ZA200301160B - High affinity small molecule C5A receptor modulators. - Google Patents
High affinity small molecule C5A receptor modulators. Download PDFInfo
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- ZA200301160B ZA200301160B ZA200301160A ZA200301160A ZA200301160B ZA 200301160 B ZA200301160 B ZA 200301160B ZA 200301160 A ZA200301160 A ZA 200301160A ZA 200301160 A ZA200301160 A ZA 200301160A ZA 200301160 B ZA200301160 B ZA 200301160B
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- alkyl
- amino
- mono
- alkoxy
- alkynyl
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- 108010059426 Anaphylatoxin C5a Receptor Proteins 0.000 title 1
- 102000005590 Anaphylatoxin C5a Receptor Human genes 0.000 title 1
- 150000003384 small molecules Chemical class 0.000 title 1
- -1 (cycloalkyljalkyl Chemical group 0.000 claims 806
- 125000000217 alkyl group Chemical group 0.000 claims 693
- 125000003545 alkoxy group Chemical group 0.000 claims 407
- 125000001188 haloalkyl group Chemical group 0.000 claims 362
- 125000000304 alkynyl group Chemical group 0.000 claims 350
- 125000003342 alkenyl group Chemical group 0.000 claims 348
- 229910052736 halogen Inorganic materials 0.000 claims 347
- 150000002367 halogens Chemical class 0.000 claims 347
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 344
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 311
- 125000004093 cyano group Chemical group *C#N 0.000 claims 309
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 259
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 244
- 125000000753 cycloalkyl group Chemical group 0.000 claims 238
- 125000003282 alkyl amino group Chemical group 0.000 claims 224
- 229910052739 hydrogen Inorganic materials 0.000 claims 193
- 239000001257 hydrogen Substances 0.000 claims 193
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 180
- 150000002431 hydrogen Chemical class 0.000 claims 139
- 125000001544 thienyl group Chemical group 0.000 claims 106
- 150000001875 compounds Chemical class 0.000 claims 105
- 125000004076 pyridyl group Chemical group 0.000 claims 98
- 239000011575 calcium Substances 0.000 claims 88
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 87
- 125000004663 dialkyl amino group Chemical group 0.000 claims 83
- 125000003373 pyrazinyl group Chemical group 0.000 claims 83
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 78
- 125000001041 indolyl group Chemical group 0.000 claims 75
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims 73
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 71
- 125000000842 isoxazolyl group Chemical group 0.000 claims 71
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 claims 70
- 125000001624 naphthyl group Chemical group 0.000 claims 70
- 150000002148 esters Chemical class 0.000 claims 68
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 67
- 229910052760 oxygen Inorganic materials 0.000 claims 67
- 239000001301 oxygen Substances 0.000 claims 67
- 125000001424 substituent group Chemical group 0.000 claims 67
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 66
- 150000001735 carboxylic acids Chemical class 0.000 claims 66
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 65
- 125000002619 bicyclic group Chemical group 0.000 claims 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 63
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims 58
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 56
- 125000002541 furyl group Chemical group 0.000 claims 46
- 125000003710 aryl alkyl group Chemical group 0.000 claims 44
- 229910052799 carbon Inorganic materials 0.000 claims 44
- 125000001072 heteroaryl group Chemical group 0.000 claims 44
- 125000005842 heteroatom Chemical group 0.000 claims 44
- 125000002883 imidazolyl group Chemical group 0.000 claims 44
- 125000001786 isothiazolyl group Chemical group 0.000 claims 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 42
- 125000003226 pyrazolyl group Chemical group 0.000 claims 42
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims 42
- 125000003831 tetrazolyl group Chemical group 0.000 claims 42
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 41
- 125000000168 pyrrolyl group Chemical group 0.000 claims 41
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 41
- 125000001425 triazolyl group Chemical group 0.000 claims 41
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 40
- 125000002971 oxazolyl group Chemical group 0.000 claims 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 39
- 125000000335 thiazolyl group Chemical group 0.000 claims 39
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 37
- 125000005605 benzo group Chemical group 0.000 claims 33
- 125000003884 phenylalkyl group Chemical group 0.000 claims 33
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 30
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 30
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims 30
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims 30
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims 30
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 30
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 29
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 28
- 125000000547 substituted alkyl group Chemical group 0.000 claims 28
- 125000004426 substituted alkynyl group Chemical group 0.000 claims 28
- 229910014585 C2-Ce Inorganic materials 0.000 claims 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 23
- 150000003839 salts Chemical class 0.000 claims 20
- 239000000651 prodrug Substances 0.000 claims 19
- 229940002612 prodrug Drugs 0.000 claims 19
- 150000001721 carbon Chemical group 0.000 claims 18
- 125000004043 oxo group Chemical group O=* 0.000 claims 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 15
- 125000006165 cyclic alkyl group Chemical group 0.000 claims 14
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims 14
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 13
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims 12
- 125000002431 aminoalkoxy group Chemical group 0.000 claims 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 9
- 241000790917 Dioxys <bee> Species 0.000 claims 7
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 6
- 238000003556 assay Methods 0.000 claims 6
- 230000035605 chemotaxis Effects 0.000 claims 6
- 125000000623 heterocyclic group Chemical group 0.000 claims 6
- 230000001404 mediated effect Effects 0.000 claims 6
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 claims 6
- 102100031506 Complement C5 Human genes 0.000 claims 5
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 235000015429 Mirabilis expansa Nutrition 0.000 claims 2
- 244000294411 Mirabilis expansa Species 0.000 claims 2
- 150000001408 amides Chemical class 0.000 claims 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims 2
- 229910052791 calcium Inorganic materials 0.000 claims 2
- HJMZMZRCABDKKV-UHFFFAOYSA-N carbonocyanidic acid Chemical compound OC(=O)C#N HJMZMZRCABDKKV-UHFFFAOYSA-N 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- 125000004122 cyclic group Chemical group 0.000 claims 2
- 125000005945 imidazopyridyl group Chemical group 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 235000013536 miso Nutrition 0.000 claims 2
- 229920006395 saturated elastomer Polymers 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 101150107341 RERE gene Proteins 0.000 claims 1
- 229910019567 Re Re Inorganic materials 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
Description
Title: HIGH AFFINITY SMALL MOLECULE C5A RECEPTOR MODULATORS
This invention relates to low molecular weight, non-peptidic, non- peptidomimetic, organic molecules that act as modulators of mammalian complement CSa receptors, preferably ones that act as high affinity C5a recptor ligands. The invention also relates to such ligands that act as antagonists (including inverse agonists) of complement C5a receptors, preferably human C5a receptors.
This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.
CbSa, a 74 amino acid peptide, is generated in the complement cascade by the cleavage of the complement protein C5 by the complement CS convertase enzyme.
CS5a has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and chemotactic effects. Therefore, it is active in engendering both the vascular and cellular phases of inflammatory responses. Because it is a plasma protein and, therefore, generally almost instantly available at a site of an inciting stimulus, it is a key mediator in terms of initiating the complex series of events that results in augmentation and amplification of an initial inflammatory stimulus. The anaphylatoxic and chemotactic effects of the C5a peptide are believed to be mediated . through its interation with the CS5a receptor (CD88 antigen), a 52 kD membrane } bound G-protein coupled receptor (GPCR). CSa is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of inflammation and/or cellular injury. CSa is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also "primes’ or prepares neutrophils for various antibacterial functions, c.g. phagocytosis. Additionally, C5a stimulates the release of inflammatory mediators (e.g., histamines, TNF-a, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) and the . release of lysosomal enzymes and other cytotoxic components from granulocytes.
Among its other actions, CSa also promotes the production of activated oxygen radicals and the contraction of smooth muscle.
Considerable experimental evidence implicates increased levels of C5a in a number of autoimmune diseases and inflammatory and related disorders.
Antagonists that block the binding of C5a to its receptor or other agents, including inverse agonists, which modulate signal transduction associated with
C5a-receptor interactions, can inhibit the pathogenic events, including chemotaxis, associated with anaphylatoxin activity contributing to such inflammatory and autoimmune conditions. Despite many attempts, no one has previously been able to provide any small molecule {less than 700 Daltons MW, or amu) non-peptide, non- peptidomimetic, non-peptoid, C5a antagonist that is essentially free of agonist activity at the C5a receptor and that exhibits a binding affinity for the C5a receptor of less than 1 micromolar, and preferably less than 100 nanomolar.
Certain modified C5a peptides (i.e., modifications of C5a) have been identified as partial C5a antagonists and have been shown to block a number of C5a mediated actions including neutrophil chemotaxis, neutropenia and superoxide formation.
Various C5a peptidomimetic compounds have also been reported as modulating C5a activity, including cyclic peptoids (a peptoid is a peptidomimetic compound . comprising an oligomeric assemblage of naturally occurring amino acids that have , been N-substituted). Typically these CSa modulatory compounds exhibit a molecular weight greater than 500 Daltons, and generally greater than 700 Daltons.
The present invention provides novel compounds that are small molecule
C5a receptor antagonists that are non-peptide, non-peptidomimetic, and are ] preferably free of CHa receptor agonist activity, which compounds exhibit high affinity for the C5a receptor, i.e., an affinity constant for binding to the C5a receptor of less than 1 micromolar. Highly preferred compounds exhibit very high affinity for the C5a receptor, i.e., an affinity constant for binding to the C5a receptor of less than 100 nanomolar. Preferred compounds are CSa receptor antagonists (including inverse agonists). Preferred antagonists exhibit an antagonist ECso (which as usd herein includes ICso) of less than 1 micromolar, preferably less than 100 nanomolar, in an assay of CSa mediated chemotaxis. Preferred C5a receptors arc mammalian, preferably primate receptors, including human C35a receptors, and may either be cloned, recombinantly expressed receptors or naturally expressed receptors. In certain preferred embodiments, compounds of the invention exhibit an affinity for human CS5a receptors that is higher than for rodent C5a receptors, preferably at least five times higher, more preferably ten times higher.
The compounds of the present invention do not interact with dopamine receptors with even moderate affinity, i.e., they do not bind to dopamine receptors with K; values of less than 100 micromolar. Preferred compounds of the invention do not bind to any naturally occurring receptors other than C5a receptors with high affinity, and preferably they do not bind to any naturally occurring receptors other than C5a receptors with even moderate affinity.
In certain embodiments these compounds also possess one or more, and preferably two or more, three or more, four or more, or all of the following properties in that they are: 1) multi-aryl in structure (having a plurality of un-fused or fused ‘ aryl groups), 2) heteroaryl in structure, 3) orally available in vivo (such that a sub- lethal or preferably a pharmaceutically acceptable oral dose can provide a detectable in vivo effect such as a reduction of C5a-induced neutropenia), 4) comprised of fewer than four, preferably fewer than three, or fewer than two, or no amide bonds, and 5)
capable of inhibiting leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations.
In a highly preferred aspect, the invention provides non-peptidic, non- ’ peptidomimetic, low molecular weight compounds that act as high affinity } antagonists of the human C5a receptor. Specifically exemplified representative compounds include, but are not limited to optionally substituted arylimidazoles (i.e. imidazoles having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), optionally substituted arylpyridyls (i.e.pyridvls having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), optionally substituted aryl-substituted cycloalkylimidazoles (i.e.cycloalkylimidazoles having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl}, optionally substituted arylpyrazoles (i.e.pyrazoles having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), optionally substituted benzimidazoles, optionally substituted aryl-substituted tetrahydroisoquinolines (i.e.tetrahydroisoquinolines having one or more ring substituents of optionally substituted carbocyclic aryl or optionally substituted heteroaryl), and optionally substituted biaryl carboxamides (i.e. a carboxamide that has one or more optionally substituted bi-carboxylic aryl or heteroaryl substituents). Novel intermediates useful for synthesizing compounds of the invention are also provided.
Preferred compounds of the invention are compounds of Formula I, shown below, that bind specifically, and preferably with high affinity, to C5a receptors.
The invention also provides pharmaceutical compositions comprising compounds of the invention, including those of Formula I, including otppinally < substituted arylimidazoles, optionally substituted arylpyridyls, optionally substituted aryl-substituted cycloalkylimidazoles, optionally substituted arylpyrazoles, optionally substituted benzimidazoles, optionally substituted aryl- substituted tetrahydroisoquinolines, and optionally substituted biaryl carboxamides.
The C5a receptor antagonist compounds described herein are particularly useful in the treatment of CS5a-mediated inflammation, ec.g., inflammation associated with various inflammatory and immune system disorders. The invention further comprises a method of treating a patient in need of such anti-inflammatory treatment or immune treatment an effective amount of a compound of the invention, . e.e. an amount of a compound of the invention sufficient to yield a plasma concentration of the compound (or its active metabolite, if a pro-drug) high enough to inhibit white blood cell (e.g., neutrophil) chemotaxis in vitro. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention. For treating non-human animals of any particular species, a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.
In a separate aspect, the invention provides methods of using compounds of the invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly C5a receptors, e.g., in tissue sections (e.g., via autoradiography) or in vivo (e.g., via positron emission tomography, PET, or single positron emission computed tomography, SPECT, scanning and imaging}.
The invention provides compounds and compositions that are useful as inhibitors of CSa-mediated chemotaxis (e.g., they may be used as standards in assays of such chemotaxis). The invention additionally comprises methods of inhibiting CSa-mediated cellular chemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis. These methods comprise contacting white blood cells, particularly primate white blood cells, especially human white blood cells, with one or more compounds of the invention. Preferably the concentration is sufficient to inhibit ) chemotaxis of white blood cells in an in vitro chemotaxis assay, so that the levels of chemotaxis observed in a control assay (e.g., one to which a compound of the invention has not been added) are significantly higher (significantly here measured as p<0.05 using a conventional parametric statistical analysis method such as a
N]
student’s T-test) than the levels observed in an assay to which a compound of the invention has been added.
Accordingly, a broad aspect of the invention is directed to non-peptidic ’ organic (carbon-containing) molecules, having a molecular mass of less than 700 } amu, that exhibit C5a antagonist activity or CSa inverse agonist activity with an
ECs of less than 500 nM in an assay of C5a mediated leukocyte chemotaxis.
More particularly the invention includes compounds of Formula I,
A d, d ds
AR1 AR2
LIP
Formula I wherein:
AR1 and AR2 are independently carbocyclic aryl or heteroaryl;
LIP represents an alkyl, carbocyclic aryl, heteroaryl, or arylalkyl,
A is oxygen or nitrogen; d; represents the distance between A and the geometric center of AR1 and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound; d; represents the distance between A and the geometric center of AR2 and is between 5 and 10 angstroms in at least one energetically accessible conformer of the compound; and ds represents the distance between A and the nearest atom of LIP and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound. Preferred compounds of Formula 1 exhibit antagonist (including inverse agonist) activity at C5a Receptors, and essentially no or little agonist activity at this . receptor. Preferably such compounds contain one or more heteroaryl rings. . Preferred compounds of the invention exhibit good activity in standard in vitro C5 receptor mediated chemotaxis assay, specifically the assay as specified in
Example 12, which follows and is defined below. Alternative preferred assays include the calcium mobilization assay. Preferred compounds of the invention exhibit an ECsy of about 500 nM or less in such a standard CSa mediated chemotaxis assay, more preferably an ECso of about 200 nM or less in such a } standard CS5a mediated chemotaxis assay, still more preferably an ECs of about 100, 50, 25 and 10 nM in such a standard C5a mediated chemotaxis assay, even more preferably an ECsy of about 5 nM in such a standard C5a mediated chemotaxis assay.
The invention includes additional methods such as methods for localizing
C5a recerptors in tissue section samples, comprising cotacting a tissue sample with detectably labelled one or more compounds of the invention that are preferably detectably labeled, optionally washing the contacted tissue sample, and detecting the bound compound associated with the tissue sample. Suitable detectable labels include e.g.1251, tritium, 32P, 99Tc or the like. A variety of detection methods could be employed include single emission photono computed tomography (“SPECT”).
Other aspects of the invention are discussed infra.
FIG. 1 is the sequence of SEQ ID NO-1.
Preferred compounds of the invention include carbon-containing molecules that comprise: i} having a molecular mass of less than 700 amu; ii) that is nonpeptidic; ’ iii) that exhibits C5a antagonist activity or C5a inverse agonist activity with } an ECso of less than 500 nM in an assay of C5a mediated leukocyte chemotaxis; and iv) exhibits less than 10% intrinsic agonist activity in an assay of leukocyte chemotaxis.
Among such compounds, particularly preferred are those that contain one or more heteroaryl and/or carbocyclic rings. For example, preferred are compounds of the following formula:
A d, d, ds
AR1 AR2
LIP
AR1 and AR2 are independently optionally substituted carbocyclic aryl or optionally substituted heteroaryl;
LIP represents an optionally substituted alkyl, optionally substituted carbocyclic aryl, optionally substituted heteroaryl, or optionally substituted arylalkyl,
A 1s oxygen or nitrogen; d: represents the distance between A and the geometric center of AR1 and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound, d, represents the distance between A and the geometric center of AR2 and is between 5 and 10 angstroms in at least one energetically accessible conformer of the compound; and ds represents the distance between A and the nearest atom of LIP and is between 3 and 6 angstroms in at least one energetically accessible conformer of the compound.
Preferred compounds of the invention also include heterocycles of the following formula II : 11
Ry
N nh RRs
IS war
Ary X Y
R, R;3Raa a,
or a pharmaceutically acceptable salt thereof, wherein the compound exhibits an
ECso of 1uM or less in an assay of C5a mediated chemotaxis, wherein: the ring system represented by
Op ” . is a 5 to 7 membered heterocycle that may be either aromatic or partially unsaturated;
X is N, C, or CR7, wherein R7is hydrogen, hydroxy, halogen, amino, cyano, nitro, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted (cycloalkylalkyl;
Y is Nor CH; nis 0, 1, or 2; mis 0, 1, or 2;
R and R; are independently chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; ’ Raz, Rs, Raa, Rs, and Rg are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyljalkyl;
When n is 0, R; and Rs may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted;
When n is 1, R and R; may be joined to form a cycloalkyl or hetcrocycloalkyl ring, each of which may be optionally substituted;
Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl each of which may be optionally substituted; or
R.: is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds of the above Formula II include those compounds wherein:
R and R, are independendently selected from i} hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifftuoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, : iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen,
nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Ra, Ra, Raa, Rs, and Rs are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, ) nitro, haloalkyl, and ii) alkyl. alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
R7 is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl, or
R7 is alkoxy, mono- or dialkylamino, alkyl, alkenyl, alkynyl or (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
When n is 0, R; and R; may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino;
When n is 1, R and Ra may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Rs is alkyl, alkenyl], alkynyl, cycloalkyl, (cycloalkyl)alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; or
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[dlisoxazoly], quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; or
R:is a bicyclic oxygen-containing group of the formula: ont >, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; and
Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, . cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl,
mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, and ii) bicyclic oxygen-containing groups of the formula: on) >% wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino.
