Pyrazolopyrimidines and related analogs as HSP90-inhibitors

[0001] This application relates and claims priority to U.S. Provisional Application Ser. No. 60/504,135, filed Sep. 18, 2003 and U.S. Provisional Application Ser. No. 60/591,467, filed Jul. 26, 2004. This application also relates to three other U.S. Utility applications Ser. No. 10/946,645 filed Sep 20, 2004 (now Publication No. 20050113340; Ser. No. 10/945,851 filed Sep. 20, 2004 (now Publication No. 20050107343, and Ser. No. 10/946,628 filed Sep. 20, 2004 (now Publication No. 20050113339). This application further relates to International Application PCT02/35069, filed Oct. 30, 2002, (now Publication No. WO03/37860). All the above cited U.S. utility applications, provisional applications and international application are expressly incorporated herein by reference in their entirety.

[0002] The invention relates in general to pyrazolopyrimidines and their related analogs and their broad-spectrum utility, e.g., in inhibiting heat shock protein 90 (HSP90) to thereby treat or prevent HSP90-mediated diseases.

[0003] HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. Researchers have reported that HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner J. TIBS 1999, 24, 136–141; Stepanova, L. et al. Genes Dev. 1996, 10, 1491–502; Dai, K. et al. J. Biol. Chem. 1996, 271, 22030–4). Studies further indicate that certain co-chaperones, e.g., HSP70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in its function (see, e.g., Caplan, A. Trends in Cell Biol. 1999, 9, 262–68).

[0004] Ansamycin antibiotics, e.g, herbimycin A (HA), geldanamycin (GM), and 17-allylaminogeldanamycin (17-AAG) are thought to exert their anticancerous effects by tight binding of the N-terminus pocket of HSP90, thereby destabilizing substrates that normally interact with HSP90 (Stebbins, C. et al. Cell 1997, 89, 239–250). This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al., supra; Grenert, J. P. et al. J. Biol. Chem. 1997, 272, 23843–50). Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity (Proromou, C. et al. Cell 1997, 90, 65–75; Panaretou, B. et al. EMBO J. 1998, 17, 4829–36). In vitro and in vivo studies have demonstrated that occupancy of this N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits protein folding. At high concentrations, ansamycins and other HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel, T. H. et al. Proc. Natl. Acad. Sci. USA 1999, 96, 1297–302; Schulte, T. W. et al. J. Biol. Chem. 1995, 270, 24585–8; Whitesell, L., et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324–8328). Ansamycins have also been demonstrated to inhibit the ATP-dependent release of chaperone-associated protein substrates (Schneider, C. L. et al. Proc. Natl. Acad. Sci., USA 1996, 93, 14536–41; Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270, 16580–16587). In either event, the substrates are degraded by a ubiquitin-dependent process in the proteasome (Schneider, C. L., supra; Sepp-Lorenzino, L., et al. J. Biol. Chem. 1995, 270, 16580–16587; Whitesell, L. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324–8328).

[0005] HSP90 substrate destabilization occurs in tumor and non-transformed cells alike and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al. Biochem. Biophys. Res. Commun. 1997, 239, 655–9; Schulte, T. W., et al. J. Biol. Chem. 1995, 270, 24585–8), nuclear steroid receptors (Segnitz, B.; U. Gehring J. Biol. Chem. 1997, 272, 18694–18701; Smith, D. F. et al. Mol. Cell. Biol. 1995, 15, 6804–12), v-Src (Whitesell, L., et al. Proc. Natl. Acad Sci. USA 1994, 91, 8324–8328) and certain transmembrane tyrosine kinases (Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580–16587) such as EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int. J. Cancer 1997, 70, 221–9; Miller, P. et al. Cancer Res. 1994, 54, 2724–2730; Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271, 22796–801; Schnur, R. et al. J. Med Chem. 1995, 38, 3806–3812), CDK4, and mutant p53. Erlichman et al. Proc. AACR 2001, 42, abstract 4474. The ansamycin-induced loss of these proteins leads to the selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle (Muise-Heimericks, R. C. et al. J. Biol. Chem. 1998, 273, 29864–72), and apoptosis, and/or differentiation of cells so treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59, 3935–40). Ansamycins thus hold great promise for the treatment and/or prevention of many types of cancers and proliferative disorders, and also hold promise as traditional antibiotics. However, their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation. Further, the dose limiting toxicity of ansamycins is hepatic.

[0006] In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating stroke, ischemia, multiple sclerosis, cardiac disorders, central nervous system related disorders and agents useful in promoting nerve regeneration (See, e.g., Rosen et al. WO 02/09696 (PCT/US01/23640); Degranco et al. WO 99/51223 (PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 BI; DeFranco et al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above, there are reports in the literature that fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis also may be treatable with HSP90 inhibitors. Strehlow, WO 02/02123 (PCT/US01/20578). Still further HSP90 modulation, modulators and uses thereof are reported in Application Nos. PCT/US03/04283, PCT/US02/35938, PCT/US02/16287, PCT/US02/06518, PCT/US98/09805, PCT/US00/09512, PCT/US01/09512, PCT/US01/23640, PCT/US01/46303, PCT/US01/46304, PCT/US02/06518, PCT/US02/29715, PCT/US02/35069, PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668, 60/335,391, 60/128,593, 60/337,919, 60/340,762, 60/359,484 and 60/331,893.

[0007] Recently, purine derivatives showing HSP90 inhibitory activity have been reported, e.g., in PCT/US02/35069 and PCT/US02/36075. Purine moieties are well accepted bioisosteres for a variety of ATP-dependent molecular targets, see, JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,772,606; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; EP 0178178; Eur. J. Med. Chem. 1994, 29(1), 3–9; and J. Het. Chem. 1990, 27(5), 1409. However, compounds having the desired potency, selectivity and pharmaceutical properties required for effective HSP90 inhibition in vivo have not been reported. Therefore, a need remains for additional novel and potent HSP90 inhibitors that meet the demanding biological and pharmaceutical criteria required to proceed towards human clinical trials.

[0008] The present invention is directed towards heterocyclic compounds, in particular towards pyrazolopyrimidines and related compounds that show broad utility, e.g., in inhibiting HSP90 and/or treating and preventing diseases that are HSP90-dependent.

[0009] In one aspect, the invention comprises the heterocyclic compounds as specified below in Formulae A, I and II and compounds that are produced by a synthesis process of the invention. Also included in the scope of the present invention are stereoisomeric forms, including the individual enantiomers and diastereomers, racemic mixtures, and diastereomeric mixtures, as well as polymorphs, solvates, esters, tautomers, pharmaceutically acceptable salts and prodrugs of these compounds.

[0010] In one embodiment, the invention provides compounds of Formula A, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility by inhibiting HSP90 and treating and/or preventing diseases that are HSP90-dependent.

[0011]
wherein:

• • [0012] X¹ and X² are the same or different and each is nitrogen or —CR⁶;
  • [0013] X³ is nitrogen or —CR³ wherein R³ is hydrogen, OH, a keto tautomer, —OR⁸, —CN, halogen, lower alkyl, or —C(O)R⁹;
  • [0014] X⁴ is nitrogen or —CR⁶ when X³ is nitrogen; and X⁴ is —CR⁶R⁷ when X³ is —CR³;
  • [0015] R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl;
  • [0016] R² is —NR⁸R¹⁰;
  • [0017] R⁴ is —(CH₂)_n— wherein n=0–3, —C(O), —C(S), —SO₂—, or —SO₂N—; and
  • [0018] R⁵ is alkyl, aromatic, heteroaromatic, alicyclic, or heterocyclic, each of which is optionally bi-or tri-cyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N₃, —SR⁸, —OR₈, —CN, —CO₂R⁹, —NO₂, or —NR⁸R¹⁰.

[0019] In certain embodiments, there are exclusionary provisos with respect to compounds disclosed in JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med. Chem. 1994, 29(1), 3–9; and J. Het. Chem. 1990, 27(5), 1409, which disclose compounds with —R⁴R⁵ comprising ribose or a derivative thereof, or a sugar or derivative thereof; and compounds where —R⁴R⁵ is a phosphonate or phosphonic acid, or is substituted with a phosphonate or phosphonic acid; or compounds where R⁴ is —CH₂— or —(CH₂)_n— that are connected through an oxygen atom to another group.

[0020] In another embodiment, the invention provides compounds of Formula I, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility for inhibiting HSP90 and treating and preventing diseases that are HSP90-dependent,

[0021]
wherein:

• • [0022] R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;
  • [0023] R² is —NHR⁸;
  • [0024] R³ is selected from the group consisting of hydrogen, halogen, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein:
    • [0025] the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic;
    • [0026] R⁸ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–2 of the ring atoms are heteroatoms selected from the group of O, S and N, and
    • [0027] the optional substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophenyl, furanyl, indoyl, indazoyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0028] R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;
  • [0029] R⁵is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
    • [0030] the aryl group is substituted with 3 to 5 substituents,
    • [0031] the heteroaryl group is substituted with 2 to 5 substituents,
    • [0032] the alicyclic group is substituted with 3 to 5 substituents,
    • [0033] the heterocyclic group is substituted with 3 to 5 substituents, and
    • [0034] the substituents on R⁵ are selected from the group consisting of halogen, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, indazolyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0035] R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;
  • [0036] R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0037] R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0038] R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and
  • [0039] R¹² is hydrogen or lower alkyl.

[0040] In another embodiment, the invention provides compounds of Formula II, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility for inhibiting HSP90 and treating and/or preventing diseases that are HSP90-dependent,

[0041]
wherein:

• • [0042] R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;
  • [0043] R² is —NHR⁸;
  • [0044] R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;
  • [0045] R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
    • [0046] the aryl group is substituted with 3 to 5 substituents,
    • [0047] the heteroaryl group is substituted with 2 to 5 substituents,
    • [0048] the alicyclic group is substituted with 3 to 5 substituents,
    • [0049] the heterocyclic group is substituted with 3 to 5 substituents, and
    • [0050] the substituents on R⁵ are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indoyl, and indazoyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0051] R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;
  • [0052] R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0053] R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0054] R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and
  • [0055] R¹² is hydrogen or lower alkyl; and
  • [0056] R¹⁵ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

[0057] In another embodiment, the invention provides compounds, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility for inhibiting HSP90 and treating and/or preventing diseases that are HSP90-dependent, that are prepared by the process comprising:

• • [0058] reacting a compound of Formula Y and a compound of Formula Z, wherein:
  • [0059] Y is represented by any of the following formulae:

[0060]

• • [0061] Z is L¹-R⁴—R⁵; wherein:
    • [0062] L₁ is halogen, NR⁸R¹⁰, triflate, tosylate, or mesylate;
    • [0063] R⁴ is —(CHR¹²)—, —C(O), —C(S), —S(O)—, or —SO₂—;
    • [0064] R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
      • [0065] the aryl group is substituted with 3 to 5 substituents,
      • [0066] the heteroaryl group is substituted with 2 to 5 substituents,
      • [0067] the alicyclic group is substituted with 3 to 5 substituents,
      • [0068] the heterocyclic group is substituted with 3 to 5 substituents, and
      • [0069] the substituents on R⁵ are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indoyl, and indazoyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
    • [0070] R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;
    • [0071] R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰, or —OR¹¹, wherein R¹⁰ and R¹¹ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
    • [0072] R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
    • [0073] R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
    • [0074] R¹² is hydrogen or lower alkyl;
    • [0075] R²¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;
    • [0076] R²² is —NR⁸R¹⁰;
    • [0077] R²³ is hydrogen, —OH or its keto tautomer, —OR⁸, halogen, —CN, lower alkyl, lower aryl or —C(O)R⁹;
    • [0078] R²⁴ is —CHO, —NH₂, —NO₂ or —NO;
    • [0079] R²⁵ is halogen or —OH;
    • [0080] R²⁶ is —C(O)NH₂ or C(O)OEt; and
    • [0081] R²⁷ is —NH₂, —OH or halogen.

