Inventor(s):
`
`Attorney Docket No.: 064507-5014 US
`
`PATENT APPLICATION
`
`BORON-CONTAINING SMALL MOLECULES
`
`Stephen J. Baker, a citizen of the United Kingdom, residing at
`1568 Begen Avenue, Mountain View, CA 94040
`Tsutomu Akama, a citizen of Japan, residing at
`832 Azure St, Sunnyvale, CA 94087
`Carolyn Bellinger-Kawahara, a citizen of the USA, residing at
`15 Landa Lane, Redwood City, CA 94061
`Vincent S. Hernandez, a citizen of the USA, residing at
`287 Gilchrist Ln, Watsonville, CA 95076
`Karin M. Hold, a citizen of the USA, residing at
`1908 Valdez Ave, Belmont, CA 94002
`James J Leyden, a citizen of the USA, residing at
`319 Applebrook Drive, Malvern, PA 193 5 5
`Kirk Maples, a citizen of the USA, residing at
`1195 San Moritz Drive, San Jose, CA 95132
`Jacob Plattner, a citizen of the USA, residing at
`1016 Arnita Ave., Berkeley, CA 94705
`Virginia Sanders, a citizen of the USA, residing at
`2895 Harrison St, Apt 4, San Francisco, CA 94110
`Yong-Kang Zhang, a citizen of the United States, residing at
`5151 WestmontAvenue, SanJose,CA 95130
`
`Assignee:
`
`Anacor Pharmaceuticals
`1060 East Meadow Circle
`Palo Alto, CA 94303-4230
`
`Entity:
`
`Small
`
`Todd Esker
`Reg. No. 46,690
`
`MORGAN
`LEWIS AND
`BOCKTUS
`LLP
`
`Correspondence
`Address:
`
`One Market
`Spear Street Tower
`San Francisco
`California 94105
`Tel 415 442-1000
`Fax 415 442-1001
`
`AS FILED WITH THE USPTO ON FEBRUARY 16, 2006
`
`CF AD Exhibit 1010
`
`

`
`Attorney Docket No.: 064507-5014US
`
`PATENT
`
`BORON-CONTAINING SMALL MOLECULES
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`(0001) · The present application is related to U.S. Provisional Patent Application
`
`601654,060 filed February 16, 2005, which is incorporated by reference in its entirety
`
`for all purposes.
`
`BACKGROUND FOR THE INVENTION
`
`(0002]
`
`Infections of the nail and hoof, known as ungual and/or periungual
`
`infections, pose serious problems in dermatology. These ungual and/or periungual
`
`can be caused by sources such as fungi, viruses, yeast, bacteria and parasites.
`
`Onychomycosis is an example of these serious ungual and/or periungual infections
`
`and is caused by at least one fungus. Current treatment for ungual and/or periungual
`
`infections generally falls into three categories: systemic administration of medicine;
`
`surgical removal of all or part of the nail or hoof followed by topical treatment of the
`
`exposed tissue; or topical application of conventional creams, lotions, gels or
`
`solutions, frequently including the use of bandages to keep these dosage forms in
`
`place on the nail or hoof. All of these approaches have major drawbacks. The
`
`following discussion is particularly directed to drawbacks associated with current
`
`treatment ofungual and/or periungual antifungal infections.
`
`[0003]
`
`Long term systemic (oral) administration of an antifungal agent for the
`
`treatment of onychomycosis is often required to produce a therapeutic effect in the
`
`nail bed. For example, oral treatment with the antifungal compound ketoconozole
`
`typically requires administration of200 to 400 mg/day for 6 months before any
`
`significant therapeutic benefit is realized. Such long term, high dose systemic therapy
`
`can have significant adverse effects. For example, ketoconozole has been reported to
`
`have liver toxicity effects and reduces testosterone levels in blood due to adverse
`
`effects on the testes. Patient compliance is a problem with such long term therapies
`
`especially those which involve serious adverse effects. Moreover, this type of long
`
`term oral therapy is inconvenient in the treatment of a horse or other ruminants
`
`afflicted with fungal infections of the hoof. Accordingly, the risks associated with
`
`