Additional preferred compounds of the above formula II include those wherein
R and R; are independently selected from i) hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, mono- or di(C;-
Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C;-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, and (Cs-
Cs)cycloalkyl) C,-C3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;-
Cs)alkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, . Ci1-Cs alkyl, C2-Ce alkenyl, C»-Cs alkynyl, Ci-Ce alkoxy, amino, and mono- or di(C,-C¢)alkylamino;
When n is 0, R1 and Rs may be joined to form a C3-Cs cycloalkyl or C3-Cs heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Ce alkyl,
C,-Cs alkenyl, C»-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-
Cs)alkylamino;
When n is 1, R and Rz may be joined to form a C3-Cs cycloalkyl or C3-Cy heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-C, alkyl,
Ca-Ce alkenyl, C2-Ce alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-
Ce)alkylamino;
Ra, Ra, Raa, Rs, and Rs are independently selected from i) hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy, mono- or di(C,-
Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C2-Cs alkenyl, Co-Cs alkynyl, C3-Cy cycloalkyl, and (C3-Cg cycloalkyl) C,-Cj alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-C¢ alkoxy, amino, mono- or di(Ci-
Ces)alkylamino;
Rr is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl,
Ry is alkoxy, mono- or di(Ci-Cs)alkylamino, C;-Cs alkyl, C2-Csalkenyl, C2-Ce alkynyl or (C3-Cscycloalkyl) C1-Czalkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C-Ce alkoxy, amino, and mono- or di(C;-Cs)alkylamino;
R4 is C;-Cg alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cg cycloalkyl, (C3-Cg cycloalkyl)
C1-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl,
C,-Cs alkenyl, C,-C¢ alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;-
Ce)alkylamino; or
R; is phenyl, phenyl(C:-Ca)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl], indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo|[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C.-Cs alkenyl, C2-Ce alkynyl, Ci-Cs alkoxy. amino, mono- or di(C:-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-C¢)alkylaminocarbonyl,
N-( C1-Ce¢)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1- piperidyl; or
Rais a bicyclic oxygen-containing group of the formula: 2%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl,
C2-C¢ alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C:-
Cs)alkylamino; and
Ar; and Ar; are independently chosen from phenyl, phenyl(C,-Cs)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, : benzofuranyl, isobenzofuranyl, benzo|b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,
hydroxy. acetoxy, Ci1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C;-C; alkoxy, amino, mono- or di(C;-Ce)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Cs)alkylaminocarbonyl, N-(C;-
Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; and ii) bicyclic oxygen-containing groups of the formula: 0 hr
CI wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
C»-Ce alkenyl, C:-Ce alkynyl, C-C¢ alkoxy, amino, and mono- or di{C;-
Cs)alkylamino.
Still additional preferred compounds of the aboveformula II include those compounds of the following fomula:
Ri ke -
LI
Ar 1 N \_Ar lL, RaR 2
R, 3A and additionally include those compounds of the following formula:
R, R4 nv [
AIA
R Ar,
Ro 3 } mis 0, 1, or 2;
R} is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkylalkyl,
optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
Raz, Ra, Raa, Rs, and Re are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;
Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl cach of which may be optionally substituted; or
R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Additional preferred compounds of the above formula II include those compounds of the following formula:
R, Rs nv
AS
R Ar,
R, 3 wherein: . R) is hydrogen, C;-C; alkyl, halogen or phenyl optionally substituted with C;-Cg alkyl, C;-Ce alkoxy, halogen, hydroxy, amino, or mono- or di(C;-Cs)alkylamino;
R2 is C;-Cg alkyl or C3-Cs cycloalkyl; and
Rs is hydrogen or C;-C7 alkyl.
Additional preferred compounds of the above formula II include those compounds of the following formula:
R, R4 n—~
NN
AS hy
R 2
R, 3 wherein:
Ari is phenyl, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl, benzodioxinyl, benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl,
C.-C alkenyl, Ca-Ce alkynyl, C,-Ce alkoxy, amino, mono- or di(C,-
Cs)alkylamino;
Ar; is defined as in Claim 2;
R: is hydrogen, C,-C; alkyl, halogen or phenyl optionally substituted with C;-Ce alkyl, C;-Cs alkoxy, halogen, hydroxy, amino, or mono- or di(C,-Ce)alkylamino;
Ra» is C1-Cs alkyl or Cs-Cg cycloalkyl; and :
Rj is hydrogen or C;-C7 alkyl; and
Rs is C1-Cg alkyl, C3-Cs cycloalkyl, or (C3-Cg cycloalkyl) C1-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, amino, and mono- or di(C;-Cs)alkylamino.
Additional preferred compounds of the above formula II include those compounds of the following formula:
Rj; or
N
WAI
) R Ar,
R, 3 wherein:
Ar; is phenyl, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl, benzodioxinyl, benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl,
C.-C alkenyl, Ca-Cg alkynyl, C1-Ce alkoxy, amino, mono- or di(C:-
Cs)alkylamino;
Ar, is defined as in Claim 4;
R) is hydrogen, C,;-C; alkyl, halogen or phenyl optionally substituted with C,-Cg alkyl, Ci-Cs alkosy, halogen, hydroxy, amino, or mono- or di(Ci-Ce)alkylamino;
Rj is C;1-Cs alkyl or C3-Cy cycloalkyl; and
Rs is hydrogen or C,-C; alkyl: and
Rs is phenyl, phenyl(C,-Cs)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl], isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci-C¢)alkylamino; or
R4is a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl,
C2-Cs alkenyl, C2-C¢ alkynyl, C;-Ce alkoxy, amino, and mono- or di(Ci-
Cs)alkylamino.
Additional preferred compounds of the above formula II include those compounds of the following formula:
Ri re
Pi NN
Ar, pe BY
R m2
Ro 3 wherein:
Ar; is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C»-Cs alkenyl, C2-Cs alkynyl, C;-Ce alkoxy, amino, mono- or di(C;-Cs)alkylamino;
Ar; is defined as in formula II;
Ri is hydrogen, methyl, ethyl, or optionally substituted phenyl;
R2 is C3-Cg alkyl or C3-Cs cycloalkyl; and
Rj; is hydrogen or methyl; and
R4 is C1-Cg alkyl, C3-Cs cycloalkyl, or (C3-Cs cycloalkyl) C;-Csz alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cg alkenyl, C;-Cg alkynyl, C;-Cs alkoxy, amino, and mono- or di{C,-Cs)alkylamino.
Additional preferred compounds of the above formula II include those of the following formula:
R, Rs
N [
N
AS \
R 2
Ro 3 wherein:
Ari is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, Ci1-Cs alkoxy, amino, mono- or di(C;-Ce¢)alkylamino;
Ar, is defined as in Claim 4;
R; is hydrogen. methyl, ethyl, or phenyl;
R, is C3-Cs alkyl or C3-Cs cycloalkyl; and
Rs is hydrogen or methyl; and
R4 is phenyl, phenyl(C;-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl, C2-Cs alkenyl, Co-
Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(Ci-Cs)alkylamino; or
Rs is a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Ce alkyl,
C2-Cs alkenyl, Ca-Ce alkynyl, C1-Cs alkoxy, amino, and mono- or di(C:-
Ce)alkylamino. : Still additional preferred compounds of the above formula li include of the following formula:
Ri Rs
N r
WAS
R r2
R, 3 wherein:
Ar, is phenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C-Cs alkyl, C2-Cs alkenyl, C,-Cq alkynyl, C;-Cy alkoxy, amino, mono- or di(C-Cs)alkylamino;
Ar, is chosen from phenyl, phenyl(C;-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl], indanyl, benzo[b]thiophenyl, benzodioxanyl. benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-C¢ alkenyl, Ca-
Cs alkynyl, C;-Ce alkoxy, amino, mono- or di(C,-Ce¢)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-
Cs)alkylaminocarbonyl, N-(C;-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl; or
Ar; is a bicyclic oxygen-containing groups of the formula: 0 4 oN wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
C2-Ce alkenyl, C,-C¢ alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-
Ce)alkylamino;
Rj is hydrogen, methyl, ethyl, or phenyl;
R2 is C3-Csg alkyl or C3-Cs cycloalkyl; and
Rs is hydrogen or methyl; and
R; is C1-Cy alkyl, C3-Ca cycloalkyl, or (Cz-Cs cycloalkyl) Ci-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C.-Cg alkenyl, C2-Cs alkynyl, C1-C¢ alkoxy, amino, and mono- or di(C,-Cs)alkylamino.
Still further preferred compounds of the above formula II include those of the following formula:
R4 Rs —
AS
RB Ar,
Rs 3 wherein:
Ar is phenyl, phenyl(C,-Cs)alkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C,-Cs alkenyl, C2-Cs alkynyl, Ci1-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino;
Ar; is chosen from phenyl, phenyl(C1-Cq)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, Cs-
Cs alkynyl, C,-Ce alkoxy, amino, mono- or di(C;-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-
Cs)alkylaminocarbonyl, N-(C;-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl; or
Ars; is a bicyclic oxygen-containing groups of the formula:
0 he
Od i wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acctoxy, C;-Cgalkyl,
Ca2-Cs alkenyl, C»-Cs alkynyl, C;-Cg alkoxy, amino, and mono- or di(C)-
Cs)alkylamino;
R, is hydrogen, methyl, ethyl, or phenyl;
Rj is C3-Cs alkyl or C;-Cs cycloalkyl; and
Rj; is hydrogen or methyl; and
Rs is phenyl, phenyl(C,-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz|d|isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, C2-Ce alkenyl, Cao-
Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C:-Cg)alkylamino; or
Ra4is a bicyclic oxygen-containing group of the formula: >, wherein Rj represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
C»-Cs alkenyl, C2-Cs alkynyl, C1-C¢ alkoxy, amino, and mono- or di(C;-
Ce)alkylamino.
Preferred compounds of the invention also include those of the following formula III:
R, Ry4
N [
ASA
R Ar,
Rs 3 111 or a pharmaceutically acceptable salt thereof, wherein:
Ar is phenyl, phenyl(C,-Ca)alkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy. C1-Cs alkyl, C2-Ce alkenyl, C2-C¢ alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-C¢)alkylamino;
Ar, 1s a bicyclic oxyvgen-containing groups of the formula: oe NH
Od
Re wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
C»-Ce¢ alkenyl, C2-Cs alkynyl, C1-C¢ alkoxy, amino, and mono- or di(C;-
Cs)alkylamino;
R; is selected from i) hydrogen, halogen, hydroxy, amino, C;-C¢ alkoxy, mono- or di(C;-
Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C;-Cg alkyl, C2-Ce alkenyl, C,-Ce alkynyl, C3-Cg cycloalkyl, and (Cs-
Cs)cycloalkyl) C1-Ca alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;-
Cs)alkylamino; or ) R, is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:1-Cs alkyl,
C,-Cs alkenyl, Ci-Cs alkynyl, C:-C¢ alkoxy, amino, and mono- or di(C;-
Cs)alkylamino;
R2 and Rj; are independently selected from i) hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, mono- or di(C;-
Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C,-Cs alkyl, C:-Cs alkenyl, Ca-Cs alkynyl, C3-Csg cycloalkyl, and (C3-Cs cycloalkyl) C:-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cg alkoxy, amino, mono- or di(Ci-
Ce)alkylamino; and
Rs is C1-Cg alkyl, C,-Cg alkenyl, C,-Cg alkynyl, C3-Cs cycloalkyl, (Cs-Cs cycloalkylj Ca-
Cz alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
C2-Cs alkenyl, C,-Cs alkynyl, C;-C alkoxy, amino, and mono- or di(C;-
Cs)alkylamino; or
R4 is phenyl, phenyl(Ci-Ca4)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazoly], triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently ] selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Ce alkenyl, C»-Cs alkynyl, C1-Ce alkoxy, amino, mono- or di(C,-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cg)alkylaminocarbonyl,
N-( C;-Cg)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1- piperidyl. or
R:is a bicyclic oxygen-containing group of the formula:
OS
>%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca-Cs alkenyl, C»-C; alkynyl, C;-Ce¢ alkoxy, amino, and mono- or di{C;-Cs)alkylamino.
Preferred compounds of the above formula III include those wherein:
R, is hydrogen, methyl, ethyl, or phenyl;
Raz is C3-Cy alkyl or C3-Cs cycloalkyl,
Rs is hydrogen or methyl; and
Ris C1-Cg alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, (C3-Ca cycloalkyl) Ca-
Ci alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl, C2-Cs alkenyl, C,-
Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C,-Cs)alkylamino.
Additional preferred compounds of formula III include those wherein:
Ri is hydrogen, methyl, ethyl, or phenyl;
R3 is C3-Cs alkyl or C3-Cs cycloalkyl;
Rs is hydrogen or methyl; and
Rais C1-Cg alkyl, C2-Ce alkenyl, C2-Cg alkynyl, C3-Cs cycloalkyl, {C3-Cs cycloalkyl) C;-
Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, Co-
Cs alkynyl, C:1-C¢ alkoxy, amino, and mono- or di(C;-Cg¢)alkylamino.
Still additional preferred compounds of formula Ill above include those wherein:
R) is hydrogen. methyl, ethyl, or phenyl;
R2 is C3-Cg alkyl or C3-Cs cycloalkyl,
Rs is hydrogen or methyl; and phenyl, phenyl(C,-C.)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo|b]thiophenyl, benzodioxinyl, benzodioxolyl, benz{d}isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C,-Ce alkenyl, C2-Ce alkynyl, C1-Cg alkoxy, amino, mono- or di(C,-Cs)alkylamino.
Preferred compounds of formula Ill above also include those wherein:
R; is hydrogen, methyl, ethyl, or phenyl;
R2 is C3-Cs alkyl or C3-Cs cycloalkyl;
Rj is hydrogen or methyl; and
Rs is a bicyclic oxygen-containing group of the formula:
CL
2% wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl,
C2-Cg alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, amino, and mono- or di(C:-
Cs)alkylamino.
The invention also includes compounds of the following formula IV:
R, Ria Rs
Re
N (CRsaRea)
A
Ary N N © [0
R4 Ar,
Iv or a pharmaceutically acceptable salt thereof, wherein: n is an integer from O to 3; and
Ro is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, {cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or unsubstituted;
R4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be substituted or unsubstituted; or ’
R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms,
Rs and Rj are the same or different and represent hydrogen or alkyl; or
Rs and Raa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached form a cycloalkyl ring;
Rsa and Rsa are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy;
R7 represents hydrogen or alkyl;
Ar, and Ara are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.
Also preferred are compounds of that formula IV above (such preferred compounds referred to as compounds of formula IV-A) wherein n, R;, Raa, Rs, Rs,
Rsa, Rea, and Ry are as defined in that formula IV, and
R: is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl, or haloalkyl, each or which unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluormethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
R4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinoliny}, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally : substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-
alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and -
XRg, wherein X and Rg are as defined below; or
Rs is a bicyclic oxygen-containing group of the formula: >%, wherein Rj represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Ar; and Ar: are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo|b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and ~
XRg, wherein X and Rp are as defined below;, and ii) bicyclic oxygen-containing groups of the formula: 0 1 on wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
X is independently selected at each occurrence from the group consisting of -CHa-, -
CHRc-, -O-, -S(O)a-, -NH-, -NRc-, -C(=O)NH-, -C(=0)NRc-, -S(0)uNH-, -S(O}:mNRc-, -NHC(=0])-, -NRcC(=0)-, -NHS(O)m-, ~-C(=O)NHS(O)m-, and -NR¢S(O)w- (where m is 0, 1, or 2); and
Rg and Rc. which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH(alkyl), -N(alkyl){alkvl). -NHC(O){alkyl), -N(alkyl)C(O)(alkyl), -NHS(O)«(alkyl), -S(O)x(alkyl), -
S(0)xNH(alkyl), -S(O)xN(alkyl)(alkyl), (where x is 0, 1, or 2).
Also preferred are compounds of formula IV above wherein (such preferred compounds referred to as compounds of formula IV-B) n is defined as in formula IV above, and
Rs; and Rss are the same or different and represent hydrogen or
C1-Cs alkyl; or
Rs and Raa, taken together with the carbon atom to which they are attached, form a
Cs.g cycloalkyl ring;
Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, Ci-Ce alkyl, or C1-C¢ alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached form a
Ca.s cycloalkyl ring; : Rsa and Resp, are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, Ci-Ce alkyl, and C,-C¢ alkoxy;
R: is hydrogen or
C18 alkyl, Cag alkenyl, Cs.5 alkynyl, Cs.g cycloalkyl, (Ca.g cycloalkyl} Ci.3 alkyl, or Ci-
Cs haloalkyl, each or which unsubstituted or substituted by one or more of
W( 02/49993 PCT/USHO/20816 halogen, nitro, cyano, trifluormethyl, trifluoromethoxy, Ci.3 haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;-Ce)alkylamino;
Ri is hydrogen or
Cis alkyl, C..s alkenyl, Cs alkynyl, Cs.scycloalkyl, (Cs.s cycloalkyl)Ci-salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2 alkenyl, Cos alkynyl, C,-C; alkoxy, amino and mono- or di(C;-Ce)alkylamino,
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.¢ alkenyl, Cz.¢ alkynyl, C;-C¢ alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-(
Ci-Cg)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —
XRsg, wherein X and Rg are as defined below; or
Rais a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl,
Cas alkenyl, Ca. alkynyl, C1-Cs alkoxy, amino, and mono- or di(C1-
Ce)alkylamino;
Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, Cas alkenyl, C.¢ alkynyl, C;-Ce alkoxy, amino, mono- or di(C;-Ces)alkylamino, amino(C:-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs)alkylaminocarbonyl, N-(
C.-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -XRg, wherein X and Rg are as defined below: and ii) bicyclic oxygen-containing groups of the formula: 0 i (I wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Ce alkyl,
Ca.6 alkenyl, Co. alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-
Ce)alkylamino;
X is independently selected at each occurrence from the group consisting of -CH»-, -
CHRc-, -O-, -S(O)u-, -NH-, -NR¢-, -C(=O)NH-, -C(=O)NRc-, -S(O)mNH-, -S(O)uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)n-, and -NRcS(O)m- (Where m is 0, 1, or 2); and
Rp and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C;-Cs alkyl), -NH(C:1-Cs alkyl), -N(C-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Cs alkyl)C(O)(Ci.s alkyl), -NHS(O)x(C,-Cs alkyl), -S(O}x(C1-Cs alkyl), - . S(0)xNH(C,-Cs alkyl), -S(0)«N(C:-Cs alkyl)( C1-Ce alkyl), (where x is 0, 1, or 2).
Also preferred are compounds of formula IV above (such preferred referred to as compounds of formula IV-C) wherein n, Ra, Rs, Ria, Rs, Re, Rsa, Rea, and Ry are as defined in formula IV above,
R4 is hydrogen or
C:-Cs alkyl, C»-Cs alkenyl, C»-Cs alkynyl, C;-Cscycloalkyl, (Cs-Cscycloalkyl)
C;-Csalkyl, haloalkyl, each or which may bec unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl,
C2-C¢ alkenyl, C;-C¢ alkynyl, C;-Cs alkoxy, amino and mono- or di(Ci-
Cg)alkylamino,
Rs is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C,1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C,-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Ce)alkylaminocarbonyl, N-( C;-
Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —
XRg, wherein X and Rg are as defined below; or
Rs is a bicyclic oxygen-containing group of the formula:
wherein Rj represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
C»-Cs alkenyl. C»-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-
Cg)alkylamino;
Ary is phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or substituted with up to four substituents independently selected from: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-Cs alkenyl, Ca-Cs alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-C¢)alkylamino, amino(C;-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C-
Cs)alkylaminocarbonyl, N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —-XRg, wherein X and Rp are as defined below;
Ar: is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-Ce)alkylamino, amino(C;-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;-
Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —-
XRg, wherein X and Rg are as defined below; or
Ar: is a bicyclic oXygen-containing group of the formula:
CL
. RA wherein Rp’ represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl,
C»-Cs alkenyl, C»-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-
Co)alkylamino;
X is independently selected at each occurrence from the group consisting of -CHo-, -
CHRc-, -O-, -S(O)w-, -NH-, -NR¢-, -C(=O)NH-, -C(=O)NRc-, -S(0)nNH-, -5(0)uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)u-, -C(=O)NHS(O)m-, and —NRcS(O}n- (where m is 0, 1, or 2); and
Rg and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C-Cs¢ alkyl), -NH(C1-Cs alkyl), -N(C1-Ce alkyl)(C1-Ce alkyl), -NHC(O)C1-Cs alkyl), -N{C1-Cs alkyl)C(0)(C,-Cs alkyl), -NHS{O)«(C:-C¢ alkyl), -S{O)x(C1-Cs alkyl), -
S(O)«NH(C-Cs alkyl), -S(0)xN(C1-Cs alkyl)(C1-Cs alkyl), (where x is 0, 1, or 2).
Further preferred are compounds of the above formula IV-C wherein:
R; and R4 are the same or different and represent hydrogen or methyl;
Rs and Rg are the same or different and represent hydrogen or methyl; and
Rsa and Rea are the same or different, and are independently selected at each occurrence from hydrogen and methyl.
Further preferred are compounds of the above formula IV-C wherein: ‘ R3 and R4 are hydrogen;
Rs and Rg are the same or different and represent hydrogen or methyl; and
Rs. and Rea are the same or different, and are independently selected at each occurrence from hydrogen and methyl.