[0082] In another aspect, the present invention is directed to pharmaceutical compositions comprising the compounds of the invention, in particular, the compounds of Formulae A, I and II, and compounds formed by the process of the invention, and their polymorphs, solvates, esters, tautomers, diastereomer, enantiomers, pharmaceutically acceptable salts and prodrugs thereof, and one or more pharmaceutical excipients, for use in treatment or prevention of diseases that are HSP90-dependent.

[0083] In another aspect, the invention features a method of treating an individual having an HSP90-mediated disorder by administering to the individual a pharmaceutical composition that comprises a pharmaceutically effective amount of a compound of Formula A, I or II, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, enantiomers pharmaceutically acceptable salt or prodrug thereof.

[0084] In one embodiment, the invention provides a method for treating an individual having a disorder selected from the group of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant disease.

[0085] In yet another embodiment, the invention provides a method for treating an individual having a fibrogenetic disorder, such as, for example, scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.

[0086] In another embodiment, the invention provides a combination therapy comprising the administration of a pharmaceutically effective amount of a compound of Formula I or Formula II, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt and prodrug thereof, according to any of the preceding aspects or embodiments, and at least one therapeutic agent selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. The anti-neoplastic agent may be selected from the group of alkylating agents, anti-metabolites, epidophyllotoxins antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.

[0087] Any of the above described aspects and embodiments of the invention can be combined where practical.

[0088] The individual compounds, methods and compositions prescribed do not preclude the utilization of other, unspecified steps and agents, and those of ordinary skill in the art will appreciate that additional steps and compounds may also be combined usefully within the spirit of various aspects and embodiments of the invention.

[0089] Advantages of the invention depend on the specific aspect and embodiment and may include one or more of: ease of synthesis and/or formulation, solubility, and IC₅₀ relative to previously existing compounds in the same or different classes of HSP90 inhibitors.

I. Definitions

[0090] A “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).

[0091] A “pharmaceutically acceptable salt” may be prepared for any compound of the invention having a functionality capable of forming a salt, for example, an acid or base functionality. Pharmaceutically acceptable salts may be derived from organic or inorganic acids and bases. Compounds of the invention that contain one or more basic functional groups, e.g., amino or alkylamino, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecampate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. See, e.g., Berge et al. “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66:1–19.

[0092] Compounds of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C_1-4 alkyl)₄, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. See, for example, Berge et al., supra.

[0093] Pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, metal salts and sulfonate esters.

[0094] Suitable positions for derivatization of the compounds of the invention to create “prodrugs” include but are not limited, 2-amino substitution. Those of ordinary skill in the art have the knowledge and means to accomplish this without undue experimentation. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see, e.g.,

[0095] a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309–396;

[0096] b) Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113–191; and

[0097] c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1–38. Each of which is incorporated herein by reference.

[0098] The term “prodrugs” as employed herein includes, but is not limited to, the following groups and combinations of these groups:

[0099] Amine Prodrugs:

[0100]
Hydroxy Prodrugs:

• • [0101] Acyloxyalkyl esters;
  • [0102] Alkoxycarbonyloxyalkyl esters;
  • [0103] Alkyl esters;
  • [0104] Aryl esters; and
  • [0105] Disulfide containing esters.

[0106] The term “alkyl,” alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon radical having from one to thirty carbons, more preferably one to twelve carbons. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. The term “cycloalkyl” embraces cyclic alkyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein each cyclic moiety has from three to eight carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. A “lower alkyl” is a shorter alkyl, e.g., one containing from one to six carbon atoms.

[0107] The term “alkenyl,” alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from two to thirty carbon atoms, more preferably two to eighteen carbons. Examples of alkenyl radicals include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like. The term “cycloalkenyl” refers to cyclic alkenyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkenyl radicals wherein each cyclic moiety has from three to eight carbon atoms. A “lower alkenyl” refers to an alkenyl having from two to six carbons.

[0108] The term “alkynyl,” alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from two to thirty carbon atoms, more preferably from two to twelve carbon atoms, from two to six carbon atoms as well as those having from two to four carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. The term “cycloalkynyl” refers to cyclic alkynyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkynyl radicals wherein each cyclic moiety has from three to eight carbon atoms. A “lower alkynyl” refers to an alkynyl having from two to six carbons.

[0109] The terms “heteroalkyl, heteroalkenyl and heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorous or combinations thereof.

[0110] The term “carbon chain” embraces any alkyl, alkenyl, alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group, which are linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the “chain” only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.

[0111] The term “membered ring” can embrace any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring systems as described below. The term “membered” is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, pyridine, pyran, and pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and thiophene are five-membered rings.

[0112] The term “aryl,” alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical of six to twenty ring atoms, and includes mono-aromatic rings and fused aromatic ring. A fused aromatic ring radical contains from two to four fused rings where the ring of attachment is an aromatic ring, and the other individual rings within the fused ring may be aromatic, heteroaromatic, alicyclic or heterocyclic. Further, the term aryl includes mono-aromatic ring and fused aromatic rings containing from six to twelve carbon atoms, as well as those containing from six to ten carbon atoms. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthryl, chrysenyl, and benzopyrenyl ring systems. The term “lower aryl” refers to an aryl having six to ten skeletal ring carbons, e.g., phenyl and naphthyl ring systems.

[0113] The term “heteroaryl” refers to optionally substituted aromatic radicals containing from five to twenty skeletal ring atoms and where one or more of the ring atoms is a heteroatom such as, for example, oxygen, nitrogen, sulfur, selenium and phosphorus. The term heteroaryl includes optionally substituted mono-heteroaryl radicals and fused heteroaryl radicals having at least one heteroatom (e.g., quinoline, benzothiazole). A fused heteroaryl radical may contain from two to four fused rings and where the ring of attachment is a heteroaromatic ring, the other individual rings within the fused ring system may be aromatic, heteroaromatic, alicyclic or heterocyclic. The term heteroaryl also includes mono-heteroaryls or fused heteroaryls having from five to twelve skeletal ring atoms, as well as those having from five to ten skeletal ring atoms. Examples of heteroaryls include, without limitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, benzothiozole, benzimidazole, benzoxazoles, benzothiadiazole, benzoxadiazole, benzotriazole, quinolines, isoquinolines, indolyl, purinyl, indolizinyl, thienyl and the like and their oxides. The term “lower heteroaryl” refers to a heteroaryl having five to ten skeletal ring atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.

[0114] The term “alicyclic” alone or in combination, refers to an optionally substituted saturated or unsaturated nonaromatic hydrocarbon ring system containing from three to twenty ring atoms. The term alicyclic includes mono-alicyclic and fused alicyclic radicals. A fused alicyclic may contain from two to four fused rings where the ring of attachment is an alicyclic ring, and the other individual rings within the fused-alicyclic radical may be aromatic, heteroaromatic, alicyclic and heterocyclic. The term alicyclic also includes mono-alicyclic and fused alicyclic radicals containing from three to twelve carbon atoms, as well as those containing from three to ten carbon atoms. Examples of alicyclics include, without limitation, cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl, cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The term “lower alicyclic” refers to an alicyclic having three to ten skeletal ring carbons, e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, decalinyl, and cyclohexyl.

[0115] The term “heterocyclic” refers to optionally substituted saturated or unsaturated nonaromatic ring radicals containing from five to twenty ring atoms where one or more of the ring atoms are heteroatoms such as, for example, oxygen, nitrogen, sulfur, and phosphorus. The term alicyclic includes mono-heterocyclic and fused heterocyclic ring radicals. A fused heterocyclic radical may contain from two to four fused rings where the attaching ring is a heterocyclic, and the other individual rings within the fused heterocyclic radical may be aromatic, heteroaromatic, alicyclic or heterocyclic. The term heterocyclic also includes mono-heterocyclic and fused alicyclic radicals having from five to twelve skeletal ring atoms, as well as those having from five to ten skeletal ring atoms. Example of heterocyclics include without limitation, tetrahydrofuranyl, benzodiazepinyl, tetrahydroindazolyl, dihyroquinolinyl, and the like. The term “lower heterocyclic” refers to a heterocyclic ring system having five to ten skeletal ring atoms, e.g., dihydropyranyl, pyrrolidinyl, indolyl, piperidinyl, piperazinyl, and the like.

[0116] The term “alkylaryl,” or “araalkyl,” alone or in combination, refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.

[0117] The term “arylalkyl,” alone or in combination, refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.

[0118] The term “heteroarylalkyl” refers to an alkyl radical as defined above in which one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted.

[0119] The term “alkoxy,” alone or in combination, refers to an alkyl ether radical, alkyl-O—, wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

[0120] The term “aryloxy,” alone or in combination, refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.

[0121] The term “alkylthio,” alone or in combination, refers to an alkyl thio radical, alkyl-S—, wherein the term alkyl is as defined above.

[0122] The term “arylthio,” alone or in combination, refers to an aryl thio radical, aryl-S—, wherein the term aryl is as defined above.

[0123] The term “heteroarylthio” refers to the group heteroaryl-S—, wherein the term heteroaryl is as defined above.

[0124] The term “acyl” refers to a radical —C(O)R where R includes alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl alkyl groups may be optionally substituted.

[0125] The term “acyloxy” refers to the ester group —OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl may be optionally substituted.

[0126] The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.

[0127] The term “carboxamido” refers to

[0128]
where each of R and R′ are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl, aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may be optionally substituted.

[0129] The term “oxo” refers to ═O.

[0130] The term “halogen” includes F, Cl, Br and I.

[0131] The terms “haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.

[0132] The terms “perhaloalkyl, perhaloalkyloxy and perhaloacyl” refer to alkyl, alkyloxy and acyl radicals as described above, that all the H atoms are substituted with fluorines, chlorines, bromines or iodines, or combinations thereof.

[0133] The terms “cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and heteroalkyl” include optionally substituted cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl groups.

[0134] The terms “alkylamino”, refers to the group —NHR where R is independently selected from alkyl.

