the -(CH2)—group and the Z group can be any having about 4 to about 7 ring members and optionally one available ring carbon atom or any available ring nitrogen additional heteroatom selected from O, N or S, or atOm. X and X together comprise part of an imide ring having In a variation of formula I R1 and R2 each independently about 5 to about 6 members, 50 comprise -T-(CH2), Z: X comprises H, alkyl, NO, NO, (CH),CN, hydroxylow in comprises an integer from 0 to about 7. eralkyl, or alkyl-NXX, T comprises a carbocyclic ring having 3 to about 8 ring X, Xs, and X each independently comprise H, alkyl, members, an unsaturated ring having 3 to about 8 carbon carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, atoms as ring members, an aromatic ring having 5 to about 8 CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or 55 carbonatoms as ring members, a heterocyclic ring having 3 to O-alkyl-X, wherein about 8 ring members, a heteroaromatic ring having 5 to about X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. cyclic ring, a heterotricyclic ring, a polycyclic ring or a het CONXs, SOH, COXs, wherein eropolycyclic ring; Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, 60 Z comprises aromatic ring, heteroaromatic ring, or —CX=CHXo, wherein X and Xo each independently comprise H or alkyl; m is an integer from 0 to 7: S4 y^ R R 65 S isy isy j is an integer from 0 to about 6; and =N.Y, X s X s k is an integer from 0 to about 2 US 8,853,205 B2 11 12 -continued X Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members X N- MX AS fused to an unsaturated ring having 5 ring atoms and 0 to 4 SC SC e independently selected heteroatoms as ring members, an - o Y, - N=/ Y, N S. s unsaturated ring having 5 ring atoms and 0 to 2 independently N=v, X X selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently NC SN 3. Xs selected heteroatoms as ring members or an unsaturated ring N- \ M Y, 2N s having 6 ring atoms and 0 to 3 independently selected het X X X 10 eroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroa Xi Xi, Pors, toms as ring members. \aN 2N N. 2 s In a variation of formula I R1 and R2 each independently comprise -T-(CH2)-Q-(CH2), Z: 15 m and n independently comprises an integer from 0 to x^^- Y X^^--Y about 7: N 2N or Sn 21 T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon N.'s N I x^-W atoms as ring members, an aromatic ring having 5 to about 8 x'? X- isy -ASY carbonatoms as ring members, a heterocyclic ring having 3 to Y X about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri cyclic ring, a heterotricyclic ring, a polycyclic ring or a het wherein X and Y each independently comprise, H., halo 25 eropolycyclic ring; gen, CF, CFH, N, NCS, CN, NO, NXX, OX, SX OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or SC(CH),COOXs. OC(CH)COOXs. C(CH),COOXs. OSO; Si(alkyl). alkyl-CN, O-aroyl, O(CH),OXs. Z comprises H, halogen, CF, CFH, N, NCS, CN, NO, O(CH2).NXX2, NH-acyl, NH-aroyl, CHO, C(halogen), NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO COOX, SOH, SONXX, CONXX, NHC(O)O-alkyl, 30 alkyl, SO-alkyl, SC(CH),COOX, OC(CH),COOX, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alky C(CH2)COOXs. Si(alkyl)s. O-aroyl, O(CH2)(OXs. lamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, O(CH.)NXX, alkyl-CN. NH-acyl, NH-aroyl, CHO, CXXX. —CH=CHXs, —C=CXs: C(halogen), COOX, SOH, SONXX, CONXX, NHC X and X2, each independently comprise H or alkyl, or (O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmer X and X together comprise part of a heterocyclic ring 35 capto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfo having about 4 to about 7 ring members and optionally one nyl, CXXX. —CH=CHXs —C=CXs: additional heteroatom selected from O, N or S, or X and X2, each independently comprise H or alkyl, or X and X together comprise part of an imide ring having X and X together comprise part of a heterocyclic ring about 5 to about 6 members, having about 4 to about 7 ring members and optionally one X comprises H, alkyl, NO, (CH),CN, hydroxylower 40 additional heteroatom selected from O, N or S, or alkyl, or alkyl-NXX, X and X together comprise part of an imide ring having X, Xs, and X each independently comprise H, alkyl, about 5 to about 6 members, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, X comprises H, alkyl, NO, NO, (CH2)CN, hydroxylow CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or eralkyl, or alkyl-NXX, O-alkyl-X, wherein 45 X, Xs, and X each independently comprise H, alkyl, X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, (OX), S(O)N(alkyl), S(O),Xs, S(O),OX COOXs. CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or CONXs, SOH, COXs, wherein O-alkyl-X, wherein Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) aromatic ring, heteroaromatic ring, or —CX-CHXo 50 (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. wherein CONXs, SOH, COXs, wherein X and Xo each independently comprise H or alkyl; Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, m is an integer from 0 to 7: aromatic ring, heteroaromatic ring, or —CX=CHXo, j is an integer from 0 to about 6: wherein k is an integer from 0 to about 2; and 55 X and Xo each independently comprise H or alkyl, W comprises H or alkyl. m is an integer from 0 to 7: In a variation of formula I R1 and R2 each independently j is an integer from 0 to about 6; and comprise -T-(CH2), Z: k is an integer from 0 to about 2 in comprises an integer from 0 to about 7. In a variation of formula I R1 and R2 each independently T comprises a carbocyclic ring having 3 to about 8 ring 60 comprise -T-(CH2)-Q-(CH2), Z: members, an unsaturated ring having 3 to about 8 carbon m and n independently comprises an integer from 0 to atoms as ring members, an aromatic ring having 5 to about 8 about 7: carbonatoms as ring members, a heterocyclic ring having 3 to T comprises a carbocyclic ring having 3 to about 8 ring about 8 ring members, a heteroaromatic ring having 5 to about members, an unsaturated ring having 3 to about 8 carbon 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri 65 atoms as ring members, an aromatic ring having 5 to about 8 cyclic ring, a heterotricyclic ring, a polycyclic ring or a het carbonatoms as ring members, a heterocyclic ring having 3 to eropolycyclic ring; about 8 ring members, a heteroaromatic ring having 5 to about US 8,853,205 B2 13 14 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri -continued X cyclic ring, a heterotricyclic ring, a polycyclic ring or a het eropolycyclic ring; Q comprises NH, O, S, CH=CH, C=C, CO, SO, or OSO; /- X Y, N= x7 Y, X'sY2 s Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 N=VX X ring members, an aromatic ring having about 5 to about 7 ring N&S 3. Xs members, a heteroaromatic ring having about 5 to about 7 ring N \ isy. Nu ', members, a bicyclic ring, a heterobicyclic ring, a polycyclic 10 ring, a heteropolycyclic ring; or any above group Substituted X X X on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen Xi--Y OXi, --Y Pors Y atom by a benzyl group, a Substituted benzyl group, an le N le N S 2 s X X alkoxybenzyl group, a Substituted alkoxybenzyl group, a ben 15 Zhydryl group or a Substituted benzhydryl group; and wherein x ^ x SS the connecting point between the —(CH), group and the Z group can be any available ring carbon atom or any avail S 2N or S. 2 able ring nitrogen atom. In a variation of formula I R1 and R2 each independently NY, NY, exy-" comprise -T-(CH2)-Q-(CH2), Z: x'? X- &y -AS Y m and n independently comprises an integer from 0 to Y X about 7: T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon 25 wherein X and Y each independently comprise, H., halo atoms as ring members, an aromatic ring having 5 to about 8 gen, CF, CFH, N, NCS, CN, NO, NXX, OX, SX carbonatoms as ring members, a heterocyclic ring having 3 to OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, about 8 ring members, a heteroaromatic ring having 5 to about SC(CH),COOX, OC(CH) COOXs. C(CH),COOXs. 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri Si(alkyl). alkyl-CN, O-aroyl, O(CH),OXs. cyclic ring, a heterotricyclic ring, a polycyclic ring or a het 30 O(CH2).NXX2, NH-acyl, NH-aroyl, CHO, C(halogen), eropolycyclic ring; COOX, SOH, SONXX, CONXX, NHC(O)C)-alkyl, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alky OSO; lamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi CXXX. —CH=CHXs, —C=CXs: nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 35 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofura X and X2, each independently comprise H or alkyl, or nyl; or any above group Substituted on at least one available X and X together comprise part of a heterocyclic ring ring atom by an alkyl group; or any above group Substituted having about 4 to about 7 ring members and optionally one on at least one available ring nitrogenatom by a benzyl group, additional heteroatom selected from O, N or S, or a Substituted benzyl group, an alkoxybenzyl group, a Substi 40 X and X together comprise part of an imide ring having tuted alkoxybenzyl group, a benzhydryl group or a Substi about 5 to about 6 members, tuted benzhydryl group; and wherein the connecting point X comprises H, alkyl, NO, (CH2)CN, hydroxylower between the -(CH2)—group and the Z group can be any alkyl, or alkyl-NXX, available ring carbon atom or any available ring nitrogen X, Xs, and X each independently comprise H, alkyl, atOm. 45 carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, In a variation of formula I R1 and R2 each independently CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or comprise -T-(CH2)-Q-(CH2), Z: O-alkyl-X, wherein m and n independently comprises an integer from 0 to X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) about 7: (OX), S(O)N(alkyl), S(O),Xs, S(O),OX COOXs. T comprises a carbocyclic ring having 3 to about 8 ring 50 CONXs, SOH, COXs, wherein members, an unsaturated ring having 3 to about 8 carbon Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, atoms as ring members, an aromatic ring having 5 to about 8 aromatic ring, heteroaromatic ring, or —CX=CHXo, carbonatoms as ring members, a heterocyclic ring having 3 to wherein about 8 ring members, a heteroaromatic ring having 5 to about X and Xo each independently comprise H or alkyl: 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri 55 m is an integer from 0 to 7: cyclic ring, a heterotricyclic ring, a polycyclic ring or a het j is an integer from 0 to about 6: eropolycyclic ring; k is an integer from 0 to about 2; and Q comprises NH, O, S, CH=CH, C=C, CO, SO, or W comprises H or alkyl. OSO; In a variation of formula I R1 and R2 each independently Z comprises 60 comprise -T-(CH2)-Q-(CH2), Z: m and n independently comprises an integer from 0 to about 7: T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon 65 atoms as ring members, an aromatic ring having 5 to about 8 carbonatoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about US 8,853,205 B2 15 16 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri -continued O cyclic ring, a heterotricyclic ring, a polycyclic ring or a het H eropolycyclic ring; NCN Q comprises NH, O, S, CH=CH, C=C, CO, SO, or