Further preferred are compounds of the above formula IV-C wherein:
Rs
Re ' {h n or \
CY)
JF aL or a pharmaceutically acceptable salt thereof, wherein: n is an integer from 0 to 3; and
R; is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or unsubstituted:
Rs is hydrogen or
C,-Cs alkyl, C,-Cg alkenyl, C»-Cg alkynyl, Cs-Cgcycloalkyl, (Cs-Cscycloalkyl)
C:-Csalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl,
C2-Ce alkenyl, C;-Ces alkynyl, C:-C¢ alkoxy, amino and mono- or di(Ci-
Ce)alkylamino,
R4 is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C1-Ce alkyl, C2-C¢ alkenyl, Co-Cs alkynyl, C1-C¢ alkoxy, amino, mono- or di(Ci1-Ce)alkylamino, amino(C;-Cg)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Ce)alkylaminocarbonyl, N-( Ci-
Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —
XRsp, wherein X and Rp are as defined below; or
Rs is a bicyclic oxygen-containing group of the formula:
on) >%, ) wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
C.-Ce alkenyl, C3-Cs alkynyl, C1-Ce alkoxy, amino, and mono- or di(Ci-
Cs)alkylamino;
Ar; is phenyl, naphthyl, thienyl, pyridyl, pyrimidy], dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently sclected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
Ci1-Cs alkyl, C2-Cy alkenyl, C2-Cs alkynyl, C;-Ce alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;-
Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —-
XRg, wherein X and Rp are as defined below; or
Ar; is a bicyclic oxygen-containing group of the formula: oe) - wherein Ra’ represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl,
Ca-Cs alkenyl, C;-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-
Cs)alkylamino;
X is independently selected at each occurrence from the group consisting of -CH;-, -
CHRc-, -O-, -S(O)m-, -NH-, -NRc-, -C(=0O)NH-, -C(=O)NR¢-, -S(O)uNH-, -S(O)mNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)m~, and —NRcS(O}m- (where m is 0, 1, or 2); and
Rg and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C1-Cs alkyl), -NH(C:-Cs, alkyl), -N(C,-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C;-C, alkyl), -N(Ci-Cs alkyl)C(O)(C1-Cs alkyl), -NHS(O)«(C1-Cs alkyl), -S(O)x(C1-Cs alkyl), -
S(O)xNH(C,-Cs¢ alkyl), -S(O)xN(C1-Cs alkyl)(Ci-Cs alkyl), (where x is 0, 1, or 2).
Rs and Rg are the same or different and represent hydrogen or methyl;
Rs. and Rg, are the same or different, and are independently chosen at each occurrence from hydrogen and methyl; and
Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-C¢ alkyl, C2-Cs alkenyl, C»-Cs alkynyl, C;-Cs¢ alkoxy, amino, mono- or di(Ci-Ce¢)alkylamino, and amino(Ci-Ce)alkoxy.
Further preferred are compounds of the above formula IV-C wherein:
Rs
Re
I Reo n
OT N
ZF Re [ MN
NJ Rs Ar, or a pharmaceutically acceptable salt thereof, wherein: n is an integer from O to 3; and
R4 is hydrogen or
C1-Cs alkyl, C»-Cg alkenyl, C,-Cg alkynyl, Cs-Cscycloalkyl, {Ca-Cscycloalkyl)
C:-Caalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, . Ca-Cs alkenyl, C,-Cs alkynyl, Ci-C¢ alkoxy, amino and momno- or di(Ci-
Ce)alkylamino,
R, is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C1-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C:-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-{ C;-
Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, -
XRg, wherein X and Rp are as defined below; or
Rais a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl,
C2-Ce alkenyl, C;-Cg alkynyl, C,-Cs alkoxy, amino, and mono- or di(Ci-
Cs)alkylamino;
Ar; is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C1-Cs alkyl, C2-Cg alkenyl, C2-Ce alkynyl, C;-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( Ci-
Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -
XRg, wherein X and Rp are as defined below; or
Ar; is a bicyclic oxygen-containing group of the formula:
Se. wherein Ra’ represents 0 to 3 groups selected from halogen, nitro, cvano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C)-Cs alkyl,
C,-Ce alkenyl, C»-Cg alkynyl, Ci-Ce alkoxy, amino, and mono- or di(Ci-
Cg)alkylamino;
X is independently selected at each occurrence from the group consisting of -CHa-, -
CHRc-, -O-, -S(O)m-, -NH-, -NR¢-, -C(=O)NH-, -C(=O}NR¢-, -S(O)uNH-, -S(O}uNRc-, -NHC(=0])-, -NRcC(=0)-, -NHS(O)a-, -C(=O)NHS(O)n-, and -NRcS(O)m- (where m is 0, 1, or 2); and
Rp and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C,-Cs alkyl), -NH(C,-Cs alkyl), -N(C,-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Co alkyl) C(O)(C1-Cs alkyl), -NHS(0)x(C1-Cs alkyl), -5(0)«(C1-Ce alkyl), -
S(O)xNH(C1-Cs alkyl), -S(O)xN(C:1-Cs alkyl)(Ci1-Cs alkyl}, (where x is 0, 1, or 2).
Rz is C3-Cs straight or branched chain alkyl, C2-Cg alkenyl, or C2-Cg alkynyl;
Rs and Rs are the same or different and represent hydrogen or methyl;
Rsa and Rea are the same or different, and are independently chosen at each occurrence from hydrogen and methyl; and
Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci;-C¢ alkoxy, amino, mono- or di(C;-Cg)alkylamino, and amino(C,-Cs)alkoxy.
Further preferred are compounds of the above formula IV-C wherein:
Ars, Rx, and n are as defined in formula IV-C, or a pharmaceutically acceptable salt thereof, wherein:
R., is C3-Cg straight or branched chain alkyl, C2-Cs alkenyl, or C,-Cs alkynyl; and
R. is C1-Cs straight or branched chain alkyl, C,-Cg alkenyl, or C2-Cs alkynyl.
Further preferred are compounds of the above formula IV-C, or a pharmaceutically acceptable salt thereof, wherein:
R; is C3-Cs straight or branched chain alkyl, C2-Cs alkenyl, or C2-Cs alkynyl,
Rs is phenyl, which may be unsubstituted or substituted with:
Ci-Ce¢ alkyl, C»-Cs alkenyl, C»-Cs alkynyl, C3-Cs cycloalkyl, (Cs3-Cs cycloalkyl)C;-C4 alkyl, haloalkyl, C,1-Cs alkoxy, halogen, hydroxy, amino, or mono- or di(C;-Ce)alkylamino; or
Rs is a bicyclic oxygen containing group of the formula: 0 2 ° 2 - Od 0 Ra 0 Ra wherein Ra is hydrogen, C;-Cs alkyl, C2-Cg alkenyl, C2-Ce alkynyl, Cz-Cs cycloalkyl, (C3-Cscycloalkyl) Ci-C4 alkyl, haloalkyl, alkoxy, halogen, hydroxy, amino, or mono- or di(C;-Cs)alkylamino; : Ar; is phenyl which is unsubstituted or optionally substituted or substituted with up to four groups independently selected from: halogen, C;-C7 alkyl, C,-C; alkoxy, cyano, amino, mono- or di(Ci-
Ce)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-
alkylsulfonylaminocarbonyl, 1-azetidinyl, l-pyrrolidinyl, 1-piperidyl, l-morpholino, nitro, hydroxy, acetoxy, trifluoromethyl, and trifluoromethoxy or -XRs, wherein X and Rpg are as defined for formula IV-C; or
Ar is a bicyclic oxygen-containing group of the formula: - Oo - ° IA 5 NX 5
CITY (C0 <r ~
[0] Z Ra' © Z Ra’ wherein Ra Ry’, and n are as defined in formula IV-C.
Also preferred are compounds of formula IV-C as specified above, wherein. n is an integer from 0 to 3;
Ra is C3-Cg straight or branched chain alkyl, C>-Cs alkenyl, or C2-Cg alkynyl:
Rs is C1-C3 straight or branched chain alkyl, C,-Cy alkenyl, or C»-Cg alkynyl;
Ar; is a bicyclic oxygen containing group of the formula: 0 4 © { ( 0 Ra’ 0 Ra’ wherein Ra’ represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl,
C2-C¢ alkenyl, C»-C¢ alkynyl, C;-Ce¢ alkoxy, amino, and mono- or di(Ci-
Ce)alkylamino. . Additional preferred compounds include those of the following formula V:
R; Ras
Re os : Rsh n Rea
Br be} v wherein: n is an integer from 0 to 3;
Rs and Rss are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or
R3 and Ria, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or
R; and Rg, taken together with the carbon atom to which they are attached form a cycloalkyl ring; and
Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy.
Preferred compounds of formula V include those compounds wherein:
Rj; and Rss are the same or different and represent hydrogen or C;-Cs alkyl; or
Rs; and Rasa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring of from three to six carbon atoms;
Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, C,-Cs alkyl, or C,-Cs alkoxy; or
Rs and Re, taken together with the carbon atom to which they are attached form a cycloalkyl ring of from three to six carbon atoms; and
Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, C;- : Ce alkyl, or C1-Ce alkoxy.
Preferred compounds of formula V include thosae compounds wherein:
Rs and Rs are hydrogen; and
Rs, Re, Rsa, and Rea are the same or different and represent hydrogen or methyl.
The invention also includes compounds of the following formula VI:
R; Raa Rg Re
Peo
Ari N \ lo]
Ro VI wherein: n is an integer from 0 to 3;
R; is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl, or haloalkyl, each of which may be substituted or unsubstituted;
Rs; and R4 are the same or different and represent hydrogen or alkyl; or
R3 and Raa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rsa and Resa are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; and
Ar; is unsubstituted or substituted carbocyclic aryl, unsubstituted or substituted arylalkyl, or a unsubstituted or substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.
Preferred compounds of formula VI include those compounds wherein:
Ra is Ci1-Cs straight or branched chain alkyl, C»-Cg alkenyl, C2-Cg alkynyl, C3-Cs cycloalkyl, C;-Csg (cycloalkyl)C:-Cs alkyl, or C;:-Cs haloalkyl;
R3 and Raa are the same or different and represent hydrogen or C,-Ce alkyl; or
Rj; and Raa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring of from three to six carbon atoms; and
Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, Ci1-Cs alkyl, or C;-Cs alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached form a cycloalkyl ring of from three to six carbon atoms;
Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, C;-
Cs alkyl, or C;-C, alkoxy; )
Ar; is phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or substituted with up to four substituents independently selected from: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Ci-Ce alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-
Ce)alkylaminocarbonyl, N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -XRg, wherein X and Rg are as defined below;
X is independently selected at each occurrence from the group consisting of -CHa-, -
CHRc-, -O-, -S(O)m-, -NH-, -NR¢-, -C(=0)NH-, -C(=O)NR¢-, -S(O)NH-, -
S(O)mNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)n-, and —
NReS(O)w- (Where m is 0, 1, or 2); and
Rs and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: . hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C,-Cs alkyl), -NH(C;-Cs alkyl),
-N(C1-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Cs alkyljC(O)(Ci1-Cs alkyl), -NHS(O)4(C;-Cs alkyl), -S(O)x(C1-Cs alkyl), -
S(0)xNH(C,-Cq alkyl), -S(O)xN(C;-C alkyl)(C:1-Ce alkyl), (where x is 0. 1, or 2}.
Preferred compounds of the above formula VI include those of the following formula:
R
N 5A / \ Rea
NN :
N
74 = | 2
Ry R> wherein: nis 0, 1, or 2:
Rz is C3-Cg straight or branched chain alkyl, C;-Cg alkenyl, or C;-Cs alkynyl;
Rs, Rs, Rsa, and Rea are the same or different and represent hydrogen or methyl; and
Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C,-Cg alkenyl, C3-Cg alkynyl, C;-C¢ alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(C;-Cs)alkoxy.
The invention also includes compounds of the following formula VII:
R3aRs
R; Rg
R
N SA
JR Rea
AN ho Re
R:
VII wherein:
n is an integer from 0 to 3; and
R: is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl, haloalkyl, each or which may be substituted or unsubstituted;
R; and Ria are the same or different and represent hydrogen or alkyl: or
R; and Rj, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs and Rg are the same or different and represent hydrogen or alkyl; or
Rs and Rs, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs, and Rs, are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy;
R; represents hvdrogen or alkyl; and
Ar, is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.
Preferred compounds of formula VII include those of the following formula:
Rs Re
N Rsa
AN / n Rsa / ’ pl = OH
Ry R2 wherein: n is an integer from 0 to 3; : R2 is C3-Cg straight or branched chain alkyl, C;-Cs alkenyl, or C2-Cg alkynyl;
Rs, Re, Rsa, and Rea are the same or different and represent hydrogen or methyl; and
Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, C2-Cg alkenyl, Ca-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-Cg)alkylamino, and amino(C,-Cs)alkoxy.
The invention also includes methods of syntesis of compounds of the invention. In particular, the invention includes methods to synthesis compounds of the following formula VIIL . Rep
Rs es
A="
Ry
Ary N N
LOY
Rs Ar, VIII wherein: n is an integer from 0 to 3; and
Ra: is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl, or haloalkyl, each or which may be substituted or unsubstituted;
R4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl, haloalkyl, each or which may be substituted or unsubstituted; or
Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms, - Rj and Ria are the same or different and represent hydrogen or alkyl; or
Rs and Raza, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached form a cycloalkyl ring; ' Rs, and Rg, are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy;
Ry represents hydrogen or alkyl;
Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms. the process comprising: reacting a compound of the formula:
Ry R3aRs R,
J
Pa
Ar, N Y Ry
Ry wherein Y is halogen or sulfonate ester, in a suitable solvent in the presence of a suitable base, with a secondary amine of the formula; [0
Rs Ar,
In that synthetic method, preferred are compounds (referred to as compounds of formula VIII-A) wherein n and Y are as defined above for formula VIII;
R3 and R3a are the same or different and represent hydrogen or
C,-Cs alkyl; or
Rs; and Raa, taken together with the carbon atom to which they are attached, form a
Cs. cycloalkyl ring; ) Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, C:-Cq alkyl, or C,-C; alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached form a
Ca.s cycloalkyl ring;
Rs. and Re, are the same or different, and are independently selected at cach occurrence from hydrogen, halogen, hydroxy, Ci1-Cs alkyl, and Ci-Ce alkoxy;
R: is hydrogen or
Cis alkyl, Cos alkenyl, Cas alkynyl, Ca.s cycloalkyl, (Css cycloalkyl) Ci. alkyl, or Ci-
Co haloalkyl, each or which unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluormethyl, trifluoromethoxy, Cis haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C1-Cg)alkylamino;
R4 is hydrogen or
Cis alkyl, Cag alkenyl, Cos alkynyl, Cascycloalkyl, (Cs.s cycloalkyl)C,.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2 alkenyl, Ca. alkynyl, C;-Cs alkoxy, amino and mono- or di(C;-Ce)alkylamino,
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b|thiophenyl, benzodioxany], benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, . cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2.¢ alkenyl, Ca. alkynyl, Ci-Cs alkoxy, amino, mono- or di(Ci-Ce)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of
C1-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —
XRg, wherein X and Ry are as defined below; or ’ R, is a bicyclic oxygen-containing group of the formula: aE (Cd wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl,
Ca alkenyl, Ca.¢ alkynyl, Ci-Cs alkoxy, amino, and mono- or di(Ci-
Ce)alkylamino;
Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindoly], benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d}isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cg alkyl, Ca.¢ alkenyl, Ca.6 alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci-Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-(
C,-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -XRp, wherein X and Rg are as defined below; and . ii) bicyclic oxygen-containing groups of the formula: eS)
Rg wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano,
Cz.6 alkenyl, Cas alkynyl, C1-Cs alkoxy, amino, and mono- or di{C;-
Cs)alkylamino; : X is independently selected at each occurrence from the group consisting of -CHs-, -
CHRc-, -O-, -S(O)n-, -NH-, -NR¢-, -C(=O)NH-, -C(=0)NRc¢-, -S{O}uNH-, -S(O}mNRc-, -NHC(=0)-, -NRcC(=0j}-, -NHS(O}n-, -C(=0)NHS(O}n-, and —NRcS(O)n- (where m is 0, 1, or 2}; and
Re and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C:-Cs alkyl), -NH(C,-Cs alkyl), -N(C1-Cs alkyl)(C1-Ce alkyl), -NHC(O)(C1-Cs alkyl), -N(Ci-Cs alkyl)C(O)(C1.6 alkyl), -
NHS(0)x(C1-Cs alkyl), -S(0)x(C1-Ce alkyl), -S(O)xNH(C1-Cs alkyl), -S(O}xN{C1-Cs alkyl)(
Ci-Cs alkyl), (where xis 0, 1, or 2).
The invention also includes compounds of the above formula VIII and VIII-A, and pharmaceutically acceptable salts of such compounds.
The invention also provides compounds of the following formula IX:
Rq
NTO R RsRg Rs
J
Ar; 7 mN
Rz R3R3a
Ar21x or a pharmaceutically acceptable salt thereof, wherein: mis O, 1, or 2;
R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl; or
R is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
Ri, Ra, Rj, Raa, Rs, and Re are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;
Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl each of which may be optionally substituted; or
Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar) and Ar: are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds of formula IX include those of the following formula IX-
A:
R4
NOX R R4 [ ] Arq AZ ™
R2 Rj Ary IX-A wherein Arj, Ara, R, Ry, Re, Rs, and Ry are for formula IX above.
Preferred compounds of formula IX-A above include those wherein:
i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkylalkyl, cach of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino; or
R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl. isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano. trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; and
Ri, Ra, and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, triflucromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
Rs is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl,
benzodioxinyl, benzodiozolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally ) substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy. alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, -XRg, wherein X and Rp are as defined below; or
Rais a bicyclic oxygen-containing group of the formula: 8) >%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Ar; and Ar; are independently chosen from i} phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazoly], pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —
WQO 02/49993 PCT/US00/26810 ii) bicyclic oxygen-containing groups of the formula:
NH
US
Re wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
X is independently selected at each occurrence from the group consisting of -CHa-, -
CHRc-, -O-, -S(0O)g-, -NH-, -NRc-, -C(=0O)NH-, -C(=0)NRc-, -S(O)uNH-, -S(O}uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)w-, -C(=O)NHS(O)x-, and -NRcS(O)n- (where m is 0, 1, or 2); and
Rs and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH{(alkyl), -N(alky!)(alkyl), -NHC(O)(alkyl), -N(alkyl)C(O)(alkyl), -NHS(O)x(C1-Cs alkyl), -S(O)«(alkyl), -S(O}xNH(alkyl), -S(O)xN(alkyl)(alkyl), (where x is 0, 1, or 2).
Additional preferred compounds of formula IX-A include those wherein:
Ri, Re, and Rs are independently selected from i) hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy, mono- or di(Ci-
Cs)alkylamino, cyano, nitro, haloalkyl, and : ii) C1-Cs alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (C3-Cs cycloalkyl) C,-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, C1-Cs alkoxy, amino, mono- or di(Ci-
Cs)alkylamino; ‘ Ris sclected from i) hydrogen, halogen, hydroxy, amino, C1-Cq alkoxy, mono- or di(C:-
Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C.,-Cs alkenyl, C2-Cs alkynyl, Cs-Cs cycloalkyl, and (Cs-
Cs)cycloalkyl) C1-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;-
Ce)alkylamino; or
R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl. oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
C,-Cs alkenyl, C2-Cg alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-
Ce)alkylamino;
R4 is hydrogen or
Cis alkyl, C,s alkenyl, Cas alkynyl, Ca.scycloalkyl, (Cs.s cycloalkyl)C;.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cos alkenyl, Ca. alkynyl, C1-Ce alkoxy, amino and mono- or di(Ci-Cs)alkylamino,
R4 is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl,
substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acctoxy, Ci-Cs alkyl, Ca alkenyl, Cz.s alkynyl, C;-Cs alkoxy, amino, mono- or di(Ci-Ce)alkylamino, amino(C-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cg)alkylaminocarbonyl, N-{
Ci1-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —
XRg, wherein X and Rg are as defined below; or
R4is a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
C26 alkenyl, Ca.6 alkynyl, C,-Cs alkoxy, amino, and mono- or di(C,;-
Cs)alkylamino; and
Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d}isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2. alkenyl, Ca.6 alkynyl, C;-C¢ alkoxy, amino, mono- or di(C;-Cg)alkylamino, amino(C:-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs}alkylaminocarbonyl, N-(
C1-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -XRg, wherein X and Rg are as defined below; and o) yr (Od wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
Ca.6 alkenyl, Ca, alkynyl, C,-Cp alkoxy, amino, and mono- or di(C)-
Cs)alkylamino;
X is independently selected at each occurrence from the group consisting of -CHp-, -
CHRc-, -O-, -S(0O)m-, -NH-, -NR¢-, -C(=O)NH-, -C(=0)NRc-, -S(O)uNH-, -S(0)uNRc-, -NHC(=0}-, -NRcC(=0}-, -NHS(O)m-, ~-C(=O)NHS(O)u-, and ~NRcS(O)n- (Where m is 0, 1, or 2); and
Rs and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C;-Cs alkyl), -NH(C1-Cs alkyl), -N(C;-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(Ci-Cs alkyl)C(O)(Ci.s alkyl), -NHS(O)x(C1-Cs alkyl), -S(O)x(C1-Cs alkyl), -
S(O)xNH(C1-Cs alkyl), -S(0)xN(C1-Cs alkyl){ Ci-Cs alkyl), (where x is 0, 1, or 2).