`
`parenteral treatments generate significant disincentive against their use and
`
`considerable patient non-compliance.
`
`{0004]
`
`Surgical removal of all or part of the nail followed by topical treatment
`
`also has severe drawbacks. The pain and discomfort associated with the surgery and
`
`the undesirable cosmetic appearance of the nail or nail bed represent significant
`
`problems, particularly for female patients or those more sensitive to physical
`
`appearance. Generally, this type of treatment is not realistic for ruminants such as
`horses.
`
`[0005)
`
`Topical therapy has significant problems too. Topical dosage forms such
`
`as creams, lotions, gels etc., can not keep the drug in intimate contact with the
`
`infected area for therapeutically effective periods of time. Bandages have been used
`
`to hold drug reservoirs in place in an attempt to enhance absorption of the
`
`pharmaceutical agent. However the bandages are thick, awkward, troublesome and
`
`generally lead to poor patient compliance.
`
`[0006]
`
`Hydrophilic and hydrophobic film forming topical antifungal solutions
`
`have also been developed. These dosage forms provide improved contact between the
`
`drug and the nail, but the films are not occlusive. Topical formulations for fungal
`
`infection treatment have largely tried to deliver the drug to the target site (an infected
`
`nail bed) by diffusion across or through the nail.
`
`[0007)
`
`Nail is more like hair than stratum comeum with respect to chemical
`composition and permeability. Nitrogen is the major component of the nail attesting
`
`to the nail's proteinaceous nature. The total lipid content of mature nail is 0.1-1.0%,
`
`while the stratum comeum lipid is about 10% w/w. The nail is 100-200 times thicker
`
`than the stratum com~um and has a very high affinity and capacity for binding and
`
`retaining antifungal drugs. Consequently little if any drug penetrates through the nail
`
`to reach the target site. Because of these reasons topical therapy for fungal infections
`
`have generally been ineffective.
`
`[0008)
`
`Compounds known as penetration or permeation enhancers are well
`
`known in the art to produce an increase in the permeability of skin or other body
`
`membranes to a pharmacologically active agent. The increased permeability allows an
`
`increase in the rate at which the drug permeates through the skin and enters the blood
`stream. Penetration enhancers have been successful in overcoming the
`
`2
`
`

`
`impermeability of pharmaceutical agents through the skin. However, the thin stratum
`
`comeum layer of the skin, which is about 10 to 15 cells thick and is formed naturally
`
`by cells migrating toward the skin surface from the basal layer, has been easier to
`
`penetrate than nails. Moreover, known penetration enhancers have not proven to be
`
`useful in facilitating drug migration through the nail tissue.
`
`[0009]
`
`Antimicrobial compositions for controlling bacterial and fungal infections
`
`comprising a metal chelate of 8-hydroxyquinoline and an alkyl benzene sulfonic acid
`
`have been shown to be efficacious due to the increased ability of the oleophilic group
`
`to penetrate the lipoid layers of micro-cells. The compounds however, do not
`
`effectively increase the ability to carry the pharmaceutically active antifungal through
`
`the comified layer or stratum corneum of the skin. U.S. Pat. No. 4,602,011, West et
`
`al., Jul. 22, 1986; U.S. Pat. No. 4,766,113, West et al., Aug. 23, 1988.
`
`[0010)
`
`Therefore, there is a need in the art for compounds which can effectively
`
`penetrate the nail. There is also need in the art for compounds which can effectively
`
`treat ungual and/or periungual infections. These and other needs are addressed by the
`
`current invention.
`
`SUMMARY OF THE INVENTION
`
`[0011]
`
`In a first aspect, the invention provides a compound having a structure
`
`according to Formula I:
`
`(I)
`
`wherein Bis boron. R 13 is a member selected from a negative charge, a salt
`counterion, H, substituted or unsubstituted alkyl, substituted or unsubstituted
`
`heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
`
`heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`• R23 is a member
`heteroaryl. Ml is a member selected from oxygen, sulfur and NR23
`selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted
`
`heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
`
`3
`
`