IV R4

40 R1 N wherein A, B, R1, R2 and R3 are as defined above for compounds of formula 45 W comprises S or O. wherein A, B, R2 and R3 are as defined above for com In any variation of formula II, when A is a direct bond; B is pounds of formula I. NR5 as defined above; R1 and R3 are any above described In a variation of formula IV, R1 comprises -T-(CH)-Q- variation; and W is S.; then R2 cannot be a phenyl group with (CH2), Z. 50 m and n independently comprises an integer from 0 to one or more substituents selected from branched or about 7. unbranched C-alkyl, branched or unbranched C-alkoxy, T comprises a carbocyclic ring having 3 to about 8 ring hydroxy, halogen, CF, trifluoromethylthio. trifluo members, an unsaturated ring having 3 to about 8 carbon romethoxy, nitro, amino, mono- or dialkyl(C)-amino, atoms as ring members, an aromatic ring having 5 to about 8 mono- or dialkyl (C-2)-amido, branched or unbranched 55 carbonatoms as ring members, a heterocyclic ring having 3 to (C1)-alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoyl. about 8 ring members, a heteroaromatic ring having 5 to about branched or unbranched (C1)-sulfonyl, carboxyl, cyano, 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri carbamoyl, branched or unbranched dialkyl (C-)-aminosul cyclic ring, a heterotricyclic ring, a polycyclic ring or a het fonyl, branched or unbranched monoalkyl (C1)-aminosul eropolycyclic ring. fonyl and acetyl. 60 Q comprises CH=CH, C=C. Z comprises H, halogen, CF, CFH, N, NCS, CN, NO, Another embodiment of the invention comprises can NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO nabimimetic triazole ligands represented by formula III and alkyl, SO-alkyl, SC(CH),COOX, OC(CH),COOX, their enantiomers, diastereomers, geometric isomers, race C(CH2)COOXs. Si(alkyl)s. O-aroyl, O(CH2)(OXs. mates, tautomers, rotamers, atropisomers, metabolites, in 65 O(CH.).NXX, alkyl-CN. NH-acyl, NH-aroyl, CHO, vivo hydrolysable esters, N-oxides, salts, solvates, hydrates, C(halogen), COOX, SOH, SONXX, CONXX, NHC polymorphic forms (crystalline or amorphous) or pro-drugs: (O)O-alkyl, NHSO-alkyl alkoxy, alkyl, alcohol, alkylmer US 8,853,205 B2 25 26 capto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfo 2- or 3-azetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahydrofura nyl, CXXX. —CH=CHX. —C=CXs: nyl; or any above group Substituted on at least one available X and X2, each independently comprise H or alkyl, or ring atom by an alkyl group; or any above group Substituted X and X together comprise part of a heterocyclic ring on at least one available ring nitrogenatom by a benzyl group, having about 4 to about 7 ring members and optionally one a Substituted benzyl group, an alkoxybenzyl group, a Substi additional heteroatom selected from O, N or S, or tuted alkoxybenzyl group, a benzhydryl group or a Substi X and X together comprise part of an imide ring having tuted benzhydryl group; and wherein the connecting point about 5 to about 6 members, between the —(CH) group and the Z group can be any X comprises H, alkyl, NO, NO, (CH),CN, hydroxylow available ring carbon atom or any available ring nitrogen eralkyl, or alkyl-NXX, 10 X, Xs, and X each independently comprise H, alkyl, atOm. carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, In a variation of formula IV, R1 comprises -T-(CH)-Q- (CH2), Z. CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or m and n independently comprises an integer from 0 to O-alkyl-X, wherein about 7. X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 15 (OX), S(O)N(alkyl), S(O),Xs, S(O),OX COOXs. T comprises a carbocyclic ring having 3 to about 8 ring CONXs, SOH, COXs, wherein members, an unsaturated ring having 3 to about 8 carbon Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, atoms as ring members, an aromatic ring having 5 to about 8 carbonatoms as ring members, a heterocyclic ring having 3 to aromatic ring, heteroaromatic ring, or —CX=CHXo, about 8 ring members, a heteroaromatic ring having 5 to about wherein 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri X and Xo each independently comprise H or alkyl; cyclic ring, a heterotricyclic ring, a polycyclic ring or a het m is an integer from 0 to 7: eropolycyclic ring. j is an integer from 0 to about 6; and Q comprises CH=CH, C=C. k is an integer from 0 to about 2. Z comprises In a variation of formula IV R1 comprises -T-(CH2)-Q- 25 (CH2), Z. m and n independently comprises an integer from 0 to about 7. T comprises a carbocyclic ring having 3 to about 8 ring , x x^o x^ members, an unsaturated ring having 3 to about 8 carbon 30 ( Cy atoms as ring members, an aromatic ring having 5 to about 8 =NY s X s X vs = Y, carbonatoms as ring members, a heterocyclic ring having 3 to N- N X X about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri W x X4, -HX cyclic ring, a heterotricyclic ring, a polycyclic ring or a het 35 N=75 Y. \= Y, Sl s eropolycyclic ring. N=V X X X X Q comprises CH=CH, C=C. Z comprises a carbocyclic ring having about 4 to about 7 -K( Žisx y, \is\e N M-N€is , \anKis , ring members, a heterocyclic ring having about 4 to about 7 X X ring members, an aromatic ring having about 5 to about 7 ring 40 members, a heteroaromatic ring having about 5 to about 7 ring xa Sé x Sé members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycy N 2 S 2 or clic ring; or any above group Substituted on at least one X N available ring atom by an alkyl group; or any above group 45 Xa Sé X SN N Substituted on at least one available ring nitrogen atom by a -HY XV / N ) benzyl group, a Substituted benzyl group, an alkoxybenzyl N1,N-2 \-J. X W- &4 Y group, a Substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connect x ing point between the —(CH2)—group and the Z group can 50 be any available ring carbon atom or any available ring nitro V. gen atom. In a variation of formula IV. R1 comprises -T-(CH2)-Q- (CH), Z. wherein X and Y each independently comprise, H., halo m and n independently comprises an integer from 0 to 55 gen, CF, CFH, N, NCS, CN, NO, NXX, OX, SX about 7. OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, T comprises a carbocyclic ring having 3 to about 8 ring SC(CH),COOXs. OC(CH)COOXs. C(CH),COOXs. members, an unsaturated ring having 3 to about 8 carbon Si(alkyl). alkyl-CN, O-aroyl, O(CH),OXs. atoms as ring members, an aromatic ring having 5 to about 8 O(CH2).NXX2, NH-acyl, NH-aroyl, CHO, C(halogen), carbonatoms as ring members, a heterocyclic ring having 3 to 60 COOX, SOH, SONXX, CONXX, NHC(O)O-alkyl, about 8 ring members, a heteroaromatic ring having 5 to about NHSO-alkyl alkoxy, alkyl, alcohol, alkylmercapto, alky 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri lamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, cyclic ring, a heterotricyclic ring, a polycyclic ring or a het CXXX. —CH=CHXs, —C=CXs: eropolycyclic ring. X and X2, each independently comprise H or alkyl, or Q comprises CH=CH, C=C. 65 X and X together comprise part of a heterocyclic ring Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi having about 4 to about 7 ring members and optionally one nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, additional heteroatom selected from O, N or S, or US 8,853,205 B2 27 28 X and X together comprise part of an imide ring having E comprises a C1 to about C4, linear or branched alkyl about 5 to about 6 members, group, a phenyl group, a Substituted phenyl group, a X comprises H, alkyl, NO, (CH),CN, hydroxylower benzyl group or a Substituted benzyl group. alkyl, or alkyl-NXX, In a variation of formula IV. R1 comprises -T-(CH)-Q- X, Xs, and X each independently comprise H, alkyl, 5 (CH), Z. carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, T comprises a carbocyclic ring having 3 to about 8 ring CN, SNO, S(SO)alkyl, NXX, COOX, CONX, OX, or members, an unsaturated ring having 3 to about 8 carbon O-alkyl-X, wherein atoms as ring members, an aromatic ring having 5 to about 8 X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) carbonatoms as ring members, a heterocyclic ring having 3 to 10 about 8 ring members, a heteroaromatic ring having 5 to about (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri CONXs, SOH, COXs, wherein cyclic ring, a heterotricyclic ring, a polycyclic ring or a het Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, eropolycyclic ring. aromatic ring, heteroaromatic ring, or —CX=CHXo, wherein m and n independently comprises an integer from 0 to 15 about 7. X and Xo each independently comprise H or alkyl; Q comprises CH=CH, C=C. m is an integer from 0 to 7: Z comprises j is an integer from 0 to about 6: k is an integer from 0 to about 2; and W comprises H or alkyl. In a variation of formula IV. R1 comprises -T-(CH)-Q- (CH2), Z. -N O m and n independently comprises an integer from 0 to - - about 7. A X^Na" T comprises a carbocyclic ring having 3 to about 8 ring 25 -P / N members, an unsaturated ring having 3 to about 8 carbon -N -N O r V as atoms as ring members, an aromatic ring having 5 to about 8 SeH)k A carbonatoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri 30 k is an integer from 1 to about 5. A and A. each indepen cyclic ring, a heterotricyclic ring, a polycyclic ring or a het dently comprise a C1 to about C4 alkyl group, a phenyl eropolycyclic ring. group or a substituted phenyl group. The inventive compounds in any formula, embodiment or Q comprises CH=CH, C=C. variation include any and all possible isomers and steroiso Z comprises an unsaturated ring having 5 ring atoms and 0 35 mers. In general, the compositions of the invention may be to 2 independently selected heteroatoms as ring members alternately formulated to comprise, consist of or consist fused to an unsaturated ring having 5 ring atoms and 0 to 4 essentially of any appropriate components herein disclosed. independently selected heteroatoms as ring members, an The compositions of the invention may additionally, or alter unsaturated ring having 5 ring atoms and 0 to 2 independently natively, be formulated so as to be devoid, or substantially selected heteroatoms as ring members fused to an unsaturated 40 free, of any components, materials, ingredients, adjuvants or ring having 6 or 7 ring atoms and 0 to 4 independently species used in the prior art compositions or that are otherwise selected heteroatoms as ring members or an unsaturated ring not necessary to the achievement of the function and/or objec having 6 ring atoms and 0 to 3 independently selected het tives of the present invention. eroatoms as ring members fused to an unsaturated ring having Unless otherwise specifically defined, “acyl refers to the 6 or 7 ring atoms and 0 to 4 independently selected heteroa 45 general formula—C(O)alkyl. toms as ring members Unless otherwise specifically defined, “acyloxy' refers to In a variation of formula IV. R1 comprises -T-(CH)-Q- the general formula —O-acyl. (CH2), Z. Unless otherwise specifically defined, “alcohol refers to T comprises a carbocyclic ring having 3 to about 8 ring the general formula alkyl-OH and includes primary, second members, an unsaturated ring having 3 to about 8 carbon 50 ary and tertiary variations. atoms as ring members, an aromatic ring having 5 to about 8 Unless otherwise specifically defined, “alkyl or “lower carbonatoms as ring members, a heterocyclic ring having 3 to alkyl refers to a linear, branched or cyclic alkyl group having about 8 ring members, a heteroaromatic ring having 5 to about from 1 to about 10 carbon atoms, and advantageously 1 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tri about 7 carbon atoms including, for example, methyl, ethyl, cyclic ring, a heterotricyclic ring, a polycyclic ring or a het 55 propyl, butyl, hexyl, octyl, isopropyl, isobutyl, tert-butyl, eropolycyclic ring. cyclopropyl, cyclohexyl, cyclooctyl, vinyl and allyl. The m and n independently comprises an integer from 0 to alkyl group can be saturated or unsaturated. The alkyl group about 7. can be unsubstituted, singly Substituted or, if possible, mul Q comprises CH=CH, C=C. tiply Substituted, with Substituent groups in any possible posi Z comprises 60 tion. Unless otherwise specifically limited, a cyclic alkyl group includes monocyclic, bicyclic, tricyclic, tetracyclic and polycyclic rings, for example norbornyl, adamantyl and related terpenes. Unless otherwise specifically defined, “alkoxy' refers to -O- Or -N\ /N-E 65 the general formula —O-alkyl. Unless otherwise specifically defined, “alkylmercapto' refers to the general formula—S-alkyl. US 8,853,205 B2 29 30 Unless otherwise specifically defined, “alkylamino” refers bridged rings having ring members independently selected to the general formula—(NH)-alkyl. from carbon and one or more heteroatoms, including oxygen, Unless otherwise specifically defined, “di-alkylamino” nitrogen and/or Sulfur. The heterotricyclic ring structure may refers to the general formula—N-(alkyl). Unless otherwise be saturated or unsaturated. specifically limited di-alkylamino includes cyclic amine The heterotricyclic ring structure can be unsubstituted, compounds such as piperidine and morpholine. singly substituted or, if possible, multiply substituted, with Unless otherwise specifically defined, an aromatic ring is Substituent groups in any possible position. The individual an unsaturated ring structure having about 5 to about 7 ring rings may or may not be of the same type. Examples of members and including only carbon as ring atoms. The aro heterotricyclic ring structures include carbazole, phenanthro matic ring structure can be unsubstituted, singly substituted 10 line, phenazine, 2.4,10-trioxaadamantane and tetradecahy or, if possible, multiply Substituted, with Substituent groups in dro-phenanthroline. any possible position. Unless otherwise specifically defined, a heteropolycyclic Unless otherwise specifically defined, “aryl refers to an ring structure comprises more than 3 rings that may be fused, aromatic ring system that includes only carbon as ring atoms, bridged or both fused and bridged and that have ring members for example phenyl, biphenyl or naphthyl. 15 independently selected from carbon and one or more heteroa The aryl group can be unsubstituted, singly Substituted or, toms, including oxygen, nitrogen and/or Sulfur. The het if possible, multiply Substituted, with Substituent groups in eropolycyclic ring structure can be saturated or unsaturated. any possible position. The heteropolycyclic ring structure can be unsubstituted, sin Unless otherwise specifically defined, “aroyl refers to the gly substituted or, if possible, multiply substituted, with sub general formula —C(=O)-aryl. stituent groups in any possible position. The individual rings Unless otherwise specifically defined, a bicyclic ring struc may or may not be of the same type. Examples of heteropoly ture comprises 2 fused or bridged rings that include only cyclic ring structures include azaadamantine, tropane, carbon as ring atoms. The bicyclic ring structure can be satu homotropane and 5-norbornene-2,3-dicarboximide. rated or unsaturated. The bicyclic ring structure can be unsub Unless otherwise specifically defined, the term “phenacyl stituted, singly substituted or, if possible, multiply Substi 25 refers to the general formula -phenyl-acyl. tuted, with Substituent groups in any possible position. The Unless otherwise specifically defined, a polycyclic ring individual rings may or may not be of the same type. structure comprises more than 3 rings that may be fused, Examples of bicyclic ring structures include naphthalene and bridged or both fused and bridged, and that includes carbon as bicyclooctane. ring atoms. The polycyclic ring structure can be Saturated or Unless otherwise specifically defined, a carbocyclic ring is 30 unsaturated. The polycyclic ring structure can be unsubsti a non-aromatic ring structure, Saturated or unsaturated, hav tuted, singly substituted or, if possible, multiply Substituted, ing about 3 to about 8 ring members that includes only carbon with substituent groups in any possible position. The indi as ring atoms, for example, cyclohexadiene or cyclohexane. vidual rings may or may not be of the same type. Examples of The carbocyclic ring can be unsubstituted, singly substituted polycyclic ring structures include adamantine, bicyclooctane, or, if possible, multiply Substituted, with Substituent groups in 35 norbornane and bicyclononanes. any possible position. Unless otherwise specifically defined, a spirocycle refers to Unless otherwise specifically defined, “halogen' refers to a ring system wherein a single atom is the only common an atom selected from fluorine, chlorine, bromine and iodine. member of two rings. A spirocycle can comprise a saturated Unless otherwise specifically defined, a heteroaromatic carbocyclic ring comprising about 3 to about 8 ring members, ring is an unsaturated ring structure having about 5 to about 8 40 a heterocyclic ring comprising about 3 to about 8 ring atoms ring members independently selected from carbon atoms and wherein up to about 3 ring atoms may be N. S. or O or a one or more heteroatoms, including oxygen, nitrogen and/or combination thereof. Sulfur, for example, pyridine, furan, quinoline, and their Unless otherwise specifically defined, atricyclic ring struc derivatives. The heteroaromatic ring can be unsubstituted, ture comprises 3 rings that may be fused, bridged or both singly substituted or, if possible, multiply substituted, with 45 fused and bridged, and that includes carbon as ring atoms. Substituent groups in any possible position. The tricyclic ring structure can be saturated or unsaturated. Unless otherwise specifically defined, a heterobicyclic ring The tricyclic ring structure can be unsubstituted, singly Sub structure comprises 2 fused or bridged rings having ring stituted or, if possible, multiply substituted, with substituent members independently selected from carbon and one or groups in any possible position. and may be substituted or more heteroatoms, including oxygen, nitrogen and/or Sulfur. 50 unsubstituted. The individual rings may or may not be of the The heterobicyclic ring structure can be saturated or unsatur same type. Examples of tricyclic ring structures include fluo ated. The heterobicyclic ring can be unsubstituted, singly rene and anthracene. substituted or, if possible, multiply substituted, with substitu Unless otherwise specifically limited the term substituted ent groups in any possible position. The individual rings may means substituted by a below-described substituent group in or may not be of the same type. Examples of heterobicyclic 55 any possible position. Substituent groups for the above moi ring structures include isobenzofuran and indole. eties useful in the invention are those groups that do not Unless otherwise specifically defined, a heterocyclic ring is significantly diminish the biological activity of the inventive a saturated or unsaturated ring structure having about 3 to compound. Substituent groups that do not significantly about 8 ring members independently selected from carbon diminish the biological activity of the inventive compound atoms and one or more heteroatoms, including oxygen, nitro 60 include, for example, H, halogen, N, NCS, CN, NO, gen and/or Sulfur, for example, piperidine, morpholine, pip NXX, OX, C(X), OAc, O-acyl, O-aroyl, NH-acyl, NH erazine, pyrrolidine, thiomorpholine, 1,1-dioxothiomorpho aroyl, NHCOalkyl, CHO, C(halogen), COOX, SOH, line and their derivatives. The heterocyclic ring can be POH, SONXX, CONXX, alkyl, alcohol, alkoxy, alky unsubstituted, singly Substituted or, if possible, multiply Sub lmercapto, alkylamino, di-alkylamino, Sulfonamide, thio stituted, with Substituent groups in any possible position. 65 alkoxy or methylene dioxy when the substituted structure has Unless otherwise specifically defined, a heterotricyclic two adjacent carbonatoms, wherein X and X2 each indepen ring structure comprises 3 fused, bridged, or both fused and dently comprise H or alkyl, or X and X together comprise US 8,853,205 B2 31 32 part of a heterocyclic ring having about 4 to about 7 ring As used herein, an “individual' refers to a human. An members and optionally one additional heteroatom selected "animal' refers to, for example nonhuman-primates such as from O, N or S, or X and X together comprise part of an monkeys and baboons, veterinary animals, such as rodents, imide ring having about 5 to about 6 members and X com dogs, cats, horses and the like, and farm animals, such as prises H, alkyl, hydroxyloweralkyl, or alkyl-NXX. Unless cows, pigs and the like otherwise specifically limited a Substituent group may be in In a certain embodiments, the compound disclosed in the any possible position. invention can be used in combination with other acceptable Some of the inventive compounds show a high affinity for pharmaceutical Substances. at least one of the cannabinoid receptors. Thus, another aspect In embodiments in which compounds of the disclosure is of the invention is use of at least one of the inventive com 10 used in combination with Rimonabant (Accomplia, pounds to interact with a cannabinoid receptor. Aventis) or other CB1 antagonists, it will be possible to Some of the novel heteropyrrole derivatives show selectiv ity for the CB1 cannabinoid receptor. These inventive CB1 reduce or even eliminate one or more of these side-effects, selective analogs are able to interact with the CB1 cannab particularly nausea. That is, it is possible to reduce the amount inoid receptors present in the CNS as well as the periphery 15 of Rimonabant or other CB1 antagonists administered to the without affecting the CB2 receptors to the same degree. individual who has had, is receiving or is about to receive a Therefore, still another aspect of the invention is use of at least therapeutically effective amount of the compound of the dis one of the inventive compounds to preferentially interact with closure. In one embodiment, the amount of Rimonabant a CB1 cannabinoid receptors present either in the CNS or the administered to the individual is reduced by 1.5 to 5-fold periphery. compared to the accepted therapeutic amount. The individual The inventive heteropyrrole analogs described herein, and is then dosed with a therapeutically effective amount of at physiologically acceptable salts thereof, have pharmacologi least one of the compounds of the disclosure. Of course, it is cal properties when administered in therapeutically effective also possible to increase the length of time between doses of amounts for providing a physiological response. Thus, Rimonabant with the same or similar effect. another aspect of the invention is the administration of a 25 Accordingly, one embodiment provides for a method for therapeutically effective amount of at least one of the inven reducing unwanted side-effects (one or more of nausea, diz tive compounds, or a physiologically acceptable Salt thereof, Ziness, diarrhea, and ) typically associated with to an individual or animal to provide a physiological administration of SR141716A (AccompliaTM/Rimonabant) response. or other CB1 antagonists to certain individuals. A particular A better understanding of the invention will be obtained 30 method involves administering a therapeutically effective from the following detailed description of the article and the amount of at least one of the compounds of the disclosure so desired features, properties, characteristics, and the relation as to reduce the side-effects in that individual. As discussed, of the elements as well as the process steps, one with respect the method can involve reducing the amount of SR141716A to each of the others, as set forth and exemplified in the (AccompliaTM/Rimonabant) or other CB1 antagonists admin description and illustrative embodiments. 35 istered to the individual. As will be apparent, the compounds of the invention can be DETAILED DESCRIPTION used alone or in combination with other CB1 receptor antago nists or anti-obesity agents known to the field. Examples of As used herein a “therapeutically effective amount of a such agents include SR141716A (AcompliaR/Rimonabant, compound, is the quantity of a compound which, when 40 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(pi administered to an individual or animal, results in a Suffi peridin-1-yl)-1H-pyrazole-3-carboxamide), Xenical(R) (Orl ciently high level of that compound in the individual or ani istat, (S)-(S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tride mal to cause a physiological response, for example a discern can-2-yl 2-formamido-4-methylpentanoate), MeridiaR) ible increase or decrease in stimulation of cannabinoid (, 1-(1-(4-chlorophenyl)cyclobutyl)-N,N.3-trim receptors. The inventive compounds described herein, and 45 ethylbutan-1-amine,hydrochloride monohydrate), physiologically acceptable salts thereof, have pharmacologi SR 147778 (, 5-(4-bromophenyl)-1-(2,4-dichlo cal properties when administered in therapeutically effective rophenyl)-4-ethyl-N-(piperidin-1-yl)-1H-pyrazole-3-car amounts individually or in combination for providing a physi boxamide), AVE-1625 (Drinabant, N-1-bis(4-chlorophe ological response useful to treat marijuana abuse, obesity, nyl)methyl-3-azetidinyl-N-(3,5-difluorophenyl)- lifestyle choices such as a desire to lose weight, other meta 50 methanesulfonamide), CP-945,598 (, 1-8-(2- bolic disorders including improvement in lipid profiles and Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4- insulin related deficiencies, hepatic , cardiometabolic (ethylamino)piperidine-4-carboxamide), E-6776 , congestive obstructive pulmonary disorders, (Rosonabant, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N- inflammatory bowel disease, Smoking cessation, bone (piperidin-1-yl)-4,5-dihydro-1H-pyrazole-3-carboxamide), defects, arthritis, inflammation, benign prostatic hypertrophy, 55 MK-0364 (, N-((2S,3S)-4-(4-chlorophenyl)-3-(3- asthma, migraine, chronic-intestinal pseudo obstruction, con cyanophenyl)butan-2-yl)-2-methyl-2-((5-(trifluoromethyl) stipation, , epilepsy, stress, memory disorders, pyridin-2-yl)oxy)propanamide), SLV-319 (, migraine, Vomiting, thymic disorders, dyskinesia, kinetic dis (S.E)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-N- order, anxiety disorders, psychotic disorders, cognitive dis methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximida orders, appetite disorders, mood disorders, delirious disor 60 mide), V24343, Qsymia (Qnexa, /, ders, neuropathies, Parkinson's disease, Alzheimers disease, 2-methyl-1-phenylpropan-2-amine and 2.3:4.5-Bis-O-(1- depression, psychosomatic-induced disease, diabetes, sexual methylethylidene)-B-D-fructopyranose sulfamate), Contrave dysfunctions, as well as for alcohol, opioid, nicotine and (/, 2-(tert-butylamino)-1-(3-chlorophe cocaine addiction, etc. Additionally, these analogs can be nyl)propan-1-one and 17-(cyclopropylmethyl)-4.5C.-epoxy useful in cancer chemotherapy. Typically, a “therapeutically 65 3.14-dihydroxymorphinan-6-one), Empatic (Bupropion/ effective amount of an inventive compound is believed to , 2-(tert-butylamino)-1-(3-chlorophenyl)propan range from about 0.01 mg/day to about 1,000 mg/day. 1-one and benzodisoxazol-3-ylmethanesulfonamide), US 8,853,205 B2 33 34 (Belvic (1R)-8-chloro-1-methyl-2,3,4,5-tetrahy hydrolyzable ester can be a obtained by conjugation of the dro-1H-3-benzazepine), and Phentermine (2-methyl-1-phe parent drug with a low-molecular weight alcohol or a high nylpropan-2-amine). molecular weight polyethylene glycol (PEG). In certain Compounds of the invention can also be used in combina embodiments, the compound disclosed in the invention could tion with a potassium channel opener, opiod antagonist, anti contain a nitrate ester group. convulsant agent, contraceptive agent, antipsychotic agent, In one embodiment, the compounds in the present inven anticonstipation agent, nicotine receptor agonist or partial tion could exist as enantiomers, diastereomers, geometric agonist, CB2 agonist, melanin-concentrating hormone recep isomers, racemates, tautomers, rotamers, atropisomers or torantagonist, antipsychotic agents, peroxisome proliferator 10 metabolites. activated receptors agonists, ghrelin antagonists, GLP-1 ago nist, fatty acid amide hydrolase inhibitor, an intestinal-acting In one embodiment, some compounds disclosed in the microsomal triglyceride transfer protein inhibitor, a dipepti invention can be "neutral antagonists’. These agents are said dyl-peptidase IV inhibitor, a statin, a sterol absorption inhibi to have no effect on intrinsic receptor activity at least in tor (B-lactam), Beta-3 adrenergic agonist, a biguanide, 15 certain test systems. However, these agents may be able to Sodium glucose transport (SGLT2) antagonist, cyclooxyge block receptor binding and activation, usually by a competi nase-2 inhibitor, renin inhibitor, monoamine oxidase inhibi tive agonist. tor, CETP inhibitor, ACAT inhibitor, DGAT-1 inhibitor, Mito In some embodiments, it would be desirable to have chondrial Transfer Protein inhibitor, noradrenalin-serotonin antagonists that exhibit essentially no CB1 receptor activity dopamine reuptake inhibitor or a lipase inhibitor. and which block or significantly reduce receptor activation by In one embodiment, less than five compounds of the dis a suitable agonist. It would be further desirable to have neutral closure, preferably one or two of same is used in combination antagonists of the CB1 receptor that can be used to prevent, with less than five of the known CB1 antagonists, preferably treat, or reduce the severity of symptoms of certain medical one or two of same. 25 conditions. It would be especially desirable to have neutral In one embodiment, the compound disclosed in the inven antagonists that exhibit no or minimal side-effects in vivo. tion could in itself act as a drug with a combination effect. For In another embodiment, the compound disclosed in the example compounds disclosed in the invention could dually present invention may act preferentially at the CB1 receptors act as a CB1 antagonist as well as 113-hydroxy steroid dehy 30 located in the periphery. In certain embodiments, the com drogenase-1 inhibitor. In certain embodiments, the com pounds do not penetrate the blood-brain-barrier, have pound could act dually as a CB1 antagonist as well as a nitric restricted penetration or have slow penetration. In certain oxide donor. embodiments, peripherally acting compounds may have By "physiologically acceptable salts' is meant, salts typi advantages over centrally acting compounds, for example, cally useful for pharmaceutical applications including acid 35 reduced psychotropic adverse effects. addition salts and basic salts. Examples of acid addition salts A compound acting on the CB1 receptors located in the are hydrochloride salts, hydrobromide salts, methane sul periphery could be behave either as a neutral antagonist, an fonate salts etc. Examples of basic salts are salts where the inverse agonists or a partial antagonist. cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammo 40 A compound acting on the CB1 receptors located centrally, nium ions. Other examples of physiologically acceptable could behave salts can be found in “Remington's Pharmaceutical Sciences as a neutral antagonist, an inverse agonists or a partial 17. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Com antagonist. pany, Easton, Pa., U.S.A., 1985 and more recent editions, and 45 In another embodiment, the compounds disclosed in the in Encyclopedia of Pharmaceutical Technology. invention could act either as inverse agonists with no or Polymorphic forms show improved physiochemical prop reduced side effects. In other embodiments, the compounds erties and stability for formulation purposes. In one embodi could act as partial agonists with no or reduced side effects. ment, the compounds disclosed in the invention could exist in The compounds of the present invention can be adminis various solid forms. The solid forms can be crystalline and 50 tered by a variety of known methods, including orally, rec amorphous forms, but not limited to, Solvates, hydrates, tally, or by parenteral routes (e.g., intramuscular, intravenous, hydrolyzable esters and N-oxides of the compounds defined Subcutaneous, nasal or topical). The form in which the com in the specification. These solid forms can be obtained by pounds are administered will be determined by the route of treating either the free base or their salts at a certain adjusted 55 administration. Such forms include, but are not limited to, pH and certain temperature with an solvent or a combination capsular and tablet formulations (for oral and rectal adminis of solvents. The solvents can be and not limited to a hydro tration), liquid formulations (for oral, intravenous, intramus carbon solvent such as toluene, Xylene, hexanes, heptane, or cular, Subcutaneous, ocular, intranasal, inhalation-based and petroleum ether, alcohol Such as methanol, ethanol, n-bu transdermal administration) and slow releasing microcarriers tanol, n-propanol and 2-propanol, di-isopropyl ether, ethyl 60 (for rectal, intramuscular or intravenous administration). The acetate, dichloromethane, acetic acid, acetone, tetrahydrofu formulations can also contain a physiologically acceptable ran, dichloromethane, and water. vehicle and optional adjuvants, flavorings, colorants and pre In one embodiment, in order to improve the dehepaticabil servatives. Suitable physiologically acceptable vehicles ity of the compound disclosed in the present invention for the 65 include, for example, saline, sterile water, Ringer's Solution required physiological effect, a “pro-drug of the same can be and isotonic sodium chloride Solutions. The specific dosage made available. For example, the pro-drug Such as an in-vivo level of active ingredient will depend upon a number of fac US 8,853,205 B2 35 36 tors, including, for example, biological activity of the particu into the subject. There is a waiting period while the radiop lar preparation, age, body weight, sex and general health of harmaceutical analog becomes concentrated in tissues of the individual being treated. interest Such as a cannabinoid receptor. After the waiting In another embodiment, the compounds of the present period the patient is placed in an imaging scanner and SPECT disclosure can also comprise isotopes at one or more of their 5 imaging is performed by using a gamma camera to acquire atoms. For example, the compounds can be radiolabeled with multiple two dimensional images from multiple angles. A isotopes, such as H (deuterium written as D) H (tritium computer is then used to apply an algorithm to the multiple written as T), ''C (carbon-11), C (carbon-13), C (carbon images to provide a three dimensional image. 14), "O (oxygen-15), ''O (oxygen-17), "O (oxygen-18), 10 'N (nitrogen-13), N (nitrogen-15), 'F (fluorine-18), Br TABLE 1 (bromine-75), 7Br (bromine-76), 77Br (bromine-77), Br (bromine-82), 123I (iodine-123), 'I (iodine-124), 'I (io dine-125) or 'I (iodine-131), Cl (chlorine-36) or S (sul phur-35), The present disclosure encompasses all isotopic 15 variations of the described compounds, whether natural or HO N^ unnatural, radioactive or not. H An isotope is one of two or more species of the same A \, element. Each isotope of an element will have the same num N1 ber of protons in its nucleus, the same atomic number and the same position in the Periodic Table. However each isotope of C that element will have a different number of neutrons in its I nucleus and therefore a different mass than other isotopes of that species. The term nuclide is sometimes used synony 25 mously with the term isotope. As used herein a natural isotope C has an atomic mass corresponding most closely with the atomic mass shown for that element in the Periodic Table. As used herein an unnatural isotope has an atomic mass that is 30 further removed from the atomic mass shown for that element in the Periodic Table than the natural isotope. For example, protium (hydrogen-1 or "H) is the natural isotope ofhydrogen and deuterium (hydrogen-2 or H) and tritium (hydrogen-3 or O (C)N H) are all unnatural isotopes of hydrogen. 35 HO N^ In a particular embodiment, some of the halogen contain H ing analogs, for example those analogs comprising iodide and fluoride, are potential radioactive probes for imaging in vivo - the distribution of cannabinoid receptors. For radio-imaging applications l'C, F, 125I, 12.I., 1*I, II, 75 Br, 79Br or 77Br 40 C will generally be most useful. 2 Some of the radioactive isotope containing analogs have potential as radiopharmaceutical analogs (disclosed analogs that have been labeled with radioactive isotopes). These 45 NC C radiopharmaceuticals can be administered to individuals or animals and the emitted radiation can be measured. The majority of these diagnostic tests involve the formation of an image using a camera Suitable to detect the emitted radiation. Positron emission tomography (PET) is one nuclear medicine 50 tomographic imaging technique, which produces a three-di O () mensional image or map of functional processes in a patients M N body. To conduct the PET scan, a short-lived radiopharma H ceutical analog that decays by emitting a positron is admin 55 \ istered into the subject (usually by injection into the blood f N stream). There is a waiting period while the radiopharmaceu N1 tical analog becomes concentrated in tissues of interest Such as a cannabinoid receptor. After the waiting period the patient C is placed in an imaging scanner. The Scanner collects multiple 60 2^ images and a computer is used to apply an algorithm to the multiple images and provide a three dimensional image. Single photon emission computed tomography (SPECT) is MeO C another nuclear medicine tomographic imaging technique. To 65 conduct the SPECT scan, a short-lived radiopharmaceutical analog that decays to produce a gamma ray is administered US 8,853,205 B2 37 38 TABLE 1-continued TABLE 1-continued