Additional preferred compounds of formula IX-A above include those wherein:
R is hydrogen, halogen, C,-Cs alkyl, C»-Cg alkenyl, C»-Csg alkynyl, C;-Cs cycloalkyl, (Cs-Cscycloalkyl)C,-Csalkyl, C1-Cs alkoxy, or C;-Cg haloalkyl, or
Ris a phenyl which may be substituted by up to five substituents independently chosen from C;-Cs alkyl, C»-Cg alkenyl, C»-Cs alkynyl, C;-Cs alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy, nitro, amino, mono or di(C;-
Cs)alkylamino, aminocarbonyl, sulfonamido, mono or di(C;-Cs)alkylsulfonamido, 3,4-methylenedioxy, 3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;
R; is hydrogen, Ci-Cg alkyl, Cs-Cs alkenyl, C,-Cg alkynyl, C3-Cg cycloalkyl (Ca-
Cscycloalkyl)C,-Caalkyl or C1-Cs haloalkyl; ' Ry, is C,-Cs alkyl, C.-Cs alkenyl, Ci;-Cg alkynyl, Ci-Cs cycloalkyl or (Cs-
Cscycloalkyl)Ci-Csalkyl or C1-Cg haloalkyl;
Rj is hydrogen, Ci-Cg alkyl, C2-Cs alkenyl, or C2-Cy alkynyl;
Rs is Cy-Cg alkyl, C3-Cs cycloalkyl, or (C3-Cg cycloalkyl) C;-C3 alkyl, each of which may be unsubstituted or substituted with onc or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy. haloalkyl, hydroxy, acetoxy, Ci1-C¢ alkyl, C»-Cs alkenyl, C2-Cs alkynyl, C;-C¢ alkoxy, amino, and mono- or di(C;-Cs)alkylamino; or
Ra is phenyl, phenyl(Ci-Cas)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b|thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, Co-
Ce alkynyl, C;-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino; or
Rs is a bicyclic oxygen-containing group of the formula: . 2%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifftuoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C,-Ce¢ alkoxy, amino, and mono- or di(C:-Cs)alkylamino; . and
Ar) and Ar; are independently chosen from phenyl, phenyl(C;-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b}thiopheny], benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl,
isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifltuoromethoxy, haloalkyl, hydroxy, acetoxy,
Ci1-Cs alkyl, C»-C; alkenyl, C.-Cs alkynyl, Ci-Cs alkoxy, amino, mono- or di(C1-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C.-Cs}jalkylaminocarbonyl, N-{C;-
Ces)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, and bicyclic oxygen-containing groups of the formula:
NP 1 (Xd
Re wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl,
Ca-Cs alkenyl, C,-Cg alkynyl, C,-Cs alkoxy, amino, and mono- or di(C;-
Ce)alkylamino.
Still additional preferred compounds of formula IX-A include those compounds wherein:
R is hydrogen, halogen, C;-Cg alkyl, C2-Cs alkenyl, C,-Cs alkynyl, Ci-Cs cycloalkyl, (Cs-Cecycloalkyl)Ci1-Csalkyl, C)-Cs alkoxy, or C;-Cg haloalkyl, or
Ris a phenyl which may be substituted by up to five substituents independently chosen from C,;-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C1-Cs alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy, nitro, amino, mono or di(C:-
Ce)alkylamino, aminocarbonyl, sulfonamido, mono or di(C,-Ce)alkylsulfonamido, 3,4-methylenedioxy, 3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;
Ri: is hydrogen, C;-Cg alkyl, C2-Cs alkenyl, C»-Cs alkynyl, C3-Cs cycloalkyl (Cs-
Cscycloalkyl)C)-Caalkyl or C)-Cs haloalkyl;
R; is C1-Cg alkyl, C2-Cs alkenyl, C;-Cs alkynyl, C;-Cs cycloalkyl or (C3-Cs cycloalkyl)Ci-Caalkyl or C,-Cg haloalkyl;
Rs is hydrogen, C;-Cg alkyl, C2-Cg alkenyl, or C2-Cs alkynyl;
R, is C;-Cs alkyl, C3-Cs cycloalkyl, or (Cs-Cs cycloalkyl) C1-Cy alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, Ca-C¢ alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C,-Cs}alkylamino; or
Rs is phenyl, phenyl(C,-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodicxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl, C2-Cs alkenyl, Co-
Cs alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-Ce¢)alkylamino; or
Riis a bicyclic oxygen-containing group of the formula:
Cr >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-Ce alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(Ci-Cs}alkylamino;
Ar; is phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C»-Cs alkenyl, C-Cs alkynyl, Ci-C¢ alkoxy, amino, mono- or di(Ci-
Ce)alkylamino; and
Ars is phenyl, phenyl(C;-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazoly], quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Ca2-Cs alkenyl, Cs-
Ce alkynyl, C;-Ce¢ alkoxy, amino, mono- or di(C:1-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-
Cs)alkylaminocarbonyl, N-(C,-C¢)alkylsulfonylaminocarbonyl, 1-azetidinyi, 1- ] pyrrolidinyl, and 1-piperidyl, or
Ar; is a bicyclic oxygen-containing group of the formula: me NE
C
= Rg wherein Rg represents 0 to 3 groups selected from halogen, nitro, cvano, trifluoromethyl, triflnoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
C.-C alkenyl, C2-Cs alkynyl, C,-Cg alkoxy, amino, and mono- or di(C;-
Ce)alkylamino.
Still further preferred compounds of formula IX above include those wherein
R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or phenyl;
R, is hydrogen, methyl or ethyl;
R2 is C3-Ce alkyl;
Rs is hydrogen, methyl or ethyl;
R4 is C;-Cs alkyl, C3-Cs cycloalkyl, or (C3-Cs cycloalkyl) Ci-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, C2-Ce¢ alkenyl, C»-C¢ alkynyl, C;-Cs alkoxy, amino, and mono- or di(C1-Ce)alkylamino; or
R4 is phenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C»-Cse alkenyl, Co-
Cs alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino; or
Rais a bicyclic oxygen-containing group of the formula:
CG OG or 0 2% 0 >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C;-Cs alkynyl, C1-Ce alkoxy, amino, and mono- or di(C;-Cs)alkylamino;
Ar is phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C,-Cs alkenyl, C2-Ce¢ alkynyl, C,-Cs alkoxy, amino, mono- or di(C:-
Cs)alkylamino; and
Ar; is phenyl, phenyl(C:-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-C¢ alkenyl, Ca-
Cs alkynyl, C1-C¢ alkoxy, amino, mono- or di(C,-Cs)alkylamino;
Ar; is a bicyclic oxygen-containing group of the formula: 0 5 NEN 1 a OF © Rp 0 7 Rg ) wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C;-Cs alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(Ci-Cs)alkylamino.
The invention also include compounds of the following formula X:
Ry
NTO : RsRg Rg
J
Ary = mN
R2 R3 Raa § ’ Arp X wherein: mis 0, 1, or 2;
R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyljalkyl; or
R is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
Ri, Re, Ra, Raa, Rs, and Ry are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyljalkyl;
Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl each of which may be optionally substituted; or
Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar; and Ar: are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroary! or heteroalicyclic group ’ having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds of formula X include those of the following formula X-
A:
Ry ! Xe R Ry - "
Arq 7
Re Rs X-A wherein Ari, R, Rj, Ro, Rs, R4 are as defined for formula X above.
Additional preferred compounds of formula X include those wherein:
R1, Raz, and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, C;-C; alkoxy. mono- or di(C;-
Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cg alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, and (C3-Cs cycloalkyl) C1-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkoxy, amino, mono- or di(C;-
Cs)alkylamino;
Ris selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(C:-
Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (Ca-
Cs)cycloalkyl) C)-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;- ' Ce)alkylamino; or
R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cg alkyl],
C2-Cs alkenyl, C2-Ce alkynyl, Ci-C¢ alkoxy, amino, and mono- or di(C;-
Cs)alkylamino; » R, is hydrogen or
Cis alkyl, Cas alkenyl, Cys alkynyl, Cs.scycloalkyl, (Cs.s cycloalkyl)C). alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cuz alkenyl, Cue alkynyl, C,-Cg alkoxy, amino and mono- or di(C;-Ce)alkylamino,
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo|bjthiophenyl, benzodioxany], benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl], trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cz.6 alkenyl, C26 alkynyl, C;-Ce alkoxy, amino, mono- or di(C;-C¢)alkylamino, amino(C;-C¢)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Ce)alkylaminocarbonyl, N-(
Ci-Cg)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —
XRg, wherein X and Rg are as defined below; or
Rais a bicyclic oxygen-containing group of the formula: 2%. wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl,
C..6 alkenyl, C..6 alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-
Co)alkylamino: and
Ar; and Ar» are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl. . thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indany], isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinoliny!, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Cas alkenyl, Ca.¢ alkynyl, C,-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C-Cs)alkylaminocarbonyl, N-(
Ci-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —-XRp, wherein X and Rg are as defined below; and ii) bicyclic oxygen-containing groups of the formula:
CL
Re wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl,
Ca. alkenyl, C26 alkynyl, C1-Ce alkoxy, amino, and mono- or di(Ci-
Ce)alkylamino;
X is independently selected at each occurrence from the group consisting of -CHa-, - - CHRc-, -O-, -S(0O)m-, -NH-, -NRc-, -C(=0O)NH-, -C(=0)NR¢-, -S(O)uNH-, -S(O)xuNRc-, -NHC(=0})-, -NRcC(=0)-, -NHS(O)w-, -C(=O)NHS(O)x-, and ~-NRcS(O)n- (Where m is 0, 1, or 2); and
Ry and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain ’ one or more double or triple bonds, each of which may unsubstituted or . substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C:-Cs alkyl), -NH(C;-Cs alkyl), -N(C,-Cs alkyl)(Ci-Ce alkyl), -NHC{O}{C1-Cs alkyl), -N(C:1-Cs alkyl)C(O)(C:1.¢ alkyl), -
NHS(O)x(C1-Cs alkyl}, -S(O}«(C1-Ce alkyl), -S(O)xNH(C1-Ce¢ alkyl), -S{O}:N{Ci-Cs alkyl}( Ci-Ce alkyl), (where xis 0, 1, or 2).
Additional preferred compounds of formula X above include those wherein:
R is hvdrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or phenyl;
R; is hydrogen, methyl or ethyl;
R; is C3-Cp alkyl;
Rais hydrogen, methyl or ethyl;
Rs is C;-Cg alkyl, C3-Cg cycloalkyl, or (C3-Cs cycloalkyl} Ci-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl, C2-Ce¢ alkenyl, C,-Cs alkynyl, C,-C¢ alkoxy, amino, and mono- or di(C;-Ce)alkylamino; or
Rs is phenyl, phenyl(C;-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzojbjthiopheny], benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl], quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, . trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-C¢ alkyl, C2-Cs alkenyl, C,-
Cs alkynyl, C,-C¢ alkoxy, amino, mono- or di(C;-Ce)alkylamino; or
Rs is a bicyclic oxygen-containing group of the formula:
OGL OFF or © 3%, 0 Ra ’ wherein Rj represents 0 to 3 groups sclected from halogen, nitro, cyano, . trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy. C,-C,, alkyl, C2-Ce alkenyl, C,-C, alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C,-Cs)alkylamino; and
Ar is phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-C¢ alkyl, C»-C¢ alkenyl, C»2-Cq¢ alkynyl, C;-Cs alkoxv, amino, mono- or di(Ci-
Ce)alkylamino.
The invention also includes compounds of the following formula XI:
R
= Rs Re
Sx
AN
5, R; Raa Q
Az XI or pharmaceutically acceptable salt thereof, wherein: nisO, 1, or 2;
R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyljalkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 ’ rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
R2, Rs, Raa, Rs, and Rg are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally 72 yp substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;
R and R: may be joined to form an optionally substituted saturated carbocylic ring . of from 5 to 8 members or an optionally substituted heterocyclic ring of from to 8 members;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cvcloalkyl)alkyl each of which may be optionally substituted; or
R, is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar, and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
The invention further includes compounds of the following formula XII:
R
[NT . N a " / Q
Re a XII or a pharmaceutically acceptable salt thereof, wherein:
R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, . optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; 73 y
R» and Rj are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl, } R and R3 may be joined to form an optionally substituted carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ring of from 5 ro 8 members;
Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or
R; is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar; and Ar: are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds of formula XII above include wherein R and Rj are not joined.
Also preferred are compounds of formula XII wherein:
R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyljalkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, 74 y pyrimidyl, pyrazinyl, each of which may be substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, ] amino, and mono- or dialkylamino; . R» and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkylalkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
Ri is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,
Rs is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, ) hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and -
XRp, wherein X and Rg are as defined below; or 75 y
R4 is a bicyclic oxygen-containing group of the formula: on) >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Ar and Ar; are independently chosen from 1) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyi, isoindolyl, benzofuranyl, isobenzofuranyl, benzo|b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and —
XRsg, wherein X and Rg are as defined below;, and ii) bicyclic oxygen-containing groups of the formula: oe NH (Xd
Rp wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; 76
X is independently selected at each occurrence from the group consisting of -CHa-, -
CHR¢-, -O-, -S(O)m-, -NH-, ‘NR, -C(=0O)NH-, -C(=0O)NR¢-, -S(O}uNH-, -S(O)uNRc-, -NHC(=0)-, -NRcC(=0}-, -NHS(O)n-, -C{=O)NHS(O)}u-, and -NR¢S(O)n- (where m is 0, 1, or 2J; and
Ra and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -Ofalkyl), -NH(alkyl). -N(alkyl)(alkyl}, -NHC(O}(alkyl), -N(alkyl)C(O)(alky]), -NHS(O)(alkyl), -S(O)«lalkyl), -
S(O)xNH{alkyl), -S(O)xN(alkyl)(alkyl), (where x is 0, 1, or 2).
Additional preferred compounds of formula XII include those wherein:
R is selected from i) hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, mono- or di(C;-
C¢)alkylamino, cyano, nitro, haloalkyl, and if) C1-Cg alkyl, C2-C¢ alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (Ca-
Cs)cycloalkyl) C;-C3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, triftuoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;-
Ce)alkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, : pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C1-Cs alkyl, C»-Cs alkenyl, C2-Cs alkynyl, Cy-C¢ alkoxy, amino, and mono- or di{C,-Cg)alkylamino; 77
A
R2 and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, Ci-Cs alkoxy, mono- or di(C;-
Cs)atkylamino, cyano, nitro, haloalkyl, and 1i) C1-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, Cs-Cs cycloalkyl, and (C3-Cs cycloalkyl) C,-C3 alkyl, each of which may be unsubstituted or substituted by : one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkoxy, amino, mono- or di(C;-
Cg)alkylamino;
R4 is hydrogen or
Ci.3 alkyl, Cs alkenyl, Czs alkynyl, Cs.scycloalkyl, (Cs.s cycloalkyl)C.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl, Ci. alkenyl, Ca. alkynyl, C,-C¢ alkoxy, amino and mono- or di(C,-Ce)alkylamino,
R. is phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]jthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl], cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cg alkyl, Ca.¢ alkenyl, Cz.¢ alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C:-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Cg)alkylaminocarbonyl, N-( . C,-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, ~
XRg, wherein X and Rg are as defined below; or
Rais a bicyclic oxygen-containing group of the formula:
CGT
>% wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy. acetoxy, Ci-Cs alkyl,
Ca. alkenyl, Co alkynyl, C,-Cg alkoxy, amino, and mono- or di(C,-
Csjalkylamino;
Ar; and Ars are independently chosen from 1) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl], trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, Ca. alkenyl, Cos alkynyl, C,-Ce alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;-Cg)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs)alkylaminocarbonyl, N-(
Ci-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -XRg, wherein X and Rg are as defined below; and ii) bicyclic oxygen-containing groups of the formula:
NE 1
Re wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cg alkyl,
Ca.6 alkenyl, C6 alkynyl, Ci-Cs alkoxy, amino, and mono- or di(Ci-
Cs)alkylamino; 79 y
X is independently selected at each occurrence from the group consisting of -CHy-, -
CHRc-, -O-, -S(O)w-, -NH-, -NR¢-, -C(=O)NH-, -C(=0)NRc¢-, -S(O)uNH-, -S(O}nNRc-, -NHC(=0}-, -NRcC(=0)-, -NHS(O)m-, -C{(=O)NHS(O)m-, and -NR¢S(O)n- (where m is 0, 1, or 2); ] and
Rp and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s} selected from: oxo, hydroxy, -O(C,-Ce alkyl), -NH(C1-Ce alkyl), -N(C:-C¢ alkyl)(Ci1-Cs alkyl), -NHC(O)(C1-Ce alkyl), -N(C:-Cs alkyl)C(0)(Cr-s alkyl), -NHS(O)«(C1-Cs alkyl), -S(O)x(C1-Cs alkyl), -
S(0):NH(C;-Cs alkyl), -S{O)xN{Ci-Cs alkyl){ C1-Cs alkyl), (where x is 0, 1, or 2).
Also preferred are compounds of formula XII wherein:
Ris hydrogen, halogen, hydroxy, C,-Cs alkoxy, haloalkyl, C,-Cg alkyl, C»-C¢ alkenyl,
C2-Ce alkynyl, C3-Cs cycloalkyl, and (Cs-Cs)cycloalkyl) C;-C3 alkyl, or
R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy,
C1-Cs alkyl, C3-Cs alkenyl, C»-Cg alkynyl, C;-Ce alkoxy, amino, and mono- or di(C,-Ce)alkylamino, aminocarbonyl, sufonamido, mono or di(C;-
Ce)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy;
Ra» is selected from Ci-Cg alkyl, C2-Cg alkenyl, C,-Cs alkynyl, C3-Cs cycloalkyl, (C3-Cs cycloalkyl) C;-C;z alkyl and haloalkyl;
Rj is hydrogen C;-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl,
R4 is Cis alkyl, C2. alkenyl, Co.s alkynyl, Cascycloalkyl, (Ca.s cycloalkyl)Cisalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, 80 y trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, C2. alkenyl, Cag alkynyl, C;-Cg alkoxy, amino and mono- or di(Ci-Cs)alkylamino,
R, is phenyl, phenyl(C;-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, . benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cis alkenyl, Ci. alkynyl, Ci1-C, alkoxy, amino, monao- or di(C,-Ce)alkylamino, amino(C;-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di{C,-C¢)alkylaminocarbonyl, N-( C;-
Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl,
R; is a bicyclic oxygen-containing group of the formula: on) >%, wherein Ry represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
C2.6 alkenyl, Ca. alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-
Cs)alkylamino;
Ari and Ar; are independently chosen from i) phenyl, phenyl(C1-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, and benz{d)isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, . trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca.¢ alkenyl, Cas alkynyl, C,-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, amino(C;-
Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( C,-C¢)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or 81 ii) bicyclic oxygen-containing groups of the formula: 0 | NE wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cas alkenyl, Cq.¢ alkynyl, C;-Cs alkoxy, amino, and mono- or di(C:-Cg)alkylamino.