`
`heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`, and R5a are
`, R43
`heteroaryl. JI is a member selected from (CR3aR43)n 1 and CR5a. R33
`members independently selected from H, OH, NH2, SH, substituted or unsubstituted
`alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
`
`substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and
`
`substituted or unsubstituted heteroaryl. The index nl is an integer selected from 0 to
`a, R 73
`2. WI is a member selected from C=O (carbonyl), (CR6aR73
`)ml and CR8a. R6
`and R8
`a are members independently selected from H, OH, NH2, SH, substituted or
`unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
`
`,
`
`unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
`
`unsubstituted aryl, and substituted or unsubstituted heteroaryl. The index m 1 is an
`integer selected from 0 and 1. Al is a member selected from CR93 and N. Dl is a
`member selected from CR10
`
`a and N. El is a member selected from CR1 la and N. Gl
`is a member selected from CR123 and N. R9a, R10a, R 113 and R128 are members
`independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl,
`
`substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
`
`substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and
`substituted or unsubstituted heteroaryl. The combination of nitrogens (A 1 + D 1 + E 1
`+ G 1) is an integer selected from 0 to 3. A member selected from R3
`a, R43 and R53
`and a member selected from R6a, R 73 and R83
`, together with the atoms to which they
`are attached, are optionally joined to form a 4 to 7 membered ring. R33 and R48
`,
`together with the atoms to which they are attached, are optionally joined to form a 4
`to 7 membered ring. R68 and R78
`, together with the atoms to which they are attached,
`are optionally joined to form a 4 to 7 membered ring. R93 and R 10a, together with the
`atoms to which they are attached, are optionally joined to form a 4 to 7 membered
`
`
`ring. R 10a and R118, together with the atoms to which they are attached, are optionally
`
`which they are attached, are optionally joined to form a 4 to 7 membered ring. The
`
`joined to form a 4 to 7 membered ring. R 118 and R 128, together with the atoms to
`
`aspect has the proviso that when Ml is oxygen, WI is a member selected from
`(CR33R43)n1, wherein nl is 0, JI is a member selected from (CR68R78)mi, wherein ml is
`I, Al is CR98
`
`
`, DI is CR103, El is CR118, GI is CR123
`, then R98 is not halogen, methyl,
`ethyl, or optionally joined with R ioa to a form phenyl ring; R !Oa is not unsubstituted
`phenoxy, C(CH3) 3, halogen, CF3, methoxy, ethoxy, or optionally joined with R98 to
`form a phenyl ring; R 118 is not halogen or optionally joined with R toa to form a phenyl
`
`4
`
`

`
`ring; and R12a is not halogen. The aspect has the further proviso that when Ml is
`oxygen, Wl is a member selected from (CR3aR4a)n 1, wherein nl is 0, Jl is a member
`selected from (CR6aR7a)mi, wherein ml is 1, Al is CR9a, Dl is CR103, El is CR11 a, Gl
`is CR12a, then neither R6a nor R7a are halophenyl. The aspect has the further proviso
`that when Ml is oxygen, Wl is a member selected from (CR3aR4jni, wherein nl is 0,
`Jl is a member selected from (CR6aR7a)m1, wherein ml is 1, Al is CR93, DI is CR103,
`El is CR113, Gl is CR123, and R9a, R1oa and R 113 are H, then R63, R7a and R 123 are not
`H. The aspect has the further proviso that when Ml is oxygen wherein nl is I, 11 is a
`member selected from (CR6aR73)mi, wherein ml is 0, Al is CR93, DI is CR103, El is
`CR113, G 1 is CR123, R93 is H, R.103 is H, R1 la is H, R63 is H, R73 is H, R12a is H, then Wl
`is not C=O (carbonyl). The aspect has the further proviso that when Ml is oxygen,
`Wl is CR53, Jl is CR83, Al is CR93, DI is CR103, El is CR113, Gl is CR123, R63, R73,
`R93, R 103, R 113 and R 123 are H, then R58 and R83, together with the atoms to which they
`are attached, do not form a phenyl ring.
`
`(0012]
`
`In a second aspect, the invention provides a pharmaceutical formulation
`
`comprising (a) a pharmaceutically acceptable excipient; and (b) a compound having a
`
`structure according to Formula II:
`
`(II)
`
`wherein B is boron. R lb is a member selected from a negative charge, a salt
`
`counterion, H, substituted or unsubstituted alkyl, substituted or unsubstituted
`
`heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
`
`heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`heteroaryl. M2 is a member selected from oxygen, sulfur and NR2
`b. R2
`selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted
`
`b is a member
`
`heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
`
`heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted
`heteroaryl. J2 is a member selected from (CR3bR41)n2 and CR5b. R3b, R4b, and R5b are
`members independently selected from H, OH, NH2, SH, substituted or unsubstituted
`
`5
`
`