[0135] The terms “dialkylamino”, refers to the group —NRR′ where R and R′ are alkyls.

[0136] The term “sulfide” refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II). The term “thioether” may be used interchangeably with the term “sulfide.”

[0137] The term “sulfoxide” refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).

[0138] The term “sulfone” refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).

[0139] The terms “optional” or “optionally” mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “aryl optionally mono- or di-substituted with an alkyl” means that the alkyl may but need not be present, or either one alkyl or two may be present, and the description includes situations where the aryl is substituted with one or two alkyls and situations where the aryl is not substituted with an alkyl.

[0140] “Optionally substituted” groups may be substituted or unsubstituted. The substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: lower alkyl, lower alkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, arylalkylamino, alkylthio, arylthio, heteroarylthio, oxo, carbonyl (—C(O)), carboxyesters (—C(O)OR), carboxamido (—C(O)NH₂), carboxy, acyloxy, —H, halo, —CN, —NO₂, —N₃, —SH, —H, —C(O)CH₃, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, indazolyl, esters, amides, and thioalkyls. An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH₂CF₃).

[0141] The term “pyridine-1-oxy” also means “pyridine-N-oxy.”

[0142] Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diastereomer.

[0143] A “pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients. The purpose of a pharmacological composition is to facilitate administration of a compound to an organism.

[0144] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. A physiologically acceptable carrier should not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0145] An “excipient” refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0146] A “pharmaceutically effective amount” means an amount which is capable of providing a therapeutic and/or prophylactic effect. The specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific compound administered, the route of administration, the condition being treated, and the individual being treated. A typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50–100 mg/kg of body weight of an active compound of the invention. Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as clearance rate, half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.

[0147] In some method embodiments, the preferred therapeutic effect is the inhibition, to some extent, of the growth of cells characteristic of a proliferative disorder, e.g., breast cancer. A therapeutic effect will also normally, but need not, relieve to some extent one or more of the symptoms other than cell growth or size of cell mass. A therapeutic effect may include, for example, one or more of 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cell infiltration into peripheral organs, e.g., in the instance of cancer metastasis; 3) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of cell growth; and/or 5) relieving to some extent one or more of the symptoms associated with the disorder.

[0148] As used herein, the term IC₅₀ refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. In some method embodiments of the invention, the “IC₅₀” value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.

[0149] By a “standard” is meant a positive or negative control. A negative control in the context of HER2 expression levels is, e.g., a sample possessing an amount of HER2 protein that correlates with a normal cell. A negative control may also include a sample that contains no HER2 protein. By contrast, a positive control does contain HER2 protein, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers. The controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of a diagnostic “dipstick.”

[0150] By “selectively targeting” is meant affecting one type of cell to a greater extent than another, e.g., in the case of cells with high as opposed to relatively low or normal HER2 levels.

II. Compounds of the Invention

[0151] Compounds of the invention and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, pharmaceutically acceptable salts or prodrugs show utility for inhibiting HSP90 and treating and/or preventing diseases that are HSP90-dependent.

[0152] One embodiment of the compounds of the invention is of Formula A:

[0153]
or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

• • [0154] X¹ and X₂ are the same or different and each is nitrogen or —CR⁶;
  • [0155] X³ is nitrogen or —CR³ wherein R³ is hydrogen, OH, a keto tautomer, —OR⁸, —CN, halogen, lower alkyl, or —C(O)R⁹;
  • [0156] X⁴ is nitrogen or a group CR⁶ when X³ is nitrogen, and X₄ is —CR⁶R⁷ when X₃ is —CR³;
  • [0157] R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl;
  • [0158] R² is —NR⁸R¹⁰;
  • [0159] R⁴ is —(CH₂)_n— wherein n=0–3, —C(O), —C(S), —SO₂—, or —SO₂N—; and
  • [0160] R⁵ is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, each of which is optionally bi-or tricyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, araalkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N₃, —SR⁸, —R⁸, —CN, —CO₂R⁹, —NO₂ or —NR⁸R¹⁰;

[0161] with the provisos that:

[0162] the compound is not one found or described in one or more of JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med. Chem., 1994, 29(1), 3–9; and J. Het. Chem. 1990, 27(5), 1409;

[0163] —R⁴R⁵ is not a ribose or derivative thereof, or a sugar or derivative thereof;

[0164] —R⁴R⁵ is not a phosphonate or phosphonic acid, or a group substituted with a phosphonate or phosphonic acid; and

[0165] when R⁴ is (CH₂)_n where n=0 or 1, then R⁴ and R⁵ are not connected with ‘O’, e.g., —CH₂—O—CH₂— or —CH₂—CH₂ —O—CH₂—.

[0166] In one embodiment of the compound, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof of Formula A, X₁ and X₂ are the same or different and each is nitrogen or —CR⁶; R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl; R² is —NR⁸R¹⁰; R³ is hydrogen, —OH or keto tautomer, —OR⁸, halogen, —CN, lower alkyl, or —C(O)R9; R⁴ is —(CH₂)_n— wherein n=0–3, —C(O), —C(S), —SO₂—, or —SO₂N—; and R⁵ is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, each of which is optionally bi- or tricyclic, and optionally substituted with H, halogen, lower alkyl, —SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂ or —NR⁸R¹⁰; R⁸ is hydrogen, lower alkyl, lower aryl or —(CO)R⁹; R⁹ is lower alkyl, lower aryl, lower heteroaryl, —NR⁸R¹⁰ or OR¹¹; R¹¹ is lower alkyl or lower aryl; and R¹⁰ is hydrogen or lower alkyl.

[0167] In one embodiment, the compound, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof of Formula A, R¹ is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl and C_1-4 alkyl; and R² is —NH₂; and R³ is hydrogen.

[0168] In another embodiment, R⁴ is —(CH₂)_n—, where n=0–3.

[0169] In another embodiment, R¹ is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl or C_1-4 alkyl; optionally, R² is —NH₂.

[0170] In another embodiment, R⁴ is —CH₂—.

[0171] In another embodiment, R⁴ is —(CH₂)_n—, wherein n=0–3, R¹ is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl, and C_1-4 alkyl, and R² is optionally NH₂.

[0172] In another embodiment, R¹ is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C_1-4 alkyl; and R² is optionally NH₂, R⁴ is —(CH₂)—, and R⁵ is phenyl, benzyl, or pyridyl, all optionally substituted with H, halogen, lower alkyl, —SR⁸, —OR⁸ (or cyclic ethers such as methylenedioxy), —CN, —CO₂R⁹, —NO₂, or —NR⁸R¹⁰; R⁸ is hydrogen, lower alkyl, lower aryl or —(CO)R⁹; R⁹ is lower alkyl, lower aryl, lower heteroaryl, —NR⁸R¹⁰ or —OR¹¹; R¹¹ is lower alkyl or lower aryl; and R¹⁰ is hydrogen or lower alkyl.

[0173] In another embodiment R¹ is halogen, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H or halogen, and R⁵ is phenyl optionally substituted with H, halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, —CN, —NO₂, —NH₂ or —CO₂R¹¹.

[0174] In another embodiment, R¹ is halogen, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H, and R⁵ is 2-halo-3,5-dimethoxyphenyl optionally substituted with H, halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, —CN, —NO₂, —NH₂, or —CO₂R¹¹ at the para (4-) position.

[0175] In another embodiment, R¹ is chloro, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H and R⁵ is 2-chloro-3,4,5-trimethoxyphenyl.

[0176] In another embodiment, R¹ is chloro, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H and R⁵ is 2-bromo-3,4,5-trimethoxyphenyl. In other embodiments, R⁵ is selected from 2-iodo-3,4,5-trimethoxyphenyl, 2-fluoro-3,4,5-trimethoxyphenyl, or 2-bromo-3,4,5-trimethoxyphenyl.

[0177] Any of the foregoing embodiments can be combined where feasible and appropriate.

[0178] In another aspect, the invention provides compounds of Formula A1:

[0179]
or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein

• • [0180] X¹ and X² are the same or different and each is nitrogen or CR⁶;
  • [0181] R¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;
  • [0182] R² is —NR⁸R¹⁰;
  • [0183] R³ is hydrogen, —OH or keto tautomer, —OR⁸, halogen, —CN, lower alkyl or —C(O)R⁹;
  • [0184] R⁴ is —(CH₂)_n— where n=0–3, —C(O), —C(S), —SO₂— or —SO₂N—;
  • [0185] R⁵ is alkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally bi- or tricyclic, and all optionally substituted with H, halogen, lower alkyl, —SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂ or —NR⁸R¹⁰;
  • [0186] R⁸ is hydrogen, lower alkyl, lower aryl or —(CO)R⁹;
  • [0187] R⁹ is lower alkyl, lower aryl, lower heteroaryl, —NR⁸R¹⁰ or OR¹¹;
  • [0188] R¹¹ is lower alkyl or lower aryl; and
  • [0189] R¹⁰ is hydrogen or lower alkyl.

[0190] In one embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R¹ is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C_1-4 alkyl; and R² is NH₂.

[0191] In another embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R⁴ is —(CH₂)_n—, where n=0–3.

[0192] In another embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R¹ is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C_1-4 alkyl; R² is NH₂; and R⁴ is —(CH₂)_n—, wherein n=0–3.

[0193] In another embodiment of the compounds of Formula A1, or a tautomer, pharmaceutically acceptable salt thereof, R¹ is halogen; R² is NH₂; and R⁴ is —CH₂—.

[0194] Another embodiment of the compounds of the invention is of Formula I:

[0195]
or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

• • [0196] R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;
  • [0197] R² is —NHR⁸;
  • [0198] R³ is selected from the group consisting of hydrogen, halogen, —SR⁸, —OR⁸, —CN, —C(O)R⁹, —CO₂H, —NO₂, —NR⁸R¹⁰, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein:
    • [0199] the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic;
    • [0200] R⁸ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–2 of the ring atoms are heteroatoms selected from the group of O, S and N, and
    • [0201] the optional substituents on R³ are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0202] R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;
  • [0203] R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
    • [0204] the aryl group is substituted with 3 to 5 substituents,
    • [0205] the heteroaryl group is substituted with 2 to 5 substituents,
    • [0206] the alicyclic group is substituted with 3 to 5 substituents,
    • [0207] the heterocyclic group is substituted with 3 to 5 substituents, and
    • [0208] the substituents on R⁵ are selected from the group consisting of halogen, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl furanyl, indolyl, and indazolyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0209] R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;
  • [0210] R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0211] R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0212] R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and
  • [0213] R¹² is hydrogen or lower alkyl.

[0214] In one embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is halogen or lower alkyl; R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; R⁵ is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.

[0215] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R² is —NH₂; R³ is selected from hydrogen, halogen, —SR⁸, —OR⁸, —CN, —NR⁸R¹⁰, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, lower heteroaryl, lower alicyclic, and lower heterocyclic, wherein R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl, and wherein R⁸ and R¹⁰ when taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N; and R⁵ is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.

