WO2006023586A2 - Guanylhydrazone compounds, compositions, methods of making and using - Google Patents

Guanylhydrazone compounds, compositions, methods of making and using Download PDF

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Publication number
WO2006023586A2
WO2006023586A2 PCT/US2005/029301 US2005029301W WO2006023586A2 WO 2006023586 A2 WO2006023586 A2 WO 2006023586A2 US 2005029301 W US2005029301 W US 2005029301W WO 2006023586 A2 WO2006023586 A2 WO 2006023586A2
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Prior art keywords
alkyl
phenyl
heterocyclic
alkynyl
alkenyl
Prior art date
Application number
PCT/US2005/029301
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French (fr)
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WO2006023586A3 (en
Inventor
Thais M. Sielecki-Dzurdz
Original Assignee
Cytokine Pharmasciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Priority to CA2577156A priority Critical patent/CA2577156C/en
Priority to MX2007001928A priority patent/MX2007001928A/en
Priority to AU2005277456A priority patent/AU2005277456B2/en
Priority to DK05785277.4T priority patent/DK1778265T3/en
Priority to PL05785277T priority patent/PL1778265T3/en
Priority to ES05785277T priority patent/ES2422425T3/en
Priority to JP2007527986A priority patent/JP5198863B2/en
Priority to BRPI0514452A priority patent/BRPI0514452A8/en
Priority to CN2005800281235A priority patent/CN101010094B/en
Priority to EP05785277.4A priority patent/EP1778265B1/en
Publication of WO2006023586A2 publication Critical patent/WO2006023586A2/en
Publication of WO2006023586A3 publication Critical patent/WO2006023586A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention is directed to the field of pharmacology.
  • the invention is directed to guanylhydrazone compounds.
  • the guanylhydrazone compounds or salts thereof may be used for therapeutic regimens
  • D'Souza relates to microencapsulation as a delivery vehicle for a drug.
  • guanylhydrazone compound CNI-1493 is disclosed in one embodiment.
  • Giordano et al. relates to guanylhydrazone compounds for inhibiting RNase P activity.
  • United States Patent Application Publication No. 2003/0203969 to Bevec et aL relates to pharmaceutically active aromatic guanylhydrazone compounds.
  • guanylhydrazone compounds relates to guanylhydrazone compounds and their uses to treat inflammatory conditions.
  • Guanylhydrazone compounds are disclosed.
  • nitric oxide and its importance as a second messenger in biological environments.
  • One embodiment provides a compound, having the formula:
  • X 1 , X 2 , X 3 , and X 4 each independently represent H, GhyCH — , GhyCCH 3 — , or CH 3 CO-, with the provisos that X 1 , X 2 , X 3 and X 4 are not
  • Z is one or more selected from the group consisting of:
  • a is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • b is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • x is selected from the group consisting of O 3 1, 2, 3, 4, 5, 6, 7, 8,
  • y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • n is selected from the group consisting of 0, 1, 2, 3, 4; 5, 6, 7, 8, and 9;
  • n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • a 1 and A 2 are each independently selected from the group
  • arylene in said Q and/or T may each be independently replaced with one or more
  • heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and a
  • alkylene, cycloalkylene or arylene wherein when substituted, said alkylene, cycloalkylene or arylene in
  • C 20 )alkoxy, (C 3 -C 25 )heteroaryl, (C 3 -C 25 )heterocyclic, (C 2 -C 20 )alkenyl, (C 3 -C 20 ) cycloalkenyl, (C 2 -C 20 )alkynyl, (C 5 -C 20 )cycloalkynyl, and (C 5 -C 25 )aryl groups (as substituents on said alkylene, cycloalkylene or arylene of said Q and T) may be
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 groups may be optionally and independently substituted by one to four moieties selected from the group
  • R 11 alkyl-containing groups may be taken together with any atom to which they
  • composition which includes the above
  • One embodiment provides a method, which includes administering the
  • Figure 1 is a chart showing the inhibition of TNF ⁇ release.
  • Figure 2 is a chart showing the inhibition of NO release.
  • Figure 3 shows the combined results for inhibition of nitric oxide
  • Figure 4 shows the combined results for inhibition of nitric oxide
  • FIG. 5 shows structures and results of exemplified compounds, and others.
  • the present invention relates to compounds having the formula:
  • X 1 , X 2 , X 3 , and X 4 each independently represent H, GhyCH — , GhyCCH 3 — , or CH 3 CO-, with the provisos that X 1 , X 2 , X 3 and X 4 are not simultaneously H; wherein Z is one or more selected from the group consisting of:
  • y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
  • a 1 and A 2 are each independently selected from the group
  • arylene in said Q and/or T may each be independently replaced with one or more
  • heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and a combination thereof; and wherein when substituted, said alkylene, cycloalkylene or arylene in
  • said Q and/or T are each independently substituted with one or more substituent groups selected from the group consisting of hydroxy, halo, bromo, chloro, iodo,
  • C 20 )alkoxy, (C 3 -C 25 )heteroaryl, (C 3 -C 25 )heterocyclic, (C 2 -C 20 )alkenyl, (C 3 -C 20 ) cycloalkenyl, (C 2 -C 20 )alkynyl, (C 5 -C 20 )cycloalkynyl, and (C 5 -C 25 )aryl groups (as substituents on said alkylene, cycloalkylene or arylene of said Q and T) may be
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently
  • cycloalkenyl (C 2 -C 20 )alkynyl, (C 5 -C 20 )cycloalkynyl, and (C 5 -C 25 )aryl groups (for said R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R s , R 9 , R 10 , and R" groups) may be optionally and
  • R 11 alkyl-containing groups may be taken together with any atom to which they are attached to form a three to forty membered cyclic, heterocyclic or heteroaryl
  • Z is a C 1 -C 20 alkylene, which may be branched or
  • alkylenes having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
  • Z is a branched C 1 -C 20 alkylene. In another embodiment, Z is an unbranched C 1 -C 20 alkylene.
  • Z is a saturated Ci-C 20 alkylene.
  • Z is an unsaturated C 1 -C 20 alkylene.
  • Z is an unsubstituted C 1 -C 20 alkylene.
  • Z is a substituted C 1 -C 20 alkylene.
  • Z is a C 1 -C 20 alkylene in which one or more carbons is replaced with one or more heteroatoms selected from the group
  • Z is a saturated or unsaturated, substituted or unsubstituted C 3 -C 20 cycloalkylene, and which may have one or more carbon atoms
  • Z is a saturated C 3 -C 20 cycloalkylene.
  • Z is an unsaturated C 3 -C 20 cycloalkylene.
  • Z is an unsubstituted C 3 -C 20 cycloalkylene.
  • Z is a substituted C 3 -C 20 cycloalkylene.
  • Z is a C 3 -C 20 cycloalkylene in which one or more
  • Z is a substituted or unsubstituted C 5 -C 25 arylene, wherein one or more carbon atoms in the cycloalkylene and arylene may be
  • Z is a substituted C 5 -C 25 arylene.
  • Z is an unsubstituted C 5 -C 25 arylene. In another embodiment, Z is a C 5 -C 25 arylene in which one or more carbons
  • heteroatoms selected from the group including oxygen, nitrogen, sulfur and a combination thereof.
  • Z is an — NR 8 (CO)NR 9 — group, optionally in the salt
  • Z is a — (C 6 H 4 ) — group.
  • Z is a — (CH 2 ) p — group, wherein p is 1, 2, 3, 4, 5,
  • Z is a — (C 5 H 3 N) — group.
  • Z is a — O — (CH 2 ) p — O — group, wherein p is 1, ,
  • Z is a — A — (CH 2 ) p — A — group, wherein p is 1, 2,
  • Z is a — A — (C 6 H 4 ) — A — wherein the A's are
  • Z is — O — (C 6 H 4 ) — O — , wherein the two " — O — " groups are para to each other about the phenylene ring.
  • Z is — O — (C 6 H 4 ) — O — , wherein the two " — O — " groups are meta to each other about the phenylene ring.
  • Z is — 0-CH 2 -CH 2 -O-CH 2 — CH 2 -O-. In another embodiment, Z is a group having the formula:
  • Z is a group having the formula:
  • Z is a group having the formula:
  • Z is a group having the formula:
  • Z is a group having the formula:
  • Z is a group having the formula:
  • Z is a group having the formula:
  • Z is a group having the formula:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • the compound includes the structure:
  • X 1 , X 2 , X 3 , and X 4 may each individually adopt the ortho, meta or para position on the phenylene ring relative to the Z group.
  • the X 1 , X 2 , X 3 , and X 4 are meta or para to the Z group.
  • the non-H X 1 , X 2 , X 3 , and X 4 groups are meta to both the Z group and to each other.
  • At least one of X 1 , X 2 , X 3 and X 4 is GhyCH — or
  • GhyCCH 3 — X 1 and X 2 are not simultaneously H, and X 3 and X 4 are not simultaneously H.
  • X 1 , X 2 , X 3 , and X 4 are selected from the group including GhyCH— or GhyCCH 3 — .
  • X 1 , X 2 , X 3 , and X 4 are selected from the group including GhyCH—, GhyCCH 3 — , or CH 3 CO-. In another embodiment, X 1 , X 2 , X 3 , and X 4 are each GhyCH — .
  • the X 1 , X 2 , X 3 , and X 4 are each GhyCCH 3 — .
  • the X 1 , X 2 , X 3 , and X 4 are each CH 3 CO — .
  • At least one of X 1 , X 2 , X 3 , and X 4 is CH 3 CO — .
  • the compound is in the salt form. In another embodiment, the compound is in the salt form having a
  • Z has the formula:
  • Z has the formula:
  • a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 2 , R 10 , and R 11 are defined herein.
  • Z has the formula: -(A 1 ),— (CR 2 R 3 ) - Q m _(CR 4 R 5 ) -T -(CR 6 R 7 ) z -(A 2 ) b -; wherein each of the variables a, m, n, and b are equal to 1 ; and the sum of
  • Q and T are each independently selected from the group consisting R 1O (CO)NR 1 '— , -(CO)NR 10 -, — NR 10 (CO)— , — NR 10 - , salts thereof, — O— ,
  • a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 2 , R 10 , and R 11 are defined herein; with the proviso that if Q is — NR 10 — or — O — and y is 1 then T is not
  • Z has the formula:
  • a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 2 , R 10 , and R 11 are defined herein; with the proviso that if Q is — NR 10 — or — O — and y is 1 then T is not ⁇ NR 10 — or — O— ; and with the proviso that if Q is -(CO)NR 10 -, — NR 10 (CO)— , — NR 10 - , or — O— and y is 1 then T is not -(CO)NR 10 -, — NR 10 (CO)— , — NR 10 - , or
  • Z has the formula:
  • a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 2 , R 10 , and R 11 are defined herein;
  • alkylene, arylene, and/or heteroarylene are each
  • R 1 and R 1' being each independently selected from the group including
  • R 1 and R 1' groups may be optionally and independently substituted by one to four
  • moieties selected from the group consisting of hydroxy, halo, bromo, chloro, iodo,
  • R 1 or R 1' alkyl-containing groups may be taken together with any atom to which they are attached to form a three to
  • Z has the formula: -(A ⁇ - ⁇ R ⁇ -Q ⁇ R ⁇ -T - ⁇ R ⁇ - ⁇ A 2 ),- wherein Q and T are each independently selected from the group consisting
  • substituted heteroarylene and combinations thereof; wherein A 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 2 , R 10 , and R 11 axe defined herein; wherein if substituted, the alkylene, arylene,and heteroarylene, are each
  • R 1 and R 1' being each independently selected from the group
  • said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups selected
  • said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups selected from the group consisting of (C 1 -C 20 )alkyl — O — , phenyl — O — , (C 3 - C 20 )cycloalkyl — O — , (C 3 -C 25 )heteroaryl — O — , (C 3 -C 25 )heterocyclic — O — , (C 2 -
  • said alkylene, cycloalkylene or arylene hi said Q
  • T are each independently substituted with one or more substituent groups selected from the group consisting of (C j -C ⁇ alkyl — S — , phenyl — S — , (C 3 -
  • said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups
  • T are each independently substituted with one or more substituent groups selected from the group consisting of ⁇ (C 1 -C 20 )alkyl ⁇ 2 N — , ⁇ phenyl ⁇ 2 N — , ((C 3 -
  • ⁇ pharmaceutically acceptable functional group e.g., a moiety that does not negate the pharmaceutical activity of the active compound.
  • halo groups include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy
  • alkyl groups alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups,
  • alkylene refers to a diradical alkane species that
  • alkylene may be branched or
  • any carbon atom therein may be optionally replaced with one or more heteroatoms
  • cycloalkylene refers to a diradical cycloalkane
  • the cycloalkylene may be branched or uribranched, saturated or unsaturated, and substituted or unsubstituted.
  • any carbon atom therein may be optionally replaced with one or more
  • heteroatom such as nitrogen, oxygen or sulfur or any combination thereof.
  • arylene means an aromatic diradical species having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 carbons and any subrange of carbons thereof. These may be unsubstitued or
  • any carbon atom therein may be
  • alkyl as well as the alkyl moieties of or within
  • (C 2 -C 20 )alkynyl, and perhalo(C 1 -C 20 )alkyl) include alkyl moieties having 1, 2, 3, 4,
  • the alkyl groups may be unsubstituted or
  • cyclic groups referred to herein refers to mono carbocyclic moieties having
  • alkenyl refers to unsaturated radical species having 1, 2, 3, 4, 5, 6, 7, 8, 9,
  • these moieties may have one, two, three, four or more sites of unsaturation.
  • Some nonlimiting examples of these include ethenyl,
  • alkoxy refers to alkyl — O — radical species
  • aryl means aromatic radicals having 5, 6, 7, 8, 9,
  • heteroaryl refers to an aromatic heterocyclic group with at least one heteroatom selected from O, S and N in the ring and having
  • heteroatoms may be present either alone or in any combination.
  • the heteroaryl groups may be unsubstitued or
  • One, two, three, four or more heteroatoms may be
  • the aromatic group may optionally have up to four N atoms in the ring.
  • heteroaryl groups include
  • pyridyl pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3- thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl),
  • oxadiazolyl e.g., 1,2,3-oxadiazolyl
  • thiadiazolyl e.g., 1,3,4-thiadiazolyl
  • quinolyl isoquinolyl
  • benzothienyl benzofuryl
  • indolyl and the like
  • heterocyclic refers to a cyclic group containing 3,
  • Nonlimiting examples include azetidinyl,
  • benzoxazinyl and the like examples of such monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin- 1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, l,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-
  • tetrahydrothiazin-2-yl 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-l-yl, l,4-oxazin-2-yl,

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Abstract

The present invention relates to compounds having the formula I: salts thereof; compositions comprising one or more of the compounds and/or salts thereof; methods of using; and methods of making.

Description

TITLE QF THE INVENTION
GUANYLHYDRAZONE COMPOUNDS, COMPOSITIONS, METHODS
OF MAKING AND USING
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial No.
60/601,992, filed August 17, 2004, the entire contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
Field of the Invention The present invention is directed to the field of pharmacology. In one
aspect, the invention is directed to guanylhydrazone compounds. The guanylhydrazone compounds or salts thereof may be used for therapeutic regimens
or for the identification of candidate compounds for producing effective drugs
having increased efficacy or bioavailability.
Related Art
United States Patent Application Publication No. 2004/0043079 to
D'Souza relates to microencapsulation as a delivery vehicle for a drug. The
guanylhydrazone compound CNI-1493 is disclosed in one embodiment.
United States Patent Application Publication No. 2003/0134904 to
Giordano et al. relates to guanylhydrazone compounds for inhibiting RNase P activity. United States Patent Application Publication No. 2003/0203969 to Bevec et aL relates to pharmaceutically active aromatic guanylhydrazone compounds.
United States Patent Application Publication No. 2002/0028851 to Bianchi
et al. relates to guanylhydrazone compounds and their uses to treat inflammatory conditions.
United States Patent Nos. 6,673,777 and 6,143,728 to Tracev et al. relate to guanylhydrazone compounds and their uses for treating diseases associated with T
cell activation.
United States Patent No. 6,319,894 to Tracev et al. relates to
complexes and combinations of fetuin with therapeutic agents to enhance the activity of the therapeutic agents. Guanylhydrazone compounds are disclosed.
United States Patent Nos. 6,248,787; 6,180,676; 6,022,900; 6,008,255;
5,859,062; 5,854,289; 5,849,794; 5,753,684; 5,750,573; and 5,599,984 all to Bianchi et al. relate to guanylhydrazone compounds and their uses to treat
inflammatory conditions.
The article, "Nitric Oxide: A New Paradigm for Second Messengers" in
Journal of Medicinal Chemistry, 1995, Vol. 38, No. 22, pp 4343-4362 relates to
nitric oxide and its importance as a second messenger in biological environments.
The entire contents of every reference cited herein is independently
incorporated by reference for all purposes. SUMMARY OF THE INVENTION
One embodiment provides a compound, having the formula:
Figure imgf000004_0001
or a salt thereof;
wherein X1, X2, X3, and X4 each independently represent H, GhyCH — , GhyCCH3— , or CH3CO-, with the provisos that X1, X2, X3 and X4 are not
simultaneously H;
wherein Z is one or more selected from the group consisting of:
-(A^-(CR2RV-(AV-;
-(A1X-(CR2R3) -Q1n-(CR4R5) y-(A2)b-; and
_(A>)a-(CR2R3) -Qm-(CR4R5) -T -(CR6R7) -(A2)b-;
and combinations thereof;
wherein a is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9;
wherein b is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9;
wherein x is selected from the group consisting of O3 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein m is selected from the group consisting of 0, 1, 2, 3, 4; 5, 6, 7, 8, and 9;
wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein A1 and A2 are each independently selected from the group
consisting of — NR8(CO)NR9— , -(CO)NR8-, — NR8(CO>— , — NR8- , —O—5 -S-, — S(=O)— , -SO2-, -SO2NR8-, -NR8SO2-, and salts thereof;
wherein Q and T are each independently selected from the group consisting
of — NR10(CO)NRn— , -(CO)NR10-, — NR10(CO)— , -NR10- — O— , -S-, — S(=O)— , -SO2- -SO2NR10-, -NR10SO2-, salts thereof, branched or unbranched, saturated or unsaturated, substituted or unsubstituted C1-
C20 alkylene, saturated or unsaturated, substituted or unsubstituted C3-C20
cycloalkylene, substituted or unsubstituted C5-C25 arylene, and combinations
thereof;
wherein one or more carbon atoms in any of said alkylene, cycloalkylene or
arylene in said Q and/or T may each be independently replaced with one or more
heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and a
combination thereof;
and wherein when substituted, said alkylene, cycloalkylene or arylene in
said Q and/or T are each independently substituted with one or more substituent
groups selected from the group consisting of hydroxy, halo, bromo, chloro, iodo,
fluoro, -N3, -CN, -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3- C2o)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-
C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5- C25)aryl, perhalo(CrC20)alkyl, (CrC20)alkyl— O— , phenyl— O— , (C3-
C20)cycloalkyl— O— , (C3-C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2- C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5- C20)cycloalkynyl— O— , (C5-C25)aryl— O— , perhalo(CrC20)alkyl— O— , (C1-
C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— ,
(C3-C25)heterocyclic — S — , (C2-C20)alkenyl — S — , (C3-C20)cycloalkenyl — S — ,
(C2-C20)alkynyl— S— , (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(C,- C20)alkyl— S— , (C,-C20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-Cyhetøroaiyl— SO2-, (C3- C25)heterocyclic— SO2- , (C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-,
(C2-C20)alkynyl— SO2- , (C5-C20)cycloalkynyl— SO2- , (C5-C25)aryl— SO2- ,
perhalo(CrC20)alkyl— SO2- , H2N-SO2- (CrC20)alkyl— NH-SO2-, phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1-
C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3- C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20)
cycloalkenyl— NH-SO2-, (C2-C20)alkynyl— NH-SO2-, (C5-
C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr
C20)alkyl— NH-SO2-, {(CrC20)alkyl}2N— SO2- , {phenyl}2N— SO2- , ((C3- C20)cycloalkyl}2N— SO2- , {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2- , ((C3-C25)heterocyclic}2N— SO2- , ((C2- C20)alkenyl}2N— SO2- ((C2-C20)alkynyl}2N— SO2- ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(Cr C20)alkyl}2N— SO2- , (CrC20)alkyl-SO2— NH- , phenyl-SO2— NH- , (C3- C20)cycloalkyl-SO2— NH- , (C1-C20)EIkOXy-SO2-NH-, (C3-C25)heteroaryl-
SO2-NH- (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- , (C3- C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-S O2-NH-, (C5-C20)cycloalkynyl-
SO2-NH- (C5-C25)SIyI-SO2- NH- , perhalo^-C^alkyl-SO;,— NH- (C1- C20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- , (C1-
C20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-
C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- , (C5-
C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
{(CrC20)alkyl}2N— (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , {(C3-C25)heteroaryl}2N— , {(C3-C25)heterocyclic}2N— , ((C2- C20)alkenyl}2N— ((C3-C20)cycloalkenyl}2N— ((C2-C20)alkynyl}2N— ((C5-
C20)cycloalkynyl}2N— ((C5-C25)Er7I)2N- (perhalo^rC^alkyll.N— (C1- C20)alkyl— (C=O)-NH- phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH- (C3-
C25)heteroaryl — (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5-
C25)aryl— (C=O)-NH-, perhalo(C1-C20)alkyl— (C=O)-NH- (C1-
C20)alkyl— (C=O)- (((CrC20)alkyl)N}— phenyl— (C=O)- (((CrC20)alkyl)N}— , (C3-C20)cycloalkyl— (C=O)- (((CrC20)alkyl)N}— , (C1-
C20)alkoxy— (C=O)- (((CrC20)alkyl)N}— (C3-C25)heteroaryl— (C=0)-(((Cr C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- (((CrC20)alkyl)N}— , (C2- C20)alkenyl-(C=O)— (((C1-C20)EUCyI)NI- (C3-C20) cycloalkenyl— (C-O)- {((CrC20)alkyl)N}— (C2-C20)alkynyl— (C=O)- {((Cr
C20)alkyl)N}— (C5-C20)cycloaikynyl— (C=O)- {((CrC20)alkyl)N}— (C5-
C25)aryl— (C=O)- {((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O>-{((Cr C20)alkyl)N}— , phenyl-(C=O)— NH- , phenyl-(OO)— {(phenyl)N}—, (C1- C20)alkyl-(C=O>— {(phenyl)N}— , (C3-C20)cycloalkyl-(C==O)— ((phenyl)N}—5 (C1-C^aIkOXy-(C=O)- {(phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- {(phenyl)N}— , (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— , (C2- C20)alkenyl-(C=O)— {(phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)-{(phenyl)N}— (C2-C20)alkynyl-(C=O)— {(phenyl)N}— (C5-
C20)cycloalkynyl-(C=O>— {(phenyl)N}— (C5-C25)aryl-(C=O)— {(phenyl)N}— perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3- C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(O=O)-, (C3-
C25)heteroaryl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2- C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)aryl— NH- (C=O)- , perhalo(CrC20)alkyl— NH- (C=O)- , (C1-
C20)alkyl}2N — (C=O)- {phenyl} {(CrC20)alkyl}N— (C=O)- ((C3-
C20)cycloalkyl} ((C1-C20)alkyl}N— (C=O)-, ((CrC20)alkoXy} ((C1-
C20)alkyl}N— (C=O) — ,{(C3-C25)heteroaryl} ((CrC20)alkyl}N— (C=O)-, ((C3-
C25)heterocyclic} {(CrC20)alkyl}N— (C=O)-, ((C2-C20)alkenyl> ((C1-
C20)alkyl}N— (C=O)-, {(C3-C20)cycloalkenyl} ((C,-C20)alkyl}N— (C=O)-, ((C2-C20)alkynyl} {(CrC20)alkyl}N-(C=O)— {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- ■{(C5-C25)aryl}{(CI-C20)alkyl}N— (C=O)- (perhalo(Cr C20)alkyl}{(CrC20)alkyl}N-((--O)— , {phenyl}2N— (C=O)- ((C3- C20)cycloalkyl} {phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (phenyl)N— (C=O)- ,((C3-C25)heteroaiyl} (phenyl}N— (C=O)-, ((C3-C25)heterocyclic} (phenyl }N— (C=O) — , ((C2-
C20)alkenyl} (phenyl}N— (C=O)- ((C3-C20)cycloalkenyl} (phenyl)N— (C=O)-,
{(C2-C20)alkynyl}(phenyl}N— (C=O)- ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, ((C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(CrC20)alkyl}(phenyl}N— (C=O)- , HO-(C=O)-, (C1- C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3- C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-, perhalo(CrC20)alkyl— (C=O)- , phenyl— (C=O)-, (C1-
C20)alkyl — O — (C=O) — , (C3-C25)heteroaryl — O — (C=O) — , (C3-
C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5- C25)aryl — O — (C=O) — , perhalo(CrC20)alkyl — O — (C=O) — ,
phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O-,
phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
wherein each of the aforesaid (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1-
C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (as substituents on said alkylene, cycloalkylene or arylene of said Q and T) may be
optionally and independently substituted by one to four moieties selected from the group consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, — N3, — CN,
-NC, — SH, -NO2, -NH2, (C1-C20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1- C20)alkoxy, (C3-C25)heteroaryl3 (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo(Cr
C20)alkyl, (CrC20)alkyl— O— , phenyl— O— (C3-C20)cycloalkyl— O— , (C3-
C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2-C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5-C20)cycloalkynyl— O— , (C5-
C25)aryl— O— , perhalo(CrC20)alkyl— O— , (CrC20)alkyl— S— , phenyl— S-, (C3- C20)cycloalkyl — S — , (C3-C25)heteroaryl — S — , (C3-C25)heterocyclic — S — , (C2-
C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5-
C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(CrC20)alkyl— S— , (C1- C20)alkyl — SO2-, phenyl— SO2-, (C3-C20)cycloalkyl— SO2- , (C1-
C20)alkoxy — SO2 — , (C3-C25)heteroaryl — SO2 — , (C3-C25)heterocyclic — SO2 — ,
(C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2- ,
(C5-C20)cycloalkynyl— SO2-, (C5-C25)aryl— SO2-, perhalo(CrC20)alkyl— SO2-,.