Also preferred are compounds of formula XII wherein:
R, Rs, Ra, Rs, and Ars are as defined in formula XII;
Ar; is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:i-Cs alkyl, Ca alkenyl, Ci. alkynyl, C1-C¢ alkoxy, amino, mono- or di(Ci-
Cg)alkylamino, and amino(C;-Cs)alkoxy.
Also preferred are compounds of formula XII wherein:
R, Ry, and Rj are as defined in formula XII;
Ar; is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, triftuoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Caz. alkenyl, Czs alkynyl, C;-C¢ alkoxy, amino, mono- or di(Ci-
Cs)alkylamino, and amino(C;-Cs)alkoxy;
R4 is Ca.Cs alkyl, C2.Cg alkenyl, C2.Cs alkynyl, Ci.Cscycloalkyl, (Css cycloalkyl)C;.
Caalkyl, C;-Cg haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, : Cqo6 alkenyl, Cys alkynyl, C;-Ce¢ alkoxy, amino and mono- or di(C;-
Cs)alkylamino,
Rs is phenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benzfd}isoxazolyl, each of which 82 may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Ce alkyl, C26 alkenyl, Ca.s alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Cg)alkylamino, amino(C;-
Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-{ C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl;
Ar: is phenyl, phenyl](C,-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz|d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cvano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca. alkenyl, Ca6 alkynyl, Ci1-Cs alkoxy, amino, mono- or di(C;-Cg)alkylamino, amino(C,-
Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar: is bicyclic oxygen-containing groups of the formula:
A: 1
Rg wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C,.6 alkenyl, C26 alkynyl, C;-C¢ alkoxy, amino, and mono- or di(C;-Ce)alkylamino.
Also preferred are compounds of formula XII wherein:
Ris hydrogen, C,-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C3-Cs cycloalkyl, or (Cs-
Cs)cycloalkyl) C1-Cj alkyl, or
R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, 83
C,-Cs alkyl, C2-Cg alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C-Ce)alkylamino, aminocarbonyl, sufonamido, mono or di(Ci-
Ce)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylenc)dioxy;
Rais C3-Co alkyl; } Rj; is hydrogen, methyl, or ethyl;
R, is C3.Cs alkyl, C..Cs alkenyl, C,.Cs alkynyl, Ca.Cscycloalkyl, (Cs.s cycloalkyl)C,.
Cialkyl, C;-Cg haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl,
Cos alkenyl, Cas alkynyl, C;-C¢ alkoxy, amino and mono- or di(Ci-
Cg)alkylamino,
Rs is phenyl, phenyl(Ci-C4jalkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromany], dihyvdrobenzofuranyl, naphthyl, indolyl, indanyl, benzo{bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl, Cz.¢ alkenyl, Cz alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;-
Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C1-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl;
Ar is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca.6 alkenyl, Ca.¢ alkynyl, C1-C¢ alkoxy, amino, mono- or di(C;-
Cs)alkylamino, and amino(C;-Cs)alkoxy; : Ar is phenyl, phenyl(Ci-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromany], dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiopheny], benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, 84 y trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, Ca.s alkenyl, Cap alkynyl, C,-Cs alkoxy, amino, mono- or di(C,-C¢)alkylamino, amino(Ci-
Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cg)alkylaminocarbonyl. N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or :
Ars is bicyclic oxygen-containing groups of the formula: ° NA ( = Re wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy. Ci-Cg alkyl, Cas alkenvl, C,.¢ alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C:-Cs)alkylamino.
Also preferred are compounds of formula XII wherein:
R is hydrogen, C;-Cs alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C3-Cg cycloalkyl, or (Cs-
Cs)cycloalkyl) C,-C3 alkyl, or phenyl;
Rais C3-Cs alkyl;
Rs is hydrogen, methyl, or ethyl;
Rs is C3.Cs alkyl, C2.Cs alkenyl, C,.Cs alkynyl, Cis.Cscycloalkyl, (Cs-s cycloalkyl)Ci.-
Csalkyl, C1-Cs haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl,
C26 alkenyl, C.¢ alkynyl, C;-C¢ alkoxy, amino and mono- or di(Ci-
Cs)alkylamino;
Ar; is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Ce alkyl, C2. alkenyl, Co.¢ alkynyl, C;-Cs alkoxy, amino, mono- or di(C-
Ce)alkylamino, and amino(C;-Cg¢)alkoxy; and
Ar; is phenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]jthiophenyl,
benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, ) trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C..Ce alkenyl, Ca.
Ce alkynyl, C,-Cg alkoxy, amino, mono- or di(C,-C¢)alkylamino, amino(C-
Celalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs)alkylaminocarbonyl, N-( C;-Cg)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar; is bicyclic oxygen-containing groups of the formula: >a wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Cz.6 alkenyl, C2.6 alkynyl, C:-Cs alkoxy, amino, and mono- or di(C:-Ce)alkylamino.
Also preferred are compounds of formula XII wherein:
R is hydrogen, C;-Cg alkyl, C2-Cs alkenyl, C2-C¢ alkynyl, C3-Cg cycloalkyl, or (Cs-
Cg)cycloalkyl) C;-Cs alkyl, or phenyl;
Rais C3-Cg alkyl;
Rs is hydrogen, methyl, or ethyl;
Rs is phenyl, phenyl(C;-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiopheny], benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups . independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.¢ alkenyl, Cz.6 alkynyl, Ci-C¢ alkoxy, amino, mono- or di(Ci-Ce)alkylamino, amino(C;-
Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-{ C1-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl;
Ar; is phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy. acetoxy, C:i-Ce alkyl, Co. alkenyl, Cz. alkynyl, C,-Cg alkoxy, amino, mono- or di(C;-
Ce)alkylamino, and amino(C;-Ce)alkoxy;
Ara is phenyl, phenyl(C;-C4)alkyl. thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophcnyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl], trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.¢ alkenyl, Ca. alkynyl, C,-Cs alkoxy, amino, mono- or di{(C;-Ce¢)alkylamino, amino(C;-
Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cg)alkylaminocarbonyl, N-( C,-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar; is bicyclic oxygen-containing groups of the formula: ony - wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Ca6 alkenyl, Cz. alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Cs)alkylamino.
The invention also includes compounds of the following formula XIII: o An
AN »
EL m Ar 2
Ar Xl : or a pharmaceutically acceptable salt thereof, wherein:
nisl,2,or3 m represents a carbon chain that may be substituted with hydrogen, halogen, : cyano, nitro amino, mono or dialkyl amino, alkenyl, alkynyl, alkoxy, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, or cycloalkyl, and n is 1, 2, or 3;
Ar, Ara, and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
R; represents up to <4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH,), mono or dialkylaminocarbonyl, sulfonamido, and mono or dialkylsulfonamido.
Also preferred are compounds of formula XIII wherein n, m, and R; are defined as for formula XIII above;
Ar; and Ar; are independently chosen from phenyl, pyridyl, and pyrimidinyl each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy, acetoxy, mono- or di(C,-Cg)alkylamino, cyano, nitro, C;-C¢ haloalkyl,
C1-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C3-Cs cycloalkyl, (C3-Cscycloalkyl)
C1-Csalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH>), mono or di(C,-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C;-Ce)alkylsulfonamido; and
Ar, represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl, each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C1-Cg alkoxy, acetoxy, mono- or di(C;-Cs)alkylamino, cyano, nitro, Ci-Cs haloalkyl, 88
C;-Co alkyl, C2-Cg alkenyl, C>-Ce alkynyl, C3-Cs cycloalkyl, (C3-Cscycloalkyl)
C,-Csalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH2}, mono or di(C:-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di{C:-Cs)alkylsulfonamido.
Also preferred are compounds of formula XIII above wherein: x
IRs 0
RL NJ §
N
“x -
RS
Ri, Rs, and Rs each represent up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C:-C¢ alkoxy, acetoxy, mono- or di(C:-Cg)alkylamino, cyano, nitro, Ci-Ce haloalkyl, C)-Cs alkyl, C2-Ce alkenyl, C2-C¢ alkynyl, Cs3-Cs cycloalkyl, (Cs-Cscycloalkyl) Cy-Caalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH3), mono or di(C,-Ce¢)alkylaminocarbonyl, sulfonamido, and mono or di(Ci-
Cs)alkylsulfonamido; and represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl, each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Ce¢ alkoxy, acetoxy, mono- or di(Ci-Cs)alkylamino, cyano, nitro, C1-Ce haloalkyl, C,-Ce alkyl, C2-Cs alkenyl, C2-Cg alkynyl, C3-Cs cycloalkyl, (Cs-Cscycloalkyl) Ci-Czalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH), mono or di(C;:-Cs)alkylaminocarbonyl, sulfonamido, 3,4- methylenedioxy, ethylenedioxy, and mono or di(C;-Cs)alkylsulfonamido.
The invention also includes compounds of the followinf formula XIV:
RT
F iy ar,
Ary 0) or a pharmaceutically acceptable salt, thereof, wherein:
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONHa.), mono or di(C:-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, cthylenedioxy, and mono or dialkylsulfonamido;
R, is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl each of which may be optionally substituted; or
R, is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds of formula XIV include those (referred to herein as compounds of formula XIV-A) wherein
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, acetoxy, mono- or di(Ci-Cs)alkylamino, cyano, nitro, C;-
Cs haloalkyl, Ci-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, (Cs-
Cs cycloalkyl) C1-C;3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH,),
mono or di(C;-Ces)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(Ci-Cs)alkylsulfonamido;
Ry is Cig alkyl, C25 alkenyl, C23 alkynyl, Csscycloalkyl, (Ca.s cycloalkyl)C,.4alkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cs. alkenyl, Ca. alkynyl, C,-Cs alkoxy, amino and mono- or di(C;-Cg)alkylamino, or
Ri is phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalky]l, pyridyl. pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, benzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Ce alkyl,
Cz.6 alkenyl, Cs.c alkynyl, Ci1-Cs alkoxy, amino, mono- or di(C1-Cs)alkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Ce)alkylaminocarbonyl, N-( C;-
Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl;
Ar, is chosen from phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, and pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
Ca. alkenyl, Ca. alkynyl, C,-Cs alkoxy, amino, mono- or di(Ci-Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, and N-(C;-
Ce)alkylsulfonylaminocarbonyl; and
Ary is chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, pyrrolyl, pyrrolylalkyl, furanyl, furanylalkyl, thienyl, thienylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimidylalkyl, pyrazinyl, pyrazinylalkyl, benzimidazolyl, benzimidazolylalkyl, imidazopyrdinyl, imidazopyrdinylalkyl, naphthyl, . napthylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, benzofuranyl,
benzofuranylalkyl, benzodioxinyl, benzodioxinylalkyl, benzodioxolyl, benzodioxolylalkyl, quinolinyl, quinclinylalkyl, isoquinolinyl, isoquinolinylalkyl, each of which may be optionally substituted or substituted with up to four groups independently selected from: } halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Ca alkenyl, Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C:-Cs)alkylamino, mono- or di(C;-Cs)alkyvlamino(C;-
Ce)alkyl, amino(C:-Cs)alkoxy, Ci-C, alkoxyC,-Ce alkyl, C1-Cs alkoxyC;-C¢ alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-C¢)alkylaminocarbonyl, N-(C,-
Cs)alkylsulfonylaminocarbonyl, benzyl (which may be unsubstituted or substituted with one or more substituents independently chosen from halogen, C;-Cealkyl, and C;-
Csalkoxy), -C;-Cs alkylNR2R3 or —C;-Csalkoxy NR2R3 wherein the point of attachment to
Ar; is at the C;-Cs alkyl or C1-Ce alkoxy, and Rz and Rs are hydrogen, or straight or branched chain alkyl and are optionally substituted with halogen, hydroxy, or C;-Cs alkoxy and R; and R3 may be taken together with the nitrogen to which they are attached to form a heterocycloalkyl group.
Preferred compopunds of formula XIV-A include those wherein:
SW;
N
“Mar, : oO o£]
wherein:
Ars is as defined in Claim in formula XIV-A;
Rx represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C:-Cs alkoxy, acetoxy, mono- or di(Ci-Cs)alkylamino, cyano, nitro, C,-Cy haloalkyl, C;-Cs alkyl, Ca-Ce alkenyl, and C.-Cs alkynyl; and
Ri is Ci-Cealkyl, C;.Cscycloalkyl, (C3.Cs cycloalkyl)Ci.Caalkyl, phenyl, phenylC;-
Cealkyl, chromanyl, chromanylC,-Csalkyl, imidazolyl, imidazolylC,-Csalkyl ,pyridyl, pyridylC;-Cesalkyl, pyrimidyl, pyrimidylC,-Cealkyl,pyrazinyl, pyrazinylC,;-Cgsalkyl, indolyl, indolylC;-Csalkyl, indanyl, indanylC,-Csalkyl, benzodioxolyl, or benzodioxolylC,-Cesalkyl each or which may be unsubstituted or substituted with up to 4 substituents selected from halogen. nitro, cvano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Cas alkenyl, Ca.¢ alkynyl, Ci-Cs alkoxy, amino and mono- or di{C;-Ce)alkylamino.
Additional preferred compounds of formula XIV-A includes those of the following formula: . (J 1
N
“ar, o o£] wherein:
Rx represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy substituted with 0-2 Rj, acetoxy, mono- or : - di(C,-Ce)alkylamino, cyano, nitro, C;-Cs haloalkyl, C;-Ce alkyl, C2-Cs alkenyl, and C.-Cs alkynyl;
R; is phenyl, phenylCi-Cs alkyl, C3-Cs cycloalkyl, C3-Cs cycloalky(Ci-Cs alkyl), naphthyl, napthvlCi-Csalkyl, indanyl, indanylC,-Cs alkyl, benzodioxolanyl, or benzodioxolanylC)-Cs alkyl, each of which may be substituted by up to 4 groups chosen from halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(C,-Csp)alkylamino, cyano, nitro, Ci-Cs haloalkyl, C;-Cs alkyl; and
Ar, represents phenyl, benzyl, indanyl, indanyl-CH.-, benzodioxolanyl, or benzodioxolanyl-CH.-; each of which is substituted by up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy, acetoxy, mono- or di(C:-Cg¢)alkylamino, cyano, nitro, C1-C¢ haloalkyl, C;-Ce alkyl, C2-Cs alkenyl, and
Ca2-Ce alkynyl.
Additional preferred compounds of formula XIV includes those wherein:
Ar; is as defined for formula XIV;
R represents up to 4 groups independently chosen from hydrogen, halogen, amino,
C1-Cs alkoxy, C;-Cs alkyl, trifluoromethyl, and trifluoromethoxy;
R; is phenyl, benzyl, C3-Cs cycloalkyl, C3-Cs cycloalkyl{C1-Ca alkyl), naphthyl, naphthyl-CHa-, indanyl, indandyl-CHas-, benzodioxolanyl-CH,-, or benzodioxolanyl, each of which may be substituted by up to 4 groups chosen from halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di{Ci-
Cs)alkylamino, cyano, nitro, C;-Cs haloalkyl, C.-Cs alkyl; and
Ar) is chosen from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, C,.Cs alkoxy, C1-Ce alkyl, and amino.
Also preferred are compounds of the formula XIV above wherein:
R represents up to 4 groups independently chosen from hydrogen, halogen, amino,
C1-Cs alkoxy, Ci-Cs alkyl, trifluoromethyl, and trifluoromethoxy;
R; is benzyl which is unsubstituted or substituted by up to 4 groups chosen from halogen, hydroxy, amino, C,-Cy alkoxy, acetoxy, mono- or di(Ci-
Ce)alkylamino, cyano, nitro, C1-C¢ haloalkyl, Ci-Cs alkyl;
Ari is chosen from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, Ci.Co alkoxy, C;-Ce alkyl, and amino; and
Ars is chosen from phenyl, benzyl, indolyl, indolyl-CH:-, indanyl, indanyl-CH.-, chromanyl, chromanyl-CH»-, benzofuranyl, benzofuranyl-CHo-, benzodioxinyl. benzodioxinyl-CH»-, benzodioxolyl-CH-, and benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from: halogen, nitro, cyano. trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cas alkenyl, Cas alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C;-Cs)alkylamino.
Preferred compounds of formula XIV also include thos eof the following formula IV-B:
Rest \ gC)
N 0) R,
N m 1 " —/R, wherein:
mis 0, 1, 2, or 3, and Ah represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy. ethoxy, hydoxy, halogen, or amino;
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C1-Cealkyl, C2-Cs alkenyl, Ci-Csalkynyl, C)-C; alkoxy, acetoxy, mono- or di(C,-Cs)alkylamino;
Rx and Ry cach represent up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Ce¢ alkoxy, acetoxy, mono- or di(Ci-
Cs)alkylamino, cyano, nitro, C1-Cs haloalkyl, C;-Cs alkyl, C2-Cs alkenyl, and
C2-Ce alkynyl; and
R: and R. are independently selected from C,-Cealkyl, C3.Cscycloalkyl, (C3.Ca cycloalkyl)C,.Caalkyl, phenyl, phenylC,-Cealkyl, pyridyl, and pyridylCi-
Csalkyl, each or which may be unsubstituted or substituted with up to 4 substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, Cz. alkenyl, Cz.6 alkynyl, C1-Ce alkoxy, amino and mono- or di(C1-Ce)alkylamino.
The invention also provides compounds of the following formula XV:
Ary o=(
N
CO 4
NNT
R2 or a pharmaceutically acceptable salt thereof, wherein; : mis 0, 1, 2, or 3, and Ah represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino;
nis 0, 1, 2, or 3, and AI represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino,
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkvl, alkenyl, alkynyl, cycloalkyl, and(cycloalkyl)alkyl;
Ra 1s i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl) alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy. haloalkyl, hydroxy, acetoxy, alkoxy, amino, mono- or dialkylamino; and
Ar; and Ar» are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
Preferred compounds of formula XV include those of the following formula: mis 1 and Ah represents a carbon chain which is unsubstituted; nis 1 and A represents a carbon chain which is unsubstituted;
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-C¢ alkoxy, acetoxy, mono- or di(C,-C¢)alkylamino, cyano, nitro, C;-
Cs haloalkyl, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C2-Ce cycloalkyl, and(Cs-Cs cycloalkyl) C;-Cq alkyl;
R; is C3-Csg alkyl or C3-Cs cycloalkyl;
Ari and Ar: are independently chosen from phenyl, phenyl(Ci-Ca)alkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, and pyrazinyl, each of which may be unsubstituted or optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hvdroxy, acetoxy,
Ci-C; alkyl, C.-Cy alkenyl, C2-Cg alkynyl, C;-Cq alkoxy, amino, mono- or di(C,-Ce)alkylamino.
Compounds of the invention may have one or more asymmetric centers or planes. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
Some compounds of the invention may exist as tautomers. Unless otherwise specified any description or claim of one tautomeric form is intended to encompass the other tautomer.
Specifically preferred compounds include those shown in the FIGS. 1 through 6. In those figures, the substituent X depicts the moiety linkage to the base compound whose strucutre is shown at the top of each Figure.