10 NC)

15 C. C

4

25

O () 30 M N H

N / 35

C 2 40

AcS

5 45

50 O (C) M N H \ 55 N /

C C

2 60

I MSS C

6 65 US 8,853,205 B2 39 40 TABLE 1-continued TABLE 1-continued

10

15

ONO 13 10

25

30

C

40 C SCN C

11 45

50

55

60

NC C

65 15 US 8,853,205 B2 41 42 TABLE 1-continued TABLE 1-continued

O

S O O O y(C) ONO N 10 ( \, \ ( \, N1 Cl 15 Br

C C 19 16

25

O

S Cy 30 N M N H

35

c. 40 C

C

17 45

50 (C) M N H 55

NH2 2. 60 c

C C 65 21 US 8,853,205 B2 43 44 TABLE 1-continued TABLE 1-continued

O ()N 5 M N O H (C) 10 N/ N N / \N N 15 C 2

NC C

22 NC C

25

25

30 O

\ 35 N N N C 2 C c. 40

C O 26 23 45

50 O (C) M N H 55 \ N N

C

60

C C

65 c.27 24

US 8,853,205 B2 47 48 TABLE 1-continued TABLE 1-continued

US 8,853,205 B2 49 50 TABLE 1-continued TABLE 1-continued

The invention will be further described in more detail by 42 65 the following synthetic examples. These examples are offered to illustrate the invention, and are not to be construed in any way as limiting the scope of the invention. US 8,853,205 B2 51 52 Compound Synthesis and Formulation nomorpholine (0.41 g, 4 mmol) at 0°C. and stirred for 25 min at that temperature. To this was added a solution of ester from Example 1 step C (700 mg, 1.3 mmol) in dichloroethane (5 mL). The reaction was brought to RT and stirred at that temperature for 1-(4-(4-cyanobut-1-ynyl)phenyl)-2-(2,4-dichlorophe 8 h. The reaction was quenched with dilute HCl and the nyl)-N-morpholino-5-(pyrrolidin-1-ylmethyl)-1H organic layer was extracted with dichloromethane. The com imidazole-4-carboxamide (compound 12) bined extracts were dried over anhydrous MgSO, filtered and evaporated under reduced pressure. Purification by column Step A chromatography gave the amide as an off-white solid (500 10 mg, 60%). N-(4-bromophenyl)-2,4-dichlorobenzimidamide 'HNMR (500 MHz, CDC1-d)8.39 (s.1H), 7.65 (d. J=8.30 Hz, 2H), 7.34 (s, 1H), 7.27-7.32 (m, 1H), 7.22-7.26 (m, 1H), To a magnetically stirred solution of EtMgBr (3.3 mL, 3M 7.05 (d. J=8.30 Hz, 2H), 3.87 (t, J=4.39 Hz, 4H), 3.83 (s. 2H), in diethyl ether, 10 mmol) in THF (30 mL) 4-bromoaniline 2.94 (br. S., 4H), 2.50 (br. s., 4H), 1.69 (br. S., 4H) (1.72 g, 10 mmol) was slowly added portion wise. After the 15 solution was stirred for 30 min., 2,4-dichlorobenzonitrile Step D (1.72 g, 10 mmol) was added. The resulting solution was stirred at room temperature (RT) overnight. The reaction The amide from step C (500 mg. 0.79 mmol) was taken and mixture was quenched with water and extracted with ethyl Subjected to the Sonogashira reaction as was performed in acetate. The combined extracts were dried over anhydrous example 3F to give compound 12 (200 mg, 47.5%). MgSO filtered and evaporated under reduced pressure to H NMR (500 MHz, CDC1-d) 8.19-8.52 (m. 1H), 7.47 (d. give the benzimidamide as an off-white solid (2.45 g, 71.2%). J=7.81 Hz, 3H), 7.35 (d. J=1.95 Hz, 3H), 7.29-7.30 (m. 1H), 7.25-7.28 (m, 1H), 4.04-4.92 (m, 2H), 3.90 (t, J=4.39 Hz, Step B 4H), 2.98 (br. S., 4H), 2.73-2.88 (m, 2H), 2.63-2.74 (m, 2H), 25 2.02 (br. S., 4H), 1.74 (none, 4H) Ethyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5- methyl-1H-imidazole-4-carboxylate Example 2 To a magnetically stirred solution of above imidamide 4-(4-(1-(2,4-dichlorophenyl)-4-methyl-3-(piperidin from step A (2.45 g, 7 mmol) in 30 mL anhydrous toluene 30 1-ylcarbamoyl)-1H-pyrazol-5-yl)phenyl)but-3-ynyl were added ethyl 3-bromo-2-oxobutanoate (1.48 g. 7 mmol) nitrate (compound 10) and NaCO (0.74g, 7 mmol). The contents were stirred at 100° C. for 12 hours. The reaction was brought to RT. The To a stirred solution of compound 51-(2,4-dichlorophe reaction mixture was quenched with water and extracted with nyl)-5-(4-(4-iodobut-1-ynyl)phenyl)-4-methyl-N-(piperi ethyl acetate. The combined extracts were dried over anhy 35 din-1-yl)-1H-pyrazole-3-carboxamide (60 mg, 0.9 mmol) drous MgSO, filtered and evaporated under reduced pres taken in acetonitrile (20 ml) and to that silver nitrate (33.5 mg. Sure. Purification by column chromatography gave the ester 0.19 mmol) was added. The reaction mixture was heated for as pale white solid (1.5 g., 46.4%). 2 hours. After cooling to RT, the precipitate was filtered. The filtrate was concentrated to give an oily residue which was Step C 40 subsequently dissolved in dichloromethane (20 ml). This was washed with 2x5 ml water and the organic layer was dried 2-(2,4-dichlorophenyl)-1-(4-iodophenyl)-N-mor over anhydrous sodium Sulfate, filtered, and evaporated. pholino-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4- Flash column chromatography on silica gel with petroleum carboxamide (compound 8) ether?ethyl acetate (1:1) gave compound 2 (40 mg, 74.6% 45 yield) as a white solid. To a magnetically stirred solution of ester from step B (1.5 H NMR (500 MHz, CDC1-d) 7.65 (s, 1H), 7.43 (s, 1H), g, 3.3 mmol) in carbon tetrachloride (20 mL) N-bromosuc 7.36 (d. J=8.30 Hz, 2H), 7.29-7.33 (m, 2H), 7.07 (d. J=8.30 cinimide (0.58g, 3.3 mmol) was added along with a catalytic Hz, 2H), 4.64 (t, J=6.84 Hz, 2H), 2.74-3.02 (m, 6H), 2.39 (s. amount of and 2,2'-azobisisobutyronitrile (AIBN, 15 mg). 3H), 1.69-1.90 (m, 4H), 1.45 (br. S., 2H) The resulting mixture was refluxed for 3 h. After cooling to 50 RT, the precipitate was filtered. The filtrate was washed with Example 3 2x50 ml water and the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. Flash column chro 5-(4-(4-cyanobut-1-ynyl)phenyl)-1-(2,4-dichlorophe matography on silica gel with petroleum ether?ethyl acetate nyl)-4-methyl-N-(1,1-dioxothiomorpholino)-1H (1:9) gave bromo derivative (1 mg, 56% yield) as a pale 55 pyrazole-3-carboxamide (compound 15) yellow solid. The bromo derivative (1 g, 1.88 mmol) was taken in acetonitrile (50 ml) and to that Hunnig's base (0.26g, Step A 2 mmol) and pyrrolidine (0.14g, 2 mmol) were added. The reaction mixture was heated at 60-65° C. for 1 h hour. After 4'-iodopropiophenone cooling the reaction mixture was concentrated to give an oily 60 residue which was subsequently dissolved in dichlo Iodobenzene (100 g, 0.49 mol) was taken in a dry 1 L 3 romethane (50 ml). This was washed with 2x25ml water and neck flask equipped with a Ninlet and to it 200 ml of CS was the organic layer was dried over anhydrous Sodium Sulfate, added. The contents were cooled to 0-5°C. and then AlCls (80 filtered, and evaporated. Flash column chromatography on g, 0.6 moles) and Subsequently propionyl chloride (60 g, 0.64 silica gel with petroleum ether/ethyl acetate (1:1) gave ester 65 mol) were added while keeping the temperature (internal) at (700 mg, 71.2%) as a white solid. To the suspension of AlCl 5-10°C. The contents were stirred for 24 hrs. The reaction (0.53 g, 4 mmol) in dichloroethane (20 mL) was added 4-ami mixture was poured into a 5 liter plastic beaker containing 1 US 8,853,205 B2 53 54 L of 10% HC1+1 Kg of crushed ice. The resultant slurry was and the mixture was acidified to pH ~2 using concentrated extracted with 1 L of ethyl acetate. The organic layer was HC1. The organic layer was separated, washed with 100 ml of separated and washed with 2x500 ml of water and 500 ml of brine, dried over Sodium Sulphate and concentrated to give the brine. The organic layer was dried over Sodium Sulphate and acid. This was taken directly to the next step (9.4g, 100%). concentrated at 40° C. to give 4'-iodopropiophenone (48 g. 5 "H NMR (500 MHz, CDC1-d) 7.70 (d. J=8.30 Hz, 2H), 38%). 7.44 (s, 1H), 7.30-7.38 (m, 2H), 6.90 (d. J=8.30 Hz, 2H), 2.37 "H NMR (500 MHz, CDC1-d) 7.82 (d. 2H), 7.67 (d. (s, 3H) J=8.30 Hz, 2H), 2.96 (q, J=7.00 Hz, 2H), 1.22 (t, J=7.32 Hz, 3H) Step E 10 Step B 1-(2,4-dichlorophenyl)-4-methyl-5-(4-iodophenyl)- N-(1,1-dioxothiomorpholino)-1H-pyrazole-3-car Lithium-4-ethoxy-1-(4-iodophenyl)-2-methyl-3,4- boxamide (compound 16) dioxobut-1-en-1-olate 15 The acid (7.5 g. 15.8 mmol) obtained from step D was 4'-iodopropiophenone obtained from step A was taken in a taken in a 500 ml 1 neck flask equipped with a nitrogen inlet 2L 3 neck flask equipped with a nitrogen inlet. To that 500 ml and to it 200 ml of DCM, 4-aminothiomorpholine-1,1-diox of diethyl ether was added and the contents were cooled at -78° C. using a dry-ice acetone bath. The reaction mixture ide (2.61 g, 17.4 mmol), TBTU (5.59 g, 17.4 mmol) and was stirred for 15 minutes. Subsequently, a 1 M solution of DIPEA (2.25 g, 17.4 mmol) were added and the contents were lithium bis(trimethylsilyl)amide in hexanes (222 ml, 0.22 stirred for 1 hour. To the reaction mixture, 100 ml of water mol) was added drop wise over 1 hour. The contents were was added and the contents were acidified to pH -2 using stirred at -78° C. an additional 1 hour after diethyl oxalate concentrated HC1. The organic layer was separated, washed which (32.3 g, 0.22 mol) taken in diethyl ether was added over with brine, dried over sodium sulphate and concentrated to 30 minutes. The contents were stirred for 2 hours at -78°C. 25 give the amide (3 g, 31.2%). after which the cooling bath was removed. The contents were 'HNMR (500 MHz, CDC1-d)8.07 (s, 1H), 7.67 (d.J=8.30 brought to room temperature over 10 hours. The solids were Hz, 2H), 7.45 (d. J=1.95 Hz, 1H), 7.29-7.34 (m, 1H), 7.25 (s, filtered under a stream of nitrogen and then washed with 200 1H), 6.85 (d. J=8.30 Hz, 2H), 3.44-3.66 (m, 4H), 3.26 (d. ml of ether. The solid obtained was air dried for 1 hour and J=4.88 Hz, 4H), 2.35 (s.3H) was taken as such to the next reaction directly (52g, 76.9%). 30 Step F Step C To a stirred solution of amide obtained from step E (2g, 3.3 ethyl 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4- mmol) in pyrrolidine (40 ml), under an argon atmosphere, methyl-1H-pyrazole-3-carboxylate 35 tetrakis(triphenylphosphine)palladium(0) (0.4g, 0.3 mmol) was added. The reaction mixture was stirred for 5 minatroom The lithium salt obtained from step B was taken in a 1 liter temperature, and subsequently 4-cyano-1-butyne (0.78g, 9.9 1 neck flask and to that 2,4-dichlorophenylhydrzine hydro chloride (30.3 g, 0.14 mol) and 1.5 liters of anhydrous ethanol mmol) in pyrrolidine (1.5 ml) was added over 5 minutes. The were added in on portion. The resulting mixture was stirred at 40 resulting mixture was heated at 80-85°C. for 10 h. The room temperature for 24 hours. The solids were filtered, reaction was hydrolyzed with a saturated aqueous solution of washed with ethanol and then dried under vacuum to give a ammonium chloride and extracted with ethyl acetate. The light yellow of ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-4- organic extract was dried over MgSO4 and the solvent was (4-iodophenyl)-3-methyl-4-oxobutanoate (27 g). The solids removed in vacuo. Purification by flash column chromatog were taken in a 1 L 1 neck flask and to that 1 liter of glacial 45 raphy on silica gel (eluant ethylacetate) gave compound 15 as acetic acid was added. The mixture was refluxed for 4 hours. a white solid (0.8 g., 43.7%) Acetic acid was distilled out completely and to the residue H NMR (500 MHz, CDC1-d) 8.08 (s, 1H), 7.43 (s, 1H), 500 ml of ethyl acetate was added. The organic layer was 7.37 (d. J=7.81 Hz, 2H), 7.28-7.34 (m. 1H), 7.24 (s, 1H), 7.06 separated, washed with 1 liter of water, dried over sodium (d. J=7.81 Hz, 2H), 3.56 (d. J–4.88 Hz, 4H), 3.26 (br. S., 4H), Sulphate and concentrated to give the crude ester. The ester 50 2.72-287(m, 2H), 2.57-2.71 (m, 2H), 2.37 (s.3H) was purified by column chromatography using a 10% ethyl acetate-hexane mixture to give the pure ester (15g, 57.6%). Example 4 "H NMR (500 MHz, CDC1-d) 7.69 (d. J=8.30 Hz, 2H), 7.41 (s, 1H), 7.29-7.39 (m, 2H), 6.89 (d. J=8.30 Hz, 2H), 4.48 5-(5-(4-cyanobut-1-ynyl)thiophen-2-yl)-1-(2,4- (q, J=7.32 Hz, 2H), 2.35 (s.3H), 1.37-1.53 (m, 3H) 55 dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H pyrazole-3-carboxamide (compound 34) Step D Step A 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl 1H-pyrazole-3-carboxylic acid 60 N-Methoxy-N-methylpropionamide The ester (10g, 19.9 mmoles) obtained from step C was Pyridine (17 mL, 0.4 mol) at 0°C. was added dropwise to taken in 500 ml 1 neck flask and to it 300 ml of 7:2:1 mixture a solution of O.N-dimethyl-hydroxylamine hydrochloride of THF-methanol-water along with solid lithium hydroxide (10g, 0.1 mol) and propionyl chloride (10 g, 0.1 mol) in (2.5g, 104.6 mol) was added. The mixture was refluxed for 12 65 anhydrous dichloromethane (250 mL). The solution was hours. The solvents were removed totally and to the residue stirred at room temperature for 24 h, washed with 2x50 ml of 200 ml of DCM was added. To that 100 ml of water was added 5% hydrochloric acid, 100 ml of saturated NaHCO, and 100