H2N-SO2-, (CrC20)alkyl— NH-SO2-, phenyl— NH-SO2-, (C3-
C20)cycloalkyl— NH-SO2-, (CrC20)alkoxy— NH-SO2- (C3-
C25)heteroaryl— NH-SO2-, (C3-C25)heterocyclic— NH-SO2-, (C2- C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2-, (C2-
C20)alkynyl— NH-SO2- (C5-C20)cycloalkynyl— NH-SO2-, (C5- C25)aryl— NH-SO2-, perhalo(CrC20)alkyl— NH-SO2-, ((C1-
C20)alkyl}2N— SO2- , {phenyl}2N— SO2-, {(C3-C20)cycloalkyl}2N— SO2- , ((C1- n^,
PCT7US2005/029301
C20)alkoxy}2N— SO2- , {(C3-C25)heteroaryl}2N-— SO2- , ((C3- C25)heterocyclic}2N— SO2- , {(C2-C20)alkenyl}2N— SO2- , ((C2-
C20)alkynyl}2N— SO2- , ((C5-C20)cycloalkynyl}2N— SO2- ((C5- C25)aryl}2N— SO2- , (perhalo(CrC20)alkyl}2N— SO2- , (CrC20)alkyl-
SO2-NH-, phenyl-S02— NH- , (C3-C20)cycloalkyl-SO2— NH-, (C1-
C20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-SO2— NH- , (C3-C25)heterocyclic- SO2-NH-, (C2-C20)alkenyl-SO2— NH- , (C3-C20) cycloalkenyl-S O2-NH-,
(C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl- SO2-NH-, perhalo(CrC20)alkyl-SO2— NH- , (C,-C20)alkyl— NH- ,
phenyl— NH-, (C3-C20)cycloalkyl— NH- , (CrC20)alkoxy— NH- , (C3-
C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- ,
(C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- , (C5- C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((CrC20)alkyl}2N— (phenyl}2N— , ((C3-C20)cycloalkyl}2N— , ((C1- C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— , ((C2-C20)alkynyl}2N— , ((C5-
C20)cycloalkynyl}2N— ((C5-C2S)aryl}2N— (perhalo(CrC20)alkyl}2N— (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH- (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5- C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH-, (C1-
C20)alkyl— (C=O)- (((CrC20)alkyl)N}— , phenyl— (C=O)- (((CrC20)alkyl)N}— (C3-C20)cycloalkyl— (C-O)- {((CrC20)alkyl)N}— , (C1- C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— (C3-C25)heteroaryl— (C=O)- (((C1-
C20)alkyl)N}— (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— , (C2-
C20)alkenyl— (C=O)- {((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- {((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)- (((CrC20)alkyl)N}— , (C5-
C25)aryl-(C=O)— {((C.-C^alkyφN}— , perhalo^-C^alkyl— (C=O)- (((C1- C20)alkyl)N}— phenyl-(C=O)— NH- phenyl-(C=O)— {(phenyl)N}—, (C1-
C20)alkyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkyl-(C=O)— {(phenyl)N}— , (CrC20)alkoxy-(C=O)— ((phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- ((phenyl)N}— , (C3-C25)heterocyclic-(C=O)— ((phenyl)N}— , (C2-
C20)alkenyl-(C=O>— ((phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)-{(phenyl)N}— (C2-C20)alkynyl-(C=O)— ((phenyl)N}— (C5- C20)cycloalkynyl-(C=O)— ((phenyl)N}—, (C5-C25)aryl-(C=O)— ((phenyl)N}—
perhalo(CrC20)alkyl-(C=O)— ((phenyl)N}—3 H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(C=O)--, (C3-C25)heterocyclic—-NH— (C=O)-, (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5-
C25)aryl— NH- (C=O)- , perhalo(CrC20)alkyl— NH-(C=O)-, (C1-
C20)alkyl}2N — (C=O)- {phenyl} {(CrC20)alkyl}N— (C=O)- ((C3-
C20)cycloalkyl} {(CrC20)alkyl}N-(C=O)— , {(CrC20)alkoxy} ((C1- C20)alkyl}N— (C=O)- ,{(C3-C25)heteroaryl}((CrC20)alkyl}N— (C=O)-, ((C3- 2005/029301
C25)heterocyclic} {(CrC20)alkyl}N— (C=O)- , {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)-, {(C3-C20)cycloalkenyl} ( (C rC20)alkyl}N— (C=O)- {(C2-C20)alkynyl} {(CrC20)alkyl}N— (C=O)-, {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)-, ((C5-C25)aryl}((CrC20)alkyl}N-(C=O)— (perhalo(Cr C20)alkyl} ((CrC20)alkyl}N— (C=O)-, (phenyl} 2N— (C=O)- ((C3- C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (phenyl}N— (C=O)- ,((C3-C25)heteroaryl} (phenyl}N— (C=O)- ,
((C3-C25)heterocyclic} (phenyl)N— (C=O) — , ((C2- C20)alkenyl} (phenyl}N— (C=O) — , ((C3-C20)cycloalkenyl} (ρhenyl}N— (C=O) — ,
((C2-C20)alkynyl} (phenyl}N-(C=O)— , ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, ((C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(CrC20)alkyl}(phenyl}N— (C=O)-, HO-(C=O)-, (C1- C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3-
C25)heterocyclic— (C=O)-, (C2-C20)alkenyl— (C=O)-, (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)- , (C5-C25)aryl— (C=O) perhalo(CrC20)alkyl — (C=O) — , phenyl — (C=O) — , (C1 —
C20)alkyl — O — (C=O) — , (C3-C25)heteroaryl — O — (C=O) — , (C3-
C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl—O— (C=O)-, perhalo(CrC20)alkyl—O— (C=O)-, phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O-, phenyl— (C=O) — O — , perhalo(CrC20)alkyl— (C=O)-O-, and salts thereof;
and wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are each independently
selected from the group consisting of hydrogen, hydroxy, halo, bromo, chloro,
iodo, fluoro, — N3, — CN5 -NC, — SH3 -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-
C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5- C25)aryl, perhalo(CrC20)alkyl, (C,-C20)alkyl— O— , phenyl— O— , (C3-
C20)cycloalkyl — O — , (C3-C25)heteroaryl — O — , (C3-C25)heterocyclic — O — , (C2-
C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5- C20)cycloalkynyl— O— , (C5-C25)aryl— O— , perhalo(CrC20)alkyl— O— , (C1-
C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— ,
(C3-C25)heterocyclic — S — , (C2-C20)alkenyl — S — , (C3-C20)cycloalkenyl — S — ,
(C2-C20)alkynyl— S— , (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— , ρerhalo(Cr C20)alkyl— S— , (CrC20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-
C25)heterocyclic — SO2 — , (C2-C20)alkenyl — SO2 — , (C3-C20) cycloalkenyl — SO2 — ,
(C2-C20)alkynyl— SO2-, (C5-C20)cycloalkynyl— SO2- , (C5-C25)aryl— SO2-,
perhalo(CrC20)alkyl— SO2-, H2N-SO2-, (CrC20)alkyl— NH-SO2-
phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1-
C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3-
C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20)
cycloalkenyl— NH-SO2-, (C2-C20)alkynyl— NH-SO2-, (C5-
C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr 29301
C20)alkyl— NH-SO2-, {(CrC20)alkyl}2N— SO2-, {phenyl}2N— SO2- , ((C3- C20)cycloalkyl}2N— SO2- ((CrC20)alkoxy}2N— SO2- ((C3-
C25)heteroaryl}2N— SO2- , {(C3-C25)heterocyclic}2N— SO2- , ((C2-
C20)alkenyl}2N— SO2- ((C2-C20)alkynyl}2N— SO2- ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(Cr
C20)alkyl}2N— SO2- , (CrC20)alkyl-SO2— NH- phenyl-S02— NH- , (C3- C20)cycloalkyl-SO2— NH- , (CrC20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-
SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- , (C3- C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl-
SO2-NH-, (C5-C25)aryl-SO2— NH- , perhalo(C,-C20)alkyl-SO2— NH-, (C1- C20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- , (C1-
C20)alkoxy— NH — , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-
C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- , (C5-
C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((CrC20)alkyl}2N— (phenyl}2N— , ((C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— ((C2-C20)alkynyl}2N— ((C5-
C20)cycloalkynyl}2N— {(C5-C25)aryl}2N— (perhalo(CrC20)alkyl}2N— (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2- C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5-
C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH-, (C1- C20)alkyl-<C=O)— {((CrC20)alkyl)N}— , phenyl-(C=O)— {((CrC20)alkyl)N}—
(C3-C20)cycloalkyl-(C=O)— {((CrC20)alkyl)N}- (C1- C20)alkoxy— (C=O)~{((CrC20)alkyl)N}— (C3-C25)heteroaryl— (C=O)- (((C1-
C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— (C2- C20)alkenyl-(C=O)-{((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl—(C=O)—{((CrC20)alkyl)N}—5 (C2-C20)alkynyl— (C=O)-K(C1- C20)alkyl)N}- (C5-C20)cycloalkynyl-(C=O)— {((CrC20)alkyl)N}— (C5-
C25)aryl— (C=O)- {((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)- {((Cr C20)alkyl)N}— , phenyl-(C=0)— NH-, phenyl-(C=0)— {(phenyl)N}—5 (C1-
C20)aϊkyl-(C=O)— {(phenyl)N}— , (C3-C20)cycloalkyl-(C=O)— {(plienyl)N}— , (CrC20)alkoxy-(C=O)— {(phenyl)N}— , (C3-C2S)heteroaryl-
(C=O)- {(phenyl)N}— , (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— , (C2- C20)alkenyl-(C=O)— {(phenyl)N}— , (C3-C20)cycloalkenyl-
(CM))- {(phenyl)**}—, (C2-C20)alkynyl-(C=O)-{(phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— {(phenyl)N}— , (C5-C25)aryl-(C=O)— {(phenyl)N}— , perhalo(CrC20)alkyl-(C=O>— {(phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)- (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3- C25)heteroaryl— NH-(C=O)-, (C3-C25)heterocyclic— NH-(C=O)-, (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5-
C25)aryl— NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O)-, (C1-
C20)alkyl}2N — (C=O)-, {phenyl} {(CrC20)alkyl}N— (C=O)- ((C3- C20)cycloalkyl} ((C rC20)alkyl}N— (C=O)- {(CrC20)alkoxy} ((C1- C20)alkyl}N— (C=O)- ,{(C3-C25)heteroaryl}{(CrC20)alkyl}N— (C=O)-, ((C3-
C25)heterocyclic} {(CrC20)alkyl}N^(C=O)— , {(C2-C20)alkenyl} ((C1- C20)alkyl}N— (C=O)-, ((C3-C20)cycloalkenyl} ((CrC20)alkyl}N—(C=O)—
((C2-C20)alkynyl}((C1-C20)alkyl}N— (C=O)- ((C5-C20)cycloalkynyl}((Cr C20)alkyl}N— (C=O)- , ((CrC25)aryl}((C1-C20)alkyl}N— (C=O)-, (perhalo(C,- C20)alkyl}((CrC20)alkyl}N-(C=O)— (phenyl}2N— (C=O)-, ((C3-
C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (phenyl)N— (C=O) — ,((C3-C25)heteroaryl} (phenyl}N— (C=O)-,
((C3-C25)heterocyclic} (phenyl)N— (C=O)-, ((C2-
C20)alkenyl} (phenyl}N— (C=O)-, ((C3-C20)cycloalkenyl} (phenyl}N—(C=O
((C2-C20)alkynyl} (phenyl}N-(C=O)— ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)- , ((C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(CrC20)alkyl}(phenyl}N— (C=O)-, HO-(C=O)-, (C1- C20)alkyl — (C=O) — , (C3-C25)heteroaryl — (C=O) — , (C3- C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl — (C=O) — , (C2-C20)alkynyl — (C=O) — , (C5-C25)aryl — (C=O
perhalo(CrC20)alkyl — (C=O) — , phenyl — (C=O) — , (C1 —
C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3-
C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl— O— (C=O)- , perhalo(CrC20)alkyl— O— (C=O)-,
phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3- C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)- O— , (C5-C25)aryl— (C=O)-O-, phenyl — (C=O) — 0 — , perhalo(CrC20)alkyl — (C=O) — 0 — , and salts thereof; wherein each of the aforesaid (C1-C20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1- C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (for
said R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 groups) may be optionally and independently substituted by one to four moieties selected from the group
consisting of hydroxy, halo, bromo, chloro, iodo, fiuoro, — N3, — CN, — NC, — SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (CrC20)alkoxy,
(C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl,
(C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, ρerhalo(CrC20)alkyl, (C1- C20)alkyl— O— , phenyl— O— , (C3-C20)cycloalkyl— O— , (C3-
C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2-C20)alkenyl— 0— , (C3-C20)
cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5-C20)cycloalkynyl— O— , (C5-
C25)aryl— O— , perhalo(CrC20)alkyl— 0— , (CrC20)alkyl— S— , phenyl— S-, (C3- C20)cycloalkyl^S— , (C3-C25)heteroaryl— S— , (C3-C25)heterocyclic— S— , (C2-
C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5-
C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(CrC20)alkyl— S— , (C1-
C20)alkyl— SO2- , phenyl— SO2-, (C3-C20)cycloalkyl— SO2- , (C1-
C20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-C25)heterocyclic— SO2- ,
(C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2- , (C5-C20)cycloalkynyl— SO2-, (C5-C25)aryl— SO2-, ρerhalo(CrC20)alkyl— SO2-,
H2N-SO2-, (C1-C20)alkyl— NH-SO2-, phenyl— NH-SO2-, (C3-
C20)cycloalkyl— NH-SO2-, (CrC20)alkoxy— NH-SO2-, (C3- C25)heteroaryl— NH-SO2-, (C3-C25)heterocyclic— NH-SO2--, (C2-
C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2-, (C2- C20)alkynyl— NH-SO2-, (C5-C20)cycloalkynyl— NH-SO2-, (C5-
C25)aryl— NH-SO2- perhalo(CrC20)alkyl— NH-SO2-, ((C1- C20)alkyl}2N— SO2-, {phenyl} 2N— SO2- {(C3-C20)cycloalkyl J2N-SO2-, ((C1-
C20)alkoxy}2N— SO2- , {(C3-C25)heteroaryl}2N— SO2- , ((C3- C25)heterocyclic}2N— SO2- , ((C2-C20)alkenyl}2N— SO2- , ((C2-
C20)alkynyl}2N— SO2- , {(C5-C20)cycloalkynyl}2N— SO2- , ((C5- C25)aryl}2N— SO2- , (perhalo(CrC20)alkyl}2N— SO2- , (CrC20)alkyl-
SO2-NH-, phenyl-SO2— NH- , (C3-C20)cycloalkyl-SO2— NH- , (C1-
C20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-SO2— NH- , (C3-C25)heterocyclic-
SO2-NH-, (C2-C20)alkenyl-SO2— NH- (C3-C20) cycloalkenyl-S O2-NH- (C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl-
SO2-NH- perhalo(CrC20)alkyl-SO2— NH- (CrC20)alkyl— NH-
phenyl— NH-, (C3-C20)cycloalkyl— NH- , (CrC20)alkoxy— NH- , (C3-
C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- ,
(C3-C20) cycloalkenyl— NH- (C2-C20)alkynyl— NH- (C5-
C20)cycloalkynyl— NH- , (C3-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((CrC20)alkyl}2N— (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , {(C3-C25)heteroaryl}2N— , {(C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— {(C3-C20)cycloalkenyl}2N— ((C^-C^alkynyl}^— ((C5-
C20)cycloalkynyl}2N— {(C5-C25)aryl}2N— , {perhalo^rC^alkylj.N— (C1- C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH- (CrC20)alkoxy— (C=O)-NH- (C3- C25)heteroaryl— (O=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH- (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH- (C5- C25)aryl— (C=O)-NH- perhalo(CrC20)alkyl— (C=O)-NH-, (C1-
C20)alkyl— (C=O)- {((CrC20)alkyl)N}— phenyl— (C=O)- {((CrC20)alkyl)N}— , (C3-C20)cycloalkyl— (C=O)- {((CrC20)alkyl)N}— (C1-
C20)alkoxy—(C=O)—{((C1-C20)alkyl)N}— (C3-C25)heteroaryl— (C=O)-K(C1-
C20)alkyl)N}— (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— (C2- C20)alkenyl-(C=O)-{((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- {((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1-
C20)alkyl)N}-, (C5-C20)cycloalkynyl-(C=O)— {((CrC20)alkyl)N}— , (C5- C25)aryl— (C=O)- {((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)- (((C1-
C20)alkyl)N}— , phenyl-(C=O)— NH- , phenyl-(C=O)— {(phenyl)N>— , (C1-
C20)alkyl-(C=O)— {(phenyl)N}—, (C3-C20)cycloalkyl-(C=O)— {(phenyl)N}- (CrC20)alkoxy-(C=O)— {(phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- {(phenyl)N}— , (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— , (C2-
C20)alkenyl-(C=O)— {(ρhenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- {(phenyl)N}— (C2-C20)alkynyl-(C=O)-{(phenyl)N}— , (C5-
C20)cycloalkynyl-(C=O)— {(phenyl)N}— , (C5-C25)aryl-(C=O)— {(phenyl)N}— , perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2- C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)aryl— NH-(C=O)-, perhalo(C1-C20)alkyl— NH-(C=O)-, (C1- C20)alkyl}2N — (C=O)- {phenyl} {(CrC20)alkyl}N— (C=O)- ((C3-
C20)cycloalkyl} {(CrC20)alkyl}N— (C=O)- {(CrC20)alkoxy} ((C1- C20)alkyl}N-(C=O)— ,{(C3-C25)heteroaryl} {(CrC20)alkyl}N-(C=O)— , ((C3- C25)heterocyclic} {(CrC20)alkyl}N— (C=O)-, {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)- {(C3-C20)cycloalkenyl} {(CrC20)alkyl}N— (C=O)-,
{(C2-C20)alkynyl} ( (C rC20)alkyl}N— (C=O)- {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- {(C5-C25)aryl}{(CrC20)alkyl}N— (C=O)- (perhalo^- C20)alkyl}{(CrC20)alkyl}N— (C=O)- (phenyl}2N— (C=O)-, ((C3-
C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (ρhenyl}N— (C=O) — , {(C3-C25)heteroaryl} (phenyl}N— (C=O) — , ((C3-C25)heterocyclic} (phenyl)N— (C=O)-, ((C2-
C20)alkenyl} (phenyl}N— (C=O)-, {(C3-C20)cycloalkenyl} (phenyl}N— (C=O)-,
((C2-C20)alkynyl}(phenyl}N— (C=O)- ((C5-
C20)cycloalkynyl} (phenyl)N— (C=O)- , {(C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(CrC20)alkyl}(phenyl}N— (C=O)-, HO-(C=O)-, (C1- C20)alkyl— (C=O)- , (C3-C25)heteroaryl— (C=O)-, (C3-
C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl — (C=O) — , (C2-C20)alkynyl — (C=O) — , (C5-C25)aryl — (C=O) — ,
perhalo(CrC20)alkyl — (C=O) — , phenyl — (C=O) — , (C1 —
C20)alkyl — O — (C=O) — , (C3-C25)heteroaryl — O — (C=O) — , (C3-
C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5- C25)aryl— O — (C=O)- perhalo(CrC20)alkyl—O— (C=O)- phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3- C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O-, phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
and wherein two independently chosen R2, R3, R4, R5, R6, R7, R8, R9, R10,
and R11 alkyl-containing groups may be taken together with any atom to which they
are attached to form a three to forty membered cyclic, heterocyclic or heteroaryl ring.