Addiional preferred compounds of the invention include the following (compounds structures are shown directly above the compound chemical name in many instances): 1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl methyl]jJaminomethylimidazole; 1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N- phenylmethyljamino)ethylimidazole; 1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyljjamino- methylimidazole; 1-(1-Butyl}-2-phenyl-4-methyl-5-(N-{3.4-methylenedioxyphenyl-methyl]-N- phenylmethyl)aminomethylimidazole, 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yl|methyl-N- phenylmethyl) aminomethylimidazole; 1-(1-Butyl)-2-(4-fluorophenyl}-5-(N-[3,4-methylenedioxyphenylmethyl}-N- phenylmethyl) aminomethylimidazole; 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yljmethyl-N- phenylmethyl) aminomethylimidazole; pS oc
MNS, bt 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole;
ie, 8 JI§ N “ 0 oJ 1-(1-Butyl)-2-(2-fluorophenyl)-5-(N-{1,4-benzodioxan-6-ylmethyl]-N- phenylmethyljamino- methylimidazole;
J oo N
Q <$
I J
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[naphtha-2-ylmethyl]-N- phenylmethyl)amino-methylimidazole; or ~ : \ 57 1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole;
Jou
Soe 57
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole; 1 cre 0)
NS
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[4-dimethylaminophenylmethyl]-N- phenylmethyl) aminomethylimidazole;
EE
@! N : o—/ 1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole; oO
N or
F \ 57 1-(1-Butyl}-2-(4-fluorophenyl)-5-(N,N-di[3,4- methylenedioxyphenylmethyl])amino- methylimidazole;
Pow,
J} N
S : ®] 1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-dif3,4- methylenedioxyphenylmethyljjamino- methylimidazole;
I
N
1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl]-N- phenylmethyl)amino methylimidazole; 1
Or N ! a 5S 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole;
A og N
N
] 2 , ] \ 7 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4- methylenedioxyphenylmethyl]jJamino- methylimidazole;
I.
N
] Ny : ] rd 57 1-(1-Butyl)-2 -(3-methoxyphenyl)- 5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)- aminomethylimidazole;
Jes 1-(1-Butyl)-2-pheny!-5-{1-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)amino} ethylimidazole;
i |]
N
J 5 1-(1-Pentyl)-2-phenyl-5-{N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole;
. 0,
N Oo os aya 9 o
Bis-benzo|1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-amine \ 0
J : {0 9 o
Benzo{1,3}dioxol-5-ylmethyl-benzyl-|3-butyl-5-(4-methoxy-phenyl)- 2-phenyl-3 H-imidazol-4-ylmethyl}- amine 0 : ) oO
HN
4-({Benzyl-[1-(3-butyl-2,5-diphenyl-3 H-imidazol-4-yl)-ethyl]-amino}-methyl}-benzamide
OH
N
1 \ 4-{[Benzyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-amino]-methyl}-3-chloro- phenol
N :
OH
4-({[1-(3-Butyl-2-phenyl-3 H-imidazol-4-yl}-pentyl]-cyclohexylmethyl-amino}-methyl)- phenol
N i : )
Oo
H,N 4-{[Benzyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-amino]-methyl}-benzamide = A
HN /
1-(1-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole;
J mE 1-{1-Butyl)-2-phenyl-5-(N-[1-(S}-phenylethyl]-N- phenylmethyl)aminomethylimidazole;
Ue 1] 1-(1-Butyl)-2-phenyl-5-(N-[1-{R)-phenylethyl]-N- phenylmethyl)Jaminomethylimidazole; jos
N s Cl cl 1-(1-Butyl}-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-[3,4- dichlorophenyljmethyljaminomethylimidazole;
- ne 0 od 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole;
N
OMe
OMe 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-{3,4- methoxyphenylmethyl])-aminomethylimidazole; ge 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1- propyljphenylmethyl}) aminomethylimidazole;
0
N
Cl 1-(1-Butyl})-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dichlorophenylethyl]) aminomethylimidazole; ( g ©)
NO2 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyljmethyl-N-{4- nitrophenylmethyl]) aminomethylimidazole; ee;
SZ
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1- propyloxy} phenylmethyl])aminomethylimidazole;
or N
A
: 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-[quinol-6- ylmethyl))- aminomethylimidazole;
Jee
JS
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3- dichlorophenylmethyl]}-aminomethylimidazole; 0 : 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dimethylphenylmethyl])-aminomethylimidazole;
- I £ 1-(1-Butyl)-2-pheny!-5-(N-[3,4-methylenedioxyphenyl|methyl-N-[indan-2-yl])- aminomethylimidazole;
GR i 0
Jt O 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- phenylethyl]jJamino-methylimidazole; or 1 “\. _N § :
IJ
1-(1-Propyl)-2-phenyl-5-(N-[1,4-benzodioxan-6-ylmethyl]-N- phenylmethyl)aminomethyl-imidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxy phenylmethyl]-N- phenylmethyljaminomethyl-imidazole; . 2
NG = ( J by 1-(1-Butyl)-2-phenyl-5-(N-{3,4-methylenedioxyphenylmethyl]-N- ethyl)aminomethylimidazole; x 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1- propyl])aminomethyl-imidazole;
Jos 1-(1-Butyl}-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1- butylj)Jaminomethyl-imidazole;
”
N
SF
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cycloheptylmethyl)amino-methylimidazole;
A AH
N
Jt A 1-(1-Butyl)-2-pheny!-5-(N-[3,4-methylenedioxyphenylmethyl]-N- isobutyljaminomethyl-imidazole; 0 1-(1-Buty})-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- cyclopentylethyl]Jamino-methylimidazole; : 0
I]
I% 1 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-{3- cyclopentylpropyl])amino-methylimidazole;
ges
I To 1-(1-Butyl)-2-phenyl-5-(N-(3,4-methylenedioxyphenylmethyl]-N-[1-n- octyl])aminomethyl-imidazole; >
LL
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cyclopropylmethyljamino-methylimidazole; fen i] 1-(1-Butyl)-2-phenyl-5-(N-{3,4-methylenedioxyphenylmethyl]-N- cyclopentylmethyl)amino-methylimidazole; jg os | N 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N- cyclohexylmethyl)amino-methylimidazole;
- LL
N. op BY 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t- amyl])aminomethylimidazole;
Jew 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-{1-{3- methyl}butyl)]amino-methylimidazole; 0 1 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2- dimethyl}butyl]) aminomethylimidazole; es op 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyimethyl]-N- methyl)aminomethylimidazole;
. - ~~
Ss ¢ 1-(1-Butyl}-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- thiophenylmethyl])amino-methylimidazole;
Je ®
HN / 1-(1-Butyl)-2-phenyl-5-(N-{3,4-methylenedioxyphenylmethyl]-N-[indol-5- ylmethyl])Jamino-methylimidazole;
Jou / ve 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[{1-methylindo!}-5- ylimethyl})Jaminomethylimidazole;
pes
N
N
Je cl >» 0 H 1-(1-Butyl)-2-phenyl-5-(N-{3,4-methylenedioxyphenyljmethyi-N-{4-hydroxy-2- chlorophenyl}-methyl)aminomethylimidazole;
N
Be
N is cl
HO
1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyljmethyl-N- phenylmethyl]) aminoethylimidazole;
LX
J 3 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyljmethyi-N-[2,3- dihydrobenzo|b]furan-5-yljmethyljaminomethylimidazole; 0
N
F Js
1-Butyl-2-(4-fluorophenyl)-5-({1-[N-{3,4-methylenedioxyphenyljmethyl-N- phenylmethyl]-amino)ethylimidazole;
Ly
N 0]
Bp . ~ N \_s is 1-{1-Butyl)-2-(2-thienyl}-5-(N-[3,4-methylenedioxyphenyljmethyl-N-phenylmethyl] aminomethylimidazole;
N
¢ —<
Js ‘ ]
H3CO OCHj
OCHj, 1-(1-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N-phenylmethyljamino- methylimidazole; ¢ pan
Is c ]
OCHj
OCHj 1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4- : dimethoxyphenylmethylj)aminomethyl-imidazole;
N
OI
Is A
N(CHa)2 1-(1-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl]-N- phenylmethyljaminomethyl-imidazole; oA
OI
It 4
NHC H3 1-(1-Butyl)-2-phenyl-5-(N-[4-methylaminophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole;
N
OI
NH, 1-(1-Butyl}-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl|-N- phenylmethyl)aminomethyl-imidazole); ¢ — |. p N . i
Cl
1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N- phenylmethyljaminomethylimidazole;
N
J
Ci
Cl 1-(1-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenylmethyl]-N- phenylmethyljaminomethylirmidazole;
N
OA bs
F
F
1-(1-Butyl}-2-phenyl-5-(N-[3,4-difluorophenylmethyl}-N- phenylmethyl)Jaminomethylimidazole;
N
OA
), 1-(1-Butyl)-2-phenyl-5-(N-(benzo[b}thiophen-5-ylmethyl)-N- phenylmethyljaminomethyl-imidazole;
N
OI
J : )
OFt 1-(1-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N- phenylmethyl)aminomethylimidazole;
N Br QO
OI
1-(1-Butyl)-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole;
N
OI
OMe 1-(1-Butyl)-2-phenyl-5-(N-[4-methoxyphenylmethyl]-N- phenylmethyl)aminomethylimidazole; 4 4 IM . Cl
Vd 1-(1-Butyl)-2-phenyl-5-(N-{6-chloro-3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)-aminomethylimidazole; 121 y oad
N
Je S
Cl 1-(1-Butyl}-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-[1- butyl])aminomethylimidazole; no SO {~<A
Jt A
CH, 1-(1-Butyl)-2-phenyl-5-(N-[3-methoxyphenylmethyl]-N- phenylmethyljaminomethylimidazole; 4
OI ies
F
1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-fluorophenylmethyl}-N- phenylmethyljaminomethyl-imidazole; or J
Cl 1-(1-Butyl)-2-phenyl-4-bromo-5-(N-(2,3-dichlorophenylmethyl]-N-{1- butyl])aminomethyl-imidazole;
OL
N N
Je ~~ 1-(1-Butyl)-2-phenyl-5-(N-[2,6-dichlorophenylmethyl]-N- phenylmethyljJaminomethylimidazole; 4 — Lo
N N
Iss
OH
1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl|-N- phenylmethyl)aminomethyl-imidazole; 1-(1-Butyl}-2-phenyl-4-chloro-5-(N-phenylmethyl-N-{1-butyl]Jaminomethylimidazole;
OH
N io 4-{[Benzyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-amino]-methyl}-2-methyl- phenol i : )
OH
4-{[(3-Butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-cyclohexylmethyl-amino]-methyl}-2- methyl-phenol
N rN F 0 / (3-Butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-(2,6-difluoro-benzyl)-(4-methoxy-benzyl)- amine
~o N / 0 0"
Benzo|1,3]dioxol-5-ylmethyl-butyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3 H-imidazol-4-yl methyl]-amine ~N 0 nN ) : )
SO,NH, 4-({Benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3 H-imidazol-4-ylmethyl}-amino}-methyl}- benzenesulfonamide (0) - 3 1
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3 H-imidazol-4-yl methyl}-amine
N
0 ; ad
N N
. 7 Cl ) OH 4-({Butyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3 H-imidazol -4-ylmethyl]-amino}- methyl )-3-chloro- phenol \
Oo
A ja
CO;H 4-{((3-Butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)- (4-methoxy-benzyl)-amino]-methyl}-benzoic acid
OH
N
0 [ fa
I N cl 4-({Benzyl-(3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3 H-imidazol-4-ylmethyl]-amino}-methyl)-3-chloro- phenol
™
N O
:
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3 H-imidazol-4-yl)-pentyl]-amine
Oa
N 0 oi
Benzo[1,3]|dioxol-5-yimethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3 H-imidazol-4-yl)-ethyl]-amine 0) ’ NH,
N oN 4-{[Butyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl}-amino]-methyl}-benzamide
F
0
MM jos =p \
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-fluoro-phenyl)-2- phenyl-3 H-imidazol-4-ylmet hyl}- amine
N
I ; (on 3-{{Benzyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl}-amino]-methyl}-phenol
Oo
NH,
N iN 4-{Butyl-(3-butyl-5-tert-butyl-2- phenyl-3 H-imidazol-4-ylmethyl)-amino}-methyl}-benzamide a2
LY ©
Benzyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)- (2,3-dihydro-benzo| 1,4]dioxin-6-ylmethyl)-amin €
I
I
C7 0) / (3-Butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-(2,5-difluoro-benzyl)- (4-methoxy- benzyl) -amine . “4
O
/ (3-Butyl-2,5-diphenyi-3 H-imidazol-4-ylmethyl)-(2,6 -dichioro-benzyl)-(4-methoxy-benzyl)- amine
N
/ : § ) , [ / N
OH
4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-yimethyl}-amino]-methyl}-2 6-dimethyl-phenol \ 0
N
[i : )
OH
4-({[3-Butyi-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-yimethyl]-cyclohexyimethyl-amino}-methyl})- 2 6-dimethyl-phenol \ 0 i : ) 0) [3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-yimethyl}-cyclohexylmethyl-(2,3-dihydro-benzo furan-5-ylmethyl)-amine b ~~ on \
OH
4-{[Butyl-(3-butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)-amino|-methyl}-2,6-dimethyl-phenol : i.
OH
4-({Butyl-[1-(3-butyl-2, S-diphenyl-3 H-imidazol-4-yl)-ethyl]-amino}-methyl)- 2,6 -dimethyl-phenol \
N—
Hi § ;
CO,H 4-{(3-Butyl-2,5-diphenyl-3 H-imidazol-4-ylmethyl)- (4-dimethylamino-benzyl)-amino]-methyl} -benzoic acid 131
N 0) 1 \ Or
Ory ’ [4
SS
4-{5-|(Bis-benzo|1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol- 1 -yl}-butyric acid ethyl ester
Oe i ©
Oy
N
J )~9
OH o 4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methylj-2,4-diphenyi-imidazol- 1 -yl}-butan-1-o i \
N—
N s I) ie, (4-{{(3-Butyl-2,5-diphenyl-3 H-imidazol-4-yimethyl)-cyclohexylmethyl-amino]-methyl}-phenyl)- dimethyl-amine
OI
J 2
O
1-(1-Butyl)-2-phenyl-5-(N-[4-{1-pyrrolidinyl}phenylmethyl]-N- phenylmethyljaminomethyl-imidazole; ye
OA
J A
N
~~ NT 1-(1-Butyl)-2-phenyl-5-(N-[4-diethylaminophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole;
OH
Ig 4
Ny 1-(1-Butyl)-2-phenyl-5-(N-[pyridin-2-ylmethyl}-N- phenylmethyl)aminomethylimidazole; axel
N
“1 x
1-(1-Butyl)-2-phenyl-5-(N-[pyridin-3-ylmethyl}-N- phenylmethyljaminomethylimidazole;
OAL :
N N : ig . «
N
1-{1-Butyl)-2-phenyl-5-(N-[pyridin-4-ylmethyl]-N- phenylmethyllaminomethylimidazole;
N ad
N
1-(1-Butyl)-2-phenyl-5-(N-[2-fluoro-6-chlorophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole);
N
¢ Y—<¢
Ig J !
Cl 1-(1-Butyl)-2-phenyl-5-(N-[2,4-dichlorophenylmethyl}-N-phenylmethyljaminomethyl- imidazole};
OH ~ . It
Cl
1-(1-Butyl)-2-phenyl-5-(N-[4-chlorophenylmethyl]-N- phenylmethyljaminomethylimidazole; ae {I~
OH
1-(1-Butyl})-2-phenyl-5-(N-{4-hydroxyphenylmethyl]-N- phenylmethyljaminomethylimidazole; & Pa
OCF3 1-(1-Butyl)-2-phenyl-5-(N-{4-trifluoromethoxyphenylmethyl]-N- phenylmethyljaminomethyl-imidazole); ae
OA ox
OCH3 1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-3,4-dimethoxyphenylmethyl]-N- phenylmethyl)amino-methylimidazole);
OS :
N
; Je
NO, 1-(1-Butyl)-2-phenyl-5-(N-[4-nitrophenylmethyl]-N- phenylmethyl)aminomethylimidazole;
OH
NH,» 1-(1-Butyl)-2-phenyl-5-(N-[4-aminophenylmethyl}-N- phenylmethyljaminomethylimidazole;
N Ph
OI
1-(1-Butyl)-2,4-diphenyl-5-(N-phenylmethyl-N-[1-butyl])aminomethylimidazole; a A
Je Z - 4 "™. N
NH
1-(1-Butyl)-2-phenyl-5-(N-{2-aminopyridin-5-ylmethyl]-N- phenylmethyl)aminomethyl-imidazole
OS
N
. Je 0] 1-(1-Butyl)-2-phenyl-5-(N-[2,3-dihydrobenzo[bjfuran-5-ylmethyl]-N- phenylmethyl)amino-methylimidazole;
N
{
N
OH
1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N-[1- butyl])aminomethyl-imidazole)
OI S
1-(1-Butyl)-2-phenyl-4-methyl-5-(N-phenylmethyl-N-{1-butyl]jaminomethylimidazole; ; “Ne OH oo 4 Sa) . N Cl
F
1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[2-chloro-4-hydroxy phenylmethyl}-N- phenylmethyl)-aminomethylimidazole; “NN OH
TM oN Cl
F
1-(1-Butvl)-2-(3-fluorophenyl}-5-(N-{2-chloro-4-hydroxyphenylmethyl}-N- phenylmethyl)-aminomethylimidazole;
TN
F
1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-{2,3-dichlorophenylmethyl}-N- phenylmethyljamino-methylimidazole; “Ne N
N \ \
Oo
F
. 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-{4-dimethylaminophenylmethyl]-N- phenylmethyl)amino-methylimidazole;
NHC
. NN ~ or
F
1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-{4-{1-pyrrolidinyl}phenylmethyl]-N- phenylmethyljamino-methylimidazole; “Ne OH
TN
~~
F
1-(1-Butyl)-2-(3-chlorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenylmethyl}-N- phenylmethyl] amino)ethylimidazole; 7 \ ey —
N
! 1-(1-Butyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl)aminomethylimidazole; pos
N 0]
Orr : J 1-(1-Butyl)-2-(4-fluorophenyl)-5-(1-N,N-di[3,4- methylenedioxyphenylmethyljamino)ethylimidazole;
~~ or C C . N h
F 3) . AN
HN
(
OH
2-{[5-({Butyl[(1-butyl-2,4-diphenylimidazol-5-yl}methyljamino}methyl)-2- pyridyljaminojethan-1-ol;
As discussed above, preferred compounds of the invention exhibit good activity in standard in vitro C5 receptor mediated chemotaxis assay, specifically the assay as specified in Example 12, which follows. References herein to “standard in vitro C5 receptor mediated chemotaxis assay” arc inteided to refer to that protocol as defined in Example 12 which follows. Preferred compounds of the invention exhibit an ECsg of about 100 uM or less in such a standard C5a mediated chemotaxis assay, more preferably an ECso of about 10 uM or less in such a standard CS5a mediated chemotaxis assay, still more preferably an ECse of about 1 uM in such a standard C5a mediated chemotaxis assay, even more preferably an ECs of about 0.1 pM in such a standard C5a mediated chemotaxis assay.
Additional assays suitable for determining the effects of small molecule compounds on CS5a receptor binding and receptor modulatory activity, as well as assays suitable for measuring their effects on C5a-induced neutropenia in vivo, can . be found in the published literature, for example in US patent 5,807,824, which is incorporated herein by reference for its disclosure in this regard in Examples 6-9, columns 19-23, as well as for its discussion of complement and inflammation at columns 1-2. Those of skill in the art will recognize that such assays can be readily adapted to the use of cells or animals of different species as deemed appropriate.
In one aspect of the invention, one or more compounds of the invention, preferably in solution in a pharmaceutically acceptable carrier as a pharmaceutical preparation, is used to perfuse a donor organ prior to transplantation of the organ ’ into a recipient patient. Such perfusion is preferably carried out using a solution x comprising an concentration of the compound of the invention that is an effective amount sufficient to inhibit C5a mediated effects in vitro or in vivo. Such perfusion preferably reduces the severity or frequency of one or more of the inflammatory scquelae following organ transplantation when compared to that occurring in control (including, without restriction, historical control) transplant recipients who have received transplants of donor organs that have not been so perfused.
In certain situations, the compounds of of the invention may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by . conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. :
The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 1!C, 13C, and 4C,
When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R', then said group may optionally be substituted with up to two R* groups and R’ at each occurrence is selected independently from the definition of R". Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As indicated herein, various substituents of the compounds of the present invention and various formulae set forth herein are “optionally substituted”, including, e.g., Ari, Ars, R, Ri, Ry, Rs, Raa, Rs, Rs, Re, R7, Ra, Ra’, Re, and Rc. When substituted, those substituents may be substituted at one or more of any of the available positions, typically 1, 2, 3, or 4 positions, by one or more suitable groups such as those disclosed herein.