[0216] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is halogen or lower alkyl; R² is —NH₂; R⁴ is —(CH₂)—; and R⁵ is aryl, heteroaryl, alicyclic or heterocyclic, wherein each of said aryl, heteroaryl alicyclic or heterocyclic groups is monocyclic or bicyclic.

[0217] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is halogen; R² is —NH₂; R³ is hydrogen, halogen, —SR⁸, —OR⁸, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, lower heteroaryl, or —NR⁸R¹⁰, wherein R⁸ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.

[0218] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is halogen; R² is —NH₂; R³ is hydrogen, halogen, —SR⁸, —OR⁸, lower alkyl, lower aryl, lower heteroaryl, or —NR⁸R¹⁰, wherein R⁸ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.

[0219] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is chloro or bromo; and R⁵ is a phenyl having 3 to 5 substituents.

[0220] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is chloro or bromo; and R⁵ is a pyridyl having 3 to 5 substituents.

[0221] In another embodiment of the compounds of Formula I, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is chloro or bromo; and R⁵ is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.

[0222] It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.

[0223] Another embodiment of the compounds of the invention is of Formula II:

[0224]
or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

• • [0225] R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;
  • [0226] R² is —NHR⁸;
  • [0227] R⁴ is —CHR¹²—, —C(O), —C(S), —S(O)—, or —SO₂—;
  • [0228] R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
    • [0229] the aryl group is substituted with 3 to 5 substituents,
    • [0230] the heteroaryl group is substituted with 2 to 5 substituents,
    • [0231] the alicyclic group is substituted with 3 to 5 substituents,
    • [0232] the heterocyclic group is substituted with 3 to 5 substituents, and
    • [0233] the substituents on R⁵ are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indoyl, and indazoyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0234] R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;
  • [0235] R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0236] R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0237] R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0238] R¹² is hydrogen or lower alkyl; and
  • [0239] R¹⁵ is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.

[0240] In one embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi- or tri-cyclic; and R⁹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl.

[0241] In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is halogen or lower alkyl; R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; R⁴ is —(CH₂)—, R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi- or tri-cyclic.

[0242] In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is a phenyl having 3 to 5 substituents.

[0243] In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is a pyridyl having 3 to 5 substituents.

[0244] In another embodiment of the compounds of Formula II, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.

[0245] It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.

[0246] Other embodiment of the compounds of the invention are the compounds, or polymorphs, solvates, esters, tautomers, pharmaceutically acceptable salts or prodrugs thereof, prepared by the process comprising:

• • [0247] reacting a compound of Formula Y and a compound of a Formula Z, wherein:
  • [0248] Y is represented by any of the following formulae:

[0249]

• • [0250] Z is L¹-R⁴—R⁵; wherein:
    • [0251] L¹ is halogen, NR⁸R¹⁰ triflate, tosylate, or mesylate;
    • [0252] R⁴ is —(CHR¹²)—, —C(O), —C(S), —S(O)—, or —SO₂—;
    • [0253] R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
      • [0254] the aryl group is substituted with 3 to 5 substituents,
      • [0255] the heteroaryl group is substituted with 2 to 5 substituents,
      • [0256] the alicyclic group is substituted with 3 to 5 substituents,
      • [0257] the heterocyclic group is substituted with 3 to 5 substituents, and
      • [0258] the substituents on R⁵ are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazoyl, wherein R⁸ and R¹⁰ taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0259] R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R⁹;
  • [0260] R⁹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
  • [0261] R¹⁰ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0262] R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
  • [0263] R¹² is hydrogen or lower alkyl;
  • [0264] R²¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;
  • [0265] R²² is —NR⁸R¹⁰;
  • [0266] R²³ is hydrogen, —OH or its keto tautomer, —OR⁸, halogen, —CN, lower alkyl, lower aryl or —C(O)R⁹;
  • [0267] R²⁴ is —CHO, —NH₂, —NO₂ or —NO;
  • [0268] R²⁵ is halogen or —OH;
  • [0269] R²⁶ is —C(O)NH₂ or C(O)OEt; and
  • [0270] R²⁷ is —NH₂, —OH or halogen.

[0271] In one embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, optionally mono- or bicyclic.

[0272] In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, L¹ is —Cl, —Br or —NH₂; R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl.

[0273] In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Y is a pyrazolopyrimidine.

[0274] In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt of prodrug thereof, said reaction is performed in a solvent comprising a member selected from the group of DMF, THF and DMSO.

[0275] In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt of prodrug thereof, said reaction is performed in a solvent that comprises DMF.

[0276] It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.

[0277] Illustrative species of the compounds of the invention that are based on Formula I, where R²=—NH₂ are described in TABLE 1. Prodrugs which can be employed by those compounds include, but are not limited to, those listed in the Definition section.

[0278]