One embodiment provides a composition, which includes the above
compound or salt thereof, and at least one pharmaceutically acceptable carrier, excipient, adjuvant or diluent
One embodiment provides a method, which includes administering the
above compound or salt thereof to a human.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a chart showing the inhibition of TNF α release.
Figure 2 is a chart showing the inhibition of NO release.
Figure 3 shows the combined results for inhibition of nitric oxide and
TNFα release.
Figure 4 shows the combined results for inhibition of nitric oxide and
TNFα release. Figure 5 shows structures and results of exemplified compounds, and others.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds having the formula:
Figure imgf000023_0001
salts thereof; compositions comprising one or more of the compounds and/or salts thereof; methods of using; and methods of making; wherein X1, X2, X3, and X4 each independently represent H, GhyCH — , GhyCCH3— , or CH3CO-, with the provisos that X1, X2, X3 and X4 are not simultaneously H; wherein Z is one or more selected from the group consisting of:
-(A')a-(CR2R3)x-(A2)b-;
^A\-(CR2R3) -Qm-(CR4RV-(A2)b-; and
-(A1) -(CR2R3) -Qra-(CR4R5)y-Tn-(CR6R7) -(A2)b-; and combinations thereof; wherein a is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein b is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein x is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein A1 and A2 are each independently selected from the group
consisting of — NR8(CO)NR9— , -(CO)NR8-, — NR8(CO)—, — NR8- , — O— ,
-S-, — S(=O)— , -SO2-, -SO2NR8-, -NR8SO2-, and salts thereof; wherein Q and T are each independently selected from the group consisting
of — NR10(CO)NRU— -(CO)NR10-, — NR10(CO)— , — NR10- , — O— , -S-, — S(=O)—, -SO2-, -SO2NR10-, -NR10SO2-, salts thereof,
branched or unbranched, saturated or unsaturated, substituted or unsubstituted C1-
C20 alkylene, saturated or unsaturated, substituted or unsubstituted C3-C20
cycloalkylene, substituted or unsubstituted C5-C25 arylene, and combinations
thereof;
wherein one or more carbon atoms in any of said alkylene, cycloalkylene or
arylene in said Q and/or T may each be independently replaced with one or more
heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and a combination thereof; and wherein when substituted, said alkylene, cycloalkylene or arylene in
said Q and/or T are each independently substituted with one or more substituent groups selected from the group consisting of hydroxy, halo, bromo, chloro, iodo,
fluoro, -N3, -CN3 -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3- C20)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2- C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-
C25)aryL perhalo(CrC20)alkyl, (CrC20)alkyl— O— phenyl— O— (C3-
C20)cycloalkyl — O — , (C3-C25)heteroaryl — O — , (C3-C25)heterocyclic— O — , (C2- C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5-
C20)cycloalkynyl— O— , (C5-C25)aryl— O— , perhalo(CrC20)alkyl— O— , (C1-
C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— , (C3-C25)heterocyclic— S— , (C2-C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— ,
(C2-C20)alkynyl— S— , (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(C,-
C20)alkyl— S— , (CrC20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3- C25)heterocyclic — SO2 — , (C2-C20)alkenyl — SO2 — , (C3-C20) cycloalkenyl — SO2 — ,
(C2-C20)alkynyl— SO2-, (C5-C20)cycloalkynyl— SO2-, (C5-C25)aryl— SO2-,
perhalo(CrC20)alkyl— SO2- , H2N-SO2-, (CrC20)alkyl— NH-SO2-,
phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C,- C20)alkoxy— NH-SO2-, (C3-C23)heteroaryl— NH-SO2-, (C3-
C25)heterocyclic— NH-SO2- (C2-C20)alkenyl— NH-SO2-, (C3-C20)
cycloalkenyl— NH-SO2-, (C2-C20)alkynyl— NH-SO2-, (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr C20)alkyl— NH-SO2-, {(CrC20)alkyl}2N— SO2- , {phenyl}2N— SO2- , ((C3- C20)cycloalkyl}2N— SO2- , {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2- , {(C3-C25)heterocyclic}2N— SO2- , ((C2- C20)alkenyl}2N— SO2- , {(C2-C20)alkynyl}2N— SO2-, ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(Cr
C20)alkyl}2N— SO2- , (CrC20)alkyl-SO2— NfH- phenyl-S02— NH-, (C3- C20)cycloalkyl-SO2— NH- , (CrC20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-
SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- (C3- C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-SO2— NH- , (C5~C20)cycloalkynyl- SO2-NH-, (C5-C25)aryl-SO2— NH- , perhalo(CrC20)alkyl-SO2— NH- , (C1-
C20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- , (C1-
C20JaIkOXy- NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH-, (C2- C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- , (C5-
C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((C1-C20)alkyl}2N— (phenyl}2N— ((C3-C20)cycloalkyl}2N— ((C1- C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— ((C3-C20)cycloalkenyl}2N— , {(C2-C20)alkynyl}2N— ((C5- C20)cycloalkynyl}2N— , {(C5-C25)aryl}2N— (perhalo(CrC20)alkyl}2N— , (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH- (CrC20)alkoxy— (C=O)-NH- (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2- C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5-
C25)aryl— (C=O)-NH-, perhalo(CrC2o)alkyl— (C=O)-NH- (C1-
C20)alkyl— (C=O)- (((CrC20)alkyl)N}-, phenyl-(C=O)— (((CrC20)alkyl)N}— (C3-C20)cycloalkyl— (G=O)-{((CrC20)alkyl)N}— (C1- C20)alkoxy— (C=O)- {((CrC20)alkyl)N}~, (C3-C25)heteroaryl— (C=O)- {((Cr
C20)alkyl)N}— (C3-C25)heterocycUc— (C=O)- {((CrC20)alkyl)N}—, (C2-
C20)alkenyl—(C=O)-{((CrC20)alkyl)N}— (C3-C20) cycloalkenyl— (C=O)- {((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1-
C20)alkyl)N}- (C5-C20)cycloalkynyl— (C=O)-{((CrC20)alkyl)N}— (C5-
C25)aryl— (C=O)- {((C,-C20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)- (((C1- C20)alkyl)N}—5 phenyl-(0=O)— NH- , phenyl-(C=O)— ((phenyl)N}— , (C1- . C20)alkyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkyl-(C=O)— ((phenyl)N}— ,
(CrC20)alkoxy-(C=O)— ((phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- {(phenyl)N}—5 (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— , (C2- C20)alkenyl-(C=O)— {(phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- {(phenyl)N}— (C2-C20)alkynyl-(C=O)— ((phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— ((phenyl)N}— (C5-C25)aryl-(C=O)— {(phenyl)N}- perhalo(CrC20)alkyl-(C=O)— ((phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl~NH— (C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)--, (C3-
C25)heteroaryl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5-
C25)aryl— NH-(C=O)-, perhalo(C1-C20)alkyl— NH-(C=O)-, (C1- C20)alkyl}2N— (C=O)- (phenyl} ((CrC20)alkyl}N— (C=O)-, ((C3- C20)cycloalkyl} ((C rC20)alkyl}N— (C=O)- ((C1-C2JaIk0Xy) ((C1- C20)alkyl}N-(C=O)— ,((C3-C25)heteroaiyl} ((CrC20)alkyl}N-(C=O)— , ((C3- C25)heterocyclic} {(CrC20)alkyl}N— (C=O)- , {(C2-C20)alkenyl} ((C1- C20)alkyl}N— (O=O)- , {(C3-C20)cycloalkenyl} {(CrC20)alkyl}N— (C=O)-,
{(C2-C20)alkynyl} ((C1-C^aIk7I)N- (C=O)- ((C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- {(C5-C25)aryl}((CrC20)alkyl}N— (C=O)-, {perhalo(C,- C20)alkyl}((CrC20)alkyl}N— (C=O)- (phenyl}2N— (C=O)- ((C3- C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy } (phenyl}N— (C=O)-, ((C3-C25)heteroaryl} (phenyl)N— (C=O)- ,
((C3-C25)heterocyclic} (phenyl}N— (C=O)-, ((C2- C20)alkenyl} (phenyl}N— (C=O)- , ((C3-C20)cycloalkenyl} (phenyl}N— (C=O)-,
((C2-C20)alkynyl} (phenyl}N— (C=O)-, ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)- , ((C5-C25)aryl} (phenyl}N— (C=O)- ,
(perhalo(CrC20)alkyl}{phenyl}N— (C=O)-, HO-(C=O)-, (C1-
C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3- C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl — (C=O)-, (C5-C25)aryl— (C=O)- ,
perhalo(CrC20)alkyl — (C=O) — , phenyl — (C=O) — , (Cj —
C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3-
C25)heterocyclic—O— (C=O)-, (C2-C20)alkenyl—O— (C=O)-, (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl—O— (C=O)-, perhalo(CrC20)alkyl—O— (C=O)-,
phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3- C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (O=O)- O— , (C5-C25)aryl— (C=O)-O-, phenyl— (O=O)-O-, perhalo(CrC20)alkyl— (C=O)-O-, and salts thereof;
wherein each of the aforesaid (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1-
C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (as substituents on said alkylene, cycloalkylene or arylene of said Q and T) may be
optionally and independently substituted by one to four moieties selected from the
group consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, — N3, — CN, -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1-
C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20)
cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo(Cr
C20)alkyl, (CrC20)alkyl— O— , phenyl— O— , (C3-C20)cycloalkyl— O— , (C3- C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2-C20)alkenyl— O— , (C3-C20) cycloalkenyl — O — , (C2-C20)alkynyl — O — , (C5-C20)cycloalkynyl — O — , (C5-
C25)aryl— O— , perhalo(CrC20)alkyl— O— , (CrC20)alkyl— S— , phenyl— S-, (C3-
C20)cycloalkyl — S-, (C3-C25)heteroaryl — S — , (C3-C25)heterocyclic — S — , (C2-
C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5-
C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(C,-C20)alkyl— S— , (C1-
C20)alkyl— SO2- , phenyl— SO2-, (C3-C20)cycloalkyl— SO2- , (C1-
C20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-C25)heterocyclic— SO2- ,
(C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2- ,
(C5-C20)cycloalkynyl— SO2- , (C5-C25)aryl— SO2- , perhalo(C rC20)alkyl— SO2- , H2N-SO2-, (CrC20)alkyl— NH-SO2-, phenyl— NH-SO2-, (C3-
C20)cycloalkyl— NH-SO2-, (CrC20)alkoxy— NH-SO2-, (C3- C25)heteroaryl— NH-SO2-, (C3-C25)heterocyclic— NH-SO2-, (C2-
C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2-, (C2- C20)alkynyl— NH-SO2-, (C5-C20)cycloalkynyl— NH-SO2-, (C5-
C25)aryl— NH-SO2-, perhalo(CrC20)alkyl— NH-SO2-, ((C1-
C20)alkyl}2N— SO2- , (phenyl}2N— SO2- , {(C3-C20)cycloalkyl}2N— SO2- , ((C1-
C20)alkoxy}2N— SO2- , ((C^C^heteroaryl^N— SO2-, ((C3- C25)heterocyclic}2N— SO2- , ((C2-C20)alkenyl}2N— SO2- , ((C2-
C20)alkynyl}2N— SO2- , ((C5-C20)cycloalkynyl}2N— SO2- , ((C5- C25)aryl}2N— SO2- , (perhalo(CrC20)alkyl}2N— SO2- , (CrC20)alkyl-
SO2-NH-, phenyl-SO2— NH- , (C3-C20)cycloalkyl-SO2— NH- , (C1-
C20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-SO2— NH- , (C3-C25)heterocyclic- SO2-NH-, (C2-C20)alkenyl-SO2— NH- , (C3-C20) cycloalkenyl-SO2— NH- ,
(C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl-SO2— NH-, (C5-C25)aryl- SO2-NH-, perhalo(CrC20)alkyl-SO2— NH- , (CrC20)alkyl— NH- ,
phenyl— NH-, (C3-C20)cycloalkyl— NH- , (CrC20)alkoxy— NH- , (C3-
C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- ,
(C3-C20) cycloalkenyl— NH-, (C2-C20)alkynyl— NH- , (C5- C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , ρerhalo(CrC20)alkyl— NH- ,
((C1-C20)^yI)2N- (phenyl}2N- ((C3-C20)cycloalkyl}2N— ((C1- C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— {(C3-C20)cycloalkenyl}2N— , ((C2-C20)alkynyl}2N— , ((C5-
C20)cycloalkynyl}2N— , ((C5-C25)aryl}2N— , (perhalo(CI-C20)alkyl}2N— (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH-, (C3- C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH- (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH- (C5-C20)cycloalkynyl— (C=O)-NH- (C5-
C25)aryl— (C=O)-NH-, perhalo(C,-C20)alkyl— (C=O)-NH-, (C1- C20)alkyl— (C=O)- {((CrC20)alkyl)N}— phenyl— (C=O)- {((CrC20)alkyl)N}— , (C3-C20)cycloalkyl— (C=O)- {((CrC20)alkyl)N}—, (C1-
C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— , (C3-C25)heteroaryl— (C=O)- (((C1- C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— (C2- C20)alkenyl— (C=O)-{((CrC20)alkyl)N}—, (C3-C20)
cycloalkenyl— (C=O)- {((CrC20)alkyl)N}— , (C2-C20)alkynyl— <C=0)— (((C1-
C20)alkyl)N}-, (C5-C20)cycloalkynyl— (C=O)- (((CrC20)alkyl)N}— (C5-
C25)aryl—(C=O)-(((C1-C20)alkyl)N}— perhalo(C1-C20)alkyl— (C=O)-(^C1- C20)alkyl)N}— , phenyl-(C=O>— NH- phenyl-(C=O)— ((phenyl)N}— , (C1-
C20)alkyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkyl-(C=O)— {(phenyl)N}— , (CrC20)alkoxy-(C=O)— {(phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- ((phenyl)N}— , (C3-C25)heterocyclic-(C=O)— ((phenyl)N}— , (C2- C20)alkenyl-(C=O)— ((ρhenyl)N>— , (C3-C20)cycloalkenyl-
(C=O)- ((phenyl)N}— (C2-C20)alkynyl-(C=O)— ((phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— ((phenyl)N}— , (C5-C25)aryl-(C=O)— {(phenyl)N}— , perhalo(CrC20)alkyl-(C=O)— ((phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3- C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2- C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O) — , (C2- C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)aryl— NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O)-, (C1-
C20)alkyl}2N — (C=O)- {phenyl} {(Q-C^alkyljN— (C=O)-, ((C3- C20)cycloalkyl} {(CrC20)alkyl}N— (C=O)- {(CrC20)alkoxy} ((C1-
C20)alkyl}N— (C=O)-, {(C3-C25)heteroaryl} ((CrC20)alkyl}N— (C=O)-, ((C3- C25)heterocyclic} {(CrC20)alkyl}N— (C=O)- , {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)- ((C3-C20)cycloalkenyl} {(CrC20)alkyl}N— (C=O)- {(C2-C20)alkynyl} {(CrC20)alkyl}N— (C=O)- {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- ((C5-C25)aryl}((CrC20)alkyl}N— (C=O)- (perhalo(Cr
C20)alkyl} {(CrC20)alkyl}N-(C=O)—, (phenyl}2N— (C=O)- ((C3- C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (phenyl}N— (C=O)-, {(C3-C25)heteroaryl} (phenyl}N— (C=O)-, {(C3-C2S)heterocyclic} (phenyl}N— (C=O)-, ((C2-
C20)alkenyl} (phenyl}N— (C=O)-, {(C3-C20)cycloalkenyl} (phenyl}N— (C=O)-,
((C2-C20)alkynyl}(phenyl}N-(C=O)— , ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, {(C5-C25)aryl} (phenyl}N— (C=O)-,
{perhalo(CrC20)alkyl}(phenyl}N— (C=O)-, HO-(C=O)-, (C1-
C20)alkyl — (C=O) — , (C3-C25)heteroaryl — (C=O) — , (C3-
C25)heterocyclic— (C=O)-, (C2-C20)alkenyl— (C=O)-, (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-,
perhalo(CrC20)alkyl— (C=O)-, phenyl— (C=O)-, (C1-
C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl— O — (C=O)-, (C3- C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— 0— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5- C25)aryl— O— (C=O)- , perhalo(CrC20)alkyl— O— (C=O)- , phenyl— 0-(C=O)- (C1- C20)alkyl— (C=O)-O-, (C3- C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — 0 — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aiyl— (C=O)-O-,
phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof; and
wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are each independently
selected from the group consisting of hydrogen, hydroxy, halo, bromo, chloro,
iodo, fluoro, — N3, -CN, -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2- C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-
C25)aryl, ρerhalo(CrC20)alkyl, (CrC20)alkyl— O— , phenyl— O— , (C3-
C20)cycloalkyl— O— , (C3-C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2- C20)alkenyl— O — , (C3-C20) cycloalkenyl— 0—, (C2-C20)alkynyl— O— , (C5-
C20)cycloalkynyl— O— , (C5-C25)aryl— O— , perhalo(CrC20)alkyl— O— , (C1-
C20)alkyl— S— , phenyl— S — , (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— , (C3-C25)heterocyclic — S — , (C2-C20)alkenyl — S — , (C3-C20)cycloalkenyl — S — ,
(C2-C20)alkynyl— S— , (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(C,- C20)alkyl— S— , (CrC20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-
C25)heterocyclic — SO2-, (C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2- , (C5-C20)cycloalkynyl— SO2- (C5-C25)aryl— SO2-, perhalo(CrC20)alkyl— SO2- , H2N-SO2-, (CrC20)alkyl— NH-SO2- phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1- C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3-
C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2- (C2-C20)alkynyl— NH-SO2- (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr
C20)alkyl— NH-SO2- {(CrC20)alkyl}2N— SO2- {phenyl}2N— SO2- ((C3- C20)cycloalkyl}2N— SO2- {(CrC20)alkoxy}2N— SO2- ((C3- C25)heteroaryl}2N— SO2- , ((C3-C25)heterocyclic}2N— SO2- , ((C2-
C20)allenyl}2N— SO2- ((C2-C20)alkynyl}2N— SO2-, ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2--, (perhalo(Cr
C20)alkyl}2N— SO2- , (C ,-C20)alkyl-S O2-NH- phenyl-SO2— NH- , (C3-
C20)cycloalkyl-SO2— NH- , (CrC20)alkoxy-SO2— NH- , (C3-C25)heteroaryl- SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-S O2-NH-, (C3- C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl-
SO2-NH-, (C5-C25)aryl-SO2— NH- , perhalo(CrC20)alkyl-SO2— NH- , (C1-
C20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- , (C1-
C20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-
C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH-, (C2-C20)alkynyl— NH- , (C5-
C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((CrC20)alkyl}2N— (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2- C20)alkenyl}2N— {(C3-C20)cycloalkenyl}2N— ((C2-C20)alkynyl}2N— ((C5- C20)cycloalkynyl}2N— ((C5-C25)aryl}2N— (perhalo(CrC20)alkyl}2N— (C1-
C20)alkyl— (C-O)- NH- , phenyl— (C=O)-NH- (C3- C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH- (C3- C^heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (O=O)-NH-, (C2- C20)alkenyl— (C=O)-NH- (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH- (C5-C20)cycloalkynyl— (C=O)-NH- (C5- C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH-, (C1-
C20)alkyl-(C=O)-{((C1-C20)alkyl)N}-, phenyl-(C=O)-{((C1-C20)alkyl)N}- (C3-C20)cycloalkyl-(C=O)-{((C1-C20)alkyl)N}— (C1-
C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— (C3-C2S)heteroaiyl— (C=O)- (((C1- C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— (C2- C20)alkenyl— ^^-{((CrC^alkyON}— (C3-C20) cycloalkenyl— (C=O)- {((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1-
C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)- {((CrC20)alkyl)N}- (C5-