US 8,853,205 B2 59 60 concentration of cAMP produced by the cells. The results Constant(K) and the concentration of Inhibitor which causes were expressed as percent inhibition of forskolin-stimulated 50%. Inhibition (ICs) of an Enzymatic Reaction, Biochem. cAMP accumulation and EC50 curves were generated with Pharmacol., 22,3099-3102, (1973), which is incorporated by the use of GraphPad Prism software. reference herein. For example compound 2 and compound 15 did not change For the CB2 receptor binding studies, membranes were the forskolin-stimulated cAMP accumulation in CB1 trans prepared from frozen mouse spleen essentially according to fected HEK cells (FIGS. 1A and 1B) and are therefore con the procedure of P. R. Dodd et al. A Rapid Method for Pre sidered to be a CB1 neutral antagonists. paring Synaptosomes. Comparison with Alternative Proce dures, Brain Res., 226, 107-118 (1981) which is incorporated The results are from one assay done in triplicate. by reference herein. Silanized centrifuge tubes were used Reference herein to a “standard forskolin-stimulated 10 throughout to minimize receptor loss due to adsorption. The cAMP assay” or like phrase refers to the foregoing assay CB2 binding assay was conducted in the same manner as for method. the CB1 binding assay. The binding affinities (K) were also (HICP55,940 Competitive Binding Assay expressed in nanomoles (nM). Some of the inventive analogs were tested for CB1 receptor The CB1 cannabinoid receptor binding affinities (K) for binding affinity and for CB2 receptor affinity (to determine 15 Some of the compounds disclosed in the invention range selectivity). As used herein, “binding affinity” is represented between 0.5 nM and less than 100 nM. The CB2 cannabinoid by the K value which is the inhibition constant correlated receptor binding affinities (K) for the synthesized analogs with the concentration of an analog required to occupy the range between 60 nM and 5000 nM. For example, CB1 can 50% of the total number (Bmax) of the receptors. The lower nabinoid receptor binding affinity (K) for compound 2 is 7 the K value the higher the binding affinity. As used herein an nM and the CB2 cannabinoid receptor binding affinity (K) is analog is said to have “binding selectivity’ if it has higher 1672 nM. The CB1 selectivity for some of the compounds binding affinity for one receptor compared to the other recep range from 5 to greater than 5000. tor; e.g. a cannabinoid analog which has a K, of 0.1 nM for Distribution and the Blood Brain Barrier: CB1 and 10 nM for CB2, is 100 times more selective for the Mice (CD-1, weighing 25-30 g) are dosed intravenously or CB1 receptor. 25 by oral gavage with 0.1-2 mg/kg of the compound dissolved For the CB1 receptor binding studies, membranes were in appropriate vehicle. Fifteen minutes post-injection or 30 prepared from rat forebrain membranes according to the pro and 60 minutes post-gavage, the animals are sacrificed cedure of P. R. Dodd et al. A Rapid Method for Preparing humanely by decapitation followed by blood collection Synaptosomes. Comparison with Alternative Procedures, (-500LL) and tissue dissection; samples are flash frozen with Brain Res., 107-118 (1981). The binding of the novel ana 30 liquid nitrogen to prevent post-mortem degradation of the logues to the CB1 cannabinoid receptor was assessed as compounds or endogenous ligands. Tissues (plasma or brain) described in W. A. Devane et al. Determination and Charac are extracted and analyzed using a Thermo-Finnigan Quan terization of a Cannabinoid Receptor in a Rat Brain, Mol. tum Ultra triple quadrupole mass spectrometer with an Agi Pharmacol., 34, 605-613 (1988) and A. Charalambous et al. lent 1100 HPLC front-end. Chromatographic separation is 5'-azido A-THC: A Novel Photoafinity Label for the Can 35 achieved using a Phenomenex Gemini column (2x50 mm, nabinoid Receptor, J. Med. Chem., 35, 3076-3079 (1992) 5u). Hardware consists of a Finnigan TSQ Quantum Ultra with the following changes. The above articles are incorpo triple quad mass spectrometer with both an APCI and ESI rated by reference herein. source and an Agilent 1100 front end. The mass spectrometer Membranes, previously frozen at -80°C., were thawed on with mobile phase consisting of 0.1% formic acid in water ice. To the stirred suspension was added three volumes of 40 (A) and 0.1% formic acid in methanol (B). SR141716 gets TME (25 mM Tris-HCl buffer, 5 mM MgCl, and 1 mM into the brain better at 1.8%/g (% of the total dose per gram EDTA) at a pH 7.4. The suspension was incubated at 4°C. for brain) at 15 minutes post IV as compared to compound 2 30 min. At the end of the incubation, the membranes were which is 0.6%. pelleted and washed three times with TME. Those skilled in the art will recognize, or be able to ascer The treated membranes were subsequently used in the 45 tain using no more than routine experimentation, many binding assay described below. Approximately 30 Jug of equivalents to specific embodiments of the disclosure membranes were incubated in silanized 96-well microtiter described specifically herein. Such equivalents are intended plate with TME containing 0.1% essentially fatty acid-free to be encompassed in the scope of the disclosure. bovine serum albumin (BSA), 0.8 nM (HICP-55,940, and What is claimed is: various concentrations of test materials in a final Volume of 50 1. A compound represented by the following structural 200 uL. The assays were incubated for 1 hour at 30° C. and formula: then immediately filtered using Packard Filtermate 196 har vester and Whatman GF/C filterplates and washed with wash buffer (TME) containing 0.5% BSA. Radioactivity was R4 detected using MicroScint 20 scintillation cocktail added 55 directly to the dried filterplates, and the filterplates were counted using a Packard Instruments Top-Count. Nonspecific binding was assessed using 100 nM CP-55,940. Data col lected from three independent experiments performed with duplicate determinations was normalized between 100% and 60 0% specific binding for HICP-55,940, determined using buffer and 100 nM CP-55,940. The normalized data was and physiologically acceptable salts thereof, wherein: analyzed using a 4-parameter nonlinear logistic equation to A is a direct bond, yield ICso values. Data from at least two independent experi B is N(R5), ments performed in duplicate was used to calculate ICso 65 R5 is hydrogen, OH, alkyl or substituted alkyl: values which were converted to K values using the assump R2 comprises —(CH2), Z: tions of Cheng et al. Relationship Between the Inhibition n is an integer from 0 to about 7: US 8,853,205 B2 61 62 wherein Z comprises, H, halogen, CF, CFH, N, NCS, R2 comprises —(CH2), Z: CN, NO, NXX, OX, SX, OAc, OSOX, O-acyl, n is an integer from 0 to about 7; and S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi OC(CH)COOXs. C(CH)2COOXs. Si(alkyl), alkyl nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, CN, O-aroyl, O(CH),OX, O(CH2).NXX2, NH-acyl, 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy NH-aroyl, CHO, C(halogen), COOX, SOH, drofuranyl; or any above group Substituted on at least SONXX, CONXX, NHC(O)O-alkyl, NHSO2 one available ring atom by an alkyl group; or any above alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, alkoxybenzyl group, a Substituted alkoxybenzyl group, -CH=CHXs. -C=CXs: 10 a benzhydryl group or a substituted benzhydryl group; X and X2, each independently comprise H or alkyl, or and wherein the connecting point between the X and X together comprise part of a heterocyclic ring —(CH), group and the Z group can be any available having about 4 to about 7 ring members and optionally ring carbon atom or any available ring nitrogenatom; or one additional heteroatom selected from O, N or S, or R2 comprises —(CH2), Z: X and X together comprise part of an imide ring having 15 n is an integer from 0 to about 7; and about 5 to about 6 members, Z comprises X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy loweralkyl, or alkyl-NXX, X, Xs, and X each independently comprise H, alkyl, n4 y-X x^ x^, VX carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, & S X, Xy / s OX, or O-alkyl-X, wherein N. Y., X s & s SA Y: X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) N. VX N (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. 25 / X. X4, R - CONXs, SOH, COXs, wherein N= Y, \= Y, N2 N s Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, N X X X aromatic ring, heteroaromatic ring, or —CX=CHXo 4 x SS?s SSS SSS wherein M N N --Y S --Y O --Y 30 -K ŽSy, 2N , 2N , \e N X and Xo each independently comprise H or alkyl X X Wherein m is an integer from 0 to 7 23 Sé 23 SAS j is an integer from 0 to about 6, or N ld4. S. 2N-y k is an integer from 0 to about 2; or 35 R2 comprises —(CH2), Z: X N n is an integer from 0 to about 7; and Xa Sé x N N Z comprises a carbocyclic ring having about 4 to about 7 | Y x \ 1 N ) ring members, a heterocyclic ring having about 4 to S 21 Y X1\ {Y or about 7 ring members, anaromatic ring having about 5 to 40 about 7 ring members, a heteroaromatic ring having x^-w about 5 to about 7 ring members, a bicyclic ring, a V. heterobicyclic ring, a tricyclic ring, a heterotricyclic X ring, a polycyclic ring, a heteropolycyclic ring; or any above group Substituted on at least one available ring 45 wherein X and Y each independently comprise, H., halo atom by an alkyl group; or any above group Substituted gen, CF, CFH, N, NCS, ON, NO, NXX, OX, SX, on at least one available ring nitrogen atom by a benzyl OAc, OSOX, O-acyl, S-acyl, SO-alkyl, group, a Substituted benzyl group, an alkoxybenzyl SO-alkyl, SC(CH),COOX, OC(CH),COOXs. group, a Substituted alkoxybenzyl group, a benzhydryl C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, group or a Substituted benzhydryl group; and wherein 50 O(CH.),OX, O(CH.)NXX, NH-acyl, NH-aroyl, the connecting point between the -(CH2)—group and CHO, C(halogen), COOX, SOH, SONXX, the Z group can be any available ring carbon atom or any CONXX, NHC(O)C-alkyl, NHSO2-alkyl, alkoxy, available ring nitrogen atom; or alkyl, alcohol, alkylmercapto, alkylamino, di-alky R2 comprises —(CH2), Z: lamino, alkylsulfinyl or alkylsulfonyl, CXXX, 55 -CH=CHXs. -C=CXs: n is an integer from 0 to about 7; and X and X each independently comprise H or alkyl, or Z comprises a 5 member unsaturated ring having 0 to 4 X and X together comprise part of a heterocyclic ring independently selected heteroatoms as ring members, a having about 4 to about 7 ring members and optionally substituted 5 member unsaturated ring having 0 to 4 one additional heteroatom selected from O, N or S, or independently selected heteroatoms as ring members, a 60 X and X together comprise part of an imide ring having 6 member aromatic ring having 0 to 5 independently about 5 to about 6 members, Selected heteroatoms as ring members or a Substituted 6 X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy member aromatic ring having 0 to 5 independently loweralkyl, or alkyl-NXX. Selected heteroatoms; and wherein the connecting point X, Xs, and X each independently comprise H, alkyl, between the —(CH), group and the Z group can be 65 carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo any available ring carbon atom or any available ring gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, nitrogen atom; or OX, or O-alkyl-X, wherein US 8,853,205 B2 63 64 X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) X, Xs, and X each independently comprise H, alkyl, (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo CONXs, SOH, COXs, wherein gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, OX, or O-alkyl-X, wherein aromatic ring, heteroaromatic ring, or—CX=CHXo X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) wherein (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. X and Xo each independently comprise H or alkyl CONXs, SOH, COXs, wherein Wherein m is an integer from 0 to 7 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, j is an integer from 0 to about 6, or aromatic ring, heteroaromatic ring, or—CX=CHXo 10 wherein k is an integer from 0 to about 2 X and Xo each independently comprise H or alkyl W comprises H or alkyl; or Wherein m is an integer from 0 to 7 R2 comprises —(CH2), Z: j is an integer from 0 to about 6, or n is an integer from 0 to about 7; and k is an integer from 0 to about 2; or Z comprises a carbocyclic ring having 6 ring atoms fused to 15 R2 comprises -Q-(CH2), Z: a heterocyclic ring having from 5 to 7 ring atoms, a Q is optionally present and if present comprises —CH2— carbocyclic ring having 6 ring atoms fused to a het NH, —CH2—O, —CH2—S, —CH2—SO or —CH eroaromatic ring having from 5 to 7 ring atoms, a het OSO; erocyclic ring having 6 ring atoms fused to a heterocy n is an integer from 0 to about 7: clic ring having from 5 to 7 ring atoms, an heterocyclic wherein Z comprises, H, halogen, CF, CFH, N, NCS, ring having 6 ring atoms fused to a heteroaromatic ring ON, NO, NXX, OX, SX, OAc, OSOX, O-acyl, having from 5 to 7 ring atoms, an aromatic ring having 6 S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. ring atoms fused to a heterocyclic ring having from 5 to OC(CH),COOXs. C(CH),COOXs. Si(alkyl), alkyl 7 ring atoms, an aromatic ring having 6 ring atoms fused CN, O-aroyl, O(CH2)CXs, O(CH2).NXX2, NH-acyl, to a heteroaromatic ring having from 5 to 7 ring atoms, a 25 NH-aroyl, CHO, C(halogen), COOX, SOH, heteroaromatic ring having 6 ring atoms fused to a het SONXX, CONXX, NHC(O)C-alkyl, NHSO2 erocyclic ring having from 5 to 7 ring atoms or a het alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, eroaromatic ring having 6 ring atoms fused to a het di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, eroaromatic ring having from 5 to 7 ring atoms; or -CH=CHXs. -C=CXs: R2 comprises —(CH), Z: 30 X and X each independently comprise H or alkyl, or in comprises an integer from 0 to about 7; and X and X together comprise part of a heterocyclic ring Z comprises an unsaturated ring having 5 ring atoms and 0 having about 4 to about 7 ring members and optionally to 2 independently selected heteroatoms as ring mem one additional heteroatom selected from O, N or S, or bers fused to an unsaturated ring having 5 ring atoms and X and X together comprise part of an imide ring having 0 to 4 independently selected heteroatoms as ring mem 35 about 5 to about 6 members, bers, an unsaturated ring having 5 ring atoms and 0 to 2 X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy independently selected heteroatoms as ring members loweralkyl, or alkyl-NXX, fused to an unsaturated ring having 6 or 7 ring atoms and X, Xs, and X each independently comprise H, alkyl, 0 to 3 independently selected heteroatoms as ring mem carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo bers or an unsaturated ring having 6 ring atoms and 0 to 40 gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, 4 independently selected heteroatoms as ring members OX, or O-alkyl-X, wherein fused to an unsaturated ring having 6 or 7 ring atoms and X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 0 to 4 independently selected heteroatoms as ring mem (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. bers; or CONXs, SOH, COXs, wherein R2 comprises —(CH2)-Q-(CH2), Z: 45 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, Q comprises NH, O, S, —CH=CH-, -C=C , —CO, aromatic ring, heteroaromatic ring, or —CX=CHXo SO, or OSO; wherein m is an integer from 1 to about 7. X and Xo each independently comprise H or alkyl n is an integer from 0 to about 7; and Wherein m is an integer from 0 to 7 wherein Z comprises, H, halogen, CF, CFH, N, NCS, 50 j is an integer from 0 to about 6. ON, NO, NXX, OX, SX, OAc, OSOX, O-acyl, k is an integer from 0 to about 2; or S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. R2 comprises —(CH2)-Q-(CH2), Z: OC(CH)COOXs. C(CH)2COOXs. Si(alkyl), alkyl Q comprises NH, O, S, CH=CH, C=C, CO, SO, or CN, O-aroyl, O(CH)OX, O(CH.)NXX, NH-acyl, OSO; NH-aroyl, CHO, C(halogen), COOX, SOH, 55 m is an integer from 1 to about 7; SONXX, CONXX, NHC(O)O-alkyl, NHSO2 n is an integer from 0 to about 7: alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, Z comprises a bicyclic ring, a heterobicyclic ring, a tricy di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, clic ring, a heterotricyclic ring, a polycyclic ring or a -CH=CHXs. -C=CXs: heteropolycyclic ring; or X and X2, each independently comprise H or alkyl, or 60 R2 comprises —(CH2)-Q-(CH2), Z: X and X together comprise part of a heterocyclic ring Q comprises NH, O, S, CH=CH, C=C, CO, SO, or having about 4 to about 7 ring members and optionally OSO; one additional heteroatom selected from O, N or S, or m is an integer from 1 to about 7; X and X together comprise part of an imide ring having n is an integer from 0 to about 7: about 5 to about 6 members, 65 Z comprises a carbocyclic ring having about 4 to about 7 X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy ring members, a heterocyclic ring having about 4 to loweralkyl, or alkyl-NXX, about 7 ring members, an aromatic ring having about 5 to US 8,853,205 B2 65 66 about 7 ring members, a heteroaromatic ring having X -continued about 5 to about 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic Xa Sé Y xa Sé ring, a polycyclic ring, a heteropolycyclic ring or any o -HY above group Substituted on at least one available ring N 2 S 2 or atom by an alkyl group or any above group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl xa S. x'ss N group, a Substituted alkoxybenzyl group, a benzhydryl by x\, f Xy group or a Substituted benzhydryl group; and wherein 10 N 21 Y X W & Y the connecting point between the -(CH2)—group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or R2 comprises —(CH2)-Q-(CH2), Z: Q comprises NH, O, S, CH=CH, C=C, CO, SO, or 15 OSO; wherein X and Y each independently comprise m is an integer from 1 to about 7. H, halogen, CF, CFH, N, NCS, ON, NO, NXX, OX, n is an integer from 0 to about 7; and SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO Z comprises a 5 member unsaturated ring having 0 to 4 alkyl, SC(CH),COOXs. OC(CH),COOXs. independently selected heteroatoms as ring members, a C(CH),COOXs. Si(alkyl), alkyl-CN, O-aroyl, substituted 5 member unsaturated ring having 0 to 4 O(CH),OX, O(CH2).NXX2, NH-acyl, NH-aroyl, independently selected heteroatoms as ring members, a CHO, C(halogen), COOX, SOH, SONXX, 6 member aromatic ring having 0 to 5 independently CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, Selected heteroatoms as ring members or a Substituted 6 alkyl, alcohol, alkylmercapto, alkylamino, di-alky member aromatic ring having 0 to 5 independently 25 lamino, alkylsulfinyl or alkylsulfonyl, CXXX, Selected heteroatoms; and wherein the connecting point -CH=CHX -C=CXs: between the —(CH), group and the Z group can be X and X2, each independently comprise H or alkyl, or any available ring carbon atom or any available ring X and X together comprise part of a heterocyclic ring nitrogen atom; or having about 4 to about 7 ring members and optionally R2 comprises —(CH2)-Q-(CH2), Z: 30 one additional heteroatom selected from O, N or S, or Q comprises NH, O, S, CH=CH, C=C, CO, SO, or X and X together comprise part of an imide ring having OSO; about 5 to about 6 members, m is an integer from 1 to about 7. X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy n is an integer from 0 to about 7: loweralkyl, or alkyl-NXX, Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi 35 X, Xs, and X each independently comprise H, alkyl, nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, drofuranyl; or any above group Substituted on at least OX, or O-alkyl-X, wherein one available ring atom by an alkyl group; or any above X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) group Substituted on at least one available ring nitrogen 40 (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. atom by a benzyl group, a Substituted benzyl group, an CONXs, SOH, COXs, wherein alkoxybenzyl group, a Substituted alkoxybenzyl group, Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, a benzhydryl group or a Substituted benzhydryl group; aromatic ring, heteroaromatic ring, or —CX=CHXo and wherein the connecting point between the wherein —(CH), group and the Z group can be any available 45 X and Xo each independently comprise H or alkyl ring carbon atom or any available ring nitrogenatom; or Wherein m is an integer from 0 to 7 R2 comprises —(CH2)-Q-(CH2), Z: j is an integer from 0 to about 6. Q comprises NH, O, S, CH=CH, C=C, CO, SO, or k is an integer from 0 to about 2 OSO; W comprises H or alkyl; or m is an integer from 1 to about 7. 50 R2 comprises —(CH2)-Q-(CH2), Z: n is an integer from 0 to about 7; and Q comprises NH, O, S, CH=CH, C=C, CO, SO, or Z comprises OSO; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and 55 Z comprises an unsaturated ring having 5 ring atoms and 0 4 x xy exy V-X to 2 independently selected heteroatoms as ring mem bers fused to an unsaturated ring having 5 ring atoms and ( y Vy Vy -( : 0 to 4 independently selected heteroatoms as ring mem =NY, X X = 75 Y. bers, an unsaturated ring having 5 ring atoms and 0 to 2 N. VXx y1N X NSsN 60 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and (N=/ Y, 8'N=/ Y. x 2N x s 0 to 4 independently selected heteroatoms as ring mem bers or an unsaturated ring having 6 ring atoms and 0 to N=V X X X X 4 independently selected heteroatoms as ring members (x \is €is €is 65 fused to an unsaturated ring having 6 or 7 ring atoms and -K Žis y, \e N \2N \2N 0 to 4 independently selected heteroatoms as ring mem bers; or US 8,853,205 B2 67 68 R2 comprises —(CH2)-Q-(CH2), Z: X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy Q comprises NH, O, S, CH=CH, C=C, CO, SO, or loweralkyl, or alkyl-NXX. OSO; X, Xs, and X each independently comprise H, alkyl, m is an integer from 1 to about 7. carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo n is an integer from 0 to about 7; and gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, Z comprises OX, or O-alkyl-X, wherein X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. CONXs, SOH, COXs, wherein Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or—CX=CHXo wherein N-N s N/ s X and Xo each independently comprise H or alkyl Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6. k is an integer from 0 to about 2; or R2 comprises -T-(CH), Z: As \ in comprises an integer from 0 to about 7. N- , Nu-' s T comprises a carbocyclic ring having 3 to about 8 ring - members, an unsaturated ring having 3 to about 8 carbon O atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic 25 ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic N- s As s s ring, a polycyclic ring or a heteropolycyclic ring; and N1 Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to 30 about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic 35 ring, a polycyclic ring, a heteropolycyclic ring; or any above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl 40 group, a Substituted alkoxybenzyl group, a benzhydryl R2 comprises -T-(CH2), Z; group or a Substituted benzhydryl group; and wherein in comprises an integer from 0 to about 7. the connecting point between the —(CH) group and T comprises a carbocyclic ring having 3 to about 8 ring the Zgroup can be any available ring carbon atom or any members, an unsaturated ring having 3 to about 8 carbon available ring nitrogen atom; or atoms as ring members, an aromatic ring having 5 to 45 R2 comprises -T-(CH), Z: about 8 carbon atoms as ring members, a heterocyclic in comprises an integer from 0 to about 7. ring having 3 to about 8 ring members, a heteroaromatic T comprises a carbocyclic ring having 3 to about 8 ring ring having 5 to about 8 ring members, a bicyclic ring, a members, an unsaturated ring having 3 to about 8 carbon heterobicyclic ring, a tricyclic ring, a heterotricyclic atoms as ring members, an aromatic ring having 5 to ring, a polycyclic ring or a heteropolycyclic ring; and 50 about 8 carbon atoms as ring members, a heterocyclic Z comprises, H, halogen, CF, CFH, N, NCS, ON, NO, ring having 3 to about 8 ring members, a heteroaromatic NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO ring having 5 to about 8 ring members, a bicyclic ring, a alkyl, SO-alkyl, SC(CH),COOX, OC(CH),COOXs. heterobicyclic ring, a tricyclic ring, a heterotricyclic C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, ring, a polycyclic ring or a heteropolycyclic ring; and O(CH),OX, O(CH),NXX2, NH-acyl, NH-aroyl, 55 Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi CHO, C(halogen), COOX, SOH, SONXX, nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy alkyl, alcohol, alkylmercapto, alkylamino, di-alky drofuranyl; or any above group Substituted on at least lamino, alkylsulfinyl or alkylsulfonyl, CXXX, 60 one available ring atom by an alkyl group; or any above -CH=CHXs. -C=CXs: group Substituted on at least one available ring nitrogen X and X2, each independently comprise H or alkyl, or atom by a benzyl group, a Substituted benzyl group, an X and X together comprise part of a heterocyclic ring alkoxybenzyl group, a Substituted alkoxybenzyl group, having about 4 to about 7 ring members and optionally a benzhydryl group or a substituted benzhydryl group; one additional heteroatom selected from O, N or S, or 65 and wherein the connecting point between the X and X together comprise part of an imide ring having —(CH), group and the Z group can be any available about 5 to about 6 members, ring carbon atom or any available ring nitrogenatom; or US 8,853,205 B2 69 70 R2 comprises -T-(CH2), Z; X and Xo each independently comprise H or alkyl in comprises an integer from 0 to about 7. Wherein m is an integer from 0 to 7 T comprises a carbocyclic ring having 3 to about 8 ring j is an integer from 0 to about 6. members, an unsaturated ring having 3 to about 8 carbon k is an integer from 0 to about 2 atoms as ring members, an aromatic ring having 5 to W comprises H or alkyl; or about 8 carbon atoms as ring members, a heterocyclic R2 comprises -T-(CH2), Z: ring having 3 to about 8 ring members, a heteroaromatic in comprises an integer from 0 to about 7. ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic T comprises a carbocyclic ring having 3 to about 8 ring ring, a polycyclic ring or a heteropolycyclic ring; and members, an unsaturated ring having 3 to about 8 carbon 10 atoms as ring members, an aromatic ring having 5 to Z comprises about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic M. VX x^ x^ X 15 ring, a polycyclic ring or a heteropolycyclic ring; and Vy Vy -( : Z comprises an unsaturated ring having 5 ring atoms and 0 N. Y. X : X : SM Y: to 2 independently selected heteroatoms as ring mem N VX X N bers fused to an unsaturated ring having 5 ring atoms and W xSS \X4, -y XSN{ 0 to 4 independently selected heteroatoms as ring mem N=/ Y N=/ s N e N bers, an unsaturated ring having 5 ring atoms and 0 to 2 X independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and M x Néis S --Y O --Y 0 to 4 independently selected heteroatoms as ring mem 1K ŽSy, \e N , \aN , 2N , bers or an unsaturated ring having 6 ring atoms and 0 to X X 25 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and Xa ^ ex- ^ 0 to 4 independently selected heteroatoms as ring mem bers; or N 2 s N 2N O R2 comprises -T-(CH2)-Q-(CH2), Z: X N 30 m and n independently comprises an integer from 0 to Xa Sé X N N about 7: -HY X i? N. ) T comprises a carbocyclic ring having 3 to about 8 ring S 21 J. X is Y members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring hav 35 ing 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring mem bers, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a wherein X and Y each independently comprise 40 heteropolycyclic ring; H, halogen, CF, CFH, N, NCS, ON, NO, NXX, OX, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO OSO; and alkyl, SC(CH),COOXs. OC(CH),COOXs. C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, Z comprises, H, halogen, CF, CFH, N, NCS, ON, O(CH.),OX, O(CH.),NXX, NH-acyl, NH-aroyl, NO, NXX, OX, SX, OAc, OSOX, O-acyl, CHO, C(halogen), COOX, SOH, SONXX, 45 S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, OC(CH)2COOXs. C(CH)COOXs. Si(alkyl). alkyl, alcohol, alkylmercapto, alkylamino, di-alky alkyl-CN, O-aroyl, O(CH)OX, O(CH.).NXX, lamino, alkylsulfinyl or alkylsulfonyl, CXXX, NH-acyl, NH-aroyl, CHO, C(halogen), COOX, -CH=CHXs. -C=CXs: SOH, SONXX, CONXX, NHC(O)C)-alkyl, X and X each independently comprise H or alkyl, or 50 NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, X and X together comprise part of a heterocyclic ring alkylamino, di-alkylamino, alkylsulfinyl or alkylsul having about 4 to about 7 ring members and optionally fonyl, CXXX. —CH=CHXs, —C=CXs: one additional heteroatom selected from O, N or S, or X and X2, each independently comprise H or alkyl, or X and X together comprise part of an imide ring having X and X together comprise part of a heterocyclic ring about 5 to about 6 members, 55 having about 4 to about 7 ring members and optionally X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy one additional heteroatom selected from O, N or S, or loweralkyl, or alkyl-NXX, X and X together comprise part of an imide ring having X, Xs, and X each independently comprise H, alkyl, about 5 to about 6 members, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, 60 loweralkyl, or alkyl-NXX, OX, or O-alkyl-X, wherein X, Xs, and X each independently comprise H, alkyl, X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, CONXs, SOH, COXs, wherein OX, or O-alkyl-X, wherein Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, 65 X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) aromatic ring, heteroaromatic ring, or —CX=CHXo (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. wherein CONXs, SOH, COXs, wherein US 8,853,205 B2 71 72 Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, ring having 3 to about 8 ring members, a heteroaromatic aromatic ring, heteroaromatic ring, or—CX=CHXo ring having 5 to about 8 ring members, a bicyclic ring, a wherein heterobicyclic ring, a tricyclic ring, a heterotricyclic X and Xo each independently comprise H or alkyl ring, a polycyclic ring or a heteropolycyclic ring; Wherein m is an integer from 0 to 7 Q comprises N, O, S, CH=CH, C=C, CO, SO, or OSO: j is an integer from 0 to about 6. and k is an integer from 0 to about 2; or Z comprises R2 comprises -T-(CH2)-Q-(CH2), Z: m and n independently comprises an integer from 0 to about 7: 10 T comprises a carbocyclic ring having 3 to about 8 ring N4 y X x^ x^ y-X members, an unsaturated ring having 3 to about 8 carbon / y -AJY \-AJY / x atoms as ring members, an aromatic ring having 5 to S \\ Q about 8 carbon atoms as ring members, a heterocyclic =N Y, X s X s Sv Y: ring having 3 to about 8 ring members, a heteroaromatic 15 N. VX X N ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic 7N= xY, \=x^, fY, R e N- s ring, a polycyclic ring or a heteropolycyclic ring; Q comprises NH, O, S, CH=CH, C=C, CO, SO, or NFVX X X X OSO; and (,V i. SSlsN --Y SSSS --Y SSSO --Y Z comprises a carbocyclic ring having about 4 to about 7 1’& 5S Y, 2N , 2N , \e N s ring members, a heterocyclic ring having about 4 to X X about 7 ring members, anaromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having 2x1 Sé ex1. Sé about 5 to about 7 ring members, a bicyclic ring, a 25 heterobicyclic ring, a polycyclic ring, a heteropolycyclic S 2 S 2N or ring; or any above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen - atom by a benzyl group, a Substituted benzyl group, an 30 S 21 Y X \ {Y alkoxybenzyl group, a Substituted alkoxybenzyl group, W a benzhydryl group or a substituted benzhydryl group: x^1 and wherein the connecting point between the —(CH), group and the Z group can be any available =|JYX ring carbon atom or any available ring nitrogenatom; or 35 R2 comprises -T-(CH2)-Q-(CH2), Z: m and n independently comprises an integer from 0 to wherein X and Y each independently comprise about 7: H, halogen, CF, CFH, N, NCS, ON, NO, NXX, OX, T comprises a carbocyclic ring having 3 to about 8 ring SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO members, an unsaturated ring having 3 to about 8 carbon 40 alkyl, SC(CH),COOXs. OC(CH),COOXs. atoms as ring members, an aromatic ring having 5 to C(CH),COOXs. Si(alkyl), alkyl-CN, O-aroyl, about 8 carbon atoms as ring members, a heterocyclic O(CH),OX, O(CH2).NXX2, NH-acyl, NH-aroyl, ring having 3 to about 8 ring members, a heteroaromatic CHO, C(halogen), COOX, SOH, SONXX, ring having 5 to about 8 ring members, a bicyclic ring, a CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, heterobicyclic ring, a tricyclic ring, a heterotricyclic 45 alkyl, alcohol, alkylmercapto, alkylamino, di-alky ring, a polycyclic ring or a heteropolycyclic ring; lamino, alkylsulfinyl or alkylsulfonyl, CXXX, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or -CH=CHXs. -C=CXs: OSO; and Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi X and X2, each independently comprise H or alkyl, or nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 50 X and X together comprise part of a heterocyclic ring 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy having about 4 to about 7 ring members and optionally drofuranyl; or any above group Substituted on at least one additional heteroatom selected from O, N or S, or one available ring atom by an alkyl group; or any above X and X together comprise part of an imide ring having group Substituted on at least one available ring nitrogen about 5 to about 6 members, atom by a benzyl group, a Substituted benzyl group, an 55 X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy alkoxybenzyl group, a Substituted alkoxybenzyl group, loweralkyl, or alkyl-NXX, a benzhydryl group or a Substituted benzhydryl group; X, Xs, and X each independently comprise H, alkyl, and wherein the connecting point between the carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo —(CH), group and the Z group can be any available gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, ring carbon atom or any available ring nitrogenatom; or 60 R2 comprises -T-(CH)-Q-(CH), Z: OX, or O-alkyl-X, wherein m and n independently comprises an integer from 0 to X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) about 7: (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. T comprises a carbocyclic ring having 3 to about 8 ring CONXs, SOH, COXs, wherein members, an unsaturated ring having 3 to about 8 carbon 65 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, atoms as ring members, an aromatic ring having 5 to aromatic ring, heteroaromatic ring, or —CX=CHXo about 8 carbon atoms as ring members, a heterocyclic wherein US 8,853,205 B2 73 74 X and Xo each independently comprise H or alkyl Q comprises NH, O, S, CH=CH, C=C, CO, SO, or Wherein m is an integer from 0 to 7 OSO; j is an integer from 0 to about 6. Z comprises k is an integer from 0 to about 2 W comprises H or alkyl; or R2 comprises -T-(CH2)-Q-(CH2), Z: m and n independently comprises an integer from 0 to about 7: -1 - T comprises a carbocyclic ring having 3 to about 8 ring (CH2)k, (CH2)k, members, an unsaturated ring having 3 to about 8 carbon 10 atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic 15 ring, a polycyclic ring or a heteropolycyclic ring; k is an integer from 1 to about 5. Q comprises NH, O, S, CH=CH, C=C, CO, SO, or A and A. each independently comprise a C1 to about OSO; and C4 alkyl group, a phenyl group or a Substituted Z comprises an unsaturated ring having 5 ring atoms and 0 phenyl group; to 2 independently selected heteroatoms as ring mem R3 comprises bers fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring mem bers, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 25 0 to 4 independently selected heteroatoms as ring mem / bers or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members wherein G comprises CH, C(CH), C(CN) or N, fused to an unsaturated ring having 6 or 7 ring atoms and 30 L., Kand Jeach independently comprise (CH), (CH), 0 to 4 independently selected heteroatoms as ring mem C=O, O, CHOH, C(CH)OM, C(CH2)(X)Y. bers, or NM, SOSO or S, and at least one of L. KorJ is SO, R2 comprises -T-(CH)-Q-(CH), Z: T comprises a carbocyclic ring having 3 to about 8 ring n is an integer from 0 to about 7: members, an unsaturated ring having 3 to about 8 carbon M is H, alkyl, C(O)N where atoms as ring members, an aromatic ring having 5 to 35 M is H, alkyl, NMM, OMs and M. M. and Ms are about 8 carbon atoms as ring members, a heterocyclic independently H, OH or alkyl ring having 3 to about 8 ring members, a heteroaromatic and X and Y each independently comprise, H., halogen, ring having 5 to about 8 ring members, a bicyclic ring, a CF, CFH, N, NCS, ON, NO, NXX, OX, SX, heterobicyclic ring, a tricyclic ring, a heterotricyclic OAc, OSOX, O-acyl, S-acyl, SO-alkyl, ring, a polycyclic ring or a heteropolycyclic ring; 40 SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. m and n independently comprises an integer from 0 to C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, about 7: O(CH.),OX, O(CH.)NXX, NH-acyl, NH-aroyl, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or CHO, C(halogen), COOX, SOH, SONXX, OSO; and CONXX, NHC(O)C-alkyl, NHSO2-alkyl, alkoxy, Z comprises: 45 alkyl, alcohol, alkylmercapto, alkylamino, di-alky lamino, alkylsulfinyl or alkylsulfonyl, CXXX, -CH=CHX -C=CXs: X and X2, each independently comprise H or alkyl, or -O- Or -N N-E: 50 X and X together comprise part of a heterocyclic ring \ / having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or E comprises a C1 to about C4, linear or branched alkyl X and X together comprise part of an imide ring having group, a phenyl group, a Substituted phenyl group, a about 5 to about 6 members, benzyl group or a Substituted benzyl group; or 55 X comprises H, alkyl, NO, (CH),CN, hydroxylower R2 comprises -T-(CH)-Q-(CH), Z: alkyl, or alkyl-NXX, T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 X, Xs, and X each independently comprise H, alkyl, carbon atoms as ring members, an aromatic ring hav carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo ing 5 to about 8 carbon atoms as ring members, a 60 gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, heterocyclic ring having 3 to about 8 ring members, a OX, or O-alkyl-X, wherein heteroaromatic ring having 5 to about 8 ring mem X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) bers, a bicyclic ring, a heterobicyclic ring, a tricyclic (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. ring, a heterotricyclic ring, a polycyclic ring or a CONXs, SOH, COXs, wherein heteropolycyclic ring; 65 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, m and n independently comprises an integer from 0 to aromatic ring, heteroaromatic ring, or —CX=CHXo about 7: wherein US 8,853,205 B2 75 76 X and Xo each independently comprise H or alkyl ring, a polycyclic ring, a heteropolycyclic ring; or any Wherein m is an integer from 0 to 7 above group Substituted on at least one available ring j is an integer from 0 to about 6, or atom by an alkyl group; or any above group Substituted k is an integer from 0 to about 2 on at least one available ring nitrogen atom by a benzyl O group, a Substituted benzyl group, an alkoxybenzyl R1 comprises -T-(CH)-Q-(CH), Z. m and n independently comprises an integer from 0 to group, a Substituted alkoxybenzyl group, a benzhydryl about 7: group or a Substituted benzhydryl group; and wherein T comprises a carbocyclic ring having 3 to about 8 ring the connecting point between the —(CH) group and members, an unsaturated ring having 3 to about 8 carbon the Zgroup can be any available ring carbon atom or any atoms as ring members, an aromatic ring having 5 to 10 available ring nitrogen atom; or about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic R1 comprises -T-(CH2)-Q-(CH2), Z: ring having 5 to about 8 ring members, a bicyclic ring, a m and n independently comprises an integer from 0 to heterobicyclic ring, a tricyclic ring, a heterotricyclic about 7: ring, a polycyclic ring or a heteropolycyclic ring; 15 T comprises a carbocyclic ring having 3 to about 8 ring Q comprises CH=CH, C=C: Z comprises members, an unsaturated ring having 3 to about 8 carbon H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, atoms as ring members, an aromatic ring having 5 to SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO about 8 carbon atoms as ring members, a heterocyclic alkyl, SC(CH),COOXs. OC(CH),COOXs. ring having 3 to about 8 ring members, a heteroaromatic C(CH),COOXs. Si(alkyl), alkyl-CN, O-aroyl, ring having 5 to about 8 ring members, a bicyclic ring, a O(CH),OX, O(CH),NXX2, NH-acyl, NH-aroyl, heterobicyclic ring, a tricyclic ring, a heterotricyclic CHO, C(halogen), COOX, SOH, SONXX, ring, a polycyclic ring or a heteropolycyclic ring; CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, Q comprises CH=CH, C=C; and alkyl, alcohol, alkylmercapto, alkylamino, di-alky 25 lamino, alkylsulfinyl or alkylsulfonyl, CXXX, Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi -CH=CHXs. -C=CXs: nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, X and X each independently comprise H or alkyl, or 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy X and X together comprise part of a heterocyclic ring drofuranyl; or any above group Substituted on at least having about 4 to about 7 ring members and optionally 30 one available ring atom by an alkyl group; or any above one additional heteroatom selected from O, N or S, or group Substituted on at least one available ring nitrogen X and X together comprise part of an imide ring having atom by a benzyl group, a substituted benzyl group, an about 5 to about 6 members, alkoxybenzyl group, a Substituted alkoxybenzyl group, X comprises H, alkyl, NO, (CH),CN, hydroxylower a benzhydryl group or a substituted benzhydryl group; alkyl, or alkyl-NXX. 35 and wherein the connecting point between the X, Xs, and X each independently comprise H, alkyl, —(CH), group and the Z group can be any available carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo ring carbon atom or any available ring nitrogenatom; or gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, R1 comprises -T-(CH2)-Q-(CH2), Z: OX, or O-alkyl-X, wherein m and n independently comprises an integer from 0 to X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 40 about 7: (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. T comprises a carbocyclic ring having 3 to about 8 ring CONXs, SOH, COXs, wherein members, an unsaturated ring having 3 to about 8 carbon Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, atoms as ring members, an aromatic ring having 5 to aromatic ring, heteroaromatic ring, or —CX=CHXo about 8 carbon atoms as ring members, a heterocyclic wherein 45 ring having 3 to about 8 ring members, a heteroaromatic X and Xo each independently comprise H or alkyl ring having 5 to about 8 ring members, a bicyclic ring, a Wherein m is an integer from 0 to 7 heterobicyclic ring, a tricyclic ring, a heterotricyclic j is an integer from 0 to about 6, or k is an integer from 0 to about 2; or ring, a polycyclic ring or a heteropolycyclic ring; R1 comprises -T-(CH2)-Q-(CH2), Z: 50 Q comprises CH=CH, C=C; and m and n independently comprises an integer from 0 to Z comprises about 7: T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to 55 about 8 carbon atoms as ring members, a heterocyclic S4 X.W X RO K.x^n, / xW ring having 3 to about 8 ring members, a heteroaromatic K . Y. =A= Y. - Vy. ring having 5 to about 8 ring members, a bicyclic ring, a X X heterobicyclic ring, a tricyclic ring, a heterotricyclic N X X ring, a polycyclic ring or a heteropolycyclic ring; 60 / aN NXSis Ny NSNK --Y Q comprises CH=CH, C=C; and N=/ Y, Y2 s 2N s Z comprises a carbocyclic ring having about 4 to about 7 X X X ring members, a heterocyclic ring having about 4 to