TABLE 1
Exemplary Compounds of Formula I, R2 is = NH2
No.	Ex	R1	R3	R4	R5
1	5	Cl	H	CH2	3,4,5-Trimethoxyphenyl
2	6	Cl	H	CH2	2-Chloro-3,4,5-trimethoxyphenyl
3		Cl	H	CH2	2-Bromo-3,4,5-trimethoxyphenyl
4		Cl	H	CH2	2-Iodo-3,4,5-trimethoxyphenyl
5		Cl	H	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
6		Cl	H	CH2	3,4,5-Trimethylphenyl
7		Cl	H	CH2	2-Chloro-3,4,5-trimethylphenyl
8		Cl	H	CH2	2-Bromo-3,4,5-trimethylphenyl
9		Cl	H	CH2	2-Iodo-3,4,5-trimethylphenyl
10		Cl	H	CH2	2-Fluoro-3,4,5-trimethylphenyl
11		Cl	H	CH2	3,5-Dimethoxy-4-methylphenyl
12		Cl	H	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
13		Cl	H	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
14		Cl	H	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
15		Cl	H	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
16		Cl	i-pr	CH2	3,4,5-Trimethoxyphenyl
17		Cl	i-pr	CH2	2-Chloro-3,4,5-trimethoxyphenyl
18		Cl	i-pr	CH2	2-Bromo-3,4,5-trimethoxyphenyl
19		Cl	i-pr	CH2	2-Iodo-3,4,5-trimethoxyphenyl
20		Cl	i-pr	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
21		Cl	i-pr	CH2	3,4,5-Trimethyiphenyl
22		Cl	i-pr	CH2	2-Chloro-3,4,5-trimethylphenyl
23		Cl	i-pr	CH2	2-Bromo-3,4,5-trimethylphenyl
24		Cl	i-pr	CH2	2-Iodo-3,4,5-trimethylphenyl
25		Cl	i-pr	CH2	2-Fluoro-3,4,5-trimethylphenyl
26		Cl	i-pr	CH2	3,5-Dimethoxy-4-methylphenyl
27		Cl	i-pr	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
28		Cl	i-pr	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
29		Cl	i-pr	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
30		Cl	i-pr	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
31		Cl	Et	CH2	3,4,5-Trimethoxyphenyl
32		Cl	Et	CH2	2-Chloro-3,4,5-trimethoxyphenyl
33		Cl	Et	CH2	2-Bromo-3,4,5-trimethoxyphenyl
34		Cl	Et	CH2	2-Iodo-3,4,5-trimethoxyphenyl
35		Cl	Et	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
36		Cl	Et	CH2	3,4,5-Trimethylphenyl
37		Cl	Et	CH2	2-Chloro-3,4,5-trimethylphenyl
38		Cl	Et	CH2	2-Bromo-3,4,5-trimethylphenyl
39		Cl	Et	CH2	2-Iodo-3,4,5-trimethylphenyl
40		Cl	Et	CH2	2-Fluoro-3,4,5-trimethylphenyl
41		Cl	Et	CH2	3,5-Dimethoxy-4-methylphenyl
42		Cl	Et	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
43		Cl	Et	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
44		Cl	Et	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
45		Cl	Et	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
46	27	Cl	Me	CH2	3,4,5-Trimethoxyphenyl
47		Cl	Me	CH2	2-Chloro-3,4,5-trimethoxyphenyl
48		Cl	Me	CH2	2-Bromo-3,4,5-trimethoxyphenyl
49		Cl	Me	CH2	2-Iodo-3,4,5-trimethoxyphenyl
50		Cl	Me	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
51		Cl	Me	CH2	3,4,5-Trimethylphenyl
52		Cl	Me	CH2	2-Chloro-3,4,5-trimethylphenyl
53		Cl	Me	CH2	2-Bromo-3,4,5-trimethylphenyl
54		Cl	Me	CH2	2-Iodo-3,4,5-trimethylphenyl
55		Cl	Me	CH2	2-Fluoro-3,4,5-trimethylphenyl
56		Cl	Me	CH2	3,5-Dimethoxy-4-methylphenyl
57		Cl	Me	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
58		Cl	Me	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
59		Cl	Me	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
60		Cl	Me	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
61		Cl	Ph	CH2	3,4,5-Trimethoxyphenyl
62		Cl	Ph	CH2	2-Chloro-3,4,5-trimethoxyphenyl
63		Cl	Ph	CH2	2-Bromo-3,4,5-trimethoxyphenyl
64		Cl	Ph	CH2	2-Iodo-3,4,5-trimethoxyphenyl
65		Cl	Ph	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
66		Cl	Ph	CH2	3,4,5-Trimethylphenyl
67		Cl	Ph	CH2	2-Chloro-3,4,5-trimethylphenyl
68		Cl	Ph	CH2	2-Bromo-3,4,5-trimethylphenyl
69		Cl	Ph	CH2	2-Iodo-3,4,5-trimethylphenyl
70		Cl	Ph	CH2	2-Fluoro-3,4,5-trimethylphenyl
71		Cl	Ph	CH2	3,5-Dimethoxy-4-methylphenyl
72		Cl	Ph	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
73		Cl	Ph	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
74		Cl	Ph	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
75		Cl	Ph	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
76		Cl	2-Py	CH2	3,4,5-Trimethoxyphenyl
77		Cl	2-Py	CH2	2-Chloro-3,4,5-trimethoxyphenyl
78		Cl	2-Py	CH2	2-Bromo-3,4,5-trimethoxyphenyl
79		Cl	2-Py	CH2	2-Iodo-3,4,5-trimethoxyphenyl
80		Cl	2-Py	CH2	2-Fluoro-3,4,5 -trimethoxyphenyl
81		Cl	2-Py	CH2	3,4,5-Trimethylphenyl
82		Cl	2-Py	CH2	2-Chloro-3,4,5-trimethylphenyl
83		Cl	2-Py	CH2	2-Bromo-3,4,5-trimethylphenyl
84		Cl	2-Py	CH2	2-Iodo-3,4,5-trimethylphenyl
85		Cl	2-Py	CH2	2-Fluoro-3,4,5-trimethylphenyl
86		Cl	2-Py	CH2	3,5-Dimethoxy-4-methylphenyl
87		Cl	2-Py	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
88		Cl	2-Py	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
89		Cl	2-Py	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
90		Cl	2-Py	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
91		Cl	Me	CH2	3,4,5-Trimethoxyphenyl
92		Cl	Me	CH2	2-Chloro-3,4,5-trimethoxyphenyl
93		Cl	Me	CH2	2-Bromo-3,4,5-trimethoxyphenyl
94		Cl	Me	CH2	2-Iodo-3,4,5-trimethoxyphenyl
95		Cl	Me	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
96		Cl	Ph	CH2	3,4,5-Trimethylphenyl
97		Cl	Ph	CH2	2-Chloro-3,4,5-trimethylphenyl
98		Cl	Ph	CH2	2-Bromo-3,4,5-trimethylphenyl
99		Cl	Ph	CH2	2-Iodo-3,4,5-trimethylphenyl
100		Cl	Ph	CH2	2-Fluoro-3,4,5-trimethylphenyl
101		Cl	Ph	CH2	3,5-Dimethoxy-4-methylphenyl
102		Cl	Ph	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
103		Cl	Ph	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
104		Cl	Ph	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
105		Cl	Pr	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
106		Cl	Pr	CH2	3,5-Dimethoxy-4-methylphenyl
107		Cl	Pr	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
108		Cl	Pr	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
109		Cl	Pr	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
110		Cl	Pr	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
111		Cl	Pr	CH2	3,4,5-Trimethoxyphenyl
112		Cl	Pr	CH2	2-Chloro-3,4,5-trimethoxyphenyl
113		Cl	Pr	CH2	2-Bromo-3,4,5-trimethoxyphenyl
114		Cl	Pr	CH2	2-Iodo-3,4,5-trimethoxyphenyl
115		Cl	Pr	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
116		Cl	Pr	CH2	3,4,5-Trimethylphenyl
117		Cl	Pr	CH2	2-Chloro-3,4,5-trimethylphenyl
118		Cl	Pr	CH2	2-Bromo-3,4,5-trimethylphenyl
119		Cl	Pr	CH2	2-Iodo-3,4,5-trimethylphenyl
120		Cl	Pr	CH2	2-Fluoro-3,4,5-trimethylphenyl
121		Cl	Pr	CH2	3,5-Dimethoxy-4-methylphenyl
122		Cl	Pr	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
123		Cl	Pr	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
124		Cl	Pr	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
125		Cl	Pr	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
126		Br	H	CH2	3,4,5-Trimethoxyphenyl
127		Br	H	CH2	2-Chloro-3,4,5-trimethoxyphenyl
128		Br	H	CH2	2-Bromo-3,4,5-trimethoxyphenyl
129		Br	H	CH2	2-Iodo-3,4,5-trimethoxyphenyl
130		Br	H	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
131		Br	H	CH2	3,4,5-Trimethylphenyl
132		Br	H	CH2	2-Chloro-3,4,5-trimethylphenyl
133		Br	H	CH2	2-Bromo-3,4,5-trimethylphenyl
134		Br	H	CH2	2-Iodo-3,4,5-trimethylphenyl
135		Br	H	CH2	2-Fluoro-3,4,5-trimethylphenyl
136		Br	H	CH2	3,5-Dimethoxy-4-methylphenyl
137		Br	H	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
138		Br	H	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
139		Br	H	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
140		Br	H	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
141		Cl	i-Bu	CH2	3,4,5-Trimethoxyphenyl
142		Cl	i-Bu	CH2	2-Chloro-3,4,5-trimethoxyphenyl
143		Cl	i-Bu	CH2	2-Bromo-3,4,5-trimethoxyphenyl
144		Cl	i-Bu	CH2	2-Iodo-3,4,5-trimethoxyphenyl
145		Cl	i-Bu	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
146		Cl	i-Bu	CH2	3,4,5-Trimethylphenyl
147		Cl	i-Bu	CH2	2-Chloro-3,4,5-trimethylphenyl
148		Cl	i-Bu	CH2	2-Bromo-3,4,5-trimethylphenyl
149		Cl	i-Bu	CH2	2-Iodo-3,4,5-trimethylphenyl
150		Cl	i-Bu	CH2	2-Fluoro-3,4,5-trimethylphenyl
151		Cl	i-Bu	CH2	3,5-Dimethoxy-4-methylphenyl
152		Cl	i-Bu	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
153		Cl	i-Bu	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
154		Cl	i-Bu	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
155		Cl	i-Bu	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
156		Cl	CN	CH2	3,4,5-Trimethoxyphenyl
157		Cl	CN	CH2	2-Chloro-3,4,5-trimethoxyphenyl
158		Cl	CN	CH2	2-Bromo-3,4,5-trimethoxyphenyl
159		Cl	CN	CH2	2-Iodo-3,4,5-trimethoxyphenyl
160		Cl	CN	CH2	3,4,5-Trimethoxyphenyl
161		Cl	CN	CH2	2-Chloro-3,4,5-trimethoxyphenyl
162		Cl	CN	CH2	2-Bromo-3,4,5-trimethoxyphenyl
163		Cl	CN	CH2	2-Iodo-3,4,5-trimethoxyphenyl
164		Cl	CN	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
165		Cl	CN	CH2	3,4,5-Trimethylphenyl
166		Cl	CN	CH2	2-Chloro-3,4,5-trimethylphenyl
167		Cl	CN	CH2	2-Bromo-3,4,5-trimethylphenyl
168		Cl	CN	CH2	2-Iodo-3,4,5-trimethylphenyl
169		Cl	CN	CH2	2-Fluoro-3,4,5-trimethylphenyl
170		Cl	CN	CH2	3,5-Dimethoxy-4-methylphenyl
171		Cl	CN	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
172		Cl	CN	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
173		Cl	CN	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
174		Cl	CN	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
175		Cl	Cl	CH2	3,4,5-Trimethoxyphenyl
176		Cl	Cl	CH2	2-Chloro-3,4,5-trimethoxyphenyl
177		Cl	Cl	CH2	2-Bromo-3,4,5-trimethoxyphenyl
178		Cl	Cl	CH2	2-Iodo-3,4,5-trimethoxyphenyl
179		Cl	Cl	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
180		Cl	Cl	CH2	3,4,5-Trimethylphenyl
181		Cl	Cl	CH2	2-Chloro-3,4,5-trimethylphenyl
182		Cl	Cl	CH2	2-Bromo-3,4,5-trimethylphenyl
183		Cl	Cl	CH2	2-Iodo-3,4,5-trimethylphenyl
184		Cl	Cl	CH2	2-Fluoro-3,4,5-trimethylphenyl
185		Cl	Cl	CH2	3,5-Dimethoxy-4-methylphenyl
186		Cl	Cl	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
187		Cl	Cl	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
188		Cl	Cl	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
189		Cl	Cl	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
190		Cl	Br	CH2	3,4,5-Trimethoxyphenyl
191		Cl	Br	CH2	2-Chloro-3,4,5-trimethoxyphenyl
192		Cl	Br	CH2	2-Bromo-3,4,5-trimethoxyphenyl
193		Cl	Br	CH2	2-Iodo-3,4,5-trimethoxyphenyl
194		Cl	Br	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
195		Cl	Br	CH2	3,4,5-Trimethylphenyl
196		Cl	Br	CH2	2-Chloro-3,4,5-trimethylphenyl
197		Cl	Br	CH2	2-Bromo-3,4,5-trimethylphenyl
198		Cl	Br	CH2	2-Iodo-3,4,5-trimethylphenyl
199		Cl	Br	CH2	2-Fluoro-3,4,5-trimethylphenyl
200		Cl	Br	CH2	3,5-Dimethoxy-4-methylphenyl
201		Cl	Br	CH2	2-Chloro-3 ,5-dimethoxy-4-methylphenyl
202		Cl	Br	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
203		Cl	Br	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
204		Cl	Br	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
205		Cl	I	CH2	3,4,5-Trimethoxyphenyl
206		Cl	I	CH2	2-Chloro-3,4,5-trimethoxyphenyl
207		Cl	I	CH2	2-Bromo-3,4,5-trimethoxyphenyl
208		Cl	I	CH2	2-Iodo-3,4,5-trimethoxyphenyl
209		Cl	I	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
210		Cl	I	CH2	3,4,5-Trimethylphenyl
211		Cl	I	CH2	2-Chloro-3,4,5-trimethylphenyl
212		Cl	I	CH2	2-Bromo-3,4,5-trimethylphenyl
213		Cl	I	CH2	2-Iodo-3,4,5-trimethylphenyl
214		Cl	I	CH2	2-Fluoro-3,4,5-trimethylphenyl
215		Cl	I	CH2	3,5-Dimethoxy-4-methylphenyl
216		Cl	I	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
217		Cl	I	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
218		Cl	I	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
219		Cl	I	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
220		Cl	CH2—NMe2	CH2	3,4,5-Trimethoxyphenyl
221		Cl	CH2—NMe2	CH2	2-Chloro-3,4,5-trimethoxyphenyl
222		Cl	CH2—NMe2	CH2	2-Bromo-3,4,5-trimethoxyphenyl
223		Cl	CH2—NMe2	CH2	2-Iodo-3,4,5-trimethoxyphenyl
224		Cl	CH2—NMe2	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
225		Cl	CH2—NMe2	CH2	3,4,5-Trimethylphenyl
226		Cl	CH2—NMe2	CH2	2-Chloro-3,4,5-trimethylphenyl
227		Cl	CH2—NMe2	CH2	2-Bromo-3,4,5-trimethyiphenyl
228		Cl	CH2—NMe2	CH2	2-Iodo-3,4,5-trimethylphenyl
229		Cl	CH2—NMe2	CH2	2-Fluoro-3,4,5-trimethylphenyl
230		Cl	CH2—NMe2	CH2	3,5-Dimethoxy-4-methylphenyl
231		Cl	CH2—NMe2	CH2	2-Chloro-3,5-dimethoxy-4-methylphenyl
232		Cl	CH2—NMe2	CH2	2-Bromo-3,5-dimethoxy-4-methylphenyl
233		Cl	CH2—NMe2	CH2	2-Iodo-3,5-dimethoxy-4-methylphenyl
234		Cl	CH2—NMe2	CH2	2-Fluoro-3,5-dimethoxy-4-methylphenyl
235		Cl	3-Py	CH2	3,4,5-Trimethoxyphenyl
236		Cl	3-Py	CH2	2-Chloro-3,4,5-trimethoxyphenyl
237		Cl	3-Py	CH2	2-Bromo-3,4,5-trimethoxyphenyl
238		Cl	3-Py	CH2	2-Iodo-3,4,5-trimethoxyphenyl
239		Cl	3-Py	CH2	2-Fluoro-3,4,5-trimethoxyphenyl
240	7	Cl	H	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
241	10	Cl	H	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
242		Cl	H	CH2	6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl
243	8	Cl	H	CH2	6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl
244	14	Cl	H	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
245	15	Cl	H	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
246	9	Cl	H	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
247		Cl	H	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
248		Cl	H	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
249		Cl	H	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
250		Cl	H	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
251		Cl	H	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
252		Cl	H	CH2	3,4,5-Trimethyl-pyridin-2-yl