C25)aryl— (C=O)- (((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)- (((C1- C20)alkyl)N}— phenyl-(C=O)— NH-, phenyl-(C=O)— {(phenyl)N}—5 (C1-
C20)alkyl-(C=O)— ((phenyl)N}—, (C3-C20)cycloalkyl-(C=O)— {(phenyl)N}— (CrC20)alkoxy-(C=O)— {(phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- ((phenyl)N}— , (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— (C2- C20)alkenyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- ((phenyl)N}— (C2-C20)alkynyl-(C=O)— ((phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— ((phenyl)N}— , (C5-C25)aryl-(C=O)— ((phenyl)N}— , perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3- C25)heteroaryl— NH-(C=O)-, (C3-C25)heterocyclic— NH-(C=O)-, (C2- C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)aryl— NH-(C=O)-, perhalo(CrC20)alkyl— NH- (C=O)- , (C1- C20)alkyl}2N — (C=O)- {phenyl} {(CrC20)alkyl}N— (C=O)- ((C3- C20)cycloalkyl} {(C1-C20)alkyl}N-(C=O)— ((CrC20)alkoxy} ((C1-
C20)alkyl}N— (C=O)- ,((C3-C25)heteroaryl}((CrC20)alkyl}N— (C=O)- ((C3- C25)heterocyclic} {(CrC20)alkyl}N— (C=O)-, ((C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)-, {(C3-C20)cycloalkenyl}((CrC20)alkyl}N— (C=O)-,
((C2-C20)alkynyl} ((CrC20)alkyl}N— (C=O)-, {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- , {(C5-C25)aryl}{(CrC20)alkyl}N— (C=O)-, (perhalo(Cr C20)alkyl}((CrC20)alkyl}N-(C=O)— , (phenyl}2N— (C=O)- ((C3-
C20)cycloalkyl}(phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (phenyl}N— (C=O)-, {(C3-C25)heteroaryl} (phenyl}N— (C=O)-,
{(C3-C25)heterocyclic} (phenyl}N— (C=O) — , ((C2-
C20)alkenyl} (phenyl}N— (C=O)-, {(C3-C20)cycloalkenyl} (phenyl}N— (C=O)-, ((C2-C20)alkynyl} (phenyl }N-(C=0)—, ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, ((C5-C25)aryl} (phenyl)N— (C=O)-,
(perhalo(CrC20)alkyl}(phenyl}N— (C=O)-, HO-(C=O)-, (C1- C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3-
C25)heterocyclic— (C=O)-, (C2-C20)alkenyl— (C=O)-, (C3-C20)
cycloalkenyl — (C=O) — , (C2-C20)alkynyl — (C=O) — , (C5-C25)aryl — (C=O) — , perhalo(CrC20)alkyl — (C=O) — , phenyl — (C=O) — , (C1 —
C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3- C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20) cycloalkenyl— O— (C=O)- , (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl— O— (C=O)- , perhalo(CrC20)alkyl— O— (C=O)-,
phenyl— O— (C=O)-, (Ci- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl— (C=O)-O-, (C3-C25)heterocyclic— (C=O)-O-, (C2- C20)alkenyl— (C=O)-O — , (C3-C20) cycloalkenyl— (C=O)-O-, (C2-
C20)alkynyl— (C=O)-O-, (C5-C25)aiyl— (C=O)-O-, phenyl — (C=O) — O — , ρerhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
wherein each of the aforesaid (C,-C20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1- C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20)
cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (for said R2, R3, R4, R5, R6, R7, Rs, R9, R10, and R" groups) may be optionally and
independently substituted by one to four moieties selected from the group
consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, — N3, — CN, — NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (CrC20)alkoxy,
(C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl,
(C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo^ -C20)alkyl, (C1- C20)alkyl— O— , phenyl— O— , (C3-C20)cycloalkyl— O— , (C3-
C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2-C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5-C20)cycloalkynyl— O— , (C5-
C25)aryl— O— , perhalo(CrC20)alkyl— O— (CrC20)alkyl— S-, phenyl— S-, (C3-
C20)cycloalkyl — S — , (C3-C25)heteroaryl — S — , (C3-C25)heterocyclic — S — , (C2-
C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5-
C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(CrC20)alkyl— S— , (C1-
C20)alkyl— SO2- , phenyl— SO2-, (C3-C20)cycloalkyl— SO2- , (C1- C20)alkoxy— SO2-, (C3-C25)heteroaryl— SO2-, (C3-C25)heterocyclic— SO2-, (C2-C20)alkenyl— SO2- (C3-C20) cycloalkenyl— SO2- , (C2-C20)alkynyl— SO2- ,
(C5-C20)cycloalkynyl— SO2-, (C5-C25)aryl—SO2—, perhalo(C1-C20)alkyl— SO2-, H2N-SO2- (CrC20)alkyl— NH-SO2- phenyl— NH-SO2-, (C3- C20)cycloalkyl— NH-SO2-, (CrC20)alkoxy— NH-SO2-, (C3-
C25)heteroaryl— NH-SO2-, (C3-C25)heterocyclic— NH-SO2-, (C2- C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2-, (C2-
C20)alkynyl— NH-SO2-, (C5-C20)cycloalkynyl— NH-SO2-, (C5-
C25)aryl— NH-SO2-, perhalo(CrC20)alkyl— NH-SO2-, ((C1-
C20)alkyl}2N— SO2- {phenyl}2N— SO2- , {(C3-C20)cycloalkyl}2N— SO2- ((C1- C20)alkoxy}2N— SO2- , {(C3-C25)heteroaryl}2N— SO2- , ((C3-
C25)heterocyclic}2N— SO2- , ((C2-C20)alkenyl}2N— SO2- , ((C2- C20)alkynyl}2N— SO2-, ((C5-C20)cycloalkynyl}2N— SO2- ((C5-
C25)aryl}2N— SO2- , (perhalo(CrC20)alkyl}2N— SO2- , (CrC20)alkyl-
SO2-NH-, phenyl-SO2— NH- , (C3-C20)cycloalkyl-SO2— NH- , (C1-
C20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-SO2— NH- , (C3-C25)heterocyclic- SO2-NH-, (C2-C20)alkenyl-SO2— NH- , (C3-C20) cycloalkenyl-SO2— NH- ,
(C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl-
SO2-NH-, perhalo(CrC20)alkyl-SO2— NH- , (CrC20)alkyl— NH- ,
phenyl— NH-, (C3-C20)cycloalkyl— NH- , (CrC20)alkoxy— NH- , (C3-
C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH-, (C2-C20)alkynyl— NH- , (C5-
C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((CrC20)alkyl}2N— , (phenyl}2N— , ((C3-C20)cycloalkyl}2N— , ((C1- C20)alkoxy}2N— ,
Figure imgf000039_0001
{(C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— ((C3-C20)cycloalkenyl}2N— {(C2-C20)alkynyl}2N— ((C5- C20)cycloalkynyl}2N— ((C5-C25)aryl}2N— {perhalo(CrC20)alkyl}2N— (C1- C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH- (C3-
C20)cycloalkyl— (C=O)-NH- (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH- (C2- C20)alkenyl— (C=O)-NH- (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5-
C25)aryl— (C=O)-NH- perhalo(CrC20)alkyl— (C=O)-NH-, (C1- C20)alkyl— (C=O)- (((CrC20)alkyl)N}— phenyl— (C=O)- (((CrC20)alkyl)N}— ,
(C3-C20)cycloalkyl— (C=O)-(((CrC20)alkyl)N}— (C1-
C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— (C3-C25)heteroaiyl— (C=O)- (((C1-
C20)alkyl)N}— (C3-C25)heterocyclic— (C=O)- (((CrC20)alkyl)N}— (C2- C20)alkenyl— (C=O)- {((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- (((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1-
C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)—(((CrC20)alkyl)N}— (C5- C25)aryl-(C=O)— (((C1-C20)alkyl)N}- perhalo(C1-C20)alkyl-(C=O)— (((C1-
C20)alkyl)N}— phenyl-(C=O)— NH- phenyl-(C=O)— {(phenyl)N}—, (C1-
C20)alkyl-(C=O)— ((phenyl)N}—, (C3-C20)cycloalkyl-(C=O)— ((phenyl)N}— , (CrC20)alkoxy-(C=O)— ((ρhenyl)N}— , (C3-C25)heteroaryl-
(C=O)- ((phenyl)N}—5 (C3-C25)heterocyclic-(C=O)— ((phenyl)N}—, (C2- C20)alkenyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- ((phenyl)N}—5 (C2-C20)alkynyl-(C=O)— ((phenyl)N}— , (C5-
C20)cycloalkynyl-(C=O)— ((phenyl)N}— , (C5-C25)aryl-(C=O)— ((phenyl)N}— , perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}—5 H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3- C20)cycloalkyl— NH-(C=O)-, (C,-C20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaiyl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2- C20)alkynyl— NH-(C=O) — , (C5-C20)cycloalkynyl— NH- (C=O)- , (C5-
C25)MyI- NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O)-, (C1- C20)alkyl}2N— (C=O)-, {phenyl} {(CrC20)alkyl}N-(C=O)— ((C3- C20)cycloalkyl} {(CrC20)alkyl}N— (C=O)--, {(CrC20)alkoxy} ((C1-
C20)alkyl}N— <C=0) — ,{(C3-C25)heteroaryl} {(CrC20)alkyl}N— (C=O)-, ((C3- C25)heterocyclic} ((CrC20)alkyl}N— (C=O)-, {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)- ((C3-C20)cycloalkenyl} {(CrC20)alkyl}N— (C=O)-, {(C2-C20)alkynyl} ((C rC20)alkyl}N— (C=O)- ((C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)-, {(C5-C25)aryl} ((CrC20)alkyl}N— (C=O)-, (perhalo(Cr C20)alkyl}((CrC20)alkyl}N— (C=O)- (phenyl}2N— (C=O)-, ((C3-
C20)cycloalkyl}(phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (ρhenyl}N— (C=O) — , {(C3-C25)heteroaryl} (phenyl}N— (C=O) — ,
((C3-C25)heterocyclic} (phenyl}N— (C=O) — , ((C2-
C20)alkenyl} (phenyl }N— (C=O)-, {(C3-C20)cycloalkenyl} (phenyl}N— (C=O)-, ((C2-C20)alkynyl} (phenyl}N— (C=O)-, ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, {(C5-C25)aryl}(phenyl}N— (C=O)-,
Figure imgf000040_0001
C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3- C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20) cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)- , (C5-C25)aryl— (C=O)-,
perhalo(CrC20)alkyl— (C=O)-, phenyl— (C=O)- (C1- C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)- (C3-
C25)heterocyclic— O— (C=O) — , (C2-C20)alkenyl— O— (C=O) — , (C3-C20)
cycloalkenyl — O — (C=O) — , (C2-C20)alkynyl — O — (C=O) — , (C5- C25)aryl—O—(C=O)—, perhalo(C1-C20)alkyl—O— (C=O)-, phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O — , (C3-C20) cycloalkenyl— (C=O)-O-, (C2-
C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O- phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
and wherein two independently chosen R2, R3, R4, R5, R6, R7, R8, R9, R10,
and R11 alkyl-containing groups may be taken together with any atom to which they are attached to form a three to forty membered cyclic, heterocyclic or heteroaryl
ring.
In the present application, GhyCH— is NH2CC=NH)- NH-N=CH-; and
GhyCH3— is NH2CC=NH)-NH-N=CCH3-.
In one embodiment, Z is a C1-C20 alkylene, which may be branched or
unbranched, saturated or unsaturated, substituted or unsubstituted, and which may
have one or more carbon atoms replaced by one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and a combination thereof. This
includes alkylenes having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, and 20 carbons.
In another embodiment, Z is a branched C1-C20 alkylene. In another embodiment, Z is an unbranched C1-C20 alkylene.
In another embodiment, Z is a saturated Ci-C20 alkylene.
In another embodiment, Z is an unsaturated C1-C20 alkylene.
In another embodiment, Z is an unsubstituted C1-C20 alkylene.
In another embodiment, Z is a substituted C1-C20 alkylene.
In another embodiment, Z is a C1-C20 alkylene in which one or more carbons is replaced with one or more heteroatoms selected from the group
including oxygen, nitrogen, sulfur and a combination thereof.
In one embodiment, Z is a saturated or unsaturated, substituted or unsubstituted C3-C20 cycloalkylene, and which may have one or more carbon atoms
replaced by one or more heteroatoms selected from the group consisting of oxygen,
nitrogen, sulfur, and a combination thereof. This includes cycloalkylenes having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons.
In another embodiment, Z is a saturated C3-C20 cycloalkylene.
In another embodiment, Z is an unsaturated C3-C20 cycloalkylene.
In another embodiment, Z is an unsubstituted C3-C20 cycloalkylene. hi another embodiment, Z is a substituted C3-C20 cycloalkylene.
In another embodiment, Z is a C3-C20 cycloalkylene in which one or more
carbons is replaced with one or more heteroatoms selected from the group
including oxygen, nitrogen, sulfur and a combination thereof.
In one embodiment, Z is a substituted or unsubstituted C5-C25 arylene, wherein one or more carbon atoms in the cycloalkylene and arylene may be
replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and a combination thereof. This includes arylenes having 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 carbons.
In another embodiment, Z is a substituted C5-C25 arylene.
In another embodiment, Z is an unsubstituted C5-C25 arylene. In another embodiment, Z is a C5-C25 arylene in which one or more carbons
is replaced with one or more heteroatoms selected from the group including oxygen, nitrogen, sulfur and a combination thereof.
In one embodiment, Z is an — NR8(CO)NR9 — group, optionally in the salt
form, wherein the R groups are both hydrogen.
In another embodiment, Z is a — (C6H4) — group.
In another embodiment, Z is a — (CH2)p — group, wherein p is 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10.
In another embodiment, Z is a — (C5H3N) — group.
In another embodiment, Z is a — O — (CH2)p — O — group, wherein p is 1, ,
2, 3, 4, 5, 6, 7, 8, 9, or 10.
In another embodiment, Z is a — A — (CH2)p — A — group, wherein p is 1, 2,
3, 4, 5, 6, 7, 8, 9, or 10, and wherein the A's are each independently — NH(CO) — ,
-(CO)NH-, or -NH(CO)NH- groups.
In another embodiment, Z is a — A — (C6H4) — A — wherein the A's are
each independently —CO— -NH(CO)- -(CO)NH-, or -NH(CO)NH-
groups.
In another embodiment, Z is — O — (C6H4) — O — , wherein the two " — O — " groups are para to each other about the phenylene ring. In another embodiment, Z is — O — (C6H4) — O — , wherein the two " — O — " groups are meta to each other about the phenylene ring.
In another embodiment, Z is — 0-CH2-CH2-O-CH2 — CH2-O-. In another embodiment, Z is a group having the formula:
Figure imgf000044_0001
In another embodiment, Z is a group having the formula:
Figure imgf000044_0002
In another embodiment, Z is a group having the formula:
Figure imgf000044_0003
In another embodiment, Z is a group having the formula:
Figure imgf000045_0001
In another embodiment, Z is a group having the formula:
Figure imgf000045_0002
In another embodiment, Z is a group having the formula:
Figure imgf000045_0003
In another embodiment, Z is a group having the formula:
Figure imgf000045_0004
In another embodiment, Z is a group having the formula:
Figure imgf000046_0001
In one embodiment, the compound includes the structure:
Figure imgf000046_0002
In one embodiment, the compound includes the structure:
Figure imgf000046_0003
hi'one embodiment, the compound includes the structure:
Figure imgf000047_0001
In one embodiment, the compound includes the structure:
Figure imgf000047_0002
In one embodiment, the compound includes the structure:
Figure imgf000047_0003
■In one embodiment, the compound includes the structure:
Figure imgf000048_0001
In one embodiment, the compound includes the structure:
Figure imgf000048_0002
In one embodiment, the compound includes the structure:
Figure imgf000048_0003
In one embodiment, the compound includes the structure:
Figure imgf000049_0001
In one embodiment, the compound includes the structure:
Figure imgf000049_0002
In the compound, X1, X2, X3, and X4 may each individually adopt the ortho, meta or para position on the phenylene ring relative to the Z group. In another
embodiment, the X1, X2, X3, and X4 are meta or para to the Z group. In another
embodiment, the non-H X1, X2, X3, and X4 groups are meta to both the Z group and to each other.
As used herein, the formula "-NH(CO)-" includes the "-(CO)NH-" isomer.
In one embodiment, at least one of X1, X2, X3 and X4 is GhyCH — or
GhyCCH3 — , X1 and X2 are not simultaneously H, and X3 and X4 are not simultaneously H. In another embodiment, X1 , X2, X3, and X4 are selected from the group including GhyCH— or GhyCCH3— .
In another embodiment, X1 , X2, X3, and X4 are selected from the group including GhyCH—, GhyCCH3— , or CH3CO-. In another embodiment, X1 , X2, X3, and X4 are each GhyCH — .
In another embodiment, the X1 , X2, X3, and X4 are each GhyCCH3 — . hi another embodiment, the X1 , X2, X3, and X4 are each CH3CO — .
In another embodiment, at least one of X1 , X2, X3, and X4 is CH3CO — .
In one embodiment, the compound is in the salt form. In another embodiment, the compound is in the salt form having a
compound:salt ratio of 1:1, 1:2, 1:3, 1:4 or 2:l.
In one embodiment, Z has the formula:
-(A1X-(CR2R3) -Qm-(CR4R5)y-Tn-(CR6R7) -(A2)b-;
wherein each of the variables a, m, n, and b are equal to 1 ; and the sum of
the variables x, y and z does not exceed 12;
and wherein Q5 T, A1, R2, R3, R4, R5, R6, R7, A2, R10, and R11 are defined
herein.
hi one embodiment, Z has the formula:
-(A1)a-(CR2R3)x-Qm-(CR4R5)y-Tn-(CR6R7) -(A2)b-;
wherein each of the variables a, m, n, and b are equal to 1; and the sum of
the variables x, y and z does not exceed 12; wherein Q and T are each independently selected from the group consisting
R10(CO)NRn— -(CO)NR10- — NR10(CO)— , — NR10- salts thereof, — O— , optionally substituted alkylene, optionally substituted arylene, optionally
substituted heteroarylene, and combinations thereof; and wherein A1, R2, R3, R4, R5, R6, R7, A2, R10, and R11 are defined herein.
In one embodiment, Z has the formula: -(A1),— (CR2R3) - Qm_(CR4R5) -T -(CR6R7)z-(A2)b-; wherein each of the variables a, m, n, and b are equal to 1 ; and the sum of
the variables x, y and z does not exceed 12;
wherein Q and T are each independently selected from the group consisting R1O(CO)NR1 '— , -(CO)NR10-, — NR10(CO)— , — NR10- , salts thereof, — O— ,
optionally substituted alkylene, optionally substituted arylene, optionally
substituted heteroarylene, and combinations thereof;
and wherein A1, R2, R3, R4, R5, R6, R7, A2, R10, and R11 are defined herein; with the proviso that if Q is — NR10 — or — O — and y is 1 then T is not
— NR10- or— O— .
In one embodiment, Z has the formula:
-(A1) -(CR2R3) -Qm-(CR4R5)y-Tn-(CR6R7) -(A2)b-;
wherein each of the variables a, m, n, and b are equal to 1; and the sum of
the variables x, y and z does not exceed 12;
wherein Q and T are each independently selected from the group consisting
R10CCO)NR1 !— , -(CO)NR10-, — NR10(CO)— , — NR10- , salts thereof, — O— , optionally substituted alkylene, optionally substituted arylene, optionally
substituted heteroarylene, and combinations thereof;
and wherein A1, R2, R3, R4, R5, R6, R7, A2, R10, and R11 are defined herein; with the proviso that if Q is — NR10 — or — O — and y is 1 then T is not ~NR10— or — O— ; and with the proviso that if Q is -(CO)NR10-, — NR10(CO)— , — NR10- , or — O— and y is 1 then T is not -(CO)NR10-, — NR10(CO)— , — NR10- , or
— O— .