about 7 ring members, anaromatic ring having about 5 to N o about 7 ring members, a heteroaromatic ring having 65 S. S. RSS, about 5 to about 7 ring members, a bicyclic ring, a - X, N2 s \2N s \2N s heterobicyclic ring, a tricyclic ring, a heterotricyclic US 8,853,205 B2 77 78 X -continued X fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring mem Xa Sé Xa Sé bers or an unsaturated ring having 6 ring atoms and 0 to | --Y, || Y or 3 independently selected heteroatoms as ring members N-S 2 N-Sue fused to an unsaturated ring having 6 or 7 ring atoms and X 0 to 4 independently selected heteroatoms as ring mem 21 Sé X NN XN Y. bers; or --Y Y- / - NY R1 comprises -T-(CH)-Q-(CH), Z: 21 XW t XW N T comprises a carbocyclic ring having 3 to about 8 ring 10 members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a 15 heterobicyclic ring, a tricyclic ring, a heterotricyclic wherein X and Y each independently comprise ring, a polycyclic ring or a heteropolycyclic ring; H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, m and n independently comprises an integer from 0 to SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO about 7: alkyl, SC(CH),COOXs. OC(CH),COOXs. Q comprises CH=CH, C=C: C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, Z comprises O(CH.),OX, O(CH.),NXX, NH-acyl, NH-aroyl, CHO, C(halogen), COOX, SOH, SONXX, CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alky lamino, alkylsulfinyl or alkylsulfonyl, CXXX, 25 -O- Or -N N-E -CH=CHXs. -C=CXs: \ / X and X each independently comprise H or alkyl, or X and X together comprise part of a heterocyclic ring E comprises a C1 to about C4, linear or branched alkyl having about 4 to about 7 ring members and optionally group, a phenyl group, a Substituted phenyl group, a one additional heteroatom selected from O, N or S, or 30 benzyl group or a Substituted benzyl group; or X and X together comprise part of an imide ring having R1 comprises -T-(CH2)-Q-(CH2), Z: about 5 to about 6 members, T comprises a carbocyclic ring having 3 to about 8 ring X comprises H, alkyl, NO, (CH),CN, hydroxylower members, an unsaturated ring having 3 to about 8 carbon alkyl, or alkyl-NXX, atoms as ring members, an aromatic ring having 5 to X, Xs, and X each independently comprise H, alkyl, 35 about 8 carbon atoms as ring members, a heterocyclic carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo ring having 3 to about 8 ring members, a heteroaromatic gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, ring having 5 to about 8 ring members, a bicyclic ring, a OX, or O-alkyl-X, wherein heterobicyclic ring, a tricyclic ring, a heterotricyclic X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) ring, a polycyclic ring or a heteropolycyclic ring; (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. 40 m and n independently comprises an integer from 0 to CONXs, SOH, COXs, wherein about 7: Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, Q comprises CH=CH, C=C; and aromatic ring, heteroaromatic ring, or —CX=CHXo Z comprises wherein X and Xo each independently comprise H or alkyl 45 Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6. / k is an integer from 0 to about 2, -N O -( —(f W comprises H or alkyl; or -N(1 (CH2)k