`
`alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
`
`substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and
`
`substituted or unsubstituted heteroaryl. The index n2 is an integer selected from 0 to
`b, R7
`2. W2 is a member selected from C=O (carbonyl), (CR6bR7b)m2 and CR8
`b. R6
`
`b,
`
`and R Sb are members independently selected from H, OH, NH2, SH, substituted or
`unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
`
`unsubstituted aryl, and substituted or unsubstituted heteroaryl. The index m2 is an
`integer selected from 0 and 1. A2 is a member selected from CR9b and N. D2 is a
`
`member selected from CR10
`b and N. E2 is a member selected from CR11
`b and N. G2
`b and R12
`is a member selected from CR12
`b and N. R9b, R 10b, R 11
`b are members
`independently selected from H, OH, NH2, SH, substituted or unsubstituted alkyl,
`substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
`
`b
`
`b,
`
`substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and
`substituted or unsubstituted heteroaryl. The combination of nitrogens (A2 + D2 + E2
`b, R4
`+ G2) is an integer selected from 0 to 3. A member selected from R3
`b and R5
`
`
`h, R7b and R 8h, together with the atoms to which they
`and a member selected from R6
`are attached, are optionally joined to form a 4 to 7 membered ring. R3
`b and R4
`together with the atoms to which they are attached, are optionally joined to form a 4
`to 7 membered ring. R6
`b and R7
`b, together with the atoms to which they are attached,
`are optionally joined to form a 4 to 7 membered ring. R9
`b and R 10
`atoms to which they are attached, are optionally joined to form a 4 to 7 membered
`ring. R 10
`b and R11
`h, together with the atoms to which they are attached, are optionally
`
`joined to form a 4 to 7 membered ring. R 11 b and R 12
`which they are attached, are optionally joined to form a 4 to 7 membered ring.
`
`b, together with the
`
`b, together with the atoms to
`
`(0013)
`
`In anothe~ aspect, the invention provides a method of killing a
`microorganism, comprising contacting the microorganism with a therpeutically
`
`effective amount of a compound of the invention.
`
`(0014)
`
`In another aspect, the invention provides a method of inhibiting
`
`microorganism growth, comprising contacting the microorganism with a
`
`therpeutically effective amount ofa compound of the invention.
`
`6
`
`

`
`[0015)
`
`In another aspect, the invention provides a method of treating an infection
`
`in an animal, comprising administering to the animal a therpeutically effective amount
`
`ofa compound of the invention.
`
`[0016)
`
`In another aspect, the invention provides a method of preventing an
`
`infection in an animal, comprising administering to the animal a therpeutically
`
`effective amount of a compound of the invention.
`
`[0017]
`
`In another aspect, the invention provides a method of treating a systemic
`
`infection or an ungual or periungual infection in a human, comprising administering
`
`to the animal a therpeutically effective amount of a compound of the invention.
`
`[0018)
`
`In another aspect, the invention provides a method of treating
`
`onychomycosis in a human, comprising administering to the animal a therpeutically
`
`effective amount of a compound of the invention.
`
`(0019)
`
`In another aspect, the invention provides a method of synthesizing a
`
`compound of the invention.
`
`[0020)
`
`In another aspect, the invention provides a method of delivering a
`
`compound from the dorsal layer of the nail plate to the nail bed. The method
`
`comprises contacting said cell with a compound capable of penetrating the nail plate,
`
`under conditions sufficient to penetrate said nail plate, and thereby delivering the
`
`compound. The compound has a molecular weight of between about 100 and about
`
`200 Da. The compound also has a log P value of between about 1.0 and about 2.6.
`
`The compound has a water solubility between about 0.1 mg/mL and 1.0 g/mL
`
`octanol/saturated water.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0021)
`
`FIG. 1 is a table of minimum inhibitory concentration (MIC) data ofCBO
`
`against various fungi.
`
`(0022)
`
`FIG. 2A displays minimum inhibitory concentration (MIC) for CIO,
`
`ciclopirox, terbinafine, fluconazole and itraconazole (comparator drugs) against 19
`
`test strains of fungi.
`
`7
`
`