In another embodiment, Z has the formula:
-(A!)a-(CR2R3) -Qm-(CR4R5)y-Tn-(CR6R7) -(A2)b-
wherein Q and T are each independently selected from the group consisting
R10(CO)NRn— , -(CO)NR10-, — NR10(CO)— , — NR10- , salts thereof, — O— optionally substituted alkylene, optionally substituted arylene, optionally
substituted heteroarylene, and combinations thereof; wherein A1, R2, R3, R4, R5, R6, R7, A2, R10, and R11 are defined herein;
wherein if substituted, the alkylene, arylene, and/or heteroarylene are each
independently substituted with 0 to 4 groups selected from the group consisting of
H, halogen, OR, NR1R1', NR1CO, CONR1, COR1, SR1, SO2R1, SO2NR1, SOR1, alkyl, aryl, heteroalkyl, and heteroaryl, salts thereof, and combinations thereof;
R1 and R1' being each independently selected from the group including
hydrogen, hydroxy, halo, bromo, chloro, iodo, fluoro, — N3, — CN, — NC, — SH,
-NO2, -NH25 (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (CrC20)alkoxy, (C3- C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-
C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo(CrC20)alkyl, (C1-
C20)alkyl— O— , phenyl— 0—, (C3-C20)cycloalkyl— O— , (C3-
C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2-C20)alkenyl— O— , (C3-C20)
cycloalkenyl— 0—, (C2-C20)alkynyl— O— , (C5-C20)cycloalkynyl— O— , (C5- C25)aiyl— O— , ρerhalo(CrC20)alkyl— O— , (CrC20)alkyl— S— , phenyl— S-, (C3-
C20)cycloalkyl — S — , (C3-C25)heteroaryl — S — , (C3-C25)heterocyclic — S — , (C2- C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5- C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(CrC20)alkyl— S— , (C1-
C20)alkyl— SO2- , phenyl— SO2-, (C3-C20)cycloalkyl— SO2- . (C1-
C20)alkoxy— SO2-, (C3-C25)heteroaryl— SO2-, (C3-C25)heterocyclic— SO2-, (C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2- ,
(C5-C20)cycloalkynyl— SO2- , (C5-C25)aryl— SO2- , ρerhalo(CrC20)alkyl— SO2- , H2N-SO2- (CrC20)alkyl— NH-SO2-, phenyl— NH-SO2- (C3- C20)cycloalkyl— NH-SO2-, (CrC20)alkoxy— NH-SO2-, (C3-
C25)heteroaryl— NH-SO2-, (C3-C25)heterocyclic— NH-SO2-, (C2- C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2-, (C2-
C20)alkynyl— NH-SO2-, (C5-C20)cycloalkynyl— NH-SO2-, (C5- C25)aryl— NH-SO2-, perhalo(CrC20)alkyl— NH-SO2-, ((C1-
C20)alkyl}2N— SO2- {phenyl}2N— SO2- {(C3-C20)cycloalkyl}2N— SO2-, ((C1-
C20)alkoxy}2N— SO2- , {(C3-C25)heteroaryl}2N— SO2- , ((C3-
C25)heterocyclic}2N— SO2- , ((C2-C20)alkenyl}2N— SO2- , ((C2-
C20)alkynyl}2N— SO2- , ((C5-C20)cycloalkynyl}2N— SO2- .((C5-
C25)aryl}2N— SO2- , (perhalo(CrC20)alkyl}2N— SO2- , (CrC20)alkyl-
SO2-NH-, phenyl-SO2— NH- , (C3-C20)cycloalkyl-SO2— NH-, (C1-
C20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-SO2— NH- , (C3-C25)heterocyclic-
SO2-NH-, (C2-C20)alkenyl-SO2— NH- , (C3-C20) cycloalkenyl-SO2— NH- ,
(C2-C20)alkynyl-SO2— NH- (C5-C20)cycloalkynyl-SO2— NH-, (C5-C25)aryl-
SO2-NH-, perhalo(C1-C20)alkyl-SO2— NH- , (CrC20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- , (CrC20)alkoxy— NH- (C3-
C25)heteroaryl— NH — , (Q-C^heterocyclic — NH — , (C2-C20)alkenyl— NH — , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- (C5- C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
{(CrC20)alkyl}2N— , (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , {(C3-C25)heteroaryl}2N— , {(C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— ((C2-C20)alkynyl}2N— ((C5- C20)cycloalkynyl}2N— , ((C5-C25)aryl}2N— , (perhalo(CrC20)alkyl}2N— , (C1- C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH- (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaiyl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2- C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH- (C5-C20)cycloalkynyl— (C=O)-NH-, (C5-
C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH- (C1-
C20)alkyl-(C=O)—{((CrC20)alkyl)N}— phenyl— (C=O)-(((CrC20)alkyl)N}— (C3-C20)cycloalkyl— (C=O)- (((CrC20)alkyl)N}— , (C1-
C20)alkoxy— (C=O)- {((CrC20)alkyl)N}—, (C3-C25)heteroaryl— (C=O)- (((C1- C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— , (C2-
C20)alkenyl-(C=O)-(((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- (((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)- (((CrC20)alkyl)N}—, (C5-
C25)aiyl— (C=O)- (((CrC20)alkyl)N}— , perhalo(CrC20)alkyl— (C=O)- (((C1- C20)alkyl)N}— , phenyl-(C=O)— NH-, phenyl-(C=O)— ((phenyl)N}— , (C1-
C20)alkyl-(C=O)— ((phenyl)N}—3 (C3-C20)cycloalkyl-(C=O)— {(phenyl)N}— (CrC20)alkoxy-(O=O)— {(phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- {(phenyl)N}—, (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— (C2- C20)alkenyl-(C=O)— {(phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- {(phenyl)N}— (C2-C20)alkynyl-(C=O)— {(phenyl)N}—3 (C5- C20)cycloalkynyl-(C=O)— {(phenyl)N}— (C5-C25)aryl-(C=O)— {(phenyl)N}— perhalo(CrC20)alkyl-(C=O)— {(phenyl)N>— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3- C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(O=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH- (C=O)- , (C5-C20)cycloalkynyl— NH- (C=O)- , (C5-
C25)aryl— NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O)-, (C1-
C20)alkyl}2N — (C=O)- , {phenyl} {(CrC^alkylJN— (C=O)-, ((C3- C20)cycloalkyl} {(CrC20)alkyl}N— (C=O)-, ((CrC20)alkoxy} ((C1-
C20)alkyl}N— (C=O)- ,{(C3-C25)heteroaryl} ((CrC20)alkyl}N— (C=O)-, ((C3-
C25)heterocyclic} {(CrC20)alkyl}N— (C=O)- , {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)-, {(C3-C20)cycloalkenyl}((CrC20)alkyl}N— (C=O)-,
{(C2-C20)alkynyl} {(CrC20)alkyl}N— (C=O)- {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- , {(C5-C25)aiyl}{(C1-C20)alkyl}N-(C=O)— (perhalo(Cr
C20)alkyl} { (C rC20)alkyl}N— (C=O)-, (phenyl}2N— (C=O)-, ((C3- C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy}(phenyl}N— (C=O)- ,((C3-C25)heteroaryl}(phenyl}N— (C=O)-, ((C3-C25)heterocyclic} (phenyl)N— (C=O)-, ((C2-
C20)alkenyl} (phenyl}N— (C=O)-, ((C3-C20)cycloalkenyl} (phenyl}N— (C=O)-, {(C2-C20)alkynyl} {phenyl}N— (C=O)- ((C5-
C20)cycloalkynyl}{phenyl}N— (C=O)-, {(C5-C25)aryl} {phenyl}N— (C=O)-,
{perhalo(C,-C20)alkyl}{phenyl}N— (C=O) — , HO-(C=O)-, (C1- C20)alkyl — (C=O)-; (C3-C25)heteroaryl— (C=O)-, (C3- C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)- , (C2-C20)alkynyl— (C=O)- , (C5-C25)aryl— (C=O)-, perhalo(C,-C20)alkyl— (C=O)-, phenyl— (C=O) — , (C1-
C20)alkyl — 0-(C=O)- (C3-C25)heteroaryl—O— (C=O)-, (C3- C23)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20) cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl — O— (C=O)- , perhalo(C,-C20)alkyl— O— (C=O)-,
phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2-
C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O-, phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
wherein each of the aforesaid (Cj-C20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1-
C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (of the
R1 and R1' groups) may be optionally and independently substituted by one to four
moieties selected from the group consisting of hydroxy, halo, bromo, chloro, iodo,
fluoro, -N3, -CN, -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-
C20)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2- C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5- C25)aryl, perhalo(CrC20)alkyL (CrC20)alkyl— O— , phenyl— O— , (C3-
C20)cycloalkyl — O — , (C3-C25)heteroaryl — O — , (C3-C25)heterocyclic — O — , (C2-
C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5- C20)cycloalkynyl— O— , (C5-C25)aryl— O— , perhalo(CrC20)alkyl— O— , (C1-
C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— , (C3-C25)heterocyclic — S — . (C2-C20)alkenyl — S — , (C3-C20)cycloalkenyl — S — ,
(C2-C20)alkynyl— S— , (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(Cr C20)alkyl— S— , (CrC20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3- C25)heterocyclic— SO2- , (C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-,
(C2-C20)alkynyl— SO2- (C5-C20)cycloalkynyl— SO2- (C5-C25)aryl— SO2-, perhalo(CrC20)alkyl— SO2-, H2N-SO2-, (CrC20)alkyl— NH-SO2-,
phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1-
C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3- C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— -NH-SO2-, (C3-C20)
cycloalkenyl— NH-SO2-, (C2-C20)alkynyl— NH-SO2-, (C5-
C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(C,-
C20)alkyl— NH-SO2- {(CrC20)alkyl}2N— SO2- {phenyl}2N— SO2- , ((C3-
C20)cycloalkyl}2N— SO2- , {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2- , ((C3-C25)heterocyclic}2N— SO2- , ((C2- C20)alkenyl}2N— SO2- , ((C2-C20)alkynyl}2N— SO2- , ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(Cr C20)alkyl}2N— SO2- (CrC20)alkyl-SO2— NH- , phenyl-SO2— NH- (C3-
C20)cycloalkyl-SO2— NH- , (CrC20)alkoxy-SO2— NH- , (C3-C25)heteroaiyl- SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- , (C3- C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-SO2— NH- , (C5-C20)cycloalkynyl- SO2-NH- (C5-C25)aryl-SO2— NH-, perhalo(C1-C20)alkyl-SO2— NH- (C1-
C20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- , (C1- C20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-
C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- , (C5- C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- , {(C1-C20)alkyl}2N— {phenyl}2N— , {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , {(C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— ((C2- C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— , ((C2-C20)alkynyl}2N— , ((C5-
C20)cycloalkynyl}2N— , ((C5-C25)aryl}2N— , (perhalo(CrC20)alkyl}2N— , (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3- C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5-
C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH-, (Cr C20)alkyl-(C=O)-(((CrC20)alkyl)N}— phenyl— (C=O)-(((CrC20)alkyl)N}—
(C3-C20)cycloalkyl-(C=O)— (((CrC20)alkyl)N}— , (C1-
C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— , (C3-C25)heteroaryl— (C=O)- (((C1-
C20)alkyl)N}— (C3-C25)heterocyclic-(C=O)-(((CrC20)alkyl)N}— (C2-
C20)alkenyl—(C=O)—(((CrC20)alkyl)N}— (C3-C20) cycloalkenyl— (C=O)- (((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1-
C20)alkyl)N}— (C5-C20)cycloalkynyl-(C=O)-{((CrC20)alkyl)N}— (C5- C25)aryl— (C=O)- {((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)- (((C1- C20)alkyl)N}— phenyl-(C=O)— NH- , phenyl-(C=O)— ((phenyl)N}— , (C1-
C20)alkyl-(C=O)— {(phenyl)N}— , (C3-C20)cycloalkyl-(C=O)— {(phenyl)N}—5
(CrC20)alkoxy-(C=O)— {(phenyl)N}— , (C3-C25)heteroaryl- (C=O)- {(phenyl)N}— , (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— , (C2- C20)alkenyl-(C=O)— |(phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- {(phenyl)N}— (C2-C20)alkynyl-(C=O)-{(phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— {(phenyl)N}— , (C5-C25)aryl-(C=O)— {(phenyl)N}— , perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}—5 H2N(C=O)-, (C1- C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH- (C=O)- , (CrC20)alkoxy— NH-(C=O)-, (C3- C25)heteroaryl— NH-(C=O)-, (C3-C25)heterocyclic— NH-(C=O)-, (C2- C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5-
C25)aryl— NH- (C=O)- , perhalo(CrC20)alkyl— NH-(C=O)-, (C1-
C20)alkyl}2N — (C=O)- (phenyl} ((CrC20)alkyl}N— (C=O)- ((C3-
C20)cycloalkyl} ((C1-C20)^k7I)N-(C=O)- ((CrC20)alkoxy} ((C1-
C20)alkyl}N— (C=O)- ((C3-C25)heteroaryl} ((CrC20)alkyl}N-(C=O)— , ((C3-
C25)heterocyclic} ((CrC20)alkyl}N— (C=O)-, ((C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)- {(C3-C20)cycloalkenyl} ((CrC20)alkyl}N— (C=O)-,
((C2-C20)alkynyl} ((CrC20)alkyl}N— (C=O)- ((C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- ((C5-C25)aryl} ( (C 1-C20)alkyl}N— (C=O)- (perhalo(Cr
C20)alkyl}((CrC20)alkyl}N-(C=O)— , (phenyl}2N-(C=O)— , ((C3- C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1- C20)alkoxy} {phenyl}N— (C=O)- , {(C3-C25)heteroaryl} {phenyl}N— (C=O)-, {(C3-C25)heterocyclic} {phenyl}N— (C=O)- , {(C2-
C20)alkenyl} {phenyl}N— (C=O)- , {(C3-C20)cycloalkenyl} {phenyl}N— (C=O)-,
{(C2-C20)alkynyl} {phenyl}N-(C=O)— , {(C5- C20)cycloalkynyl} (phenyl)N— (C=O)- {(C5-C25)aryl} {phenyl}N— (C=O)-,
{perhalo(CrC20)alkyl}{phenyl}N— (C=O)-, HO-(C=O)-, (C1- C20)alkyl — (C=O) — , (C3-C25)heteroaryl — (C=O) — , (C3-
C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-, perhalo(C,-C20)alkyl— (C=O)-, phenyl— (C=O)-, (C1-
C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3- C25)heterocyclic—O— (C=O)-, (C2-C20)alkenyl—O— (C=O)-, (C3-C20) cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aiyl—O— (C=O)-, perhalo (C1- C20)alkyl— O— (C=O)-, phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl — (C=O) — O — , (C3-C20) cycloalkenyl — (C=O) — O — , (C2-
C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O-,
phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
and wherein two independently chosen R1 or R1' alkyl-containing groups may be taken together with any atom to which they are attached to form a three to
forty membered cyclic, heterocyclic or heteroaryl ring.
In another embodiment, Z has the formula: -(A^ -^^R^-Q^^R^-T -^R^-^A2),- wherein Q and T are each independently selected from the group consisting
R10CCO)NR1 — , -(CO)NR10-, — NR10(CO)— , -NR10-, salts thereof, —0—, optionally substituted alkylene, optionally substituted arylene, optionally
substituted heteroarylene, and combinations thereof; wherein A1, R2, R3, R4, R5, R6, R7, A2, R10, and R11 axe defined herein; wherein if substituted, the alkylene, arylene,and heteroarylene, are each
independently substituted with 0 to 4 groups selected from the group consisting of
H, halogen, OR, NR1R1', NR1CO, CONR1, COR1, SR1, SO2R1, SO2NR1, SOR1,
alkyl, aryl, heteroalkyl, and heteroaryl, salts thereof, and combinations thereof; and wherein R1 and R1' being each independently selected from the group
including alkyl, aryl, heteroalkyl, and heteroaryl.
In one embodiment, said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups selected
from the group consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, — N3,
— CN, — NC, — SH, — NO2, — NH2, salts thereof, and combinations thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl,
(CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20)
cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo(Cr
C20)alkyl, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups selected from the group consisting of (C1-C20)alkyl — O — , phenyl — O — , (C3- C20)cycloalkyl — O — , (C3-C25)heteroaryl — O — , (C3-C25)heterocyclic — O — , (C2-
C20)alkenyl— O— , (C3-C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5- C20)cycloalkynyl — O — , (C5-C25)aryl — O — , ρerhalo(C1-C20)alkyl — O — , and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene hi said Q
and/or T are each independently substituted with one or more substituent groups selected from the group consisting of (Cj-C^alkyl — S — , phenyl — S — , (C3-
C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— , (C3-C25)heterocyclic— S— , (C2-
C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5- C20)cycloalkynyl — S — , (C5-C25)aryl — S — , perhalo(C1-C20)alkyl — S — , and a
combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of (C1-C20)alkyl — SO2 — , phenyl — SO2 — , (C3- C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-
C25)heterocyclic — SO2 — , (C2-C20)alkenyl — SO2 — , (C3-C20) cycloalkenyl — SO2 — ,
(C2-C20)alkynyl— SO2-, (C5-C20)cycloalkynyl— SO2-, (C5-C25)aryl— SO2-,
perhalo(C,-C20)alkyl — SO2 — , and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of H2N — SO2 — , (C1-C20)alkyl — NH — SO2 — ,
phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1-
C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3- C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2- (C2-C20)alkynyl— NH-SO2- (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, PeAaIo(C1- C20)alkyl — NH — SO2 — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of {(CrC20)alkyl}2N — SO2 — ,
{phenyl}2N— SO2-, {(C3-C20)cycloalkyl}2N— SO2- ((C1- C20)alkoxy}2N— SO2- , ((C3-C25)heteroaryl}2N— SO2- , ((C3-
C2S)heterocyclic}2N— SO2- , ((C2-C20)alkenyl}2N— SO2- , ((C2-
C20)alkynyl}2N— SO2- {(C5-C20)cycloalkynyl}2N— SO2- ((C5-
C25)aryl}2N— SO2- , (perhalo(CrC20)alkyl}2N— SO2- , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of (Cj-C20)alkyl-SO2 — NH — , phenyl-
SO2-NH-, (C3-C20)cycloalkyl-SO2— NH- , (CrC20)alkoxy-SO2— NH- , (C3-
C25)heteroaryl-SO2— NH- , (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-
SO2-NH-, (C3-C20) cycloalkenyl-SO2— NH- , (C2-C20)aϊkynyl-SO2— NH- ,
(C5-C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl-SO2— NH- , perhalo(CrC20)alkyl-
SO2 — NH — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of (C1-C20)alkyl — NH — , phenyl — NH — , (C3-
C20)cycloalkyl— NH- , (CrC20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3- C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- ,
(C2-C20)alkynyl— NH- , (C5-C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(C1-C20)alkyl — NH — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups selected from the group consisting of {(C1-C20)alkyl}2N — , {phenyl}2N — , ((C3-
C20)cycloalkyl}2N— , {(CrC20)alkoxy}2N— {(C3-C25)heteroaryl}2N— ((C3-
C25)heterocyclic}2N— , ((C2-C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— , ((C2- C20)alkynyl}2N— ((C5-C20)cycloalkynyl}2N— ((C5-C25)aryl}2N— {perhalo(C,- C20)alkyl}2N — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups selected from the group consisting of (C1-C20)alkyl — (C=O) — NH — ,
phenyl— (C=O)-NH-, (C3-C20)cycloalkyl— (C-O)-NH-, (C1-
C20)alkoxy— (C=O)-NH-, (C3-C25)heteroaryl— (C=O)-NH-, (C3-
C25)heterocyclic— (C=O)-NH-, (C2-C20)alkenyl— (C=O)-NH-, (C3-C20)
cycloalkenyl— (C=O)-NH-, (C2-C20)alkynyl— (C=O)-NH-, (C5-
C20)cycloalkynyl— (C=O)-NH-, (C5-C25)aryl— (C=O)-NH-, ρerhalo(Cr
C20)alkyl — (C=O) — NH — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of (CrC20)alkyl — (C=O) — (((C1- C20)alkyl)N}— phenyl-(C=O)-(((C1-C20)alkyl)N}— , (C3-
C20)cycloalkyl— (C=O)- {((CrC20)alkyl)N}— , (CrC20)alkoxy— (C=O)- (((C1- C20)alkyl)N}— (C3-C25)heteroaryl— (C=O)- {((CrC20)alkyl)N}— (C3- C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}—, (C2- C20)alkenyl-(C=O)—{((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- {((CrC20)alkyl)N}— 3 (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— , (C5-C20)cycloalkynyl— (C=O)-{((CrC20)alkyl)N}— (C5-
C25)aiyl—(C=O)—{((C1-C20)alkyl)N}—, perhalo(C1-C20)alkyl— (C=O)-K(C1- C20)alkyl)N} — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q and/or T are each independently substituted with one or more substituent groups selected from the group consisting of phenyl-(C=O) — NH — , phenyl-
(C=O)-{(phenyl)N}— (CrC20)alkyl-(C=O)— {(phenyl)N}— (C3-
C20)cycloalkyl-(C=O)— {(phenyl)N}— , (CrC20)alkoxy-(C=O)— {(phenyl)N}— , (C3-C25)heteroaryl-(C=0)- {(phenyl)N}~ , (C3-C25)heterocyclic-
(C=O)- {(phenyl)N}— (C2-C20)alkenyl-(C=O)— {(phenyl)N}—5 (C3-
C20)cycloalkenyl-(C=O)— {(phenyl)N}— , (C2-C20)alkynyl-
(C=O)- {(phenyl)N}—3 (C5-C20)cycloalkynyl-(C=O)— {(phenyl)N}—5 (C5- C25)aryl-(C=O)— {(phenyl)N}— , perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}—
salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting OfH2N(C=O) — , (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3- C25)heteroaryl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2- C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)aryl— NH- (C=O)- , perhalo(CrC20)alkyl— NH-(C=O)-, salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups selected from the group consisting of {CrC20)alkyl}2N — (C=O) — , {phenyl} ((C1-
C20)alkyl}N— (C=O)- {(C3-C20)cycloalkyl}{(CrC20)alkyl}N— (C=O)- , ((C1-
C20)alkoxy} {(CrC20)alkyl}N— (C=O)- ,{(C3-C2S)heteroaryl} ((C1-
C20)alkyl}N— (C=O)- , ((C3-C25)heterocyclic}((C1-C20)alkyl}N— (C=O) — , ((C2- C20)alkenyl}
Figure imgf000066_0001
{(C3-C20)cycloalkenyl} ((C1-
C20)alkyl}N— (C=O)- {(C2-C20)alkynyl}((C1-C20)alkyl}N-(C=O)— , ((C5-
C20)cycloalkynyl}((CrC20)alkyl}N-(C=O)— {(C5-C25)aryl} ((C1- C20)alkyl}N— (C=O)-, {perhalo(CrC20)alkyl} ((CrC20)alkyl}N— (C=O)-, salts
thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting of (phenyl}2N — (C=O) — , ((C3-
C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy} (phenyl }N— (C=O) — , {(C3-C25)heteroaryl} (phenyl }N— (C=O) — ,
{(C3-C25)heterocyclic} (phenyl}N— (C=O) — , ((C2-
C20)alkenyl} (phenyl }N— (C=O) — , {(C3-C20)cycloalkenyl} (phenyl}N— (C=O)-, {(C2-C20)alkynyl} (phenyl }N-(C=O)—, ((C5- C20)cycloalkynyl} (phenyl)N— (C=O)- , {(C5-C25)aryl} (phenyl}N— (C=O)-, {perhalo(CrC20)alkyl}{phenyl}N — (C=O) — , salts thereof, and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups selected from the group consisting of HO — (C=O) — , (C1 — C20)alkyl — (C=O) — ,
(C3-C25)heteroaryl — (C=O) — , (C3-C25)heterocyclic — (C=O) — , (C2- C20)alkenyl— (C=O)-, (C3-C20) cycloalkenyl— (C=O)- , (C2-
C20)alkynyl— (C=O)-, (C5-C25)aryl— (O=O)- , perhalo(Cr v C20)alkyl — (C=O) — , phenyl — (C=O) — , and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting Of(C1 — C20)alkyl — O — (C=O) — , (C3- C25)heteroaryl — O — (C=O) — , (C3-C25)heterocyclic — O — (C=O) — , (C2- C20)alkenyl—O— (C=O)-, (C3-C20) cycloalkenyl— O— (C=O)-, (C2-
C20)alkynyl— O— (C=O)- , (C5-C25)aryl— O— (C=O)- , perhalo(C,-
C20)alkyl — O — (C=O) — , phenyl — O — (C=O) — , and a combination thereof.
In another embodiment, said alkylene, cycloalkylene or arylene in said Q
and/or T are each independently substituted with one or more substituent groups
selected from the group consisting Of (C1 — C20)alkyl — (C=O) — O — , (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2-
C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O- phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and a combination thereof. When the Z group or any of its constituent A, Q, T, or CRR groups are substituted, the substituent is preferably a pharmaceutically acceptable or suitable
substituent. This type of substituent is intended to mean a chemically and
■ pharmaceutically acceptable functional group (e.g., a moiety that does not negate the pharmaceutical activity of the active compound.)
In one embodiment, the suitable pharmaceutically acceptable substituents
include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy
groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups,
aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or
heteroaralkoxy groups, HO — (C =0) — groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl
groups, alkylaminocarbonyl groups, dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups and the
like.
As used herein, the term, "alkylene" refers to a diradical alkane species that
contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons
or any subrange of carbons therebetween. The alkylene may be branched or
unbranched, saturated or unsaturated, and substituted or unsubstituted. In addition,
any carbon atom therein may be optionally replaced with one or more heteroatoms
such as nitrogen, oxygen or sulfur or any combination thereof.
As used herein, the term, "cycloalkylene" refers to a diradical cycloalkane
species that contains 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 ring carbons or any subrange of carbons therebetween. The cycloalkylene may be branched or uribranched, saturated or unsaturated, and substituted or unsubstituted. In addition, any carbon atom therein may be optionally replaced with one or more
heteroatom such as nitrogen, oxygen or sulfur or any combination thereof.
As used herein, the term "arylene" means an aromatic diradical species having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 carbons and any subrange of carbons thereof. These may be unsubstitued or
substituted as indicated herein. In addition, any carbon atom therein may be
optionally replaced with one or more heteroatom such as nitrogen, oxygen or sulfur or any combination thereof to form a heteroarylene. As used herein, the term "alkyl" as well as the alkyl moieties of or within
other groups referred to herein (e.g., (C,-C20)alkyl, (CrC2o)alkoxy, (C2-C20)alkenyl,
(C2-C20)alkynyl, and perhalo(C1-C20)alkyl) include alkyl moieties having 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons or any subrange of carbons therebetween. They may be linear or branched (such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl, etc.). They
may be saturated or unsaturated as indicated by the "alkenyl" or "alkynyl"
terminology. Other than the perhaloalkyl, which are completely substituted by one
or more of the same or different halogens, the alkyl groups may be unsubstituted or
substitued as indicated herein.
As used herein, the term "cycloalkyl" as well as the other moieties having
cyclic groups referred to herein (for example (C3-C2o)cycloalkyl, (C3-C20) cycloalkenyl and (C5-C20)cycloalkynyl) refers to mono carbocyclic moieties having
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 ring carbons or any subrange of carbons therebetween. They may be unsubstituted or substituted as indicated herein.