R1 comprises -T-(CH2)-Q-(CH2), Z: 50 m and n independently comprises an integer from 0 to about 7: T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to 55 about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic k is an integer from 1 to about 5, and ring having 5 to about 8 ring members, a bicyclic ring, a A and A. each independently comprise a C1 to about C4 heterobicyclic ring, a tricyclic ring, a heterotricyclic alkyl group, a phenyl group or a substituted phenyl ring, a polycyclic ring or a heteropolycyclic ring; 60 group; or Q comprises CH=CH, C=C; and R1 comprises —(CH), Z: Z comprises an unsaturated ring having 5 ring atoms and 0 n is an integer from 0 to about 7: to 2 independently selected heteroatoms as ring mem wherein Z comprises, H, halogen, CF, CFH, N, NCS, bers fused to an unsaturated ring having 5 ring atoms and ON, NO, NXX, OX, SX, OAc, OSOX, O-acyl, 0 to 4 independently selected heteroatoms as ring mem 65 S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. bers, an unsaturated ring having 5 ring atoms and 0 to 2 OC(CH)COOXs. C(CH)2COOXs, Si(alkyl), alkyl independently selected heteroatoms as ring members CN, O-aroyl, O(CH2)CXs, O(CH2).NXX2, NH-acyl, US 8,853,205 B2 79 80 NH-aroyl, CHO, C(halogen), COOX, SOH, alkoxybenzyl group, a Substituted alkoxybenzyl group, SONXX, CONXX, NHC(O)O-alkyl, NHSO2 a benzhydryl group or a substituted benzhydryl group; alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, and wherein the connecting point between the di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, —(CH), group and the Z group can be any available -CH=CHXs. -C=CXs: ring carbon atom or any available ring nitrogenatom; or X and X2, each independently comprise H or alkyl, or X and X together comprise part of a heterocyclic ring R1 comprises —(CH2), Z: having about 4 to about 7 ring members and optionally n is an integer from 0 to about 7; and one additional heteroatom selected from O, N or S, or Z comprises X and X together comprise part of an imide ring having 10 about 5 to about 6 members, X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy loweralkyl, or alkyl-NXX, X, Xs, and X each independently comprise H, alkyl, SA& X*S \x), y \,xy y / X*y carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo 15 sy, \-A-1, \-A/. - Vy. gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, X X OX, or O-alkyl-X, wherein N X X X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 7 xA N Sls -y NSNK --Y (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. N=/Y, Y2 s 2N , CONXs, SOH, COXs, wherein Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, X X X