`
`(0023)
`
`FIG. 2B displays minimum fungicidal concentration (MFC) for ClO,
`
`ciclopirox, terbinafine and itraconazole (comparator drugs) against 2 test strains of
`
`fungi.
`
`(0024)
`
`FIG. 3 displays a comparison of Normalized ClO and Ciclopirox
`
`Equivalent in Each Part ofNail Plate Samples after 14-day Treatment.
`
`[0025)
`
`FIG. 4 displays a comparison of ClO and Ciclopirox Equivalent in Cotton
`
`Ball Supporting Bed Samples after 14-day Treatment.
`
`[0026]
`
`FIG. 5 displays the results of a placebo for ClO (50:50 propylene glycol
`
`and ethyl acetate) applied per day over five days. Full carpet growth of the organism
`
`T. rubrum was observed.
`
`[0027]
`
`FIG. 6 displays the results ofa 40 µL/cm 2 aliquot of ClO I 0% w/v
`solution applied per day over five days. Zones of inhibition (in the order of the cells
`
`shown in the figure) of 100%, 67%, 46%, 57%, 38% and 71 % were observed for the
`
`growth of T. rubrum. Green arrow indicates the measurement of zone of inhibition.
`
`FIG. 7 displays the results of a 40 µL/cm2 aliquot of ClO l 0% w/v
`[0028)
`solution applied per day over five days. Zones of inhibition (in the order of the cells
`
`shown in the figure) of74%, 86%, 100%, 82%, 100% and 84% were observed for the
`
`growth of T. rubrum.
`
`[0029)
`
`FIG. 8 displays the results of a 40 µL/cm 2 aliquot of 8% ciclopirox in w/w
`commercial lacquer applied per day over five days. No zone of inhibition observed;
`
`full carpet growth of T. rubrum.
`
`[0030)
`
`FIG. 9 displays the results of a 40 µL/cm 2 aliquot of 5% arnorolfine w/v in
`commercial lacquer applied per day over five days. No zone of inhibition observed;
`
`full carpet growth of T. rubrum.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`I. Definitions and Abbreviations
`
`[0031] The abbreviations used herein generally have their conventional meaning
`
`within the chemical and biological arts.
`
`[0032)
`
`"Compound of the invention," as used herein refers to the compounds
`
`discussed herein, pharmaceutically acceptable salts and prodrugs of these compounds.
`
`8
`
`

`
`[0033} MIC, or minimum inhibitory concentration, is the point where compound
`
`stops more than 90% of cell growth relative to an untreated control.
`
`(0034} Where substituent groups are specified by their conventional chemical
`
`formulae, written from left to right, they equally encompass the chemically identical
`
`substituents, which would result from writing the structure from right to left, e.g.,
`-CH20- is intended to also recite -OCH2-.
`
`(0035) The term "poly" as used herein means at least 2. For example, a polyvalent
`
`metal ion is a metal ion having a valency of at least 2.
`
`(0036}
`
`"Moiety" refers to the radical of a molecule that is attached to another
`
`moiety.
`
`(0037] The symbol .JVV'V' , whether utilized as a bond or displayed perpendicular to
`
`a bond, indicates the point at which the displayed moiety is attached to the remainder
`
`of the molecule.
`
`(0038) The term "alkyl," by itself or as part of another substituent, means, unless
`
`otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or
`
`combination thereof, which may be fully saturated, mono- or polyunsaturated and can
`
`include di- and multivalent radicals, having the number of carbon atoms designated
`(i.e. C 1-C 10 means one to ten carbons). Examples of saturated hydrocarbon radicals
`include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n(cid:173)
`
`butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,
`
`cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n(cid:173)
`
`heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more
`
`double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are
`not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-
`
`pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the
`
`higher homologs and isomers. The term "alkyl," unless otherwise noted, is also
`
`meant to include those derivatives of alkyl defined in more detail below, such as
`
`"heteroalkyl." Alkyl groups that are limited to hydrocarbon groups are termed
`"homoalkyl".
`
`[0039] The term "alkylene" by itself or as part of another substituent means a
`
`divalent radical derived from an alkane, as exemplified, but not limited, by -
`
`9
`
`