As used herein, the terms, "alkenyl," "alkynyl," "cycloalkynyl," and "cycloalkenyl" refer to unsaturated radical species having 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 113 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons (or, for the cyclic species 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 ring carbons) or any subrange of carbons or ring carbons therebetween. They may be branched or
unbranched, and they may be unsubstituted or substituted as indicated herein. These groups have one or more than one site of unsaturation, i.e., one or more
double or triple bonds. For example, these moieties may have one, two, three, four or more sites of unsaturation. Some nonlimiting examples of these include ethenyl,
«
1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.
As used herein, the term, "alkoxy" refers to alkyl — O — radical species
having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 carbons or any subrange of carbons therebetween. They may be unsubstituted or
substituted as indicated herein.
As used herein, the term "halogen" or "halo" includes fluoro, chloro, bromo
or iodo, and any combination thereof.
As used herein, the term "aryl" means aromatic radicals having 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 carbons and any subrange of carbons thereof. These may be unsubstitued or substituted as indicated
herein. Nonlimiting examples include phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. As used herein, the term "heteroaryl" refers to an aromatic heterocyclic group with at least one heteroatom selected from O, S and N in the ring and having
3, 4, 5, 6, 1, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 ring carbons and any subrange of carbons thereof. The heteroatoms may be present either alone or in any combination. The heteroaryl groups may be unsubstitued or
substituted as indicated herein. One, two, three, four or more heteroatoms may be
present. In addition to said heteroatom, the aromatic group may optionally have up to four N atoms in the ring. Nonlimiting examples of heteroaryl groups include
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3- thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl),
oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; which are
optionally unsubstituted or substituted with one or more substituent groups as
indicated herein.
The term "heterocyclic" as -used herein refers to a cyclic group containing 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 ring
carbons and any subrange of carbons thereof carbon atoms and hetero atoms
selected from N, O, S or NR'. Nonlimiting examples include azetidinyl,
tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,
tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl,
oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl,
benzoxazinyl and the like. Examples of such monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin- 1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, l,3-oxazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-
3-yl, l,2-pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, thiomorpholinyl, 1,2-
tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-l-yl, l,4-oxazin-2-yl,
l,2,5-oxathiazin-4-yl and the like; which may be unsubstituted or optionally substituted with one or more substituents as indicated herein.
The compounds herein can be synthesized according to known methods by
one of ordinary skill in the art.
The entire contents of the CRC Handbook of Chemistry and Physics, 66th
edition (1985-86), are incorporated herein by reference for all purposes, the same
as set forth at length.
The entire contents of G.P. Moss, P.A.S. Smith and D. Tavernier, Pure and
Applied Chemistry, 67, 1307-1375 (1995) are incorporated herein by reference for
all purposes.
The entire contents of the International Union of Pure and Applied
Chemistry Compendium of Chemical Terminology ("The Gold Book") 2nd edition,
(1997) Edited by A. D. McNaught and A. Wilkinson are incorporated herein by reference for all purposes.
The compounds herein are suitable for administration to subjects,
preferably human, in need of the prevention and/or treatment of various indications
for CNI- 1493 known in the art and already incorporated herein by reference. These include those conditions set out in United States Patent Application Publication Nos. 2003/0134904 to Giordano et al: 2003/0203969 to Bevec et al.: and 2002/0028851 to Bianchi et al.: and United States Patent Nos. 6,673,777;
6,143,728; 6,319,894; 6,248,787; 6,180,676; 6,022,900; 6,008,255; 5,859,062; 5,854,289; 5,849,794; 5,753,684; 5,750,573; and 5,599,984.
The present inventor has carried out in vitro assays and have measured the activity of the present compounds on the inhibition of LPS-induced nitric oxide
and TNFα secretion from murine macrophage cells. The inventors have found,
surprisingly and unexpectedly that NO and TNFα activity can be resolved, and it is
possible to dissect apart the NO and TNFα activity with compounds having potency in an NO assay which are relatively inactive for TNFα. The inventors have
also found that it is possible to provide good "mixed" inhibitors and also more selective TNFα inhibitors. Both TNF activity as well as possible biological targets
are contemplated herein. In particular, the compounds herein are particularly useful for
administration to a subject, preferably human, to prevent or reduce the generation
of nitric oxide (NO) or in anti-TNF alpha therapy, or to treat or prevent any
condition or disease mediated by either or both of NO and TNF alpha. In one
embodiment, the compounds may be symmetrical, i.e., have the same groups on
either side of the Z linker. In another embodiment, the compounds may be asymmetrical, i.e., have different groups on either side of the linker. In this regard,
the linker Z itself is not included in the calculus of symmetry/asymmetry, e.g., a compound having an asymmetrical linker group Z connected to symmetrical end
groups would be a symmetrical compound. In one embodiment, a mixture of symmetrical and asymmetrical compounds may be administered. In one embodiment, both asymmetrical and symmetrical compounds are suitable for administration to a subject, preferably human, to prevent or reduce the generation
of nitric oxide (NO) or in anti-TNF alpha therapy, or to treat or prevent any condition or disease mediated by either or both of NO and TNF alpha. In another
embodiment, asymmetrical compounds exhibit more pronounced anti-TNF alpha activity. In another embodiment, the symmetrical compounds exhibit more
pronounced anti-NO activity.
The compounds herein are basic and may if desired form pharmaceutically
acceptable salts with organic and inorganic acids. Nonlimiting examples of suitable acids for such acid addition salt formation are hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric
acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid,
hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic
acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid,
naphthylsulfonic acid, sulfanilic acid, camphersulfonic acid, china acid, mandelic
acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic
acid, d-o-tolyltartraric acid, tartronic acid, α-toluic acid, (o, m, p)-toluic acid,
naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to
those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional
manner.
In one embodiment, the compound is in the form of mucate, isethionate,
acetate, glutamate, L-lactate, L-tartrate, tosylate, mesylate, fumarate, maleate, citrate, sulfate and combinations thereof. Compositions containing mixtures of salts are possible.
The free base forms may be regenerated by treating the salt with a suitable
dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their
corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their
corresponding free base forms.
One embodiment relates to pharmaceutical compositions comprising at least one compound and/or pharmaceutically acceptable salt thereof as an active
ingredient and a pharmaceutically acceptable carrier, excipient, adjuvant and/or
diluent.
The compounds can also be administered in a form of their
pharmaceutically active salts optionally using substantially nontoxic
pharmaceutically acceptable carriers, excipients, adjuvants or diluents. The
compositions may be prepared in any conventional solid or liquid carrier or diluent
and optionally any conventional pharmaceutically-made adjuvant at suitable dosage
level in a known way. The preferred preparations are in administrable form which
is suitable for oral application. These administrable forms, for example, include pills, tablets, film tablets, coated tablets, capsules, powders and deposits. Forms other than orally administrable forms are also possible. The compounds and/or pharmaceutical preparations containing said compounds may be
administered by any appropriate means, including but not limited to injection (intravenous, intraperitoneal, intramuscular, subcutaneous) by absorption through
epithelial or mucocutaneous linings (oral mucosa, rectal and vaginal epithelial linings, nasopharyngial mucosa, intestinal mucosa); orally, rectally, transdermally,
topically, intradermally, intragastrally, intracutanly, intravaginally, intravasally,
intranasally, intrabuccally, percutanly, sublingually, or any other means available within the pharmaceutical arts.
The pharmaceutical compositions, containing at least one compound and/or pharmaceutically acceptable salts thereof as an active ingredient, will typically be
administered in admixture with suitable carrier materials suitably selected with
respect to the intended form of administration, i.e. oral tablets, capsules (either
solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with
conventional pharmaceutical practices. For example, for oral administration in the
form of tablets or capsules, the active drug component may be combined with any
oral nontoxic pharmaceutically acceptable inert carrier, such as lactose, starch,
sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc,
mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or
needed, suitable binders, lubricants, disintegrating agents and coloring agents may
also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent by weight of the inventive compound, salt
thereof, or a mixture of compound and salt, which range includes all values and subranges therebetween, including 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, and 90 % by weight.
Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate,
carboxymethyl-cellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium
benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents
and preservatives may also be included where appropriate. Some of the terms
noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.
Additionally, the compounds or compositions may be formulated in sustained release form to provide the rate controlled release of any one or more of
the components or active ingredients to optimize the therapeutic effects, i.e.
antihistaminic activity and the like. Suitable dosage forms for sustained release
include layered tablets containing layers of various disintegration rates or
controlled release polymeric matrices impregnated with the active components and
shaped in tablet form or capsules containing such impregnated or encapsulated
porous polymeric matrices. *
Liquid form preparations include solutions, suspensions and emulsions.
Nonlimiting examples include water, ethanol, ethanolic, water-ethanol or
water-propylene glycol solutions for parenteral injections or addition of sweeteners
and opacifϊers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically
acceptable carrier such as inert compressed gas, e.g. nitrogen.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten
homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or
parenteral administration. Such liquid forms include solutions, suspensions and
emulsions.
The compounds may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and
can be included in a transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
The term capsule refers to a special container or enclosure made of methyl
cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or
containing compositions comprising the active ingredients. Hard shell capsules are
typically made of blends of relatively high gel strength bone and pork skin gelatins.
The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.
Oral gels refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
Suitable diluents are substances that usually make up the major portion of the composition or dosage form.
Suitable diluents include sugars such as lactose, sucrose, mannitol and
sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range
from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight.
The term disintegrants refers to materials added to the composition to help
it break apart (disintegrate) and release the medicaments. Suitable disintegrants
include starches, "cold water soluble" modified starches such as sodium
carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar,
tragacanth and agar, cellulose derivatives such as methylcellulose and sodium
carboxymethylcellulose, microcrystalline celluloses and cross-linked
microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic
acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The
amount of disintegrant in the composition can range from about 2 to about 20% by
weight of the composition, more preferably from about 5 to about 10% by weight. Binders characterize substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the
formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and
ammonium calcium alginate; cellulosic materials such as methylcellulose and
sodium carboxymethylcellulose and hydroxypropyl-methylcellulose;
polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by
weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
Lubricant refers to a substance added to the dosage form to enable the
tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as
magnesium stearate, calcium stearate or potassium stearate; stearic acid; high
melting point waxes; and water soluble lubricants such as sodium chloride, sodium
benzoate, sodium acetate, sodium oleate, polyethylene glycols and d,l-leucine.
Lubricants are usually added at the very last step before compression, since they
must be present on the surfaces of the granules and in between them and the parts
of the tablet press. The amount of lubricant in the composition can range from
about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to
about 2%, more preferably from about 0.3 to about 1.5% by weight. Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition
can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
Coloring agents are excipients that provide coloration to the composition or
the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of
the coloring agent can vary from about 0.1 to about 5% by weight of the
composition, preferably from about 0.1 to about 1%.
Techniques for the formulation and administration of the compounds may
be found in "Remington's Pharmaceutical Sciences" Mack Publishing Co., Easton
Pa, the entire contents of which are hereby incorporated by reference. A suitable composition comprising at least one compound of the invention may be a solution
of the compound in a suitable liquid pharmaceutical carrier or any other
formulation such as tablets, pills, film tablets, coated tablets, dragees, capsules,
powders and deposits, gels, syrups, slurries, suspensions, emulsions, and the like.
The term "treating" as used herein refers to reversing, alleviating, inhibiting
the progress of, or preventing the disorder or condition to which the term applies,
or one or more symptoms of the disorder or condition. The term "treatment" as used herein refers to the act of treating as the term is defined above.
The compounds can exist in several tautomeric forms, and geometric
isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of tautomers in solution. In solid form, usually one tautomer predominates. Even though one
tautomer may be described, the present invention includes all tautomers of the present compounds.
The present invention also includes atropisomers. Atropisomers refer to
compounds that can be separated into rotationally restricted isomers. These compounds may contain olefin-like double bonds. When such bonds are present, the compounds exist as cis and trans configurations and as mixtures thereof.
The compound may exist in any convenient crystalline, semicrystalline, or
amorphous form. These may be achieved via typical crystallization routes including vacuum crystallization or spray drying. Depending on the solublity
desired, the amorphous form obtained by, e.g., spray-drying may be preferred. The spray drying may be carried out from aqueous, ethanolic, organic, or mixed
aqueous ethanolic solutions of the compound or its salt or a mixture thereof. The compound may exist in a form comprising one or more waters of hydration.
The present invention also includes isotopically-labeled acid compounds, which are identical to those recited above, but for the fact that one or more atoms
are replaced by an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of isotopes that
can be incorporated into compounds include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N,
180, 170, 31P, 32P, 35S, i8F, and 36Cl, respectively. Compounds, prodrugs thereof,
and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within
the scope of this invention. Certain isotopically-labeled compounds, for example, those into which radioactive isotopes such as 3H and 14C are incorporated, are
useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon- 14, i.e., 14C3 isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium,
i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced dosage requirements
and, hence, it would be preferred in some circumstances. Isotopically labeled compounds and/or prodrugs can generally be prepared by substituting a readily
available isotopically labeled reagent for a non-isotopically labeled reagent.
EXAMPLES
The following experimental and tabular examples were prepared hi
accordance with methods available to one of ordinary skill in the art. Below, "MF" means molecular formula, and "MW" means molecular weight in grams/mole.
Analog 7
Figure imgf000083_0001
3,5-Diacetylaniline (150 mg, 0.847 mmol) and pyridine (0.16 mL, 1.7 mmol) were combined in 20 mL of methylene chloride and cooled to O0C. Adipoyl chloride (0.17 mL, 0.91 mmol) was added. After stirring for 15 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 15
hours. Water was then added and the mixture was filtered. The solid was collected and boiled in a 1/1 mixture of acetone/methanol (30 mL). After cooling
the mixture to room temperature, the mixture was filtered again and the solid was
collected. The off-white solid was very clean diamide product (142 mg, 0.305
mmol). LC/MS (EI) 465 (M+l), 487 (M+Na).
Figure imgf000084_0001
The diamide (142 mg, 0.306 mmol) was suspended in 4 mL of 2-
methoxyethanol. Concentrated HCl (27 μL, 0.43 mmol) and 1.3 mL of water were
added and the mixture was heated to 5O0C. Aminoguanidine hydrochloride (68 mg, 0.62 mmol) was added and the mixture was stirred at 6O0C for four hours.
Ethanol (2 mL) was added and the reaction was stirred at room temperature for two days. The mixture was filtered. LC/MS showed only a 50% conversion of starting
material to product and the trisubstituted product. The mixture of solids was subjected to the reaction conditions again, except the water was omitted. After 10 hours, the reaction was cooled to room temperature and stirred for two days. Water (5 mL) was added to the reaction mixture. It was then filtered and washed with 10
mL of water. The solid was collected and dried to give 97 mg of pure material. The aqueous filtrate did contain more of the product but the purity was much less.
1H NMR (DMSOd5) δ 11.03 (s, 4H), 10.19 (s, 2H), 8.12 (s, 4H), 8.05 (s, 2H), 7.73
(broad s, 12H), 2.36 (m, 16H), 1.66 (broad s, 4H); LC/MS (EI) 689 (M+l), 711
(M+Na).
Analog 8
Figure imgf000085_0001
3,5-Diacetylaniline (200 mg, 1.13 mmol) and pyridine (0.18 mL, 1.7 mmol)
were combined in 10 mL of methylene chloride. Suberoyl chloride (0.11 mL, 0.62
mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. Water was then added and the mixture was filtered. The solid was
collected and boiled in a 1/1 mixture of acetone/methanol. After cooling the mixture to room temperature, the mixture was filtered again and the solid was
collected. The white solid was very clean diamide product (168 mg, 60%); LC/MS
(EI) 493 (M+l), 515 (M+Na).
Figure imgf000086_0001
The diamide (166 mg, 0.337 mmol) was suspended in 10 mL of 2- methoxyethanol. Aminoguanidine hydrochloride (298 mg, 2.69 mmol) was added and the mixture was heated with stirring to 1150C. After eight hours, the reaction
mixture became a clear solution. Another 289 mg of the aminoguanidine
hydrochloride was added and the mixture stirred at 1150C for 15 hours. A white
precipitate was now visible. The reaction mixture was cooled to room temperature
and filtered. The solids were washed with 20 mL of water, collected and dried.
Recrystallization from 25 mL of methanol gave the product as a white solid (145
mg, 50%): 1H NMR (DMSO^) δ 11.04 (s, 4H), 10.14 (s, 2H), 8.10 (s, 4H)5 8.05 (s, 2H), 7.75 (broad s, 12H), 2.36 (m, 16H), 1.62 (broad s, 4H), 1.35 (broad s, 4H);
LC/MS (EI) 717 (M+l), 739 (M+Na).
Analog 9 >
Figure imgf000087_0001
2,5-Thiophenedicarboxylic acid (200 mg, 1.16 mmol) was suspended in 4
niL of methylene chloride. Oxalyl chloride (0.25 mL, 2.9 mmol) was added. One
drop of dimethylformamide was then added. The evolution of gas was observed.
After 20 minutes, it had stopped and another drop of dimethylformamide was added. This was repeated for one hour. The solvent was removed from the
reaction mixture and the yellow solid was dried by a vacuum pump. The diacid chloride was used without further purification.
3,5-Diacetylaniline (150 mg, 0.847 mmol) and pyridine (0.14 mL, 1.2
mmol) were combined in 4 mL of methylene chloride. The crude 2,5-
thiophenedicarboxylic acid chloride (89 mg, 0.42 mmol) in 3 mL of methylene
chloride was slowly added to the solution. The reaction mixture was stirred at
room temperature for 1 day. A lot of starting aniline was still present by LC/MS.
More of the diacid chloride (89 mg, 0.42 mmol) in 2 mL of methylene chloride was added to the reaction mixture. The mixture was stirred for 36 hours. Water was
added and the mixture was filtered. The solids product (164 mg, 79%) were collected and used without further purification: LC/MS (EI) 491 (M+l), 513 (M+Na).
Figure imgf000088_0001
The diamide (164 mg, 0.334 mmol) was suspended in 10 rnL of 2-
methoxyethanol. The aminoguandine hydrochloride (296 mg, 2.67 mmol) was
added and the mixture was heated to 850C with stirring for 1 day. Aminoguanidine hydrochloride (296, 2.67 mmol) was added again and the reaction temperature was
raised to 1150C and stirred 8 hours. The addition was repeated and the stirring was
continued for 18 hours. The reaction mixture was cooled to room temperature.
The mixture was filtered and the solids were washed with 20 mL of water. The
solid was collected and titurated with methylene chloride. Further purification was
accomplished by recrystalization from 25 mL of boiling ethanol and gave the
product as a beige solid (179 mg, 63%): 1H NMR (OMSOd6) δ 11.05 (s, 4H)5
10.79 (s, 2H), 8.37 (s, 4H), 8.28 (s, 2H), 8.12 (s, 2H), 2.41 (s, 12 H); LC/MS (EI) 715 (M+l); 737 (M+Na).
Figure imgf000089_0001
Sebacic acid monomethyl ester (238 nig, 1.10 mmol) was suspended in 4
niL of methylene chloride. Oxalyl chloride (0.12 mL, 1.3 mmol) was added. One drop of dirnethylformarnide was then added. The evolution of gas was observed.
After 20 minutes, it had stopped and another drop of dimethylformamide was added. This was repeated for one hour. The solvent was removed from the
reaction mixture and the yellow solid was dried by a vacuum pump. The acid
chloride was used without further purification.
3,5-Diacetylaniline (133 mg, 0.750 mmol) and pyridine (0.21 mL, 1.5 mmol) were combined in 5 mL of methylene chloride. The acid chloride (194 mg,
0.825 mmol) in 3 mL of methylene chloride was slowly added. The reaction
mixture was stirred at room temperature for 5 hours. An aqueous, saturated
solution of sodium bicarbonate was added and the mixture continued stirring for 30
minutes. The two phases were separated and the aqueous solution was extracted with methylene chloride. The organics were combined and dried over sodium
sulfate. The product was purified by column chromatography using 3:1 methylene
chloride:ethyl acetate as the eluent. This gave 210 mg (75%) of the desired product as an off-white solid: LC/MS (EI) 376 (M+l).
Figure imgf000090_0001
Figure imgf000090_0002
The monomethyl ester amide (210 nig, 0.559 mmol) was dissolved in a 3:1 mixture of methanol: water. Lithium hydroxide monohydrate (47 mg, 1.1 mmol)
was added and the reaction mixture was stirred for one day. The methanol was
removed by rotary evaporation. The residue was diluted with 30 niL of water and
was extracted three times with 20 mL of ethyl acetate. The aqueous layer was
acidified to a pH~2 using 1 mL of 6N hydrochloric acid solution. The aqueous
layer was then extracted again three times with 20 mL of ethyl acetate. The
organics from this last extraction were combined and dried over sodium sulfate.
The mixture was then filtered and the solvent removed by rotary evaporation. The
residue was purified by trituration with methylene chloride to give the pure product as a white solid (121 mg, 61%): 1H NMR (OMSOd6) δ 10.28 (s, IH), 8.42 (s, 2H)3
8.14 (s, IH)3 2.63 (s, 6H), 2.34 (t, J= 7.6 Hz3 2 H), 2.18 (t, J= 7.3 Hz32H)3 1.60
(m, 2H)3 1.49 (m, 2H)3 1.28 (m, 8H); LC/MS (EI) 715 (M+l); 737 (M+Na).
Figure imgf000091_0001
The diamide (149 mg, 0.341 mmol) was suspended in 10 mL of 2- methoxyethanol. The aminoguanidine hydrochloride (113 mg, 1.02 mmol) was
added and the mixture was heated to 950C for 8 hours. More aminoguanidine hydrochloride (113 mg, 1.02 mmol) was added and the reaction mixture continued
to be stirred at 95° to 1000C for another 15 hours. Conversion was still not complete and aminoguanidine hydrochloride (226 mg, 2.04 mmol) was added
again and the temperature was raised to 12O0C and heated for 8 hours. The
addition was repeated the mixture was stirred another 15 hours at that temperature.