aromatic ring, heteroaromatic ring, or —CX=CHXo N o wherein x \sis Y SSS Y Sis Y X and Xo each independently comprise H or alkyl > £, N2 \le \-N Wherein m is an integer from 0 to 7 25 X X j is an integer from 0 to about 6, or 2X1 SAS 2x1 Sás k is an integer from 0 to about 2; or R1 comprises —(CH), Z: S | 4.--Y, S || 2N Y n is an integer from 0 to about 7; and X Z comprises a carbocyclic ring having about 4 to about 7 30 N ring members, a heterocyclic ring having about 4 to x Sé X SN XY. about 7 ring members, an aromatic ring having about 5 to -HY X Y- X-W- tiif Y or about 7 ring members, a heteroaromatic ring having N1,N-21 th? \ . about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic 35 x^-w ring, a polycyclic ring, a heteropolycyclic ring; or any above group Substituted on at least one available ring V. atom by an alkyl group; or any above group Substituted X on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl 40 wherein X and Y each independently comprise, H., halo group, a Substituted alkoxybenzyl group, a benzhydryl gen, CF, CFH, N, NCS, CN, NO, NXX, OX, SX, group or a Substituted benzhydryl group; and wherein OAc, OSOX, O-acyl, S-acyl, SO-alkyl, the connecting point between the -(CH2)—group and SO-alkyl, SC(CH),COOX, OC(CH),COOXs. the Z group can be any available ring carbon atom or any C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, available ring nitrogen atom; or 45 O(CH.),OX, O(CH.)NXX, NH-acyl, NH-aroyl, R1 comprises —(CH2), Z: CHO, C(halogen), COOX, SOH, SONXX, n is an integer from 0 to about 7; and CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, Z comprises a 5 member unsaturated ring having 0 to 4 alkyl, alcohol, alkylmercapto, alkylamino, di-alky independently selected heteroatoms as ring members, a lamino, alkylsulfinyl or alkylsulfonyl, CXXX, substituted 5 member unsaturated ring having 0 to 4 50 -CH=CHX -C=CXs: independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 5 independently X and X each independently comprise H or alkyl, or Selected heteroatoms as ring members or a Substituted 6 X and X together comprise part of a heterocyclic ring member aromatic ring having 0 to 5 independently having about 4 to about 7 ring members and optionally Selected heteroatoms; and wherein the connecting point 55 one additional heteroatom selected from O, N or S, or between the —(CH) group and the Z group can be X and X together comprise part of an imide ring having any available ring carbon atom or any available ring about 5 to about 6 members, nitrogen atom; or X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy R1 comprises —(CH2), Z: loweralkyl, or alkyl-NXX, n is an integer from 0 to about 7; and 60 Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi X, Xs, and X each independently comprise H, alkyl, nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, drofuranyl; or any above group Substituted on at least OX, or O-alkyl-X, wherein one available ring atom by an alkyl group; or any above 65 X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) group Substituted on at least one available ring nitrogen (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. atom by a benzyl group, a Substituted benzyl group, an CONXs, SOH, COXs, wherein US 8,853,205 B2 81 82 Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) aromatic ring, heteroaromatic ring, or—CX=CHXo (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. wherein CONXs, SOH, COXs, wherein X and Xo each independently comprise H or alkyl Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, Wherein m is an integer from 0 to 7 aromatic ring, heteroaromatic ring, or —CX=CHXo j is an integer from 0 to about 6, or wherein k is an integer from 0 to about 2 X and Xo each independently comprise H or alkyl W comprises H or alkyl; or Wherein m is an integer from 0 to 7 R1 comprises —(CH), Z: j is an integer from 0 to about 6, or n is an integer from 0 to about 7; and 10 k is an integer from 0 to about 2; or Z comprises a carbocyclic ring having 6 ring atoms fused to R1 comprises -Q-(CH2), Z: a heterocyclic ring having from 5 to 7 ring atoms, a Q is optionally present and if present comprises —CH2— carbocyclic ring having 6 ring atoms fused to a het NH, —CH2—O, —CH2—S, —CH2—SO or —CH eroaromatic ring having from 5 to 7 ring atoms, a het OSO; erocyclic ring having 6 ring atoms fused to a heterocy 15 n is an integer from 0 to about 7: clic ring having from 5 to 7 ring atoms, an heterocyclic wherein Z comprises, H, halogen, CF, CFH, N, NCS, ring having 6 ring atoms fused to a heteroaromatic ring ON, NO, NXX, OX, SX, OAc, OSOX, O-acyl, having from 5 to 7 ring atoms, an aromatic ring having 6 S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. ring atoms fused to a heterocyclic ring having from 5 to OC(CH)COOXs. C(CH)2COOXs, Si(alkyl), alkyl 7 ring atoms, an aromatic ring having 6 ring atoms fused CN, O-aroyl, O(CH2)CXs, O(CH2).NXX2, NH-acyl, to a heteroaromatic ring having from 5 to 7 ring atoms, a NH-aroyl, CHO, C(halogen), COOX, SOH, heteroaromatic ring having 6 ring atoms fused to a het SONXX, CONXX, NHC(O)C-alkyl, NHSO2 erocyclic ring having from 5 to 7 ring atoms or a het alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, eroaromatic ring having 6 ring atoms fused to a het di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, eroaromatic ring having from 5 to 7 ring atoms; or 25 -CH=CHXs. -C=CXs: R1 comprises —(CH2), Z: X and X2, each independently comprise H or alkyl, or in comprises an integer from 0 to about 7; and X and X together comprise part of a heterocyclic ring Z comprises an unsaturated ring having 5 ring atoms and 0 having about 4 to about 7 ring members and optionally to 2 independently selected heteroatoms as ring mem one additional heteroatom selected from O, N or S, or bers fused to an unsaturated ring having 5 ring atoms and 30 X and X together comprise part of an imide ring having 0 to 4 independently selected heteroatoms as ring mem about 5 to about 6 members, bers, an unsaturated ring having 5 ring atoms and 0 to 2 X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy independently selected heteroatoms as ring members loweralkyl, or alkyl-NXX. fused to an unsaturated ring having 6 or 7 ring atoms and X, Xs, and X each independently comprise H, alkyl, 0 to 3 independently selected heteroatoms as ring mem 35 carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo bers or an unsaturated ring having 6 ring atoms and 0 to gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, 4 independently selected heteroatoms as ring members OX, or O-alkyl-X, wherein fused to an unsaturated ring having 6 or 7 ring atoms and X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) 0 to 4 independently selected heteroatoms as ring mem (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. bers; or 40 CONXs, SOH, COXs, wherein R1 comprises —(CH2)-Q-(CH2), Z: Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, Q comprises NH, O, S, —CH=CH-, -C=C , —CO, aromatic ring, heteroaromatic ring, or—CX=CHXo SO, or OSO; wherein m is an integer from 1 to about 7. X and Xo each independently comprise H or alkyl n is an integer from 0 to about 7; and 45 Wherein m is an integer from 0 to 7 wherein Z comprises, H, halogen, CF, CFH, N, NCS, j is an integer from 0 to about 6. ON, NO, NXX, OX, SX, OAc, OSOX, O-acyl, k is an integer from 0 to about 2; or S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. R1 comprises —(CH2)-Q-(CH2), Z: OC(CH),COOXs. C(CH),COOXs. Si(alkyl), alkyl Q comprises NH, O, S, CH=CH, C=C, CO, SO, or CN, O-aroyl, O(CH),OX, O(CH2).NXX2, NH-acyl, 50 OSO; NH-aroyl, CHO, C(halogen), COOX, SOH, m is an integer from 1 to about 7; SONXX, CONXX, NHC(O)C-alkyl, NHSO2 n is an integer from 0 to about 7: alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, Z comprises a bicyclic ring, a heterobicyclic ring, a tricy di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, clic ring, a heterotricyclic ring, a polycyclic ring or a -CH=CHXs. -C=CXs: 55 heteropolycyclic ring; or X and X each independently comprise H or alkyl, or R1 comprises —(CH)-Q-(CH), Z: X and X together comprise part of a heterocyclic ring Q comprises NH, O, S, CH=CH, C=C, CO, SO, or having about 4 to about 7 ring members and optionally OSO; one additional heteroatom selected from O, N or S, or m is an integer from 1 to about 7; X and X together comprise part of an imide ring having 60 n is an integer from 0 to about 7: about 5 to about 6 members, Z comprises a carbocyclic ring having about 4 to about 7 X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy ring members, a heterocyclic ring having about 4 to loweralkyl, or alkyl-NXX. about 7 ring members, an aromatic ring having about 5 to X, Xs, and X each independently comprise H, alkyl, about 7 ring members, a heteroaromatic ring having carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo 65 about 5 to about 7 ring members; a bicyclic ring, a gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, heterobicyclic ring, a tricyclic ring, a heterotricyclic OX, or O-alkyl-X, wherein ring, a polycyclic ring, a heteropolycyclic ring or any US 8,853,205 B2 83 84 above group Substituted on at least one available ring atom by an alkyl group or any above group Substituted X -continued X on at least one available ring nitrogen atom by a benzyl Xa Sé Xa Sé group, a Substituted benzyl group, an alkoxybenzyl | --Y, || Y or group, a Substituted alkoxybenzyl group, a benzhydryl N-Na N-Sue group or a Substituted benzhydryl group; and wherein X the connecting point between the -(CH) group and 21 Sé X NN XN Y. the Z group can be any available ring carbon atom or any --Y Y- / - NY available ring nitrogen atom; or 2 XW t XV NCl R1 comprises —(CH)-Q-(CH), Z: 10 Q comprises NH, O, S, CH=CH, C=C, CO, SO, or OSO; m is an integer from 1 to about 7. n is an integer from 0 to about 7; and 15 Z comprises a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a wherein X and Y each independently comprise substituted 5 member unsaturated ring having 0 to 4 H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, independently selected heteroatoms as ring members, a SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO 6 member aromatic ring having 0 to 5 independently alkyl, SC(CH),COOXs. OC(CH),COOXs. C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, Selected heteroatoms as ring members or a Substituted 6 O(CH.),OX, O(CH.)NXX, NH-acyl, NH-aroyl, member aromatic ring having 0 to 5 independently CHO, C(halogen), COOX, SOH, SONXX, Selected heteroatoms; and wherein the connecting point CONXX, NHC(O)C-alkyl, NHSO2-alkyl, alkoxy, between the —(CH), group and the Z group can be alkyl, alcohol, alkylmercapto, alkylamino, di-alky any available ring carbon atom or any available ring 25 lamino, alkylsulfinyl or alkylsulfonyl, CXXX, nitrogen atom; or -CH=CHXs. -C=CXs: R1 comprises —(CH2)-Q-(CH2), Z: X and X each independently comprise H or alkyl, or Q comprises NH, O, S, CH=CH, C=C, CO, SO, or X and X together comprise part of a heterocyclic ring OSO; having about 4 to about 7 ring members and optionally 30 one additional heteroatom selected from O, N or S, or m is an integer from 1 to about 7. X and X together comprise part of an imide ring having n is an integer from 0 to about 7. about 5 to about 6 members, Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, loweralkyl, or alkyl-NXX, 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy 35 X, Xs, and X each independently comprise H, alkyl, drofuranyl; or any above group Substituted on at least carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo one available ring atom by an alkyl group; or any above gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, group Substituted on at least one available ring nitrogen OX, or O-alkyl-X, wherein atom by a benzyl group, a Substituted benzyl group, an X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) alkoxybenzyl group, a Substituted alkoxybenzyl group, 40 (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. a benzhydryl group or a Substituted benzhydryl group; CONXs, SOH, COXs, wherein and wherein the connecting point between the Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, —(CH), group and the Z group can be any available aromatic ring, heteroaromatic ring, or —CX=CHXo ring carbon atom or any available ring nitrogenatom; or wherein R1 comprises —(CH)-Q-(CH), Z: 45 X and Xo each independently comprise H or alkyl Wherein m is an integer from 0 to 7 Q comprises NH, O, S, CH=CH, C=C, CO, SO, or j is an integer from 0 to about 6. OSO; k is an integer from 0 to about 2 m is an integer from 1 to about 7. W comprises H or alkyl; or n is an integer from 0 to about 7; and 50 R1 comprises —(CH2)-Q-(CH2), Z: Z comprises Q comprises NH, O, S, CH=CH, C=C, CO, SO, or OSO; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and S4 s X ey x^, / x 55 Z comprises an unsaturated ring having 5 ring atoms and 0 K W . Y. (=A= Y. - Vy.W to 2 independently selected heteroatoms as ring mem X X bers fused to an unsaturated ring having 5 ring atoms and N- MX X 0 to 4 independently selected heteroatoms as ring mem x1V As s NSSN bers, an unsaturated ring having 5 ring atoms and 0 to 2 ( N N y Y --Y 60 independently selected heteroatoms as ring members N=/ Y, N2 s 2N s fused to an unsaturated ring having 6 or 7 ring atoms and X X X 0 to 4 independently selected heteroatoms as ring mem N=y-X S&S Y&?s S&S bers or an unsaturated ring having 6 ring atoms and 0 to K \, N --Y s --Y O --Y 4 independently selected heteroatoms as ring members 65 fused to an unsaturated ring having 6 or 7 ring atoms and 1’& k Y N2 s \e N s \2N s 0 to 4 independently selected heteroatoms as ring mem bers; or US 8,853,205 B2 85 86 R1 comprises —(CH2)-Q-(CH2), Z: X, Xs, and X each independently comprise H, alkyl, Q comprises NH, O, S, CH=CH, C=C, CO, SO, or carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo OSO; gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, m is an integer from 1 to about 7. OX, or O-alkyl-X, wherein n is an integer from 0 to about 7; and X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) Z comprises (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. CONXs, SOH, COXs, wherein Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or—CX=CHXo wherein X and Xo each independently comprise H or alkyl Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6. k is an integer from 0 to about 2; or 15 R1 comprises -T-(CH2), Z: in comprises an integer from 0 to about 7. T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and 25 Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a S 30 heterobicyclic ring, a tricyclic ring, a heterotricyclic H O ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen atom by a benzyl 35 group, a Substituted benzyl group, an alkoxybenzyl group, a Substituted alkoxybenzyl group, a benzhydryl group or a Substituted benzhydryl group; and wherein the connecting point between the —(CH2)—group and the Zgroup can be any available ring carbon atom or any R1 comprises -T-(CH2), Z; 40 available ring nitrogen atom; or in comprises an integer from 0 to about 7. R1 comprises -T-(CH2), Z: T comprises a carbocyclic ring having 3 to about 8 ring in comprises an integer from 0 to about 7. members, an unsaturated ring having 3 to about 8 carbon T comprises a carbocyclic ring having 3 to about 8 ring atoms as ring members, an aromatic ring having 5 to members, an unsaturated ring having 3 to about 8 carbon about 8 carbon atoms as ring members, a heterocyclic 45 atoms as ring members, an aromatic ring having 5 to ring having 3 to about 8 ring members, a heteroaromatic about 8 carbon atoms as ring members, a heterocyclic ring having 5 to about 8 ring members, a bicyclic ring, a ring having 3 to about 8 ring members, a heteroaromatic heterobicyclic ring, a tricyclic ring, a heterotricyclic ring having 5 to about 8 ring members, a bicyclic ring, a ring, a polycyclic ring or a heteropolycyclic ring; and heterobicyclic ring, a tricyclic ring, a heterotricyclic Z comprises, H, halogen, CF, CFH, N, NCS, CN, NO, 50 ring, a polycyclic ring or a heteropolycyclic ring; and NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi alkyl, SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy O(CH.),OX, O(CH.),NXX, NH-acyl, NH-aroyl, drofuranyl; or any above group Substituted on at least CHO, C(halogen), COOX, SOH, SONXX, 55 one available ring atom by an alkyl group; or any above CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, group Substituted on at least one available ring nitrogen alkyl, alcohol, alkylmercapto, alkylamino, di-alky atom by a benzyl group, a Substituted benzyl group, an lamino, alkylsulfinyl or alkylsulfonyl, CXXX, alkoxybenzyl group, a Substituted alkoxybenzyl group, -CH=CHXs. -C=CXs: a benzhydryl group or a substituted benzhydryl group; X and X2, each independently comprise H or alkyl, or 60 and wherein the connecting point between the X and X together comprise part of a heterocyclic ring —(CH), group and the Z group can be any available having about 4 to about 7 ring members and optionally ring carbon atom or any available ring nitrogenatom; or one additional heteroatom selected from O, N or S, or R1 comprises -T-(CH), Z: X and X together comprise part of an imide ring having in comprises an integer from 0 to about 7. about 5 to about 6 members, 65 T comprises a carbocyclic ring having 3 to about 8 ring X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy members, an unsaturated ring having 3 to about 8 carbon loweralkyl, or alkyl-NXX, atoms as ring members, an aromatic ring having 5 to US 8,853,205 B2 87 88 about 8 carbon atoms as ring members, a heterocyclic j is an integer from 0 to about 6. ring having 3 to about 8 ring members, a heteroaromatic k is an integer from 0 to about 2 ring having 5 to about 8 ring members, a bicyclic ring, a W comprises H or alkyl; or heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and 5 R1 comprises -T-(CH), Z: Z comprises in comprises an integer from 0 to about 7. T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to 10 about 8 carbon atoms as ring members, a heterocyclic SA& Sx* Sx), v Klyxy / x*y ring having 3 to about 8 ring members, a heteroaromatic Sy, \-A-/ \-A-/ =/ Y. ring having 5 to about 8 ring members, a bicyclic ring, a N X X heterobicyclic ring, a tricyclic ring, a heterotricyclic X ring, a polycyclic ring or a heteropolycyclic ring; and a &?s N's N 15 Z comprises an unsaturated ring having 5 ring atoms and 0 Sty. Nd:Y. S.- to 2 independently selected heteroatoms as ring mem X X X bers fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring mem x Sis Y Sis Sis bers, an unsaturated ring having 5 ring atoms and 0 to 2 cx £, N2 M-N MN independently selected heteroatoms as ring members Y, s s s fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring mem x^-yée YS e sa× e hy. e ly O bers or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members N-S2 N-N-N 25 fused to an unsaturated ring having 6 or 7 ring atoms and X 0 to 4 independently selected heteroatoms as ring mem x Sé NX N Xy bers; or R1 comprises -T-Q-(CH2), Z. x/x Y 30 each n independently comprises an integer from 0 to about Y 7; T comprises a carbocyclic ring having 3 to about 8 ring -AJY members, an unsaturated ring having 3 to about 8 carbon e atoms as ring members, an aromatic ring having 5 to \ 35 about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic wherein X and Y each independently comprise ring having 5 to about 8 ring members, a bicyclic ring, a H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, heterobicyclic ring, a tricyclic ring, a heterotricyclic SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO ring, a polycyclic ring or a heteropolycyclic ring; alkyl, SC(CH),COOXs. OC(CH),COOXs. 40 Q comprises CH=CH, C=C: C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, Z comprises H. halogen, CF, CFH, N, NCS, CN, NO, O(CH.),OX, O(CH.),NXX, NH-acyl, NH-aroyl, NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO CHO, C(halogen), COOX, SOH, SONXX, alkyl, SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, C(CH),COOXs. Si(alkyl), alkyl-CN, O-aroyl, alkyl, alcohol, alkylmercapto, alkylamino, di-alky 45 O(CH),OX, O(CH2).NXX2, NH-acyl, NH-aroyl, lamino, alkylsulfinyl or alkylsulfonyl, CXXX, CHO, C(halogen), COOX, SOH, SONXX, -CH=CHX -C=CXs: CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, X and X2, each independently comprise H or alkyl, or alkyl, alcohol, alkylmercapto, alkylamino, di-alky X and X together comprise part of a heterocyclic ring lamino, alkylsulfinyl or alkylsulfonyl, CXXX, having about 4 to about 7 ring members and optionally 50 one additional heteroatom selected from O, N or S, or -CH=CHXs. -C=CXs: X and X together comprise part of an imide ring having X and X2, each independently comprise H or alkyl, or about 5 to about 6 members, X and X together comprise part of a heterocyclic ring X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy having about 4 to about 7 ring members and optionally loweralkyl, or alkyl-NXX, 55 one additional heteroatom selected from O, N or S, or X, Xs, and X each independently comprise H, alkyl, X and X together comprise part of an imide ring having carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo about 5 to about 6 members, gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, X comprises H, alkyl, NO, (CH),CN, hydroxylower OX, or O-alkyl-X, wherein alkyl, or alkyl-NXX, X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) 60 (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. X, Xs, and X each independently comprise H, alkyl, CONXs, SOH, COXs, wherein carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, aromatic ring, heteroaromatic ring, or —CX=CHXo OX, or O-alkyl-X, wherein wherein 65 X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) X and Xo each independently comprise H or alkyl (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. Wherein m is an integer from 0 to 7 CONXs, SOH, COXs, wherein US 8,853,205 B2 89 90 Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, ring having 5 to about 8 ring members, a bicyclic ring, a aromatic ring, heteroaromatic ring, or—CX=CHXo heterobicyclic ring, a tricyclic ring, a heterotricyclic wherein ring, a polycyclic ring or a heteropolycyclic ring; X and Xo each independently comprise H or alkyl Q comprises CH=CH, C=C; and Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or Z comprises k is an integer from 0 to about 2; or R1 comprises -T-Q-(CH2), Z; each nindependently comprises an integer from 0 to about 7; 10 SA& X*S. S.x), Sy Olyxy / x*y T comprises a carbocyclic ring having 3 to about 8 ring =N.Y., A. s s =/ Y, members, an unsaturated ring having 3 to about 8 carbon X X atoms as ring members, an aromatic ring having 5 to X about 8 carbon atoms as ring members, a heterocyclic x XSis NSN ring having 3 to about 8 ring members, a heteroaromatic 15 ( X N -y Q -HY ring having 5 to about 8 ring members, a bicyclic ring, a N=/ Y, N2 s 2N s heterobicyclic ring, a tricyclic ring, a heterotricyclic X X X ring, a polycyclic ring or a heteropolycyclic ring; N=y-X S&S YSS S&S Q comprises CH=CH, C=C; and K Y N 2 s -- Y O - - Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to -X × N2 \-N \-N about 7 ring members, anaromatic ring having about 5 to x^-yée sas e sas× about 7 ring members, a heteroaromatic ring having e hy. e ly O about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic 25 N-N4 N-Sue' X ring, a polycyclic ring, a heteropolycyclic ring; or any W N above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted xé ^ Y N R Y. Y on at least one available ring nitrogen atom by a benzyl N 2 * th? X\ { group, a Substituted benzyl group, an alkoxybenzyl 30 group, a Substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH) group and e-AJY the Z group can be any available ring carbon atom or any \ available ring nitrogen atom; or 35 R1 comprises -T-Q-(CH2), Z; each nindependently comprises an integer from 0 to about wherein X and Y each independently comprise 7; H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, T comprises a carbocyclic ring having 3 to about 8 ring SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO members, an unsaturated ring having 3 to about 8 carbon 40 alkyl, SC(CH),COOXs. OC(CH),COOXs. atoms as ring members, an aromatic ring having 5 to C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, about 8 carbon atoms as ring members, a heterocyclic O(CH.),OX, O(CH.)NXX, NH-acyl, NH-aroyl, ring having 3 to about 8 ring members, a heteroaromatic CHO, C(halogen), COOX, SOH, SONXX, ring having 5 to about 8 ring members, a bicyclic ring, a CONXX, NHC(O)C-alkyl, NHSO2-alkyl, alkoxy, heterobicyclic ring, a tricyclic ring, a heterotricyclic 45 alkyl, alcohol, alkylmercapto, alkylamino, di-alky ring, a polycyclic ring or a heteropolycyclic ring; lamino, alkylsulfinyl or alkylsulfonyl, CXXX, Q comprises CH=CH, C=C; and -CH=CHXs. -C=CXs: Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi X and X2, each independently comprise H or alkyl, or nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, X and X together comprise part of a heterocyclic ring 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy 50 drofuranyl; or any above group Substituted on at least having about 4 to about 7 ring members and optionally one available ring atom by an alkyl group; or any above one additional heteroatom selected from O, N or S, or group Substituted on at least one available ring nitrogen X and X together comprise part of an imide ring having atom by a benzyl group, a Substituted benzyl group, an about 5 to about 6 members, alkoxybenzyl group, a Substituted alkoxybenzyl group, 55 X comprises H, alkyl, NO, (CH2)CN, hydroxylower a benzhydryl group or a Substituted benzhydryl group; alkyl, or alkyl-NXX, and wherein the connecting point between the X, Xs, and X each independently comprise H, alkyl, —(CH), group and the Z group can be any available carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo ring carbon atom or any available ring nitrogenatom; or gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, R1 comprises -T-Q-(CH2), Z; 60 each nindependently comprises an integer from 0 to about OX, or O-alkyl-X, wherein 7; X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) T comprises a carbocyclic ring having 3 to about 8 ring (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. members, an unsaturated ring having 3 to about 8 carbon CONXs, SOH, COXs, wherein atoms as ring members, an aromatic ring having 5 to 65 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, about 8 carbon atoms as ring members, a heterocyclic aromatic ring, heteroaromatic ring, or —CX=CHXo ring having 3 to about 8 ring members, a heteroaromatic wherein US 8,853,205 B2 91 92 X and Xo each independently comprise H or alkyl each n independently comprises an integer from 0 to about 7; Wherein m is an integer from 0 to 7 Q comprises CH=CH, C=C; and j is an integer from 0 to about 6. Z comprises k is an integer from 0 to about 2, W comprises H or alkyl; or R1 comprises -T-Q-(CH), Z: / O -N O each nindependently comprises an integer from 0 to about (CH2)k -( 7; 10 ( ) -< T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic 15 ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic k is an integer from 1 to about 5, and ring, a polycyclic ring or a heteropolycyclic ring; A and A. each independently comprise a C1 to about C4 alkyl group, a phenyl group or a substituted phenyl Q comprises CH=CH, C=C; and group; and Z comprises an unsaturated ring having 5 ring atoms and 0 R4 comprises H, halogen, CF, CFH, N, NCS, CN, NO, to 2 independently selected heteroatoms as ring mem NXX, OH, ONO, SX, OAc, OSOX, O-acyl, bers fused to an unsaturated ring having 5 ring atoms and S-acyl, SO-alkyl, SO-alkyl, SC(CH)COOXs. 0 to 4 independently selected heteroatoms as ring mem OC(CH),COOXs. C(CH),COOXs. Si(alkyl), alkyl bers, an unsaturated ring having 5 ring atoms and 0 to 2 25 CN, O-aroyl, O(CH2)CX, O(CH2).NXX2, NH-acyl, independently selected heteroatoms as ring members NH-aroyl, CHO, C(halogen), COOX, SOH, fused to an unsaturated ring having 6 or 7 ring atoms and SONXX, CONXX, NHC(O)C-alkyl, NHSO2 0 to 4 independently selected heteroatoms as ring mem alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, bers or an unsaturated ring having 6 ring atoms and 0 to di-alkylamino, alkylsulfinyl oralkylsulfonyl, CXXX, 3 independently selected heteroatoms as ring members 30 -CH=CHX -C=CXs: fused to an unsaturated ring having 6 or 7 ring atoms and X and X2, each independently comprise H or alkyl, or 0 to 4 independently selected heteroatoms as ring mem X and X, together comprise part of a heterocyclic ring bers; or having about 4 to about 7 ring members and optionally R1 comprises -T-Q-(CH), Z: one additional heteroatom selected from O, N or S, or 35 X and X together comprise part of an imide ring having T comprises a carbocyclic ring having 3 to about 8 ring about 5 to about 6 members, members, an unsaturated ring having 3 to about 8 carbon X comprises H, alkyl, NO, (CH2)CN, hydroxylower atoms as ring members, an aromatic ring having 5 to alkyl, or alkyl-NXX. about 8 carbon atoms as ring members, a heterocyclic X, Xs, and X each independently comprise H, alkyl, ring having 3 to about 8 ring members, a heteroaromatic carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo ring having 5 to about 8 ring members, a bicyclic ring, a 40 gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, heterobicyclic ring, a tricyclic ring, a heterotricyclic OX, or O-alkyl-X, wherein ring, a polycyclic ring or a heteropolycyclic ring; X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) each nindependently comprises an integer from 0 to about (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. CONXs, SOH, COXs, wherein 7; 45 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, Q comprises CH=CH, C=C: aromatic ring, heteroaromatic ring, or —CX=CHXo Z comprises wherein X and Xo each independently comprise H or alkyl Wherein m is an integer from 0 to 7 50 j is an integer from 0 to about 6, or k is an integer from 0 to about 2; or R4 comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to E comprises a C1 to about C4, linear or branched alkyl 55 about 7 ring members, a heteroaromatic ring having group, a phenyl group, a Substituted phenyl group, a about 5 to about 7 ring members, a bicyclic ring, a benzyl group or a Substituted benzyl group; or heterobicyclic ring, a tricyclic ring, a heterotricyclic R1 comprises -T-Q-(CH2), Z; ring, a polycyclic ring or a heteropolycyclic ring; or T comprises a carbocyclic ring having 3 to about 8 ring 60 R4 comprises members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a 65 dy dy heterobicyclic ring, a tricyclic ring, a heterotricyclic N-N Nu-N ring, a polycyclic ring or a heteropolycyclic ring; US 8,853,205 B2 93 94 -continued about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl group, a Substituted alkoxybenzyl group, a benzhydryl group or a Substituted benzhydryl group; and wherein 10 the connecting point between the —(CH) group and the Zgroup can be any available ring carbon atom or any available ring nitrogen atom; or R4 comprises —(CH), Z: d is an integer from 1 to about 6; and 15 Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy S drofuranyl; or any above group Substituted on at least H O one ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl group, a Substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the 25 —(CH) group and the Z group can be any available ring carbon atom or any available ring nitrogenatom; or R4 comprises —(CH2)-Q-(CH2), Z: R4 comprises —(CH2), Z: Q comprises NH, O, S, CH=CH, C=C, CO, SO, or d is an integer from 1 to about 6: OSO; 30 m is an integer from 1 to about 7; Z comprises H, halogen, CF, CFH, N, NCS, CN, NO, n is an integer from 0 to about 7; and NXX, OX, SX, OAc, OSOX, O-acyl, S-acyl, SO Z comprises alkyl, SO-alkyl, SC(CH),COOX, OC(CH),COOXs. H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO O(CH),OX, O(CH),NXX2, NH-acyl, NH-aroyl, 35 alkyl, SC(CH),COOXs. OC(CH),COOXs. CHO, C(halogen), COOX, SOH, SONXX, C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, O(CH),OX, O(CH2).NXX2, NH-acyl, NH-aroyl, alkyl, alcohol, alkylmercapto, alkylamino, di-alky CHO, C(halogen), COOX, SOH, SONXX, lamino, alkylsulfinyl or alkylsulfonyl, CXXX, CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, -CH=CHXs. -C=CXs: 40 alkyl, alcohol, alkylmercapto, alkylamino, di-alky X and X2, each independently comprise H or alkyl, or lamino, alkylsulfinyl or alkylsulfonyl, CXXX, X and X together comprise part of a heterocyclic ring -CH=CHX -C=CXs: having about 4 to about 7 ring members and optionally X and X2, each independently comprise H or alkyl, or one additional heteroatom selected from O, N or S, or X and X together comprise part of a heterocyclic ring X and X together comprise part of an imide ring having 45 having about 4 to about 7 ring members and optionally about 5 to about 6 members, one additional heteroatom selected from O, N or S, or X comprises H, alkyl, NO, (CH),CN, hydroxylower X and X together comprise part of an imide ring having alkyl, or alkyl-NXX, about 5 to about 6 members, X, Xs, and X each independently comprise H, alkyl, X comprises H, alkyl, NO, (CH),CN, hydroxylower carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo 50 alkyl, or alkyl-NXX, gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, X, Xs, and X each independently comprise H, alkyl, OX, or O-alkyl-X, wherein carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) gen, CN, SNO, S(SO)alkyl, NXX COOX, CONX, (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. OX, or O-alkyl-X, wherein CONXs, SOH, COXs, wherein 55 X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. aromatic ring, heteroaromatic ring, or —CX=CHXo CONXs, SOH, COXs, wherein wherein Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, X and Xo each independently comprise H or alkyl aromatic ring, heteroaromatic ring, or —CX=CHXo Wherein m is an integer from 0 to 7 60 wherein j is an integer from 0 to about 6. X and Xo each independently comprise H or alkyl k is an integer from 0 to about 2; or Wherein m is an integer from 0 to 7 R4 comprises —(CH), Z: j is an integer from 0 to about 6, or d is an integer from 1 to about 6; and k is an integer from 0 to about 2; or Z comprises a carbocyclic ring having about 4 to about 7 65 R4 comprises —(CH2)-Q-(CH2), Z: ring members, a heterocyclic ring having about 4 to Q comprises NH, O, S, CH=CH, C=C, CO, SO, or about 7 ring members, anaromatic ring having about 5 to OSO; US 8,853,205 B2 95 96 m is an integer from 1 to about 7. -continued n is an integer from 0 to about 7; and W Z comprises a carbocyclic ring having about 4 to about 7 xx^1 ring members, a heterocyclic ring having about 4 to about 7 ring members, anaromatic ring having about 5 to V. about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic wherein X and Y each independently comprise ring, a polycyclic ring, a heteropolycyclic ring; or any H, halogen, CF, CFH, N, NCS, CN, NO, NXX, OX, above group Substituted on at least one available ring 10 SX, OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO alkyl, SC(CH),COOXs. OC(CH),COOXs. atom by an alkyl group; or any above group Substituted C(CH),COOXs. Si(alkyl), alkyl-CN, O-aroyl, on at least one available ring nitrogen atom by a benzyl O(CH),OX, O(CH2).NXX2, NH-acyl, NH-aroyl, group, a Substituted benzyl group, an alkoxybenzyl CHO, C(halogen), COOX, SOH, SONXX, group, a Substituted alkoxybenzyl group, a benzhydryl 15 CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, group or a Substituted benzhydryl group; and wherein alkyl, alcohol, alkylmercapto, alkylamino, di-alky the connecting point between the -(CH2)—group and lamino, alkylsulfinyl or alkylsulfonyl, CXXX, the Z group can be any available ring carbon atom or any -CH=CHXs. -C=CXs: available ring nitrogen atom; or X and X2, each independently comprise H or alkyl, or R4 comprises —(CH2)-Q-(CH2), Z: X and X together comprise part of a heterocyclic ring Q comprises NH, O, S, CH=CH, C=C, CO, SO, or having about 4 to about 7 ring members and optionally OSO; m is an integer from 1 to about 7. one additional heteroatom selected from O, N or S, or n is an integer from 0 to about 7; and X and X together comprise part of an imide ring having Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidi 25 about 5 to about 6 members, nyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, X comprises H, alkyl, NO, (CH2)CN, hydroxylower 1-, 2- or 3-aZetidinyl, 1- or 2-piperazinyl, 2- or 3-tetrahy alkyl, or alkyl-NXX. drofuranyl; or any above group Substituted on at least X, Xs, and X each independently comprise H, alkyl, one available ring atom by an alkyl, or any above group carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo Substituted on at least one available ring nitrogen atom 30 gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, by a benzyl group, a Substituted benzyl group, an OX, or O-alkyl-X, wherein alkoxybenzyl group, a substituted alkoxybenzyl group, X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) a benzhydryl group or a Substituted benzhydryl group; (OX), S(O)N(alkyl), S(O),Xs, S(O).OXs. COOXs. and wherein the connecting point between the CONXs, SOH, COXs, wherein —(CH), group and the Z group can be any available 35 Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, ring carbon atom or any available ring nitrogenatom; or aromatic ring, heteroaromatic ring, or —CX=CHXo R4 comprises —(CH2)-Q-(CH2), Z: wherein Q comprises NH, O, S, CH=CH, C=C, CO, SO, or X and Xo each independently comprise H or alkyl OSO; Wherein m is an integer from 0 to 7 m is an integer from 1 to about 7. 40 n is an integer from 0 to about 7; and j is an integer from 0 to about 6. Z comprises k is an integer from 0 to about 2, W comprises H or alkyl. 2. A pharmaceutical composition containing a therapeuti 45 cally effective amount of at least one compound of claim 1. 3. A method of modulating the function of cannabinoid = Y, =\-lO, Y. =\-lO, Y. (- Vy., receptors in an individual or animal comprising administer X X ing to the individual or animal a therapeutically effective N X X amount of at least one compound of claim 1. y x (SIS NSN 50 4. The method of claim 3 comprising selectively stimulat -( CN N. Y Q --Y ing a CB1 cannabinoid receptor in said individual or animal. N=/ Y, N2 s 2 N s 5. A method of treating or reducing the severity of a con X X X dition selected from the group consisting of obesity; meta NeX S&?s S&S S&S 55 bolic disorders consisting of insulin related deficiencies and K N N --Y S Y O lipid profiles, hepatic diseases, cardiometabolic diseases, dia -K 5