Suitable groups or “substituted” moities of compounds of the invention include c.g., halogen such as fluoro, chloro, bromo or iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a Cis alkanoyl group such as acyl and the like; carboxamide; alkyl groups including those groups having 1 to about 12 carbon . atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon, or 2, 3, 4, 5 or 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, Sor 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfiny! linkages and from 1 to about 12 carbon atoms, or 1, 2, 3,4, 5, or 6 carbon atoms; alkylsulfony! groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms, or 1}, 2, 3, 4, 5, or 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl (e.g. an Ar group being a substituted or unsubstituted biphenyl moiety); arylalkyl having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with benzyl being a preferred group; aralkoxy having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with O-benzyl being a preferred group; or a heteroaromatic or heteroalicyclic group having 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl.
} As used herein, "alkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.
Examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
Preferred alkyl groups are C,;-Cgs and Cis alkyl groups. Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, 3-pentyl. The term Ci. alkyl as used herein includes alkyl groups consisting of 1 to 6 carbon atoms, which may contain a cyclopropyl moiety.
Suitable examples are methyl or ethyl. . "Cycloalkyl" is intended to include saturated ring groups, having the specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and brigded or caged saturated ring groups such as norbornane or adamantane and the like.
In the term "(Cie cycloalkyl)Ci-4 alkyl’, as defined above, the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethy!l and cyclohexylethyl. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds, which may occur in any stable point along the chain, such as ethenyl and propenyl. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -Cu(X!)wi(H2v+1-zwy) where v = 1 to 3; Xi = F(i=1), Cl(i=2), Br(i=3), I(i=4) and Iwi<2v+1]). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy ’ include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2- butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
As used herein, the term “carbocyclic aryl” indicates aromatic groups containing only carbon in the aromatic ring. Such aromatic groups may be further substituted with carbon or non-carbon atoms or groups. Typical carbocyclic aryl groups contain 1 to 3 separate of fused rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. Specifically preferred carbocyclic aryl groups include phenyl, napthyl, including 1-naphthyl and 2-naphthyl, and acenaphthyl. . By the term “energetically accessible conformer” is meant any conformer of a compound that falls within about a 15 Kcal/mol window above the lowest energy conformation (as for example that found in a monte carlo or systematic confirmational search) by using MM2, MM3, or MMFF force fields as implemented in molecular modeling software such as MacroModel® v 7.0, Schrédinger, Inc.,
Portland, Oregon United Stats and Jersey City, New Jersey, United States, http://www. schrodinger.com or the like.
Peptidomimetic compounds are generally compounds with "chemical structures derived from bioactive peptides which imitate natural molecules” (Murray Goodman and Seonggu Ro, "Peptidomimetics for Drug Design" chapter twenty in Burger's Medicinal Chemistry and Drug Discovery, Volume 1: Principles and Practice, Manfred E. Wolff, ed. John Wiley & Sons, Inc., NY, 1995, pp. 801- 861.) As used herein and in the claims, the term peptidomimetic additionally comprises peptoid compounds, which are compounds that comprise oligomers of N- substituted natural amino acids, and the term further comprises any compound having more than two amide bonds.
As used herein, the terms "heteroaryl" and -“heteroalicyclic” group are intended to indicate a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10- membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The term heteroaryl indicates that the group contains at least 1 aromatic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized.
It is preferred that when the total number of S and 0 atoms in the heterocycle cxceeds 1, then these heteroatoms are not adjacent to one another. It is : preferred that the total number of S and O atoms in the heterocycle is not more than 1, 2, or 3, more typically 1 or 2. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heteroaryl groups and other heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b|tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrroly], quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienocoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Preferred heteroaryl groups include, but are not limited to, pyridinyl,
pyrimidinyl, furanyl, and thienyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The term “halogen” indicates fluorine, chlorine, bromine, or iodine.
The term “pharmaceutically acceptable salts” includes, but is not limited to : non-toxic salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrite or salts with an organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, salicylate and stearate. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. The present invention also encompasses the prodrugs of the compounds disclosed.
Examples of bicyclic oxygen containing groups of the formula:
Ni -.
Ra (Ra may also be indicated Rg) include the following: ’ / ya pa as I
Ra Ra \ © 0 0
WL “A I~ __ 0 / 4 O 4 \ “J Ra
SNe 20a @ \ ~~ 0
Methods of Treating Patients
The present invention provides methods of treating patients suffering from diseases or disorders involving pathologic activation of CSa receptors. Such diseases and disorders may include the following.
Such disorders that may be autoimmune in nature and are suitable for treatment in accordance with the present invention include e.g. rheumatoid arthritis, systemic lupus erythematosus (and associated glomerulonephritis), psoriasis, Crohn’s discase, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, . myasthenia gravis, autoimmune hemolytic and thrombocytopenic states,
Goodpasture’s syndrome (and associated glomerulonephritis and pulmonary hemorrhage), and immunovasculitis. Such inflammatory and related conditions include neutropenia, sepsis, septic shock, Alzheimer’s disease, stroke, inflammation associated with severe burns, lung injury, myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, traumatic central nervous system injury and ischemic heart disease, and ischemia- reperfusion injury, as well as acute (adult) respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), tissue graft rejection, and hyperacute rejection of transplanted organs. Also included are pathologic sequellae associated with insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephropathy, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, as occurs, for example, during extracorporeal circulation of blood (e.g., during hemodialysis or via a heart- lung machine, for example, in association with vascular surgery such as coronary artery bypass grafting or heart valve replacement) such as extracorporeal post- dialysis syndrome, or in association with contact with other artificial vessel or container surfaces (e.g., ventricular assist devices, artificial heart machines, transfusion tubing, blood storage bags, plasmapheresis, plateletpheresis, and the like).
Treatment methods of the invention include in general administration to a patient a therapeutically effective amount of one or more compounds of the invention. Suitable patients include those subjects suffering from or susceptible to (i.e. propylactic treatment) a disorder or disease identified herein. Typical patients for treatment in accordance with the invention include mammals, particularly primates, cspecially humans. Other suitable subjects include domesticated companion animals such as a dog, cat, horse, and the like, or a livestock animal such as cattle, pig, sheep and the like.
Pharmaceutical Preparations
The compounds of the invention may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes injections and the like, such as subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, intrasternal, spinal, intrathecal, and like injection or infusion techniques, with subcutaneous, intramuscular and intravascular injections or infusions being preferred. In addition, there is provided a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier. One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
The pharmaceutical compositions containing compounds of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for ’ example starch, gelatin or acacia, and lubricating agents, for example magnesium } stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived ‘ from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such : as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of the invention may also be administered in the form of suppositories e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of the invention may be administered parenterally, preferably in a sterile non-toxic, pyrogen-free medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment or preventions of conditions involving pathogenic CSa activity, particularly those disorders list in the “background of the invention” section (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage ’ regimen of 4 times daily, three times daily, or less is preferred, with a dosage regimen of once daily or 2 times daily being particularly preferred.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed. the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination . (i.e., other drugs being administered to the paticnt), the severity of the particular disease undergoing therapy, and other factors, including the judgment of the prescribing medical practitioner.
Preferred compounds of the invention will have favorable pharmacological properties. Such properties include, but are not limited to bioavailability (e.g., oral bioavailibilty, preferably high enough to permit oral administration of doses of less than 2 grams, preferably of less than or equal to one gram), low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Distribution in the body to sites of complement activity is also desirable, e.g., compounds used to treat CNS disorders will preferably penetrate the blood brain barrier, while low brain levels of compounds used to treat periphereal disorders are typically preferred.
Assays may be used to predict these desirable pharmacological properties.
Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage required for the effective administration of a compound. In vivo half-lifes of compounds may be predicted, e.g., from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
Preparation of compounds
Representative methods for preparing the compounds of the invention are shown in the following Schemes. Schemes 1 and 2 show the preparation of arylimidazole compounds. Scheme 1 illustrates the preparation of arylimidazole compounds where . R; is hydrogen or halogen. Scheme 2 represents of the preparation of aryl imidazole compounds where R; is alkyl. Within Schemes 1 and 2 the variables Ar, Ar2, Ry, Rq,
Rj; and Rs ~ are defined as above for Formula L
Schemel. Synthesis of 1-Alkyl-2-aryl-5-aminomethylimidazoles
NH NH
OH, HCI
MeOH, (8) R,NH, : Ar;-CN —_—> Ary ——F—» Ar,
OMe NHR, 11 12
N N
— 1 N~ CHO ——» ! N
R, Rz oH 13 14 a
Ar, N N_ An )
R2 Rj
Ry
N Rs
A N Ar
Ar, N ~~ M2
R; Rj
As shown in Scheme 1, an appropriately substituted arylnitrile 10 is converted to the imidate 11 via treatment with hydrogen chloride gas in methanol followed by subsequent treatment with base to release the free base. Amidine 12 is prepared from 11 by treatment with a primary amine. 2-Arylimidazole-4-carboxaldehyde 13 is prepared from 12 by one of several methods described in the chemical literature,
for instance, by treatment with 2-bromo-3-isopropoxyacrolein in the presence of base. See, for example, J. Org, Chem., 62: 8449 (Shilcrat et al., 1997).
Aldehyde 13 can then be transformed into hydroxymethylimidazole 14 either by reduction (for cases where Rs; is hydrogen) or by treatment with the appropriate . organometallic (for cases where Rs is C1-C6 alkyl). The hydroxy group of 14 is converted to either a halogen or sulfonate ester leaving group. Treatment of this intermediate with an appropriate secondary amine in the presence of base provides 2-aryl-4-aminomethylimidazole 15. Alternatively , the aminoalkyl functionality of may be elaborated by sequential amination-acylation-reduction steps. In situations where R; is a halogen, it may be prepared from 15 {R:=H) by treatment with the molecular halogen, a halosuccinimide or the like.
As shown in Scheme 2, an appropriately substituted 2-aryl-4- substitutedimidazole 20 can be N-alkylated by treatment with base such as sodium hydride and an alkyl halide or alkylsulfonate ester to provide the trisubstituted imidazole 21. Hydroxymethylation of 21 under the conditions of the Mannich reaction provides hydroxymethylimidazole 22. In examples where Rs; is alkyl, hydroxymethyl derivative 24 is prepared from 22 by oxidation to aldehyde 23 and subsequent treatment with an appropriate organometallic reagent such as an alkyl lithium or Grignard reagent. Conversion of 22 or 24 to the desired 2-aryl-5- aminomethylimidazoles is carried out by conversion of the hydroxymethyl to a halogen or sulfonate ester leaving group followed by treatment with a secondary amine. Alternatively, the aminoalkyl functionality of the 2-aryl-S- aminomethylimidazole product may be elaborated by sequential amination- acylation-reduction steps.
Scheme 2. Synthesis of 2-Arvlimidazoles
Where R, is alkyl:
N— NE N—- Ri
A T Base A T HCHO /
Ary N — An N —> An OH
R,X | Acetic acid N
H R2 Ro ” 9 21 22
Where Rj is alkyl:
N R1 N R,
MnO, A 1 A \
Ary Ar, OH 22 —_— N CHO ——— N
R
2 Ro Ry 23 23
Where Rj is hydrogen
N Ri Ry 22 > A \
Ary N
N h
Ro Rs; Arp
The 2-aryl-4-substitutedimidazole 20 may be prepared by methods described in the chemical literature, for instance, via condensation of an arylamidine with a halomethyl or hydroxymethyl ketone.
Cycloalkylimidazoles
An illustration of the preparation of compounds of the Cycloalkylimidazole compounds of the present invention is given in Scheme 3. Within Scheme 3 the variables n, Ar), Ara, Ry, Rs, Raa, Rs, Rs, Rs, Rsa, Rea, R7 and X are defined previously.
Scheme 3. Preparation of Cvcloalkylimidazoles
Raa Rs
Re
NH Rj : PY (CRsaCRéa)n
MeO
Ar, NH + \
A 0 2 Br 31
Raa 6 3a Re
Rs (CRsaCRega)n
N \
J °
Ary I
R
R 5 3a Re
R3 (CR5,CRgaln
N
Dak
X Compound 33 X=O0H
Ar N Compound 34 X = halogen or sulphonate ester
Ra
R
R 5 3a Rg
Ra (CR5,CRga)n
N
IRIN
N
, Ar N ( N—ar
Ry 2 35
R2
As shown in Scheme 3, an appropriately substituted arylamidine 30 is condensed with an appropriately substituted 2-halo-3-alkoxyenone 31 to provide a 2-aryl-4,5-
cycloalkylimidazole 32. The ketone functionality of 32 can be either reduced (Ry =
H) or treated with an appropriate organometallic (for cases where Ry is alkyl) to give the cyclic alcohol 33. Compounds of general formula 34 can be prepared from 33 by one of several methods described in the chemical literature, for instance, by . treatment with thionyl chloride or by treatment with an alkyl or arylsulphonyl chloride in the presence of base.
Compounds of formula 34 can then be transformed into compounds of general Formula 35 by direct treatment with the appropriate secondary amine.
Alternatively, the X functionality of 34 may be transformed into a tertiary amine in a stepwise manner. In this case, 34 would be treated with a primary amine to provide an intermediate secondary amine. This, in turn, could be alkylated to give cycloalkyvlimidazole compounds of the invention.
Pyridines
An illustration of the preparation of pyridine compounds of the present invention is given in Scheme 4. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. Within Scheme 4 the variables
Ari, Arg, R, Ri, Ra, Rs, and Rs are defined as previously described.
Scheme 4. Preparation of Aryl pyridines . x R Ry > —/\ R
N“ So Hooc COOH y
Ar] Ar; 2 cooH
R.
R2 40 41
R; R,
NT XR R;-M NTO R
LL — LL on
Ar, CHO Ar,
R, R, 42 43
R
1 R,
NTO R Rs R [ NTO Ra » NH —>» [
Ar, A | FF N
R Ar 1 MN
R, 3 Rs
R; Ar 2 44 = 45
As shown in Scheme 4, an appropriately substituted 4-phenyloxazole 40 is condensed with an appropriately substituted maleic acid to provide a 2- phenylisonicotinic acid 41. The carboxylic acid functionality of 41 can be reduced directly to the primary alcohol (43, Rs; = H) or converted by methods known to the art to an intermediate aldehyde 42 and subsequently treated with the appropriate organometallic (for cases where Ri is alkyl) to give a secondary alcohol 43.
Compounds of general formula 44 can be prepared from 43 by one of several methods described in the chemical literature, for instance, by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a primary amine. Compounds of formula 44 can then be transformed into compounds of formula 45 by direct treatment with the appropriate alkylating agent or, alternatively, by reductive alkylation.
Alternatively, the tertiary amine functionality of formula 45 may be realized directly from compounds of formula 43 by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a secondary amine.
Pyrazoles
An illustration of the preparation of arylpyrazole compounds of the present invention is given in Scheme 5. Within Scheme 5 the variables Ar, Ars, Ri, R2, Rs, and Rs are defined as previously described.
Scheme 5. Preparation of Arylpyrazoles
Ry
H 0 oO + Alkyl == 0
J AN ZN R AN “Alkyl
Arq N 2 y/ —_— Ar, 50 51 R, rd | 52
Ry R,
N= O—H N= O—H
N—/
Ary Rs ar / lo]
R,; R, 53 = 56
Ra
Ry R, ( = LG iP TH
Ar Ry _N / 0 Arn
R Ar, 2 R, 54 57
Ry ha
Ry ( Ry
N= N Ri ( /\ N= N
N—/ Ar \
Ary R; 2 A VY A
R, Ar{ 2
R; 58 58
As shown in Scheme 5, an appropriately substituted phenylhydrazine adduct 50 is condensed with an appropriately substituted a-ketoester 51, in the presence of a Lewis acid, preferably ZnCl,, with heating at 50 - 200 °C, preferably at 125 oC to provide a 1-phenylpyrazole ester 52. The carboxylic acid functionality of 52 can be reduced directly to the primary alcohol (53, Rs = H) or converted by methods known to the art to an intermediate aldehyde and subsequently treated with the appropriate the appropriate organometallic (for cases where Rs is alkyl) to give a secondary alcohol 53. Compounds of general formula 54, where LG represents a leaving group, can be prepared from 53 by one of several methods described in the . chemical literature, for instance, by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a primary amine. Compounds of formula 54 can then be transformed into compounds of formula 58 by sequential treatment with the appropriate primary amine followed by direct alkylation or reductive alkylation of the intermediate secondary amine. Alternatively, the tertiary amine functionality of formula 58 may be realized directly from compounds of formula 53 by initial treatment with thionyl chloride or with an alkyl or arylsulphonyl chloride in the presence of base, followed by subsequent condensation with a secondary amine.
An alternative route to the preparation of compounds of Formula §8 from the 1-phenylpyrazole ester 52 may be realized by hydrolysis of 52 to a carboxylic acid of general structure 56, followed by amide formation to provide 57 and, finally, reduction of the amide functionality to the tertiary amine of 58 (Rs=H).
Scheme 6. Preparation of 2-(1-aryl-1,2,3,4-tetrahvdroiso quinolin-2-yl} acetamides and bicyclics of other ring sizes (n=0, 1, 2, 3, etc} [fe Rs te (CHzIn P NP (Chan | A
SSIES LY
4 No A, oo 9 NA
R2 | 2 & Re ] _Z Re
ANY 3 gy
R¢ Rs : 60 61 62
The 2-(1,2,3,4-tetrahydroisoquinolin-2-yl) acetamides of general formula 62 of the present invention may be prepared according to the procedure described graphically in Scheme 6, wherein a compound of general Formula 60, prepared according to literature procedures, (for example: Scully, Frank E., Jr.; Schlager,
John J. Synthesis of dihydroisoquinolines and 1-substituted tetrahydroisoquinolines. Heterocycles (1982), 19(4), 653-6 or Shinohara,
Tatsumi; Takeda, Akira; Toda, Jun; Terasawa, Noriyo; Sano, Takehiro. A highly efficient synthesis of 1-methyl-, 1-benzyl-, and 1-phenyl-1,2,3,4- tetrahydroisoquinolines by a modified Pummerer reaction. Heterocycles (1997), 46: 555-566.) is combined (in an appropiate solvent in the presence of an organic or inorganic base) with an appropriately substituted acetamide derivative possessing a leaving group X at its 2 position. For example, X may be halogen, alkyl or aryl sulfonate, or polyfluoroalkylisulfonate. Acetamides of general Formula 61 may be prepared via condensation of the appropriate secondary amine with a 2- haloacetylhalide (such as 2-chloroacaetyl chloride) in the presence of base.
Alternatively acetamides of general formula 61 can be prepared by condensation of the appropriate secondary amine with either a 2-(alkylsulfonylester)acetic acid or 2- (arylsulfonylester)acetic acid in the pressence of an coupling agent such as CDI or the like.
Within Scheme 6, Rj, Rs, Rs, Rs and Rs may be the same or different and are chosen from hydrogen, halogen, C;-Cs alkyl, C,-Cs alkoxy, hydroxy, trifluoromethyl, trifluoromethoxyl, cyano, nitro, hydroxy carbonyl (COOH), aminocarbonyl (CONH2), mono or dialkylaminocarbonyl, sulfonamido, mono or dialkylsulfonamido, amino, mono- or di-alkylamino, aceto, acetoxy or 3,4-methylenedioxy or ethylenedioxy. The term n refers to an integer from 1 to 3. Re may be C;-Cy straight or branched chain alkyl, benzyl (substituted or unsubstituted), phenylethyl (substituted or unsubstituted), phenylpropyl (substituted or unsubstituted), or may be cycloalkyl fused with an aromatic group such as 1,2,3,4-tetrahydronaphthyl, 1- or 2- indanyl or suberanyl.
Scheme 7. Preparation of Ortho Biarylamides
Rj Rs
R; Rs 1. SOC}; or R, R,
CDI
————
R, OH 2 R.RNH NRsRs
Ri
X 0° X 0 70 7
Suzuki or Stille
R; coupling
R, Ra
NRsR
R, 576
Ar o 72
The preparation of the ortho biarylamides of the present invention may be carried out via a series of chemical transformations similar to those displayed graphically in Scheme 7. An individual skilled in the art may find modifications of one or several of the synthetic steps described herein without diverting significantly from the overall synthetic scheme.