The mixture was then cooled to room temperature and the solvent was removed by
rotary evaporation. The residue was heated with 25 mL of methanol until it
dissolved completely. A small amount of water (1 mL) was added and the mixture
was cooled to room temperature. The crystals that formed were collected to give
pure product (60 mg, 28%): 1HMVlR (DMSO^) δ 11.29 (s, 2H), 10.16 (s, IH),
9.91 (s, IH), 8.72 (s, IH), 8.12 (s, 2H), 8.04 (s, IH), 7.84 (broad s, 6H), 7.59 (d, J
= 7.7 Hz, 2 H), 7.27 (t, J= 8.0 Hz, 2H), 7.00 (t, J= 7.4 Hz, IH), 4.69 (s, IH), 2.38 (s, 6H), 2.31 (m, 4H), 1.59 (m, 4H), 1.30 (broad s, 8H); LC/MS (EI) 549 (M+l), 571 (M+Na). Analog 11
Figure imgf000092_0001
3-Acetylaniline (201 mg, 1.49 mmol) and pyridine (0.18 niL, 1.7 tnmol)
were combined in 10 niL methylene chloride. Sebacoyl chloride (0.18 niL, 0.85
mmol) was slowly added and the reaction mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate (5 mL) was added and the mixture was stirred for 30 minutes. The mixture was filtered and the
solids collected. This gave 310 mg (95%) of the product as a white solid: LC/MS
(EI) 437 (M+l), 459 (M+Na).
H
Figure imgf000092_0002
The diamide (272 mg, 0.623 mmol) was suspended in 10 mL of 2- methoxyethanol. The aminoguanidine hydrochloride (207 mg, 1.87 mmol) was
added and the mixture was heated to 1150C and was stirred for 8 hours. More aminoguanidine hydrochloride (207 mg, 1.87 mmol) was added and the mixture continued to stir at 1150C for one day. The mixture was then cooled to room
temperature and the solvent was removed by rotary evaporation. The residue was
dissolved in 8 mL of hot methanol and 1 mL of water was added. The mixture was allowed to slow cool to room temperature and set for 2 days. The mixture was
filtered and the crystals were collected to give pure product (248 mg, 64%): 1H
NMR (DMSOd6) δ 10.98 (s, 2H), 10.00 (s, 2H), 7.98 (s, 2H), 7.72 (m, 8H), 7.33 (t,
J= 8.0 Hz, 2H), 3.30 (s, 2 H), 2.30 (m, 10H), 1.59 (m, 4H), 1.30 (s, 8H); LC/MS (EI) 549 (M+l); 571 (M+Na).
Other compounds:
30 mg of mono-aminoguanidine were prepared. From the method of synthesis and purification, this was probably the free base. The material was very
high quality, on the order of 97-98% by HPLC. The NMR data was also clean.
Figure imgf000094_0001
Tetra-aminoguanidine compound:
The acid chloride route was chosen for these compounds, since there was less contamination with DCC by-products.
Figure imgf000095_0001
Tetra-acetyl compound:
Figure imgf000096_0001
Tris-aminoguanidine compound:
Using conditions similar to the mono-aminoguanidine synthesis, the tetra-
acetyl compound was dissolved completely in CH3CN: THF and a solution of
amino-guanidinine hydrochloride in methanol was added. Only two equivalents of
amino-guanidine were used, since the object was to make the bis-amino guanidine
impurity. However, this reaction produced mono and tris amino-guanidine, with
very little bis. The tris amino-guanidine precipitated from the reaction mixture
along with some mono, resulting in a 3:1 mixture. Attempts to purify this by
chromatography were not successful, but chromatography will be tried again.
However, it may turn out that each compound behaves differently, and each will
require a different purification scheme.
Figure imgf000097_0001
The following compounds were prepaϊ" ed.
Figure imgf000098_0001
Figure imgf000098_0002
Analog 2
Reaction scheme to Analog 12 intermediate:
Figure imgf000099_0001
Analog 12 Intermediate
Anti-Inflammatory Activity in RAW 264.7 Cells:
The present inventors measured the ability of eight test articles to inhibit
LPS-induced nitric oxide and TNF cc secretion from murine macrophage cells.
This study was performed according to the protocol, testing facility
standard operating procedures and to the principles of the US FDA Good
Laboratory Practice Regulations.
Compounds:
Analog 5
Analog 6
Analog 7
Analog 9
Analog 10
Analog 11
Analog 12
Analog 13 ,
CNI- 1493
Methods:
The studies were conducted in RAW 264.7 cultures.
Culture of RAW 264.7 Cells: RAW 264.7 murine macrophage cells (ATCC, TIB-71) were maintained at
5% CO2, 370C in RPMI media (Fisher 15-040-CV, 1 mg/L glutathione) with 10%
fetal bovine serum (fbs, Fisher, lot 05069F) plus 2 mM L-glutamine and
penicillin/streptomycin. The cells were subcultured every two to three days. Cells
were plated in tissue culture treated 96 well plates at a density of 1 x 105 cells/well and incubated at 5% CO2, 370C for at least one hour prior to initiation of the assay. The cells were washed with RPMI with 10% fbs prior to the initiation of the assay. Anti-Inflammatory Activity:
The compounds were weighed, dissolved in DMSO for stock solutions of
10 mg/mL and serially diluted in RPMI. The plated RAW 264.7 cells were pretreated in duplicate with the test compounds, control (CNI- 1493) or vehicle for
1 hour at final concentrations of 0, 0.1, 1.0, 10, and 100 μg/mL. The cells were stimulated with 100 ng/niL LPS (E. coli 0111 :B4) and incubated at 5% CO2, 370C for 24 hours. The media was collected and stored at -2O0C. TNFα Quantitation:
Murine TNFα was measured by ELISA (BioSource or comparable commercial source) following the suppliers instructions. The stored media was diluted 1:30.
Nitric Oxide (Nitrite) Measurement:
To 50 μL of cell-free media, 50 μL of Oriess Reagent (1 part 0.1% naphthylethylenediamine diHCl, 1 part 1.32% sulfanamide in 60% acetic acid)
was added and incubated for no more than 5 minutes at ambient temperature. The
samples were read on a microtiter plate reader at 540 nm and compared to a 0.1-5
nmol nitrite standard curve.
The entirety of each of the following references is hereby incorporated by reference:
Bianchi, M et al., MoI Med, 1995, 1:254-266.
Bianchi, M et al., J Exp Med, 1996, 183: 927-936. Results and Discussion:
Four compounds, Analog 10, Analog 12, Analog 5 and Analog 11 inhibit
release of TNFa from LPS-induced RAW 264.7 cells with IC50 values of
8.8,26.7,27.7 and 47.6 μg/mL, respectively (Figure 1). CNI- 1493 inhibits release of TNFα at an IC50 of approximately 8 μg/mL. The remaining compounds have little (IC50 > 50 μg/mL) or no (IC50 > 100 μg/mL) effect on TNFα release.
Nitric oxide release is inhibited by CNI- 1493 (Figure 2) with an IC50 of
approximately 5.5 μg/mL. Nitric oxide release is inhibited with IC50 values of < 1 μg/mL by Analog 5, Analog 12 and Analog 7 and to a lesser extent by the remaining compounds (Figure 2).
Figures 3 and 4 show the combined results for inhibition of nitric oxide
and TNFα release. No absolute correlation appears to exist between activity for
nitric oxide inhibition and inhibition of TNFα release.
Figure 5 shows structures and results of these and other compounds.
Conclusions:
Analog 10, Analog 12, Analog 5 and Analog 11 inhibit release of TNFα
from LPS-induced RAW 264.7 cells with IC50 values of 8.8, 26.7, 27.7 and 47.6
μg/mL, respectively.
Analog 5, Analog 12 and Analog 7 inhibit nitric oxide release with IC50
values of < 1 μg/mL.
No absolute correlation appears to exist between activity for nitric oxide
inhibition and inhibition of TNFα release.
It will be understood that various changes in the details, materials and arrangements of the parts which have been described and illustrated in order to explain the nature of this invention may be made by those skilled in the art
without departing from the principle and scope of the invention as expressed in the following claims.

Claims

1. A compound, having the formula:
Figure imgf000104_0001
or a salt thereof;
wherein X1, X2, X3, and X4 each independently represent H, GhyCH — ,
OhyCCH3— , or CH3CO-, with the provisos that X1, X2, X3 and X4 are not simultaneously H;
wherein Z is one or more selected from the group consisting of:
Figure imgf000104_0002
and combinations thereof; wherein a is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9;
wherein b is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9;
wherein x is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9;
wherein y is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; wherein z is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8,
and 9; wherein A1 and A2 are each independently selected from the group
consisting of — NR8(CO)NR9— , -(CO)NR8- — NR8(CO)— , — NR8- , — O— -S-, — S(=O>— , -SO2-, -SO2NR8- -NR8SO2-, and salts
thereof; wherein Q and T are each independently selected from the group
consisting of — NR10(CO)NRU— -(CO)NR10- — NR10(CO)— , — NR10-, — O— , — S— — S(=O)~ -SO2-, -SO2NR10-, -NR10SO2-, salts thereof, branched or unbranched, saturated or unsaturated, substituted or unsubstituted C1-
C20 alkylene, saturated or unsaturated, substituted or unsubstituted C3-C20
cycloalkylene, substituted or unsubstituted C5-C25 arylene, and combinations
thereof; wherein one or more carbon atoms in any of said alkylene, cycloalkylene
or arylene in said Q and/or T may each be independently replaced with one or
more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur,
and a combination thereof; and wherein when substituted, said alkylene, cycloalkylene or arylene in
said Q and/or T are each independently substituted with one or more substituent groups selected from the group consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, -N35 -CN3 -NC, — SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3- C20)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-
C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-
C^aryl, perhalo(CrC20)alkyl, (CrC20)alkyl— O— , phenyl— 0—, (C3- C20)cycloalkyl — O — , (C3-C2S)heteroaryl — O — , (C3-C25)heterocyclic — O — , (C2-
C20)alkenyl— O— , (C3-C20) cycloalkenyl— O-— , (C2-C20)alkynyl— O— , (C5- C20)cycloalkynyl — O — , (C5-C25)aryl — O — , perhalo(CrC20)alkyl — O — , (C1-
C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S — , (C3-C25)heterocyclic — S — , (C2-C20)alkenyl — S — , (C3-C20)cycloalkenyl — S — ,
(C2-C20)alkynyl— S— , (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(CrC20)alkyl— S— , (CrC20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-
C25)heterocyclic— SO2- , (C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— -SO2-, (C5-C20)cycloalkynyl— SO2-,
(C5-C25)aryl— SO2- , perhalo(CrC20)alkyl— SO2- , H2N-SO2-, (C1-
C20)alkyl— NH-SO2-, phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-,
(C,-C20)alkoxy— NH-SO2-, (C3-C25)heteroaτyl— NH-SO2-, (C3-
C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20)
cycloalkenyl— NH-SO2-, (C2-C20)alkynyl— NH-SO2-, (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr
C20)alkyl— NH-SO2- {(CrC20)alkyl}2N— SO2- , {phenyl}2N— SO2- , ((C3-
C20)cycloalkyl}2N-SO2— , {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2- , ((C3-C25)heterocyclic}2N— SO2- , ((C2- C20)alkenyl}2N— SO2- ((C2-C20)alkynyl}2N— SO2-, ((C5- C20)cycloalkynyl}2N— SO2- , {(C5-C25)aiyl}2N— SO2- , (perhalo(Cr
C2Q)alkyl}2N— SO2- , (CrC20)alkyl-SO2— NH- phenyl-SO2— NH- (C3- C20)cycloalkyl-SO2— NH- , (C rC20)alkoxy-S O2-NH-, (C3-C25)heteroaryl-
SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)aikenyl-SO2— NH- , (C3-C20) cycloalkenyl-SO2— NH- , (C2-C2Q)alkynyl-SO2— NH- , (C5-
C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl-SO2— NH- , ρerhalo(CrC20)alkyl- SO2-NH-, (C,-C20)alkyl— NH- phenyl— NH-, (C3-C20)cycloalkyl— NH- ,
(CrC20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- , (C5-C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl~-NH— ,
((CrC20)alkyl}2N— {phenyl}2N— , {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , {(C3-C25)heteroaryl}2N— , {(C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— ((C2-C20)alkynyl}2N— ((C5- C20)cycloalkynyl}2N— , ((C5-C25)aryl}2N— , (perhalo(CrC2Q)alkyl}2N— , (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5- C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH-, (C1-
C20)alkyl-(C=O)-(((CrC20)alkyl)N}— , phenyl— (C=O)- (((C1-
C20)alkyl)N}—, (C3-C20)cycloalkyl— (O=O)- {((CrC20)alkyl)N}—, (C1-
C20)alkoxy— (C=O)- (((CrC20)alkyl)N}— (C3-C25)heteroaryl— (C=O)- (((C1-
C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- {((C1-C20)alkyl)N}— , (C2- C20)alkenyl—(C=O)—{((CrC20)alkyl)N}— (C3-C20) cycloalkenyl— (C=O)- {((CrC20)alkyl)N}—5 (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)- {((CrC20)alkyl)N}— (C5-
C25)aiyl— (C=O)- {((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=Q)- (((C1- C20)alkyl)N}— , phenyl-(C=O)— NH- phenyl-(C=O>— {(phenyl)N}—, (C1-
C20)alkyl-(C=O)— ((phenyl)N}— (C3-C20)cycloalkyl-(C=O)— ((phenyl)N}— (CrC20)alkoxy-(C=O)— ((phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- {(phenyl)N}— , (C3-C25)heterocyclic-(C-O)— ((phenyl)N}—3 (C2-
C20)alkenyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkenyl- (C=O)- ((phenyl)N}— , (C2-C20)alkynyl-(C=O)— ((phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— ((phenyl)N}— (C5-C25)aryl-(C=O)— ((phenyl)N}— perhalo(C1-C20)alkyl-(C=O)— ((phenyl)N>— , H2N(C=O)-, (C1- C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(C=O)-, (C3-C25)heterocyclic— NH-(C=O)-, (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2- C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5-
C25)aryl— NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O)-, (C1- C20)alkyl}2N — (C=O)- (phenyl} ((CrC20)alkyl}N— (C=O)- ((C3- C20)cycloalkyl} ((CrC20)alkyl}N— (C=O)- ((CrC20)alkoxy} ((C1-
C20)alkyl}N— (C=O)- ((C3-C25)heteroaryl} ((CrC20)alkyl}N— (C=O)- ((C3- C25)heterocyclic} ((CrC20)alkyl}N— (C=O)-, ((C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)-, ((C3-C20)cycloalkenyl}((CrC20)alkyl}N— (C=O)-, ((C2-C20)alkynyl} ((CrC20)alkyl}N-(C=O)— ((C5-C20)cycloalkynyl} ((C1- C20)alkyl}N— (C-O)- {(C5-C25)aryl} {(CrC20)alkyl}N— (C=O)-
{perhalo(C1-C20)alkyl}{(CrC20)alkyl}N— (C=O)-, {phenyl}2N— (C=O)- {(C3-C20)cycloalkyl}{phenyl}N— (C=O)- ((C1-
C20)alkoxy} {phenyl}N— (C=O)-, {(C3-C25)heteroaryl> (phenyl}N— (C=O)-, {(C3-C25)heterocyclic}{phenyl}N— (C=O) — , ((C2- C20)alkenyl} (phenyl}N— (C=O)-, ((C3-
C20)cycloalkenyl} (phenyl}N— (C=O)-, ((C2-
C20)alkynyl}(phenyl}N— (C=O)-, ((C5-
C20)cycloalkynyl} (phenyl }N— (C=O)- ((C5-C25)aryl} (phenyl }N— (C=O)- (perhalo(CrC20)alkyl} (phenyl}N— (C=O)-, HO-(C=O)-, (C1 — C20)alkyl — (C=O) — , (C3-C25)heteroaryl — (C=O) — , (C3-
C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)- , (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-,
perhalo(CrC20)alkyl— (C=O)-, phenyl— (C=O)-, (C1- C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3-
C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl— O— (C=O)- , perhalo(CrC20)alkyl— O— (C=O)-,
phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O)-O- phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
wherein each of the aforesaid (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20)
cycloalkenyl, (C2-C2o)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (as substituents on said alkylene, cycloalkylene or arylene of said Q and T) may be
optionally and independently substituted by one to four moieties selected from the
group consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, — N3, — CN, -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1-
C20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo(Cr
C20)alkyl, (CrC20)alkyl— O— , phenyl— O— , (C3-C20)cycloalkyl— O— , (C3-
C25)heteroaryl— O— , (C3-C25)heterocyclic— O— , (C2-C20)alkenyl— O— , (C3-
C20) cycloalkenyl— O— , (C2-C20)alkynyl— O— , (C5-C20)cycloalkynyl— O— , (C5-
C25)aryl— 0— , ρerhalo(CrC20)alkyl— O— , (C,-C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl — S — , (C3-C25)heteroaryl — S — , (C3-C25)heterocyclic — S — ,
(C2-C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5-
C20)cycloalkynyl— S— , (C5-C25)aryl— S— , ρerhalo(CrC20)alkyl— S— , (C1-
C20)alkyl— SO2- , phenyl— SO2-, (C3-C20)cycloalkyl— SO2- , (C1-
C20)alkoxy—SO2—, (C3-C25)heteroaryl— SO2-, (C3-C25)heterocyclic— SO2-,
(C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2- ,
(C5-C20)cycloalkynyl— SO2- , (C5-C25)aryl— SO2- , ρerhalo(Cr
C20)alkyl— SO2- , H2N-SO2-, (CrC20)alkyl— NH-SO2-,
phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1-
C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3-
C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2-, (C2-C20)alkynyl— NH-SO2-, (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr
C20)alkyl— NH-SO2- {(CrC20)alkyl}2N— SO2- , {phenyl}2N— SO2- , ((C3- C20)cycloalkyl}2N— SO2- , {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2-, ((C3-C25)heterocyclic}2N— SO2- , ((C2- C20)alkenyl}2N— SO2- ((C2-C20)alkynyl}2N— SO2- ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(C,-
C20)alkyl}2N— SO2- (CrC20)alkyl-SO2— NH- phenyl-S02— NH-, (C3- C20)cycloalkyl-SO2— NH- , (CrC20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-
SO2-NH- (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- ,
(C3-C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-S O2-NH-, (C5-
C20)cycloalkynyl-SO2— NH-, (C5-C25)aryl-SO2— NH- , perhalo(CrC20)alkyl-
SO2-NH- (C1-C20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- ,
(C,-C20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- , (C2-C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH- , (C2-C20)alkynyl— NH- ,
(C5-C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(C rC20)alkyl— NH- ,
{(CrC20)alkyl}2N— , (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2-
C20)alkenyl}2N— , ((C3-C20)cycloalkenyl}2N— , ((C2-C20)alkynyl}2N— , ((C5-
C20)cycloalkynyl}2N— ((C5-C25)aryl}2N— (PeAaIo(C1 -C20)alkyl}2N— (C1- C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH-, (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2- C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2-
C20)alkynyl— (C=O)-NH- (C5-C20)cycloalkynyl— (C=O)-NH-, (C5- C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH- (C1-
C20)alkyl— (C=O)-{((CrC20)alkyl)N}— phenyl— (C=O)- (((C1-
C20)alkyl)N}—, (C3-C20)cycloalkyl— (C=O)- (((CrC20)alkyl)N}— , (C1- C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— 5 (C3-C25)heteroaryl— (C=O)- (((C1- C20)alkyl)N}— , (C3-C25)heterocyclic— (C=O)- (((CrC20)alkyl)N}— (C2- C20)alkenyl— (C=O)- (((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- (((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— (C5-C20)cycloalkynyl-(C=O)-(((C1-C20)alkyl)N}— (C5- C25)aryl— (C=O)- (((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)- (((C1- C20)alkyl)N}— , phenyl-(C=O)— NH- , phenyl-(C=O)— ((phenyl)N}—3 (C1-