253		Cl	H	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
254		Cl	H	CH2	4,5,6-Trimethoxypyridin-2-yl
255		Cl	H	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
256		Cl	H	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
257		Cl	H	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
258		Cl	H	CH2	3,4,5-Trimethoxy-pyridin-2-yl
259		Cl	H	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
260		Cl	H	CH2	3-Bromo-3,4,5-trimethoxy-pyridin-2-yl
261		Cl	H	CH2	3-Chloro-3,4,5-trimethoxy-pyridin-2-yl
262		Cl	H	CH2	4,5,6-Trimethyl-pyridin-2-yl
263		Cl	H	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
264		Cl	H	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
265		Cl	H	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
266		Cl	H	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
267		Cl	H	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
268		Cl	H	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
269		Cl	H	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
270		Cl	H	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
271		Cl	H	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
272		Cl	H	CH2	2,6-Dimethyl-pyridin-4-yl
273		Cl	H	CH2	2,3,6-Trimethyl-pyridin-4-yl
274		Cl	H	CH2	2,3,6-Trimethoxy-pyridin-4-yl
275		Cl	H	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
276		Cl	H	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
277		Cl	H	CH2	2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl
278		Cl	H	CH2	2,6-Dimethyl-1-oxy-pyridin-4-yl
279		Cl	H	CH2	2,3,6-Trimethyl-1-oxy-pyridin-4-yl
280		Cl	H	CH2	2,3,6-Trimethoxy-1-oxy-pyridin-4-yl
281		Cl	H	CH2	2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl
282		Cl	H	CH2	2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl
283		Cl	H	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
284		Cl	H	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
285	31	Cl	i-pr	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
286		Cl	i-pr	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
287		Cl	i-pr	CH2	6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl
288		Cl	i-pr	CH2	6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl
289		Cl	i-pr	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
290		Cl	i-pr	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
291		Cl	i-pr	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
292		Cl	i-pr	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
293		Cl	i-pr	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
294		Cl	i-pr	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
295		Cl	i-pr	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
296		Cl	i-pr	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
297		Cl	i-pr	CH2	3,4,5-Trimethyl-pyridin-2-yl
298		Cl	i-pr	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
299		Cl	i-pr	CH2	4,5,6-Trimethoxypyridin-2-yl
300		Cl	i-pr	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
301		Cl	i-pr	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
302		Cl	i-pr	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
303		Cl	i-pr	CH2	3,4,5-Trimethoxy-pyridin-2-yl
304		Cl	i-pr	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
305		Cl	i-pr	CH2	3-Bromo-3,4,5-trimethoxy-pyridin-2-yl
306		Cl	i-pr	CH2	3-Chloro-3,4,5-trimethoxy-pyridin-2-yl
307		Cl	i-pr	CH2	4,5,6-Trimethyl-pyridin-2-yl
308		Cl	i-pr	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
309		Cl	i-pr	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
310		Cl	i-pr	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
311		Cl	i-pr	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
312		Cl	i-pr	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
313		Cl	i-pr	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
314		Cl	i-pr	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
315		Cl	i-pr	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
316		Cl	i-pr	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
317		Cl	i-pr	CH2	2,6-Dimethyl-pyridin-4-yl
318		Cl	i-pr	CH2	2,3,6-Trimethyl-pyridin-4-yl
319		Cl	i-pr	CH2	2,3,6-Trimethoxy-pyridin-4-yl
320		Cl	i-pr	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
321		Cl	i-pr	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
322		Cl	i-pr	CH2	2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl
323		Cl	i-pr	CH2	2,6-Dimethyl-1-oxy-pyridin-4-yl
324		Cl	i-pr	CH2	2,3,6-Trimethyl-1-oxy-pyridin-4-yl
325		Cl	i-pr	CH2	2,3 ,6-Trimethoxy-1-oxy-pyridin-4-yl
326		Cl	i-pr	CH2	2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl
327		Cl	i-pr	CH2	2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl
328		Cl	i-pr	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
329		Cl	i-pr	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
330	23	Cl	Me	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
331		Cl	Me	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
332	28	Cl	Me	CH2	3,5-Dimethyl-4-bromopyridin-2-yI
333	24	Cl	Me	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
334	26	Cl	Me	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
335	25	Cl	Me	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
336		Cl	Me	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
337		Cl	Me	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
338		Cl	Me	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
339		Cl	Me	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
340		Cl	Me	CH2	3,4,5-Trimethyl-pyridin-2-yl
341		Cl	Me	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
342		Cl	Me	CH2	4,5,6-Trimethoxypyridin-2-yl
343		Cl	Me	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
344		Cl	Me	CH2	3,4,5-Trimethoxy-pyridin-2-yl
345		Cl	Me	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
346		Cl	Me	CH2	4,5,6-Trimethyl-pyridin-2-yl
347		Cl	Me	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
348		Cl	Me	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
349		Cl	Me	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
350		Cl	Me	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
351		Cl	Me	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
352		Cl	Me	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
353		Cl	Me	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
354		Cl	Me	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
355		Cl	Me	CH2	2,6-Dimethyl-3 -methoxypyridin-4-yl
356		Cl	Me	CH2	2,6-Dimethyl-pyridin-4-yl
357		Cl	Me	CH2	2,3,6-Trimethyl-pyridin-4-yl
358		Cl	Me	CH2	2,3,6-Trimethoxy-pyridin-4-yl
359		Cl	Me	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
360		Cl	Me	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
361		Cl	Me	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
362		Cl	Me	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
363	29	Cl	Et	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
364		Cl	Et	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
365		Cl	Et	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
366		Cl	Et	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
367	30	Cl	Et	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
368		Cl	Et	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
369		Cl	Et	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
370		Cl	Et	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
371		Cl	Et	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
372		Cl	Et	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
373		Cl	Et	CH2	3,4,5-Trimethyl-pyridin-2-yl
374		Cl	Et	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
375		Cl	Et	CH2	4,5,6-Trimethoxypyridin-2-yl
376		Cl	Et	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
377		Cl	Et	CH2	3,4,5-Trimethoxy-pyridin-2-yl
378		Cl	Et	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
379		Cl	Et	CH2	4,5,6-Trimethyl-pyridin-2-yl
380		Cl	Et	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
381		Cl	Et	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
382		Cl	Et	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
383		Cl	Et	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
384		Cl	Et	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
385		Cl	Et	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
386		Cl	Et	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
387		Cl	Et	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
388		Cl	Et	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
389		Cl	Et	CH2	2,6-Dimethyl-pyridin-4-yl
390		Cl	Et	CH2	2,3,6-Trimethyl-pyridin-4-yl
391		Cl	Et	CH2	2,3,6-Trimethoxy-pyridin-4-yl
392		Cl	Et	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
393		Cl	Et	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
394		Cl	Et	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
395		Cl	Et	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
396		Cl	2-Py	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
397		Cl	2-Py	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
398		Cl	2-Py	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
399		Cl	2-Py	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
400		Cl	2-Py	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
401		Cl	2-Py	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
402		Cl	2-Py	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
403		Cl	2-Py	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
404		Cl	2-Py	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
405		Cl	2-Py	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
406		Cl	2-Py	CH2	3,4,5-Trimethyl-pyridin-2-yl
407		Cl	2-Py	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
408		Cl	2-Py	CH2	4,5,6-Trimethoxypyridin-2-yl
409		Cl	2-Py	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
410		Cl	2-Py	CH2	3,4,5-Trimethoxy-pyridin-2-yl
411		Cl	2-Py	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
412		Cl	2-Py	CH2	4,5,6-Trimethyl-pyridin-2-yl
413		Cl	2-Py	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
414		Cl	2-Py	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
415		Cl	2-Py	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
416		Cl	2-Py	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
417		Cl	2-Py	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
418		Cl	2-Py	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
419		Cl	2-Py	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
420		Cl	2-Py	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
421		Cl	2-Py	CH2	2,6-Dimethyl-3 -methoxypyridin-4-yl
422		Cl	2-Py	CH2	2,6-Dimethyl-pyridin-4-yl
423		Cl	2-Py	CH2	2,3,6-Trimethyl-pyridin-4-yl
424		Cl	2-Py	CH2	2,3,6-Trimethoxy-pyridin-4-yl
425		Cl	2-Py	CH2	2,6-Dimethyl-3 -bromopyridin-4-yl
426		Cl	2-Py	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
427		Cl	2-Py	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
428		Cl	2-Py	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
429	32	Cl	Ph	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
430		Cl	Ph	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
431	34	Cl	Ph	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
432		Cl	Ph	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
433	33	Cl	Ph	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
434	35	Cl	Ph	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
435		Cl	Ph	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
436		Cl	Ph	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
437		Cl	Ph	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
438		Cl	Ph	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
439		Cl	Ph	CH2	3,4,5-Trimethyl-pyridin-2-yl
440		Cl	Ph	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
441		Cl	Ph	CH2	4,5,6-Trimethoxypyridin-2-yl
442		Cl	Ph	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
443		Cl	Ph	CH2	3,4,5-Trimethoxy-pyridin-2-yl
444		Cl	Ph	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
445		Cl	Ph	CH2	4,5,6-Trimethyl-pyridin-2-yl
446		Cl	Ph	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
447		Cl	Ph	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
448		Cl	Ph	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
449		Cl	Ph	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
450		Cl	Ph	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
451		Cl	Ph	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
452		Cl	Ph	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
453		Cl	Ph	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
454		Cl	Ph	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
455		Cl	Ph	CH2	2,6-Dimethyl-pyridin-4-yl
456		Cl	Ph	CH2	2,3,6-Trimethyl-pyridin-4-yl
457		Cl	Ph	CH2	2,3,6-Trimethoxy-pyridin-4-yl
458		Cl	Ph	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
459		Cl	Ph	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
460		Cl	Ph	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
461		Cl	Ph	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
462		Cl	3-Py	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
463		Cl	3-Py	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
464		Cl	3-Py	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
465		Cl	3-Py	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
466		Cl	3-Py	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