US 8,853,205 B2 99 100 -continued members, a bicyclic ring, a heterobicyclic ring, a tricyclic 42 ring, a heterotricyclic ring, a polycyclic ring, a heteropolycy clic ring; or any above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted on at least one available ring nitrogen atom by a benzyl group, a Substituted benzyl group, an alkoxybenzyl group, a Substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connect ing point between the —(CH2)—group and the Z group can be any available ring carbon atom or any available ring nitro 10 gen atom; or R2 comprises —(CH), Z: n is an integer from 0 to about 7; and Z comprises

15 M. VX V-X —NSY, \-AS Y, \-AGSY, -(\— :Y, X X N. VX X N N=VX W X. ASX NSN K 2. N= Y, \ fY, N---X 1& ŽSy.A.

25 --Y, S --Y, --Y,

e S e S e ×sas e ×as 30 hy. hy 2

o Y- A- In Y 35 Y X / Xy N O N 2 Y Sé\-W 8. A compound of claim 1, and physiologically accepted salts thereof, consisting of the following structure: \Sy 40 X

15 wherein X and Y each independently comprise, H., halo gen, CF, CFH, N, NCS, ON, NO, NXX, OX, SX, 45 OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, SC(CH),COOX, OC(CH),COOXs. C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, O(CH.),OX, O(CH.)NXX, NH-acyl, NH-aroyl, CHO, C(halogen), COOX, SOH, SONXX, CONXX, NHC(O)C-alkyl, NHSO2-alkyl, alkoxy, 50 alkyl, alcohol, alkylmercapto, alkylamino, di-alky lamino, alkylsulfinyl or alkylsulfonyl, CXXX, -CH=CHXs. -C=CXs: X and X each independently comprise H or alkyl, or X and X together comprise part of a heterocyclic ring 55 having about 4 to about 7 ring members and optionally one additional heteroatom selected from O, N or S, or X and X together comprise part of an imide ring having about 5 to about 6 members, NC C X comprises H, alkyl, aryl, NO, (CH),CN, hydroxy 60 loweralkyl, or alkyl-NXX, 9. A compound of claim 1, wherein X, Xs, and X each independently comprise H, alkyl, R2 comprises —(CH2), Z: carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo n is an integer from 0 to about 7; and gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, Z comprises a carbocyclic ring having about 4 to about 7 ring OX, or O-alkyl-X, wherein members, a heterocyclic ring having about 4 to about 7 ring 65 X, comprises H, alkyl, NO, NO, P(O)(OXs), PH(O) members, an aromatic ring having about 5 to about 7 ring (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. members, a heteroaromatic ring having about 5 to about 7 ring CONXs, SOH, COXs, wherein US 8,853,205 B2 101 102 Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, -continued aromatic ring, heteroaromatic ring, or—CX=CHXo X (N wherein x Sé N N X and Xo each independently comprise H or alkyl Wherein m is an integer from 0 to 7 N j is an integer from 0 to about 6, or k is an integer from 0 to about 2 W comprises H or alkyl; or R2 comprises —(CH), Z: 10 n is an integer from 0 to about 7; and Z comprises a carbocyclic ring having 6 ring atoms fused to wherein X and Y each independently comprise, H., halo a heterocyclic ring having from 5 to 7 ring atoms, a gen, CF, CFH, N, NCS, ON, NO, NXX, OX, SX, carbocyclic ring having 6 ring atoms fused to a het OAc, OSOX, O-acyl, S-acyl, SO-alkyl, eroaromatic ring having from 5 to 7 ring atoms, a het 15 SO-alkyl, SC(CH),COOXs. OC(CH),COOXs. erocyclic ring having 6 ring atoms fused to a heterocy C(CH)COOXs. Si(alkyl), alkyl-CN, O-aroyl, clic ring having from 5 to 7 ring atoms, an heterocyclic O(CH),OX, O(CH2).NXX2, NH-acyl, NH-aroyl, ring having 6 ring atoms fused to a heteroaromatic ring CHO, C(halogen), COOX, SOH, SONXX, having from 5 to 7 ring atoms, an aromatic ring having 6 CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, ring atoms fused to a heterocyclic ring having from 5 to alkyl, alcohol, alkylmercapto, alkylamino, di-alky 7 ring atoms, an aromatic ring having 6 ring atoms fused lamino, alkylsulfinyl or alkylsulfonyl, CXXX, to a heteroaromatic ring having from 5 to 7 ring atoms, a -CH=CHXs. -C=CXs: heteroaromatic ring having 6 ring atoms fused to a het X and X each independently comprise H or alkyl, or erocyclic ring having from 5 to 7 ring atoms or a het X and X together comprise part of a heterocyclic ring eroaromatic ring having 6 ring atoms fused to a het 25 having about 4 to about 7 ring members and optionally eroaromatic ring having from 5 to 7 ring atoms; one additional heteroatom selected from O, N or S, or R1 comprises -T-Q-(CH2), Z; X and X together comprise part of an imide ring having n is an integer from 0 to about 7: about 5 to about 6 members, T comprises a carbocyclic ring having 3 to about 8 ring X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy members, an unsaturated ring having 3 to about 8 carbon 30 loweralkyl, or alkyl-NXX. atoms as ring members, an aromatic ring having 5 to X, Xs, and X each independently comprise H, alkyl, about 8 carbon atoms as ring members, a heterocyclic carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo ring having 3 to about 8 ring members, a heteroaromatic gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, ring having 5 to about 8 ring members, a bicyclic ring, a OX, or O-alkyl-X, wherein heterobicyclic ring, a tricyclic ring, a heterotricyclic 35 X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) ring, a polycyclic ring or a heteropolycyclic ring; (OXs), S(O)N(alkyl), S(O), Xs, S(O)OXs. COOXs. CONXs, SOH, COXs, wherein Q comprises C=C. Xs comprises H. alkyl, carbocyclic ring, heterocyclic ring, 10. A compound of claim 1, wherein aromatic ring, heteroaromatic ring, or —CX=CHXo R2 comprises —(CH2), Z: 40 wherein n is 0; and X and Xo each independently comprise H or alkyl Z comprises an aromatic ring having about 5 to about 7 ring Wherein m is an integer from 0 to 7 members, a heteroaromatic ring having about 5 to about j is an integer from 0 to about 6, or 7 ring members; or k is an integer from 0 to about 2 R2 comprises —(CH), Z: 45 W comprises H or alkyl; or n is an integer from 0 to about 7; and R1 comprises -T-Q-(CH2), Z: n is an integer from 0 to about 7: Z comprises T comprises an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 50 to about 8 ring members; Q comprises C=C. f f 11. A compound of claim 1, wherein Kl,& S. V.S.-AS Y, V.\-ASY, - R2 comprises —(CH2), Z: X X N NS n is an integer from 0 to about 7; and VX FVX 55 Z comprises a carbocyclic ring having about 4 to about 7 x x \'s ( ). ring members, a heterocyclic ring having about 4 to N=/ N.Y, N.\ S. Y. N---X 1&x Ž < Y, about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having X X X about 5 to about 7 ring members, a bicyclic ring, a 60 heterobicyclic ring, a tricyclic ring, a heterotricyclic Yá Yá Xá. ring, a polycyclic ring, a heteropolycyclic ring; or any \e N \- \- above group Substituted on at least one available ring atom by an alkyl group; or any above group Substituted xa Sé 23 Sé on at least one available ring nitrogen atom by a benzyl 65 group, a Substituted benzyl group, an alkoxybenzyl N 2 group, a Substituted alkoxybenzyl group, a benzhydryl group or a Substituted benzhydryl group; and wherein US 8,853,205 B2 103 104 the connecting point between the -(CH2)—group and k is an integer from 0 to about 2 the Z group can be any available ring carbon atom or any W comprises H or alkyl; or available ring nitrogen atom; or R2 comprises —(CH2), Z: R2 comprises —(CH2), Z: n is an integer from 0 to about 7; and n is an integer from 0 to about 7; and Z comprises Z comprises a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a het A MX V-X eroaromatic ring having from 5 to 7 ring atoms, a het 10 erocyclic ring having 6 ring atoms fused to a heterocy \-NY, \-AS Y, \-ASY, — Y, clic ring having from 5 to 7 ring atoms, an heterocyclic X X ring having 6 ring atoms fused to a heteroaromatic ring N NS having from 5 to 7 ring atoms, an aromatic ring having 6 VX FVX ring atoms fused to a heterocyclic ring having from 5 to x \'ss--X ( w, 15 7 ring atoms, an aromatic ring having 6 ring atoms fused 7 y, \ isy. N-S v 7 y. to a heteroaromatic ring having from 5 to 7 ring atoms, a X X X heteroaromatic ring having 6 ring atoms fused to a het erocyclic ring having from 5 to 7 ring atoms or a het o S --Y, O - - , eroaromatic ring having 6 ring atoms fused to a het \e N \e N eroaromatic ring having from 5 to 7 ring atoms; X X R1 comprises -T-Q-(CH2), Z. xa Sé 23 Sé n is an integer from 0 to about 7: --Y, --Y T comprises an aromatic ring having 5 to about 8 carbon N-N4 N-N-N 25 atoms as ring members or a heteroaromatic ring having X N N 5 to about 8 ring members: xa Sé NSN NN SR Q comprises C=C; and S 21 -Y X t / x Y or Z comprises CN, alkyl-CN, or ONO. 30 12. A compound of claim 1 wherein Nay-W R2 comprises —(CH2), Z: n is an integer from 0 to about 7: Z is OX; and

35 X is NO2. wherein X and Y each independently comprise, H., halo 13. A compound of claim 1 wherein gen, CF, CFH, N, NCS, ON, NO, NXX, OX, SX, R1 comprises -T-Q-(CH2), Z: OAc, OSOX, O-acyl, S-acyl, SO-alkyl, SO-alkyl, n is an integer from 0 to about 7: SC(CH),COOXs. OC(CH),COOXs. T comprises a carbocyclic ring having 3 to about 8 ring C(CH),COOXs. Si(alkyl), alkyl-CN, O-aroyl, 40 members, an unsaturated ring having 3 to about 8 carbon O(CH),OX, O(CH),NXX2, NH-acyl, NH-aroyl, atoms as ring members, an aromatic ring having 5 to CHO, C(halogen), COOX, SOH, SONXX, about 8 carbon atoms as ring members, a heterocyclic CONXX, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, ring having 3 to about 8 ring members, a heteroaromatic alkyl, alcohol, alkylmercapto, alkylamino, di-alky ring having 5 to about 8 ring members, a bicyclic ring, a lamino, alkylsulfinyl or alkylsulfonyl, CXXX, 45 heterobicyclic ring, a tricyclic ring, a heterotricyclic -CH=CHXs. -C=CXs: X and X each independently comprise H or alkyl, or ring, a polycyclic ring or a heteropolycyclic ring; X and X together comprise part of a heterocyclic ring Z is OX; and having about 4 to about 7 ring members and optionally X is NO2. one additional heteroatom selected from O, N or S, or 50 14. A compound of claim 1 wherein X and X together comprise part of an imide ring having about 5 to about 6 members, R4 comprises —(CH), Z, or—(CH)-Q-(CH), Z. X comprises H, alkyl, aryl, NO, (CH2)CN, hydroxy 15. A compound of claim 1, wherein loweralkyl, or alkyl-NXX. R1 comprises X, Xs, and X each independently comprise H, alkyl, 55 carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halo gen, CN, SNO, S(SO)alkyl, NXX, COOX, CONX, —(CH), Z: OX, or O-alkyl-X, wherein —(CH)-Q-(CH), Z: X, comprises H, alkyl, NO, NO, P(O)(OX), PH(O) -T-(CH2), Z; or (OXs), S(O)N(alkyl), S(O), Xs, S(O).OXs. COOXs. 60 CONXs, SOH, COXs, wherein -T-Q-(CH2), Z; and Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, R2 comprises aromatic ring, heteroaromatic ring, or—CX=CHXo —(CH2), Z: wherein X and Xo each independently comprise H or alkyl 65 Wherein m is an integer from 0 to 7 -T-(CH2), Z; or j is an integer from 0 to about 6, or

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,853,205 B2 Page 1. Of 5 APPLICATIONNO. : 13/202499 DATED : October 7, 2014 INVENTOR(S) : Makriyannis et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

In the Claims

Column 62, line 46: delete “ON” and insert --CN--

Column 63, line 51: delete “ON” and insert --CN--

Column 64, line 21: delete “ON” and insert --CN--

Column 66, line 17: delete “ON” and insert --CN--

Column 67, line 51: delete “ON” and insert --CN--

Column 69, line 41: delete “ON” and insert --CN--

Column 70, line 43: delete “ON” and insert --CN--

Column 72, line 38: delete “ON” and insert --CN--

Signed and Sealed this Twelfth Day of May, 2015 74-4-04- 2% 4 Michelle K. Lee Director of the United States Patent and Trademark Office CERTIFICATE OF CORRECTION (continued) Page 2 of 5 U.S. Pat. No. 8,853,205 B2 Column 74, lines 5-10: A. N delete “ –4. ** and insert -- ch 2.")k

Column 74, line 38: delete “ON” and insert --CN--

Column 76, line 60: Ns &' 's N Y YNXNs delete “ 2 and insert -- N

Column 76, line 65: X-yYasisf N-75-yX delete “ N and insert -- as N,

Column 78, line 64: delete “ON” and insert --CN--

Column 80, lines 15-20: Y's,N --Y Y'NxNs delete 66 N at N 99 and inserto -- NaN

K S&fs Ya N N N Y delete “ N e and inserto -- --

Column 81, line 47: delete “ON” and insert --CN--

Column 82, line 17: delete “ON” and insert --CN--

Column 83, line 60: N Y sN Y Y Ns N X stN o Ns N delete “ and insert -- CERTIFICATE OF CORRECTION (continued) Page 3 of 5 U.S. Pat. No. 8,853,205 B2 Column 83, line 65: N

Column 87, line 15: N \ly-- NNN X delete: n N " and insert. N a N

Column 87, line 20: \sis X N'--Y NY7 Y delete “ Yel and insert -- van,

Column 90, line 15:

Yy-- NNN--X delete: Yi N and insert - N'-se

Column 90, line 20: siss NY7.X delete “ Ye and insert -- ' --

Column 95, line 50: --Y Y N delete n a N and inserto - N'--X

Column 95, line 55: Ki?sf X N'-N Y N- Y CERTIFICATE OF CORRECTION (continued) Page 4 of 5 U.S. Pat. No. 8,853,205 B2 Column 98, between lines 45-65: 3S y O N - y N1 C

S f C

delete “ NC and

insert --

Column 99, lines 20-35:

O

N N N H N S C

delete “ C and insert -- C 44

Column 100, line 44: delete “ON” and insert --CN-- CERTIFICATE OF CORRECTION (continued) Page 5 of 5 U.S. Pat. No. 8,853,205 B2 Column 102, line 13: delete “ON” and insert --CN--

Column 103, line 37: delete “ON” and insert --CN--