C20)alkyl-(C=O)— ((ρhenyl)N}—3 (C3-C20)cycloalkyl-(C=O)— ((phenyl)N}— , (C1-C20)alkoxy-(C=O)— ((phenyl)N}— , (C3-C25)heteroaryl- (C=O)- ((phenyl)N}— , (C3-C25)heterocyclic-(C=O)— ((phenyl)N}— , (C2-
C20)alkenyl-(C=O)— {(ρhenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)- ((phenyl)N}— (C2-C20)alkynyl-(C=O)— ((phenyl)N}—3 (C5-
C20)cycloalkynyl-(C=O)— {(phenyl)N}— , (C5-C25)aryl-(C=O)— ((phenyl)N}— ,
perhalo(CrC20)alkyl-(C=O)— {(phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(C=O)-, (C3-C25)heterocyclic— NH-(C=O)-, (C2-
C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)aryl— NH- (C=O)- , perhalo(CrC20)alkyl— NH-(C=O)-, (C1- C20)alkyl}2N — (C=O)- (phenyl} ((CrC20)alkyl}N-(C=O)—, ((C3- C20)cycloalkyl} {(CrC20)alkyl}N-(C=O)— , ((C1-C20)EIk0Xy) ((C1-
C20)alkyl}N— (C=O)- ,{(C3-C25)heteroaryl}{(CrC20)alkyl}N— (C=O)- , ((C3- C25)heterocyclic} {(CrC20)alkyl}N— (C=O)- , ((C2-C2o)alkenyl}((Cr
C20)alkyl}N— (C=O)-, ((C3-C20)cycloalkenyl}((CrC20)alkyl}N— (C=O) — , ((C2-C20)alkynyl} {(CrC20)alkyl}N— (C=O)- , ((C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N-(C=O)— ((C5-C25)aryl} ((CrC20)alkyl}N-(C=O)—
(perhalo^j-CJalkylX^rCgalkylJN— (C=O)-, (phenyl}2N— (C=O)-, ((C3-C20)cycloalkyl} (phenyl }N-(C=O)—, ((C1-
C20)alkoxy} (phenyl}N— (C=O)- ,((C3-C25)heteroaryl} (phenyl}N— (C=O)- {(C3-C25)heterocyclic} (phenyl}N— (C=O)-, ((C2-
C20)alkenyl} (phenyl)N— (C=O)-, ((C3-
C20)cycloalkenyl}(phenyl}N— (C=O) — , ((C2- C20)alkynyl} (phenyl}N— (C=O)- ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O) — , ((C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(CrC20)alkyl}(phenyl}N— (C=O)-, HO— (C=O)-, (C1- C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3-
C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-,
perhalo(CrC20)alkyl— (C=O)-, phenyl— (C=O)-, (C1-
C20)alkyl— 0— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3-
C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl — O — (C=O) — , (C2-C20)alkynyl — O — (C=O) — , (C5-
C25)aryl—O— (C=O)- perhalo(CrC20)alkyl—O— (C=O)-, phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3- C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2-
C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O- (C5-C25)aryl— (C=O)-O- phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof;
and wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are each independently
selected from the group consisting of hydrogen, hydroxy, halo, bromo, chloro,
iodo, fluoro, -N3, -CN, -NC, -SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (C^C^alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2- C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-
C25)aryl, perhalo(CrC20)alkyl, (CrC20)alkyl— O— , phenyl— O— (C3-
C20)cycloalkyl — O — , (C3-C25)heteroaryl — O — , (C3-C25)heterocyclic — O — , (C2-
C20)alkenyl— O— , (C3-C20) cycloalkenyl— 0—, (C2-C20)alkynyl— O— , (C5-
C20)cycloalkynyl— O— , (C5-C25)aryl— 0— , perhalo(CrC20)alkyl— O— , (C1- C20)alkyl— S— , phenyl— S-, (C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— ,
(C3-C25)heterocyclic — S — , (C2-C20)alkenyl — S — , (C3-C20)cycloalkenyl — S — , (C2-C20)alkynyl— S-, (C5-C20)cycloalkynyl— S— , (C5-C25)aryl— S— ,
ρerhalo(CrC20)alkyl— S— , (CrC20)alkyl— SO2- , phenyl— SO2-, (C3-
C20)cycloalkyl— SO2- , (CrC20)alkoxy— SO2- , (C3-C25)heteroaryl— SO2- , (C3-
C25)heterocyclic— SO2- , (C2-C20)alkenyl— SO2- , (C3-C20)
cycloalkenyl— SO2-, (C2-C20)alkynyl— SO2-, (C5-C20)cycloalkynyl— SO2-,
(C5-C25)aryl— SO2- , perhalo(CrC20)alkyl— SO2- , H2N-SO2-, (C1-
C20)alkyl— NH-SO2-, phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-,
(CrC20)alkoxy— NH-SO2-, (C3-C25)heteroaryl--NH— SO2- , (C3- ^heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2- (C3-C20) cycloalkenyl— NH-SO2- (C2-C20)alkynyl— NH-SO2-, (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, perhalo(Cr
C20)alkyl— NH-SO2- {(CrC20)alkyl}2N— SO2- {phenyl}2N— SO2- ((C3- C20)cycloalkyl}2N— SO2- , {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2- ,
Figure imgf000115_0001
((C2-
C20)alkenyl}2N— SO2- ((C2-C20)alkynyl}2N— SO2- ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(C,- C20)alkyl}2N— SO2- , (CrC20)alkyl-SO2— NH- , phenyl-SO2— NH- , (C3- C20)cycloalkyl-SO2— NH- , (C,-C20)alkoxy-SO2— NH- , (C3-C25)heteroaryl-
SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- , (C3-C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-S O2-NH-, (C5-
C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl-SO2— NH- , perhalo(CrC20)alkyl-
SO2-NH-, (CrC20)alkyl— NH- phenyl— NH-, (C3-C20)cycloalkyl— NH- , (C,-C20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- ,
(C2-C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH-, (C2-C20)alkynyl— NH- ,
(C5-C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- ,
((CrC20)alkyl}2N- (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2- C20)alkenyl}2N— ((C3-C20)cycloalkenyl}2N— ((C2-C20)alkynyl}2N— ((C5-
C20)cycloalkynyl}2N— ((C5-C25)aryl}2N— (perhalo(CrC20)alkyl}2N— (C1- C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3-
C20)cycloalkyl— (C=O)-NH-, (C1-C20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2- ' C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH- (C2-
C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5- C25)aryl— (C=O)-NH-, perhalo(CrC20)alkyl— (C=O)-NH-, (C1-
C20)alkyl— (C=O)- {((CrC20)alkyl)N}— phenyl— (C=O)- (((C1- C20)alkyl)N}— (C3-C20)cycloalkyl-(C=O)— {((CrC20)alkyl)N}— , (C1-
C20)alkoxy— (C=O)- {((CrC20)alkyl)N}— , (C3-C25)heteroaryl— (C=O)- (((C1-
C20)alkyl)N}—, (C3-C25)heterocyclic— (C=O)- (((C1-C20)alkyl)N}— (C2- C20)alkenyl-(C=O)—(((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- (((CrC20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)-(((CrC20)alkyl)N}— (C5-
C25)aryl-(C=O)— (((CrC20)alkyl)N}— PeAaIo(C1 -C20)alkyl— (C=O)- (((C1- C20)alkyl)N}— phenyl-(C=O)— NH- phenyl-(O=0)— ((phenyl)N}— , (C1-
C20)alkyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkyl-(C=O)— ((phenyl)N}— , (CrC20)alkoxy-(C=O)— ((phenyl)N}— , (C3-C2S)heteroaryl-
(C=O)- ((phenyl)N}— (C3-C25)heterocyclic-(C=0)— {(phenyl)N}— , (C2-
C20)alkenyl-(C=O)— ((phenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)-((phenyl)N}— (C2-C20)alkynyl-(C=O)— {(phenyl)N}— (C5-
C20)cycloalkynyl-(C=O)— ((phenyl)N}— , (C5-C25)aryl-(C=O)— ((phenyl)N}— perhalo(C1-C20)alkyl-(C=O)— ((phenyl)N}— , H2N(C=O)-, (C1-
C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)-, (C3-
C20)cycloalkyl— NH-(C=O)-, (CrC20)alkoxy— NH-(C=O)-, (C3-
C25)heteroaryl— NH-(C=O) — , (C3-C25)heterocyclic— NH-(C=O) — , (C2- C20)alkenyl— NH-(C=O)-, (C3-C20) cycloalkenyl— NH-(C=O)-, (C2-
C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5- C25)MyI- NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O) — , (C1- C20)alkyl}2N — (C=O)- {phenyl} {(CrC20)alkyl}N-(C=O)— , ((C3- C20)cycloalkyl} {(CrC20)alkyl}N-(C=O)— , {(CrC20)alkoxy} ((C1-
C20)alkyl}N— (C=O)- {(C3-C25)heteroaryl} ((CrC20)alkyl}N— (C=O)- ((C3- C25)heterocyclic} {(CrC20)alkyl}N— (C=O)-, {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)- {(C3-C20)cycloalkenyl} {(CrC20)alkyl}N— (C=O)-, {(C2-C20)alkynyl} {(CrC20)alkyl}N— (C=O)- ((C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- ((C5-C25)aryl} {(CrC20)alkyl}N— (C=O)-,
(perhalo(CrC20)alkyl} {(CrC20)alkyl}N— (C=O)-, (phenyl}2N— (C=O)-, {'(C3-C20)cycloalkyl} (phenyl}N— (C=O)-, ((C1-
C20)alkoxy}(phenyl}N— (C=O)- ,{(C3-C25)heteroaryl}(phenyl}N— (C=O)-,
((C3-C25)heterocyclic} (phenyl}N— (C=O) — , ((C2- C20)alkenyl} (phenyljN— (C=O)- ((C3- C20)cycloalkenyl} (phenyl}N— (C=O) — , ((C2-
C20)alkynyl} (phenyl}N— (C=O)-, ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, ((C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(C1-C20)alkyl}(phenyl}N— (C=O)-, HO-(C=O)-, (C1-
C20)alkyl— (C=O)-, (C3-C25)heteroaryl— (C=O)-, (C3-
C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20)
cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-,
perhalo(C,-C20)alkyl — (C=O) — , phenyl — (C=O) — , (C1 —
C20)alkyl—O— (C=O)-, (C3-C25)heteroaryl—O— (C=O)-, (C3- C25)heterocyclic — O — (C=O) — , (C2-C20)alkenyl — O — (C=O) — , (C3-C20)
cycloalkenyl— O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5- C25)aryl— O— (C=O)- , perhalo(CrC20)alkyl— O— (C=O)-, phenyl— O— (C=O)-, (C1 — C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2- C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyϊ— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aryl— (C=O) — O— ,
phenyl — (C=O) — O — , PeAaIo(C1 -C20)alkyl — (C=O) — O — , and salts thereof; wherein each of the aforesaid (C^C^alkyl, phenyl, (C3-C20)cycloalkyl,
(CrC20)alkoxy, (C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C2o)alkynyl, (C5-C20)cycloalkynyl, and (C5-C25)aryl groups (for
said R2, R3, R4, R5, R6, R7, R8, R9, R10, and R1 * groups) may be optionally and
independently substituted by one to four moieties selected from the group consisting of hydroxy, halo, bromo, chloro, iodo, fluoro, — N3, — CN, — NC,
-SH, -NO2, -NH2, (CrC20)alkyl, phenyl, (C3-C20)cycloalkyl, (C1-C20)EIkOXy,
(C3-C25)heteroaryl, (C3-C25)heterocyclic, (C2-C20)alkenyl, (C3-C20) cycloalkenyl, (C2-C20)alkynyl, (C5-C20)cycloalkynyl, (C5-C25)aryl, perhalo(CrC20)alkyl, (C1-
C20)alkyl— 0— , phenyl— 0—, (C3-C20)cycloalkyl— O— , (C3- C25)heteroaryl — O — , (C3-C25)heterocyclic — O — , (C2-C20)alkenyl — O — , (C3-
C20) cycloalkenyl— 0—, (C2-C20)alkynyl— O— , (C5-C20)cycloalkynyl— O— , (C5-
C25)aryl— O— , perhalo(CrC20)alkyl— O— , (CrC20),alkyl— S— , phenyl— S-,
(C3-C20)cycloalkyl— S— , (C3-C25)heteroaryl— S— , (C3-C25)heterocyclic— S— , (C2-C20)alkenyl— S— , (C3-C20)cycloalkenyl— S— , (C2-C20)alkynyl— S— , (C5-
C20)cycloalkynyl— S— , (C5-C25)aryl— S— , perhalo(CrC20)alkyl— S— , (C1-
C20)alkyl— SO2- , phenyl— SO2-, (C3-C20)cycloalkyl— SO2- , (C1-
C20)alkoxy — SO2 — , (C3-C25)heteroaryl — SO2 — , (C3-C25)heterocyclic — SO2 — , (C2-C20)alkenyl— SO2- , (C3-C20) cycloalkenyl— SO2- (C2-C20)alkynyl— SO2-
(C5-C20)cycloalkynyl— SO2- , (C5-C25)aryl— SO2- , perhalo(Cr C20)alkyl— SO2- H2N-SO2-, (CrC20)alkyl— NH-SO2-,
phenyl— NH-SO2-, (C3-C20)cycloalkyl— NH-SO2-, (C1- C20)alkoxy— NH-SO2-, (C3-C25)heteroaryl— NH-SO2-, (C3-
C25)heterocyclic— NH-SO2-, (C2-C20)alkenyl— NH-SO2-, (C3-C20) cycloalkenyl— NH-SO2- (C2-C20)alkynyl— NH-SO2-, (C5- C20)cycloalkynyl— NH-SO2-, (C5-C25)aryl— NH-SO2-, PeAaIo(C1-
C20)alkyl— NH-SO2- {(CrC20)alkyl}2N— SO2- {phenyl}2N— SO2- ((C3- C20)cycloalkyl}2N— SO2- -, {(CrC20)alkoxy}2N— SO2- , ((C3-
C25)heteroaryl}2N— SO2- , ((C3-C25)heterocyclic}2N— SO2- , ((C2- C20)alkenyl}2N— SO2- {(C2-C20)alkynyl}2N— SO2- , ((C5-
C20)cycloalkynyl}2N— SO2- , ((C5-C25)aryl}2N— SO2- , (perhalo(Cr
C20)alkyl}2N— SO2- (CrC20)alkyl-SO2— NH- phenyl-S O2-NH- (C3- C20)cycloalkyl-SO2— NH- , (C rC20)alkoxy-S O2-NH-, (C3-C25)heteroaryl- SO2-NH-, (C3-C25)heterocyclic-SO2— NH- , (C2-C20)alkenyl-SO2— NH- ,
(C3-C20) cycloalkenyl-SO2— NH- , (C2-C20)alkynyl-S O2-NH-, (C5-
C20)cycloalkynyl-SO2— NH- , (C5-C25)aryl-SO2— ■ NH- , perhalo(CrC20)alkyl- SO2-NH-, (CrC20)alkyl— NH- , phenyl— NH-, (C3-C20)cycloalkyl— NH- ,
(CrC20)alkoxy— NH- , (C3-C25)heteroaryl— NH- , (C3-C25)heterocyclic— NH- ,
(C2-C20)alkenyl— NH- , (C3-C20) cycloalkenyl— NH-, (C2-C20)alkynyl— NH- ,
(C5-C20)cycloalkynyl— NH- , (C5-C25)aryl— NH- , perhalo(CrC20)alkyl— NH- , ((CrC20)alkyl}2N— (phenyl}2N— {(C3-C20)cycloalkyl}2N— ((C1-
C20)alkoxy}2N— , ((C3-C25)heteroaryl}2N— , ((C3-C25)heterocyclic}2N— , ((C2- C20)alkenyl}2N— {(C3-C20)cycloalkenyl}2N— , ((C2-C20)alkynyl}2N— ((C5-
C20)cycloalkynyl}2N— ((C5-C25)aryl}2N— (perhalo(CrC20)alkyl}2N— , (C1-
C20)alkyl— (C=O)-NH-, phenyl— (C=O)-NH-, (C3- C20)cycloalkyl— (C=O)-NH- (CrC20)alkoxy— (C=O)-NH-, (C3-
C25)heteroaryl— (C=O)-NH-, (C3-C25)heterocyclic— (C=O)-NH-, (C2-
C20)alkenyl— (C=O)-NH-, (C3-C20) cycloalkenyl— (C=O)-NH-, (C2- C20)alkynyl— (C=O)-NH-, (C5-C20)cycloalkynyl— (C=O)-NH-, (C5- C25)aryl— (C=O)-NH-, perhaloO^-C^alkyl— (C=O)-NH-, (C1-
C20)alkyl— (C=O)- {((CrC20)alkyl)N}— phenyl-(C=O)— (((C1- C20)alkyl)N}— (C3-C20)cycloalkyl— (C=O)- {((CrC20)alkyl)N}— (C1-
C20)alkoxy—(C=O)—(((C1-C20)alkyl)N}— (C3-C25)heteroaryl— (C=O)-(^C1-
C20)alkyl)N}— (C3-C25)heterocyclic— (C=O)- {((CrC20)alkyl)N}— (C2-
C20)alkenyl—(C=O)—(((CrC20)alkyl)N}— (C3-C20)
cycloalkenyl— (C=O)- (((C1-C20)alkyl)N}— , (C2-C20)alkynyl— (C=O)- (((C1- C20)alkyl)N}— (C5-C20)cycloalkynyl— (C=O)- (((CrC20)alkyl)N}-, (C5-
C25)aryl— (C=O)- (((CrC20)alkyl)N}— perhalo(CrC20)alkyl— (C=O)-(((Cr
C20)alkyl)N}— , phenyl-(C=O)— NH- phenyl-(C=O)— {(phenyl)N}— , (C1-
C20)alkyl-(C=O)— ((phenyl)N}- (C3-C20)cycloalkyl-(C=O)— ((phenyl)N}—5
(CrC20)alkoxy-(C=O)— ((phenyl)N}— , (C3-C25)heteroaryl-
(C=O)- ((phenyl)N}— , (C3-C25)heterocyclic-(C=O)— {(phenyl)N}— (C2-
C20)alkenyl-(C=O)— {(ρhenyl)N}— , (C3-C20)cycloalkenyl-
(C=O)-((phenyl)N}—, (C2-C20)alkynyl-(C=O)-((phenyl)N}— (C5- C20)cycloalkynyl-(C=O)— ((phenyl)N}—, (C5-C25)aryl-(C=O)— {(phenyl)N}— ,
perhalo(CrC20)alkyl-(C=O)— ((phenyl)N}— , H2N(C=O)-, (C1- C20)alkyl— NH-(C=O)-, phenyl— NH-(C=O)- (C3- C20)cycloalkyl— NH-(C=O) — , (C,-C20)alkoxy— NH-(C=O)-, (C3- C25)heteroaryl— NH-(C=O)- (C3-C25)heterocyclic— NH-(C=O)-, (C2-
C20)alkenyl— NH- (C=O)- , (C3-C20) cycloalkenyl— NH-(C=O)-, (C2- C20)alkynyl— NH-(C=O)-, (C5-C20)cycloalkynyl— NH-(C=O)-, (C5-
C25)aryl— NH-(C=O)-, perhalo(CrC20)alkyl— NH-(C=O)-, (C1- C20)alkyl}2N -(C=O)--, {phenyl} {(CrC20)alkyl}N— (C=O)- ((C3-
C20)cycloalkyl} ((CrC20)alkyl}N-(C=O)— , {(CrC20)alkoxy} ((C1- C20)alkyl}N— (C=O)- {(C3-C25)heteroaiyl} {(CrC20)alkyl}N— (C=O)- ((C3- C25)heterocyclic} ((CrC20)alkyl}N— (C=O) — , {(C2-C20)alkenyl} ((C1-
C20)alkyl}N— (C=O)- {(C3-C20)cycloalkenyl} {(CrC20)alkyl}N— (C=O)- {(C2-C20)alkynyl} {(C1-C20)alkyl}N-(C=O)— , {(C5-C20)cycloalkynyl} ((C1-
C20)alkyl}N— (C=O)- ((C5-C25)aryl} {(CrC20)alkyl}N— (C=O)-, (perhalo(C1-C20)alkyl}((CrC20)alkyl}N— (C=O)-, (phenyl}2N— (C=O)-,
((C3-C20)cycloalkyl} (phenyl}N— (C=O)- ((C1-
C20)alkoxy}(phenyl}N— (C=O)- ,{(C3-C25)heterQaryl} (phenyl}N— (C=O) — , ((C3-C25)heterocyclic} (phenyl}N— (C=O) — , ((C2-
C20)alkenyl} (phenyl}N— (C=O)- ((C3- C20)cycloalkenyl} (phenyl}N— (C=O) — , ((C2-
C20)alkynyl}(phenyl}N— (C=O)-, ((C5-
C20)cycloalkynyl} (phenyl}N— (C=O)-, ((C5-C25)aryl} (phenyl}N— (C=O)-,
(perhalo(CrC20)alkyl} (phenyl}N— (C=O)-, HO-(C=O)- (C1- C20)alkyl — (C=O) — , (C3-C25)heteroaryl— (C=O) — , (C3- C25)heterocyclic — (C=O) — , (C2-C20)alkenyl — (C=O) — , (C3-C20) cycloalkenyl— (C=O)-, (C2-C20)alkynyl— (C=O)-, (C5-C25)aryl— (C=O)-
perhalo(CrC20)alkyl~(C=O)— , phenyl— (C=O)-, (C1- C20)alkyl— O— (C=O)-, (C3-C25)heteroaryl— O — (C=O)-, (C3-
C25)heterocyclic—O— (C=O)-, (C2-C20)alkenyl — 0-(C=O) — , (C3-C20) cycloalkenyl—O— (C=O)-, (C2-C20)alkynyl—O— (C=O)-, (C5-
C25)aryl— O— (C=O)- , perhalo(CrC20)alkyl— O— (C=O)-,
phenyl— O— (C=O)-, (C1- C20)alkyl— (C=O)-O-, (C3-
C25)heteroaryl — (C=O) — O — , (C3-C25)heterocyclic — (C=O) — O — , (C2- C20)alkenyl— (C=O)-O-, (C3-C20) cycloalkenyl— (C=O)-O-, (C2- C20)alkynyl— (C=O)-O-, (C5-C25)aiyl— (C=O)-O-,
phenyl — (C=O) — O — , perhalo(CrC20)alkyl — (C=O) — O — , and salts thereof; and wherein two independently chosen R2, R3, R4, R5, R6, R7, R8, R9, R10,
and Rπ alkyl-containing groups may be taken together with any atom to which they are attached to form a three to forty membered cyclic, heterocyclic or heteroaryl ring.
2. The compound of claim 1, wherein Z is a Cj-C20 alkylene.
3. The compound of claim 1, wherein Z is a C3-C20 cycloalkylene.
4. The compound of claim 1, wherein Z is a C5-C25 arylene.
5. The compound of claim 1, wherein Z is selected from the group
consisting of — NR8(CO)NR9— ; -(C6H4)-; — (CH2)p— ; -(C5H3N)-;
— O— (CH2)p— O — , wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
— A — (CH2)p — A — group, wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and wherein
the A's are each independently — NH(CO)-, -(CO)NH-, or— NH(CO)NH- groups; — A — (C6H4) — A — wherein the A's are each independently — CO — , -NH(CO)-, -(CO)NH-, or -NH(CO)NH- groups; — O— (C6H4,
wherein the two — O — groups are meta or para to each other about the phenylene
ring; —O— CH2-CH2-O-CH2 — CH2-O-; a group having the formula:
Figure imgf000123_0001
a group having the formula:
Figure imgf000123_0002
a group having the formula:
Figure imgf000123_0003
a group having the formula:
Figure imgf000124_0001
a group having the formula:
Figure imgf000124_0002
a group having the formula:
Figure imgf000124_0003
a group having the formula:
Figure imgf000124_0004
and a group having the formula:
Figure imgf000125_0001
6. The compound of claim 1, wherein Z has the formula: -(A1X-(CR2R3) - Qm-(CR4R5) -T -(CR6R7)z-(A2)b-
wherein each of the variables a, m, n, and b are equal to 1 ; and the sum of the variables x, y and z does not exceed 12.
7. The compound of claim 1, wherein at least one of X1, X2, X3 and X4 is GhyCH— or GhyCCH3— , X1 and X2 are not simultaneously H, and X3 and X4 are
not simultaneously H.
8. The compound of claim 1, wherein X1, X2, X3, and X4 are
independently selected from the group consisting of GhyCH — and GhyCCH3 — .
9. The compound of claim 1, wherein X1, X2, X3, and X4 are
independently selected from the group consisting of GhyCH — , GhyCCH3 — , and
CH3CO-.
10. The compound of claim 1, wherein X1, X2, X3, and X4 are each
GhyCH—.
11. The compound of claim 1 , wherein X1, X2, X3, and X4 are each GhyCCH3— .
12. The compound of claim 1, wherein X1 , X2, X3, and X4 are each CH3CO-.
13. The compound of claim 1, wherein at least one of X1, X2, X3, and X4 is CH3CO-.
14. The compound of claim 1, which is in the salt form.
15. A composition, comprising the compound of claim 1 or salt thereof,
and at least one pharmaceutically acceptable carrier, excipient, adjuvant or diluent
16. The composition of claim 15, wherein the compound is in the salt form.
17. A method, comprising administering the compound of claim 1 or salt
thereof to a human.
18. The method of claim 17, wherein the release of TNFα, NO, or both is inhibited in said human as a result of administering the compound or salt.
19. The method of claim 17, wherein the release of TNF α is inhibited in said human as a result of administering the compound or salt.
20. The method of claim 17, wherein the release of NO is inhibited in said human as a result of administering the compound or salt.
PCT/US2005/029301 2004-08-17 2005-08-17 Guanylhydrazone compounds, compositions, methods of making and using WO2006023586A2 (en)

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