467		Cl	3-Py	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
468		Cl	3-Py	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
469		Cl	3-Py	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
470		Cl	3-Py	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
471		Cl	3-Py	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
472		Cl	3-Py	CH2	3,4,5-Trimethyl-pyridin-2-yl
473		Cl	3-Py	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
474		Cl	3-Py	CH2	4,5,6-Trimethoxypyridin-2-yl
475		Cl	3-Py	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
476		Cl	3-Py	CH2	3,4,5-Trimethoxy-pyridin-2-yl
477		Cl	3-Py	CH2	3,4,5-Tnmethoxy-1-oxypyridin-2-yl
478		Cl	3-Py	CH2	4,5,6-Trimethyl-pyridin-2-yl
479		Cl	3-Py	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
480		Cl	3-Py	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
481		Cl	3-Py	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
482		Cl	3-Py	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
483		Cl	3-Py	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
484		Cl	3-Py	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
485		Cl	3-Py	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
486		Cl	3-Py	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
487		Cl	3-Py	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
488		Cl	3-Py	CH2	2,6-Dimethyl-pyridin-4-yl
489		Cl	3-Py	CH2	2,3,6-Trimethyl-pyridin-4-yl
490		Cl	3-Py	CH2	2,3,6-Trimethoxy-pyridin-4-yl
491		Cl	3-Py	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
492		Cl	3-Py	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
493		Cl	3-Py	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
494		Cl	3-Py	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
495		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
496		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
497		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
498		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
499		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
500		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
501		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
502		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
503		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
504		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
505		Cl	CH2—NMe2	CH2	3,4,5-Trimethyl-pyridin-2-yl
506		Cl	CH2—NMe2	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
507		Cl	CH2—NMe2	CH2	4,5,6-Trimethoxypyridin-2-yl
508		Cl	CH2—NMe2	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
509		Cl	CH2—NMe2	CH2	3,4,5-Trimethoxy-pyridin-2-yl
510		Cl	CH2—NMe2	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
511		Cl	CH2—NMe2	CH2	4,5,6-Trimethyl-pyridin-2-yl
512		Cl	CH2—NMe2	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
513		Cl	CH2—NMe2	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
514		Cl	CH2—NMe2	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
515		Cl	CH2—NMe2	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
516		Cl	CH2—NMe2	CH2	4,6-Dimethyl-5-bromopyridin-3-yI
517		Cl	CH2—NMe2	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
518		Cl	CH2—NMe2	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
519		Cl	CH2—NMe2	CH2	5 ,6-Dimethyl-4-chloropyridin-3-yl
520		Cl	CH2—NMe2	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
521		Cl	CH2—NMe2	CH2	2,6-Dimethyl-pyridin-4-yl
522		Cl	CH2—NMe2	CH2	2,3,6-Trimethyl-pyridin-4-yl
523		Cl	CH2—NMe2	CH2	2,3,6-Trimethoxy-pyridin-4-yl
524		Cl	CH2—NMe2	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
525		Cl	CH2—NMe2	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
526		Cl	CH2—NMe2	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
527		Cl	CH2—NMe2	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
528		Cl	2-furanyl	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
529		Cl	2-furanyl	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
530		Cl	2-furanyl	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
531		Cl	2-furanyl	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
532		Cl	2-furanyl	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
533		Cl	2-furanyl	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
534		Cl	2-furanyl	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
536		Cl	2-furanyl	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
537		Cl	2-furanyl	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
538		Cl	2-furanyl	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
539		Cl	2-furanyl	CH2	3,4,5-Trimethyl-pyridin-2-yl
540		Cl	2-furanyl	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
541		Cl	2-furanyl	CH2	4,5,6-Triinethoxypyridin-2-yl
542		Cl	2-furanyl	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
543		Cl	2-furanyl	CH2	3,4,5-Trimethoxy-pyridin-2-yl
544		Cl	2-furanyl	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
545		Cl	2-furanyl	CH2	4,5,6-Trimethyl-pyridin-2-yl
546		Cl	2-furanyl	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
547		Cl	2-furanyl	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
548		Cl	2-furanyl	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
549		Cl	2-furanyl	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
550		Cl	2-furanyl	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
551		Cl	2-furanyl	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
552		Cl	2-furanyl	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
553		Cl	2-furanyl	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
554		Cl	2-furanyl	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
555		Cl	2-furanyl	CH2	2,6-Dimethyl-pyridin-4-yl
556		Cl	2-furanyl	CH2	2,3,6-Trimethyl-pyridin-4-yl
557		Cl	2-furanyl	CH2	2,3,6-Trimethoxy-pyridin-4-yl
558		Cl	2-furanyl	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
559		Cl	2-furanyl	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
560		Cl	2-furanyl	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
561		Cl	Cl	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
562		Cl	Cl	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
563		Cl	Cl	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
564		Cl	Cl	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
565		Cl	Cl	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
566		Cl	Cl	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
567		Cl	Cl	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
568		Cl	Cl	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
569		Cl	Cl	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
570		Cl	Cl	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
571		Cl	Cl	CH2	3,4,5-Trimethyl-pyridin-2-yl
572		Cl	Cl	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
573		Cl	Cl	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
574		Cl	Cl	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
575		Cl	Cl	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
576		Cl	Br	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
577		Cl	Br	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
578		Cl	Br	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
579		Br	Br	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
580		Cl	Br	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
581		Br	Br	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
582		Cl	Br	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
583		Br	Br	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
584		Cl	Br	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
585		Br	Br	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
586		Cl	Br	CH2	3,4,5-Trimethyl-pyridin-2-yl
587		Br	Br	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
588		Cl	Br	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
589		Cl	Br	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
590		Cl	Br	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
591		Cl	I	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
592		Cl	I	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
593		Cl	I	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
594		Cl	I	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
595		Cl	I	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
596		Cl	I	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
597		Cl	I	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
598		Cl	I	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
599		Cl	I	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
600		Cl	I	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
601		Cl	I	CH2	3,4,5-Trimethyl-pyridin-2-yl
602		Cl	I	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
603		Cl	I	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
604		Cl	I	CH2	4,6-Dimethyl-5-methoxy-l-oxypyridin-3-yI
605		Cl	I	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
606		Cl	CN	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
607		Cl	CN	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
608		Cl	CN	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
609		Cl	CN	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
610		Cl	CN	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
611		Cl	CN	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
612		Cl	CN	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
613		Cl	CN	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
614		Cl	CN	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
615		Cl	CN	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
616		Cl	CN	CH2	3,4,5-Trimethyl-pyridin-2-yl
617		Cl	CN	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
618		Cl	CN	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
619		Cl	CN	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
620		Cl	CN	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
621		Cl	H	C(O)	3,5-Dimethyl-4-methoxypyridin-2-yl
622		Cl	H	C(O)	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
623		Cl	H	C(O)	3,5-Dimethyl-4-bromopyridin-2-yl
624		Cl	H	C(O)	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
625		Cl	H	C(O)	3,5-Dimethyl-4-chloropyridin-2-yl
626		Cl	H	C(O)	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
627		Cl	H	C(O)	3,5-Dimethyl-4-iodopyridin-2-yl
628		Cl	H	C(O)	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
629		Cl	H	C(O)	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
630		Cl	H	C(O)	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
631		Cl	H	C(O)	3,4,5-Trimethyl-pyridin-2-yl
632		Cl	H	C(O)	3,4,5-Trimethyl-1-oxypyridin-2-yl
633		Cl	H	C(O)	4,6-Dimethyl-5-methoxypyridin-3-yl
634		Cl	H	C(O)	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
635		Cl	H	C(O)	3,5-Dimethyl-4-aminopyridin-2-yl
636		Cl	H	S(O)	3,5-Dimethyl-4-methoxypyridin-2-yl
637		Cl	H	S(O)	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
638		Cl	H	S(O)	3,5-Dimethyl-4-bromopyridin-2-yl
639		Cl	H	S(O)	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
640		Cl	H	S(O)	3,5-Dimethyl-4-chloropyridin-2-yl
641		Cl	H	S(O)	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
642		Cl	H	S(O)	3,5-Dimethyl-4-iodopyridin-2-yl
643		Cl	H	S(O)	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
644		Cl	H	S(O)	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
645		Cl	H	S(O)	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
646		Cl	Br	S(O)	3,4,5-Trimethyl-pyridin-2-yl
647		Cl	H	S(O)	3,4,5-Trimethyl-1-oxypyridin-2-yl
648		Cl	Br	S(O)	4,6-Dimethyl-5-methoxypyridin-3-yl
649		Cl	H	S(O)	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
650		Cl	H	SO2	3,5-Dimethyl-4-methoxypyridin-2-yl
651		Cl	H	SO2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
652		Cl	H	SO2	3,5-Dimethyl-4-bromopyridin-2-yl
653		Cl	H	SO2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
654		Cl	Br	SO2	3,5-Dimethyl-4-chloropyridin-2-yl
655		Cl	H	SO2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
656		Cl	H	SO2	3,5-Dimethyl-4-iodopyridin-2-yl
657		Cl	H	SO2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
658		Cl	H	SO2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
659		Cl	H	SO2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
660		Cl	H	SO2	3,4,5-Trimethyl-pyridin-2-yl
661		Cl	H	SO2	3,4,5-Trimethyl-1-oxypyridin-2-yl
662		Cl	H	SO2	4,6-Dimethyl-5-methoxypyridin-3-yl
663		Cl	H	SO2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
664		Cl	i-pr	C(O)	3,5-Dimethyl-4-methoxypyridin-2-yI
665		Cl	i-pr	C(O)	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
666		Cl	i-pr	C(O)	3,5-Dimethyl-4-bromopyridin-2-yl
667		Cl	i-pr	C(O)	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
668		Cl	i-pr	C(O)	3,5-Dimethyl-4-chloropyridin-2-yl
669		Cl	i-pr	C(O)	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
670		Cl	i-pr	C(O)	3,5-Dimethyl-4-iodopyridin-2-yl
671		Cl	i-pr	C(O)	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
672		Cl	i-pr	C(O)	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
673		Cl	i-pr	C(O)	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
674		Cl	i-pr	C(O)	3,4,5-Trimethyl-pyridin-2-yl
675		Cl	i-pr	C(O)	3,4,5-Trimethyl-1-oxypyridin-2-yl
676		Cl	i-pr	C(O)	4,6-Dimethyl-5-methoxypyridin-3-yl
677		Cl	i-pr	C(O)	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