`
`CH2CH2CH2CH2-, and further includes those groups described below as
`"heteroalkylene." Typically, an alkyl (or alkylene) group will have from 1 to 24
`
`carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in
`
`the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or
`
`alkylene group, generally having eight or fewer carbon atoms.
`
`[0040) The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in
`
`their conventional sense, and refer to those alkyl groups attached to the remainder of
`
`the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
`
`[0041) The term "heteroalkyl," by itself or in combination with another term,
`
`means, unless otherwise stated, a stable straight or branched chain, or cyclic
`
`hydrocarbon radical, or combinations thereof, consisting of the stated number of
`carbon atoms and at leruit one heteroatom. In an exemplary embodiment, the
`
`heteroatoms can be selected from the group consisting ofB, 0, N and S, and wherein
`
`the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom
`
`may optionally be quaternized. The heteroatom(s) B, 0, N and Smay be placed at
`
`any interior position of the heteroalkyl group or at the position at which the alkyl
`
`group is attached to the remainder of the molecule. Examples include, but are not
`limited to, -CHi-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CHi-N(CH3)-CH3, -CH2-S(cid:173)
`CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CHi-S(0)2-CH3, -CH=CH-O-CH3, -CH2-
`CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be
`consecutive, such as, for example, -CHi-NH-OCH3. Similarly, the term
`"heteroalkylene" by itself or as part of another substituent means a divalent radical
`derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CHi-CH2-
`and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also
`
`occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,
`
`alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and
`
`heteroalkylene linking groups, no orientation of the linking group is implied by the
`
`direction in which the formula of the linking group is written. For example, the
`formula-C(0)2R'- represents both-C(O)iR'- and-R'C(0)2-.
`
`[0042) The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in
`
`combination with other terms, represent, unless otherwise stated, cyclic versions of
`"alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a
`
`10
`
`

`
`heteroatom can occupy the position at which the heterocycle is attached to the
`
`remainder of the molecule. Examples of cycloalkyl include, but are not limited to,
`
`cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
`
`Examples of heterocycloalkyl include, but are not limited to, 1 -{1,2,5,6-
`
`tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-
`
`morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
`
`tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
`
`[0043) The terms "halo" or "halogen," by themselves or as part of another
`
`substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine
`
`atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl
`and polyhaloalkyl. For example, the term "halo(C 1-C4)alkyl" is mean to include, but
`not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,
`and the like.
`
`{0044) The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic,
`
`substituent that can be a single ring or multiple rings (preferably from I to 3 rings),
`
`which are fused together or linked covalently. The term "heteroaryl" refers to aryl
`
`groups (or rings) that contain from one to four heteroatoms. In an exemplary
`
`embodiment, the heteroatom is selected from B, N, 0, and S, wherein the nitrogen
`
`and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally
`
`quatemized. A heteroaryl group can be attached to the remainder of the molecule
`
`through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include
`
`phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-
`pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-
`
`oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,
`
`5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
`pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-
`
`isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
`
`Substituents for each of the above noted aryl and heteroaryl ring systems are selected
`
`from the group of acceptable substituents described below.
`
`(0045) For brevity, the term "aryl" when used in combination with other terms (e.g.,
`
`aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined
`
`above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl
`
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`