678		Cl	i-pr	C(O)	3,5-Dimethyl-4-aminopyridin-2-yl
679		Cl	i-pr	S(O)	3,5-Dimethyl-4-methoxypyridin-2-yl
680		Cl	i-pr	S(O)	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
681		Cl	i-pr	S(O)	3,5-Dimethyl-4-bromopyridin-2-yl
682		Cl	i-pr	S(O)	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
683		Cl	i-pr	S(O)	3,5-Dimethyl-4-chloropyridin-2-yl
684		Cl	i-pr	S(O)	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
685		Cl	i-pr	S(O)	3,5-Dimethyl-4-iodopyridin-2-yl
686		Cl	i-pr	S(O)	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
687		Cl	i-pr	S(O)	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
688		Cl	i-pr	S(O)	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
689		Cl	i-pr	S(O)	3,4,5-Trimethyl-pyridin-2-yl
690		Cl	i-pr	S(O)	3,4,5-Trimethyl-1-oxypyridin-2-yl
691		Cl	i-pr	S(O)	4,6-Dimethyl-5-methoxypyridin-3-yl
692		Cl	i-pr	S(O)	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
693		Cl	i-pr	SO2	3,5-Dimethyl-4-methoxypyridin-2-yl
694		Cl	i-pr	SO2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
695		Cl	i-pr	SO2	3,5-Dimethyl-4-bromopyridin-2-yl
696		Cl	i-pr	SO2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
697		Cl	i-pr	SO2	3,5-Dimethyl-4-chloropyridin-2-yl
698		Cl	i-pr	SO2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
699		Cl	i-pr	SO2	3,5-Dimethyl-4-iodopyridin-2-yl
700		Cl	i-pr	SO2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
701		Cl	i-pr	SO2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
702		Cl	i-pr	SO2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
703		Cl	i-pr	SO2	3,4,5-Trimethyl-pyridin-2-yl
704		Cl	i-pr	SO2	3,4,5-Trimethyl-1-oxypyridin-2-yl
705		Cl	i-pr	SO2	4,6-Dimethyl-5-methoxypyridin-3-yl
706		Cl	i-pr	SO2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
707		Cl	H	C(O)	3,4,5-Trimethoxyphenyl
708		Cl	H	C(O)	2-Chloro-3,4,5-trimethoxyphenyl
709		Cl	H	C(O)	2-Bromo-3,4,5-trimethoxyphenyl
710		Cl	H	C(O)	3,5-Dimethyl-4-methoxyphenyl
711		Cl	H	C(O)	2-Chloro-3,5-Dimethyl-4-methoxyphenyl
712		Cl	H	C(O)	2-Bromo-3,5-Dimethyl-4-methoxyphenyl
713		Cl	H	SO2	3,4,5-Trimethoxyphenyl
714		Cl	H	SO2	2-Chloro-3,4,5-trimethoxyphenyl
715		Cl	H	SO2	2-Bromo-3,4,5-trimethoxyphenyl
716		Cl	H	SO2	3,5-Dimethyl-4-methoxyphenyl
717		Cl	H	SO2	2-Chloro-3,5-Dimethyl-4-methoxyphenyl
718		Cl	H	SO2	2-Bromo-3,5-Dimethyl-4-methoxyphenyl
719		Br	H	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
720		Br	H	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
721		Br	H	CH2	6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl
722		Br	H	CH2	6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl
723		Br	H	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
724		Br	H	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
725		Br	H	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
726		Br	H	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
727		Br	H	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
728		Br	H	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
729		Br	H	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
730		Br	H	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
731		Br	H	CH2	3,4,5-Trimethyl-pyridin-2-yl
732		Br	H	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
733		Br	H	CH2	4,5,6-Trimethoxypyridin-2-yl
734		Br	H	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
735		Br	H	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
736		Br	H	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
737		Br	H	CH2	3,4,5-Trimethoxy-pyridin-2-yl
738		Br	H	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
739		Br	H	CH2	3-Bromo-3,4,5-trimethoxy-pyridin-2-yl
740		Br	H	CH2	3-Chloro-3,4,5-trimethoxy-pyridin-2-yl
741		Br	H	CH2	4,5,6-Trimethyl-pyridin-2-yl
742		Br	H	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
743		Br	H	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
744		Br	H	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
745		Br	H	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
746		Br	H	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
747		Br	H	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
748		Br	H	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
749		Br	H	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
750		Br	H	CH2	2,6-Dimethyl-3-methoxypyridin-4-yl
751		Br	H	CH2	2,6-Dimethyl-pyridin-4-yl
752		Br	H	CH2	2,3,6-Trimethyl-pyridin-4-yl
753		Br	H	CH2	2,3,6-Trimethoxy-pyridin-4-yl
754		Br	H	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
755		Br	H	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
756		Br	H	CH2	2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl
757		Br	H	CH2	2,6-Dimethyl-1-oxy-pyridin-4-yl
758		Br	H	CH2	2,3,6-Trimethyl-1-oxy-pyridin-4-yl
759		Br	H	CH2	2,3,6-Trimethoxy-1-oxy-pyridin-4-yl
760		Br	H	CH2	2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl
761		Br	H	CH2	2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl
762		Br	H	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
763		Br	H	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
764		Br	i-pr	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
765		Br	i-pr	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
766		Br	i-pr	CH2	6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl
767		Br	i-pr	CH2	6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl
768		Br	i-pr	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
769		Br	i-pr	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
770		Br	i-pr	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
771		Br	i-pr	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
772		Br	i-pr	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
773		Br	i-pr	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
774		Br	i-pr	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
775		Br	i-pr	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yI
776		Br	i-pr	CH2	3,4,5-Trimethyl-pyridin-2-yl
777		Br	i-pr	CH2	3,4,5-Trimethyl-1-oxypyridin-2-yl
778		Br	i-pr	CH2	4,5,6-Trimethoxypyridin-2-yl
779		Br	i-pr	CH2	4,5,6-Trimethoxy-1-oxypyridin-2-yl
780		Br	i-pr	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
781		Br	i-pr	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
782		Br	i-pr	CH2	3,4,5-Trimethoxy-pyridin-2-yl
783		Br	i-pr	CH2	3,4,5-Trimethoxy-1-oxypyridin-2-yl
784		Br	i-pr	CH2	3-Bromo-3,4,5-trimethoxy-pyridin-2-yl
785		Br	i-pr	CH2	3-Chloro-3,4,5-trimethoxy-pyridin-2-yl
786		Br	i-pr	CH2	4,5,6-Trimethyl-pyridin-2-yl
787		Br	i-pr	CH2	4,5,6-Trimethyl-1-oxypyridin-2-yl
788		Br	i-pr	CH2	4,6-Dimethyl-5-methoxy-pyridin-2-yl
789		Br	i-pr	CH2	4,6-Dimethyl-5 -methoxypyridin-3 -yl
790		Br	i-pr	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
791		Br	i-pr	CH2	4,6-Dimethyl-5-bromopyridin-3-yl
792		Br	i-pr	CH2	4,6-Dimethyl-5-chloropyridin-3-yl
793		Br	i-pr	CH2	5,6-Dimethyl-4-bromopyridin-3-yl
794		Br	i-pr	CH2	5,6-Dimethyl-4-chloropyridin-3-yl
795		Br	i-pr	CH2	2,6-Dimethyl-3 -methoxypyridin-4-yl
796		Br	i-pr	CH2	2,6-Dimethyl-pyridin-4-yl
797		Br	i-pr	CH2	2,3,6-Trimethyl-pyridin-4-yl
798		Br	i-pr	CH2	2,3,6-Trimethoxy-pyridin-4-yl
799		Br	i-pr	CH2	2,6-Dimethyl-3-bromopyridin-4-yl
800		Br	i-pr	CH2	2,6-Dimethyl-3-chloropyridin-4-yl
801		Br	i-pr	CH2	2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl
802		Br	i-pr	CH2	2,6-Dimethyl-1-oxy-pyridin-4-yl
803		Br	i-pr	CH2	2,3,6-Trimethyl-1-oxy-pyridin-4-yl
804		Br	i-pr	CH2	2,3,6-Trimethoxy-1-oxy-pyridin-4-yl
805		Br	i-pr	CH2	2,6-Dimethyl-3-bromol-oxy-pyridin-4-yl
806		Br	i-pr	CH2	2,6-Dimethyl-3-chlorol-oxy-pyridin-4-yl
807		Br	i-pr	CH2	4,6-Dimethyl-5-iodopyridin-3-yl
808		Br	i-pr	CH2	3,5-Dimethyl-4-aminopyridin-2-yl
809		Br	Ph	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
810		Br	Ph	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
811		Br	Ph	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
812		Br	Ph	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
813		Br	Ph	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
814		Br	Ph	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
815		Br	Ph	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
816		Br	Ph	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
817		Br	Ph	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
818		Br	Ph	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
819		Br	Ph	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
820		Br	Ph	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
821		Br	Ph	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
822		Br	Ph	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
823		Br	Et	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
824		Br	Et	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
825		Br	Et	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
826		Br	Et	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
827		Br	Et	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
828		Br	Et	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
829		Br	Et	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
830		Br	Et	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
831		Br	Et	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
832		Br	Et	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
833		Br	Et	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
834		Br	Et	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
835		Br	Et	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
836		Br	Et	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
837		Br	Me	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
838		Br	Me	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
839		Br	Me	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
840		Br	Me	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
841		Br	Me	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
842		Br	Me	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
843		Br	Me	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
844		Br	Me	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
845		Br	Me	CH2	3,5-Dimethyl-4-thiomethyl-pyridin-2-yl
846		Br	Me	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
847		Br	Me	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
848		Br	Me	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
849		Br	Me	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
850		Br	Me	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
851		Br	2-Py	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
852		Br	2-Py	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
853		Br	2-Py	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
854		Br	2-Py	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
855		Br	2-Py	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
856		Br	2-Py	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
857		Br	2-Py	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
858		Br	2-Py	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
859		Br	2-Py	CH2	3 ,5-Dimethyl-4-thiomethyl-pyridin-2-yl
860		Br	2-Py	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
861		Br	2-Py	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
862		Br	2-Py	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
863		Br	2-Py	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
864		Br	2-Py	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl
865		Br	3-Py	CH2	3,5-Dimethyl-4-methoxypyridin-2-yl
866		Br	3-Py	CH2	3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl
867		Br	3-Py	CH2	3,5-Dimethyl-4-bromopyridin-2-yl
868		Br	3-Py	CH2	3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl
869		Br	3-Py	CH2	3,5-Dimethyl-4-chloropyridin-2-yl
870		Br	3-Py	CH2	3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl
871		Br	3-Py	CH2	3,5-Dimethyl-4-iodopyridin-2-yl
872		Br	3-Py	CH2	3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl
873		Br	3-Py	CH2	3 ,5-Dimethyl-4-thiomethyl-pyridin-2-yl
874		Br	3-Py	CH2	3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl
875		Br	3-Py	CH2	3-Bromo-4,5,6-trimethoxypyridin-2-yl
876		Br	3-Py	CH2	3-Chloro-4,5,6-trimethoxypyridin-2-yl
877		Br	3-Py	CH2	4,6-Dimethyl-5-methoxypyridin-3-yl
878		Br	3-Py	CH2	4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl

Compounds of interest in Table 1 are 1, 2, 3 16, 17, 18, 27, 28, 47, 48, 62, 63, 77, 78, 92, 93, 97, 98, 129, 130, 242, 243, 245, 246, 247, 248, 249, 250, 251, 252, 253, 267, 268, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 312, 313, 332, 333, 334, 335, 336, 337, 338, 339, 351, 352, 365, 366, 367, 368, 369, 370, 384, 385, 398, 399, 400, 401, 417, 418, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 450, 451, 464, 465, 466, 466, 467, 468, 469, 470, 471, 483, 484, 497, 498, 530, 531, 550, 551, 563, 564, 575, 576, 578, 579, 590, 591, 593, 594, 605, 606, 608, 609, 610, 621, 721, 722, 725, 726, 727, 728, 729, 730, 746, 747, 766, 767, 791, 792, 811, 812, 823, 824, 825, 826, 839, 840, 853, 854, 867, and 868, with the selected being 242, 243, 245, 246, 247, 248, 267, 268, 287, 288, 312, 313, 332, 333, 334, 335, 336, 337, 338, 339, 365, 369, 398, 417, 431, 432, 433, 434, 435, 436, 437, 438, 450, 451, 464, 465, 483, and 484.