`
`group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the
`
`like) including those alkyl groups in which a carbon atom (e.g., a methylene group)
`
`has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-
`
`pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
`
`[0046) Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and
`
`"heteroaryl") are meant to include both substituted and unsubstituted forms of the
`
`indicated radical. Preferred substituents for each type of radical are provided below.
`
`[0047} Substituents for the alkyl and heteroalkyl radicals (including those groups
`
`often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl,
`
`cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generically
`
`referred to as "alkyl group substituents," and they can be one or more of a variety of
`
`groups selected from, but not limited to: -OR', =O, =NR', =N-OR', -NR'R", -SR', -
`halogen, -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R',
`-NR'-C(O)NR"R"', -NR"C(0)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR'R")=NR'",
`-S(O)R', -S(O)iR', -S(0)2NR'R", -NRS02R', -CN and -N02 in a number ranging
`from zero to (2m'+ 1), where m' is the total number of carbon atoms in such radical.
`R', R", R'" and R"" each preferably independently refer to hydrogen, substituted or
`unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with
`1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or
`
`arylalkyl groups. When a compound of the invention includes more than one R
`
`group, for example, each of the R groups is independently selected as are each R', R'',
`
`R"' and R"" groups when more than one of these groups is present. When R' and R"
`
`are attached to the same nitrogen atom, they can be combined with the nitrogen atom
`
`to form a 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but
`
`not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of
`
`substituents, one of skill in the art will understand that the term "alkyl" is meant to
`
`include groups including carbon atoms bound to groups other than hydrogen groups,
`such as haloalkyl (e.g., -CF3 and-CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -
`C(O)CH20CH3, and the like).
`
`[0048) Similar to the substituents described for the alkyl radical, substituents for the
`
`aryl and heteroaryl groups are generically referred to as "aryl group substituents."
`
`The substituents are selected from, for example: halogen, -OR', =O, =NR', =N-OR', -
`
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`
`

`
`NR'R", -SR', -halogen, -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R'', -
`NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(0)2R', -NR-C(NR'R"R"')=NR"",
`-NR-C(NR'R")=NR"', -S(O)R', -S(O)zR', -S(O)iNR'R", -NRS02R', -CN and -N02,
`-R', -N3, -CH(Ph)2, fluoro(C 1-C4)alkoxy, and fluoro(C 1-C4)alkyl, in a number ranging
`from zero to the total number of open valences on the aromatic ring system; and
`
`where R', R", R'" and R"" are preferably independently selected from hydrogen,
`
`substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted
`
`or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound
`
`of the invention includes more than one R group, for example, each of the R groups is
`
`independently selected as are each R', R'', R"' and R"" groups when more than one of
`
`these groups is present.
`
`[0049) Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may
`
`optionally be replaced with a substituent of the formula-T-C(O)-(CRR')q-U-,
`
`wherein T and U are independently-NR-, -0-, -CRR'- or a single bond, and q is an
`
`integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the
`
`aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -
`
`A-(CH2),-B-, wherein A and B are independently -CRR' -, -0-, -NR-, -S-, -S(O)-,
`-S(0)2-, -S(0)2NR' - or a single bond, and r is an integer of from 1 to 4. One of the
`single bonds of the new ring so formed may optionally be replaced with a double
`
`bond. Alternatively, two of the substituents on adjacent atoms of the aryl or
`
`heteroaryl ring may optionally be replaced with a substituent of the formula(cid:173)
`
`(CRR')s-X-(CR"R"')d-, wheres and dare independently integers of from 0 to 3, and
`Xis -0-, -NR'-, -S-, -S(O)-, -S(0)2-, or -S(0)2NR' -. The substituents R, R', R" and
`R'" are preferably independently selected from hydrogen or substituted or
`
`unsubstituted (C1-C6)alkyl.
`
`[0050)
`
`"Ring" as used herei.n means a substituted or unsubstituted cycloalkyl,
`
`substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or
`
`substituted or unsubstituted heteroaryl. A ring includes fused ring moieties. The
`
`number of atoms in a ring is typically defined by the number of members in the ring.
`
`For example, a "5- to 7-membered ring" means there are 5 to 7 atoms in the encircling
`
`arrangement. The ring optionally included a heteroatom. Thus, the term "5- to 7-
`
`membered ring" includes, for example pyridinyl and piperidinyl. The term "ring"
`
`13
`
`

`
`further includes a ring system comprising more than one "ring", wherein each "ring"
`
`is independently defined as above.
`
`(0051] As used herein, the term "heteroatom" includes atoms other than carbon (C)
`
`and hydrogen (H).