Thus, as shown, the synthetic route begins with a benzoic acid of general structure 70 possessing a group X at the ortho position. This X group may be iodine, bromine, chlorine, sulfonate ester or polyfluoroalkylsulfonate ester. The benzoic acid may also be substituted by up to four independently chosen . substitutents represented by the variables R1-R4. Examples of suitable substituents include hydrogen, chlorine, fluorine, cyano, C;-Cs straight or branched chain alkyl,
Ci1-C¢ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, mono or dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide, alkylsulfone, acetyl, acetoxy, alkoxycarbonyl
(COOAIlky}) or dialkylaminocarbonyl (CON[alkyl]2). Additionally, two adjacent groups (i.e R; and R:, or R2 and Rs or R3 and Rs) may be taken together with a chain of from 3 to 5 methylene carbons to form a alkyl ring of from five to seven carbons fused to the benzoic acid moiety. Additionally, two adjacent groups (i.c Ry and Ru, or . R. and Rj; or R3 and Rs) may be taken together with an alkyloxy chain, for example
OCHO or OCH2CH,;0 to form an oxygen-containing moiety (in this example methylenedioxy or ethylenedioxy, respectively) fused to the benzoic acid.
This benzoic acid is then activated by conversion to an acid chloride with thionyl chloride, oxalyl chloride or the like. Alternatively, it may be activated by treatment with carbonyldiimidazole or a similar agent. The activated benzoic acid is then treated with an appropriate secondary amine in the presence of base to provide a tertiary amide of general structure 71.
Amide 71 is then converted to the biaryl structure 72 through the use of aryl coupling reactions know in the chemical literature. Examples of such reactions are the Stille reaction where an aryl trialkyltin reagent is coupled to an appropriate aryl in the presence of a catalyst such as palladium or nickel; or a Suzuki reaction where a arylboronic acid is coupled to an appropriate aryl in the presence of a nickel or palladium catalyst in the presence of base.
The group “Ar” of General structure 72 may be a phenyl which may be substituted with up to five additional independently chosen substitutents, e.g. hydrogen, halogen, cyano, C;-Ce¢ straight or branched chain alkyl, C1-C6 straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, mono or dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide, alkylsulfone, acetyl, acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl (COOAlkyl), aminocarbonyl (CONH2), monoalkylaminocarbonyl, dialkylaminocarbonyl (CON[alkyl]2, methylenedioxy or ethylenedioxy.
The Ar of General Structure 72 may also represent a heteroaryl group such as 1- or 2- thienyl or 1- or 2- furanyl. Such a heteroaryl group which may be additionally substituted by up to three independently chosen substituents, such as hydrogen, halogen, cyano, Ci-Cs straight or branched chain alkyl, Ci-Cs straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, dialkyl amino, sulfonamido, mona or dialkylsulfonamido, alkylthio e.g. methylthio, alkylsulfoxide, alkylsulfone, acetyl, acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl (COOAlky]). aminocarbonyl (CONH;), monoalkylcarbonyl, dialkylaminocarbonyl (CONlalkylja.
Scheme 8. General Preparation of Azaarvl benzamides
Rs
J B
A JN
X AY Re
X=F,(Cl
R4 CN R4 CN _ >
H
~~ N
Rj R4 A R Rj Ri
R, \ / ° R>
B
73 Rs 75 74
Acid
R
Rs Ng
Vm / \
A R
NY Re N
COOH
Re © _CONR;R, Ra -——
R 76
Ry R, 77 Rj 1
R
Rz 2 : The preparation of 2-imidazolyl, 2-pyrrazolyl and 2-(1,2,4)-triazolyl benzamides begins with an appropriately substituted benzonitrile derivative having a leaving group X at the position ortho to the carboxylic acid functionality. Most commonly this group would be a fluorine or chlorine group. This benzonitrile may be optionally substituted or additionally substituted by up to four substituents (R;-Ra) which may be the same or different (examples of such substituents are: hydrogen, halogen, cyano, C;-Cs straight or branched chain alkyl, C,-Cs straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono or dialkyl amino, sulfonamido, mono or dialkylsulfonamido, methylthio, alkylsulfoxide, alkylsulfone, acetyl, acetoxy, alkoxycarbonyl (COOAlkyl) or dialkylaminocarbonyl (CON[alkyl}2).
The benzonitrile 73 is mixed with the azaheterocycle 74 (whercin A and B may be either nitrogen or carbon with the caveat that both A and B not be carbon.
Rs; and Rs may be the same as those groups described for R;-R4.) This condensation may be carried out either in a single phase system in an appropriate solvent and base, or in a two-phase manner using a phase transfer catalyst. 2-Azaheterocyclicbenzonitrile 75 is the hydrolyzed to the corresponding benzoic acid 76 via means common to the chemical literature, for instance mineral acid.
The benzoic acid 76 is then activated via thionyl chloride, CDI or other means known to the chemical literature and condensed with an appropriately substituted secondary amine toprovide the desired final products 77.
The general methods given in Schemes 1 to 8 above for the preparation of compounds of the present invention are further illustrated by the following examples. Specifically, the methods given in Schemes 1 and 2 for the preparation of aryl imidazoles are illustrated by Examples 1-4, shown below. An example of the method shown in Scheme 3 for the preparation of cycloalkylimidazoles is given in ‘ example 5, and example of the method shown in Scheme 4 for the preparation of arylpyridines is given in example 6, and an example of the method shown in Scheme for the preparation of arylpyrazoles is given in example 7. The method shown by
Scheme 6 for the preparations of 2-(1-Aryl-1,2,3,4-tetrahydroisoquinolin-2- -yl)acetamides is further illustrated in example 8. The methods shown in Schemes 7 and 8 for the preparation of ortho biarylamides and azaarvlamides, respectively, arc exemplified in Examples 9 and 10. Unless otherwise specified all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be varied to achieve the desired end product.
Example 1. Preparation of an arvlimidazole compound: 1-(1-butvl}-2-phenyl-5-{N,N- di{3,4-methyvlenedioxyphenyl methylllaminomethylimidazole (Compound 106).
N-(n-butyl}-benzamidine (101). To a solution of methyl benzimidate hydrochloride (12 g, 0.07 mole) in dimethylformamide (DMF, 20 mL) is added 7 ml of triethylamine at 0 °C. After 2 h the reaction is filtered to remove triethylamine hydrochloride. To the filtrate is added 3.68 g of 1-butylamine and the mixture is heated to 60 °C for 6 h. After cooling the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate and concentrated to provide 13.28 g of the amidine as a yellow oil. tH NMR (400 MHz, CDCls) 8 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.95 (t, J = 7 Hz, 3H). 1-(1-Butyl)-2-phenylimidazole-5-carboxaldehyde (102). To a solution of 101 (13.28 g) and 2-bromo-3-isopropoxyacrolein (22 g} in chloroform (150 ml) is added potassium carbonate (15.5 g) and water (19 ml). The mixture is stirred at room temperature overnight. The aqueous layer is discarded and the organic layer is washed with water (3X 100 mL}, dried (Na2SO4) and concentrated. The residue is purified via flash chromatography (5% MeOH/CHCI3) to provide the desired imidazole carboxaldehyde as a pale yellow oil (21.55 g). 'H NMR (400 MHz, CDCl3) § 9.75 (s, 1H), 7.90 (s, 1H), 7.55 (m, 2H), 7.45 (m, 3H), 4.38 (t, J = 8Hz, 2H), 1.75 (m, ’ 2H), 1.22 (m, 2H), 0.91 (t, J = 7 Hz, 3H).
Representative preparation of a 1-Alkyl-2-aryl-4-aminomethylimidazole: 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylendioxyphenylmethyl}) aminomethylimidazole)
NH NH DN
OMe NH nN CHO a a —_— 100 101 102
N N
H
N N
102 pu —_— 103 104 0) \_o
O=\ o—\ 0 0 0
N N
OY DN
—_— N —— N 105 106
Q 0 1-(1-Butyl)-2-phenyl-5-hydroxymethylimidazole (103). Aldehyde 102 is dissolved in methanol (150 mL). Sodium borohydride (3 g) is added in portions.
After the addition was complete, the reaction is diluted with water and concentrated. : The residue is dissolved in ethyl acetate, washed with brine, dried (Na:SQ.) and concentrated. The product is purified by flash chromatography on silica gel (5%
MeOH/CHCIl3) to give 4.17 g of 103 as a cream colored solid. H-NMR (400 MHz,
CDCl): § 0.79 (3H, t, d=7.4), 1.18 (2H, m, d=7.4}, 1.60 (2H, m, d=7.6), 4.03 (2H, dd, d=7.6), 4.56 (2H, s), 6.84 (1H, s), 7.39-7.50 (3H, m},7.50-7.53 (2H, m). 1-(1-Butyl)-2-phenyl-5-(N-[3,4- methylenedioxyphenylmethyl))aminomethylimidazole (104). } Hydroxymethylimidazole 103 {0.82 g) is dissolved in chloroform (10 ml) and treated with thionyl chloride (1 ml). The solution is heated to 50 °C for 30 min, cooled and evaporated. The residue is washed with benzene and evaporated to give the intermediate chloromethyl hydrochloride as a white powder which is taken up in acetonitrile (30 mL}. This is added dropwise to a solution of piperonylamine (5S ml) in acetonitrile (10 ml). The reaction is allowed to stand overnight and then evaporated. The residue is taken up in ethyl acetate and washed with water. The organic laver is dried (Na,S0.4) and concentrated. Purification on silica gel (10%
MeOH /CHCI;) provides the product as a pale yellow oil {0.91 g). *H NMR (400 MHz,
CDCl3): § 0.79 (3H, t, d=7.4), 1.18 (2H, m, d=7.4), 1.56 (2H. m, d=7.4), 3.75 (4H, s), 4.04 (2H, dd, d=8), 5.92 (2H, s), 6.76 (2H, m), 6.84 (1H,s), 6.97 (1H, s), 7.38-7.44 {3H, m), 7.53-7.56 (2H, m). 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl methyl}-N-(3,4- methylenedioxyphenylcarboxy]} aminomethylimidazole (105). Compound 104 (160 mg, 0.44 mmol) is dissolved in chloroform (5S ml, pentene stabilized) and treated sequentially with piperonyloyl chloride (100 mg) and triethylamine (1 ml). The mixture is stirred at room temperature overnight. The solution is concentrated and the residue taken up in ethyl acetate. The organic is washed with water, dried (Na2S0O4) and concentrated. Purification by preparative thin layer chromatography (3% MeOH /CHCIl3) provides compound 105 as a pale yellow oil (240 mg). 'H-NMR (400 MHz, CDCl3): 8 0.75 (3H, br), 1.16 (2H, br), 1.49 (2H, br), 4.01 (2H, br), 4.54 (2H, br), 4.68 (2H, br), 5.97 (2H, s), 5.99 (2H, s), 6.66 (2H, d, d=7.2), 6.80 (2H, t, } d=8), 6.98-7.02 (2H, mj}, 7.40-7.47 (3H, m), 7.56 (2H, d, d=6.8). 1-(1-Butyl)-2-phenyl-5-(N,N-di|3,4-methylenedioxy phenylmethyl))- aminomethylimidazole (106). Amide 105 (215 mg) in tetrahydrofuran (THF, 3 ml) is added dropwise to a solution of alane (1 M in THF, 2 ml) and the resulting solution is stirred for 2.5 h at room temperature. A solution of sodium hydroxide (15%
NaOH, 1 ml} is added and the mixture is extracted with chloroform. The organic extracts are dried (Na;SO.) and concentrated. Purification by preparative thin layer chromatography (10% MeOH/CHCI3) provided compound 106 as a colorless oil (115 . mg). 'H-NMR (400 MHz, CDCl): § 0.70 (3H, t, d=7.6), 0.98 (2H, m, d=7.6}, 1.30 (2H, my), 3.44 (4H, s), 3.52 (2H, s), 3.98 {2H, dd, d=8), 5.92 (4H, s}, 6.74 (4H, s), 6.69 (2H, s), 7.02 (1H, s), 7.36-7.42 (3H, m)}, 7.54 (2H, dd, d=1.4, 6.6). The hydrochloride salt {m.p. 187-190 °C) was prepared in isopropanol.
Example 2. Preparation of 1-(1-butyl}-2-phenvi-5-(1-[N-{3.4- methylenedioxvpbenylmethyli-N-phenvimethvilaminojethylimidazole (Compound 108). 1-Butyl-2-phenyl-5-{1-hydroxyethyljimidazole (107). A solution of aldehyde 102 (230 mg) in diethyl ether (30 ml) is placed in a separatory funnel and treated with a solution of
Preparation of 1-(1-Butyl)-2-phenyli-5-(1-[N-[{3,4-methylendioxyphenylimethyl]}-
N-[phenyimethyilaminoethylimidazole)
N N
IN | NN 107 1 N Is 108 0) 0 methyl lithium (1.4 M in THF, 1.5 ml). After 10 min, the solution is washed with ’ ammonium chloride solution (1 M, 20 ml), dried (Na:SO4) and concentrated. The resulting dark oil is purified by preparative TLC (10% MeOH/CHCIs} to provide compound 107 as a colorless oil (180 mg). 'H NMR (400 MHz, CDCl) 6 7.56 (d, J = 2
Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J = 7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J = 6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t, J = 7 Hz, 3H). 1-Butyl-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]-N- phenylmethyl)aminoethylimidazole (108). A solution of compound 107 (80 mg) in . chloroform (10 ml) is treated with thionyl chloride (1 ml) and heated to 50 °C for 30 min. The solution is then concentrated, diluted with chloroform and reconcentrated to provide the intermediate chloromethyl hydrochloride as an oil. This material is taken up in chloroform (5 ml) and treated sequentially with N-benzylpiperonylamine (80 mg) and triethylamine. After stirring overnight, the reaction is washed with saturated potassium carbonate solution, dried (Na:SO4) and concentrated.
Purification by preparative thin layer chromatography (10% MeOH/CHCIls) provides compound 108 as a colorless oil (62 mg). !H NMR (400 MHz, CDCl3) § 7.46-7.43 (m, 1H), 7.2-7.3 (m, 9H), 6.74-6.86 (m, 4H), 5.94 (s, 2H), 4.82 (q, J = 6.8 Hz, 1H}, 4.33 (m, 2H), 3.78 (s, 2H}, 3.53 (s, 2H), 1.83 (d, J = 6.8 Hz, 3H), 1.62-1.68 (m, 2H), 1.21 (q, Jd = 7.8 Hz, 2H), 0.82 (t, J = 7.8 Hz, 3H).
Example 3. Preparation of 1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-[1- butyl])amino-methylimidazole (Compound 110).
Preparation of 1-(1-Butyl)-2-phenyl-4-bromo-5-[N-phenylmethyl-N-[1-butyl]) aminomethylimidazole)
N N
OL A
102 3 110
1-Butyl-2-phenyvl-5-(N-benzyl-N-butyljaminomethylimidazole ~~ (109). A solution of compound 102 (115 mg) and N-butylbenzylamine (85 mg} in toluene (10 ml) is allowed to stand overnight. Treatment of the reaction with sodium borohvdride (100 mg) and ethanol (2 mL) followed by aqueous workup and . purification on silica gel (10% MeOH/CHCIl3) provides compound 109 as a colorless oil (35 mg}. 'H NMR (400 MHz, CDCl3) § 7.2-7.5 (m, 10H), 6.98 (s, 1H), 4.0 (t, J = 8
Hz, 2H), 3.55 (s, 2H), 3.52 (s, 2H), 2.42 {t, J = 8 Hz, 2H), 1.2-1.55 (m, 6 H), 1.05 (m, 2H), 0.84 (t, J = 7 Hz, 3H}, 0.72 (t, J = 7 Hz, 3H). 1-Butyl-2-phenyl-4-bromo-5-(N-phenylmethyl-N-{1- butylj)Jaminomethylimidazole (110). To a solution of 109 (30 mg) in acetonitrile (4 mL) was added N-bromosuccinimide (16 mg). The resulting mixture was heated to 60 °C and the progress of the reaction followed by TLC. The cooled reaction mixture was diluted with ethyl acetate and washed twice with water. Purification by preparative thin layer chromatography (10% MeOH/CHCI3) provided compound 110 as a colorless oil (22 mg). 'H NMR (400 MHz, CDCl3) § 7.2-7.5 (m, 10 H), 3.98 {t, J = 8 Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H), 2.46 (t, J = 7 Hz, 2H), 1.52 (m, 2H), 1.3 (m, 4H), 0.98 {(q, J = 7 Hz, 2H), 0.84 (t, J = 7 Hz, 3H), 0.70 (t, J = 7 Hz, 3H).
Example 4. Preparation of 1-(1-Butyll-2-phenyl-4-methyl-5-({N-[3,4- methylenedioxyphenyl-methyl]-N-phenylmethyllaminomethylimidazole. (Compound 114). 1-Butyl-2-phenyl-4-methylimidazole (112). To a solution of 4-methyl-2- phenylimidazole {111, 15.8 g) in dimethylformamide (100 ml) is added sodium hydride (4.4 g, 60% in mineral oil) in small portions. After the addition is complete, the mixture was stirred for an additional 20 min and treated with l-iodobutane (18.8 g). The reaction is fitted with a reflux condensor and heated at 100 °C for 12 } h. The cooled reaction mixture is partitioned between water (300 ml) and diethyl ether (300 ml). The organic layer is washed with water (3X 200 ml), dried (Na2SO4) and concentrated to provide 20.5 g of N-butylimidazoles. Analysis by H-NMR and
GC-MS revealed mixture of 1-butyl-2-phenyl-4-methylimidazole (112) and 1-butyl-2-
phenyl-5-methvlimidazole in a ratio of 11.5/1. The mixture was carried on to the next step without purification. 1-Butyl-2-phenyl-4-methyl-5-hyvdroxymethylimidazole (113). A solution of ’ 112 (1 g) in acetic acid (10 mL} and 40% aqueous formaldehyde (2 ml] is refluxed for 14 h. The reaction is then concentrated and dried by repeated reconcentration : with toluene, The residue is purified by column chromatography (10%
MeOH /CHCl;). The fractions are assayed by GC and those fractions uncontaminated by the isomeric hydroxymethylimidazole combined. Concentration of the combined fractions provides compound 113 (320 mg) as a pale yellow oil. 'H NMR (400 MHz,
CDCl3) 8 7.4-7.6 (m, 611}, 4.61 (s, 2H, CH,0H), 4.02 (t, J = 7 Hz, 2H, NCH)), 2.22 (s, 3H, Me), 1.63 (m, 2H, 1.25 (m, 2H), 0.81 (t, J = 7 Hz, 3H).
Preparation of 1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl]-N-phenyimethyl) aminomethylimidazole
N N j { / {
H
111 112
N
{ a NL
N ll N
N meen 113 114 0 o—/ 1-Butyl-2-phenyl-4-methyl-5-(N-benzyl-N-butyljaminomethylimidazole (114).
Compound 114 (23 mg) is prepared from 113 (50 mg) in a method similar to that : used to obtain compound 108. 'H NMR (400 MHz, CDCl) § 7.5-7.55 (m,2H), 7.38- 7.42 (m, 3H), 7.23-7.30 (m, 5H), 3.95 (t, J = 7.5 Hz, 2H), 3.55 (s, 2H), 3.53 (s, 2H),
2.40 (t, J = 7 Hz, 2H), 2.22 (s, 3H), 1.25-1.40 (m, 6H), 1.05 (m, 2H), 0.82 (t, J = 7 Hz, 3H). 0.70 (t, J = 7 Hz, 3H); MS (LCMS) m/e 390 (M-+1)
Example 5. Preparation of a cycloalkylimidazole compound: 4-i{butyl(1-butvi-2- phenvl(4.5.6-trihvdrocvclopental3,2-djimidazol-6-yljjamino]jmethvli-3-chlorophenol
N-(n-butyl)-benzamidine (120). To a solution of methyl benzimidate hydrochloride (12 g. 0.07 mole) in dimethylformamide (DMF, 20 mL) is added 7 ml of triethylamine at 0 °C. After 2 h the reaction is filtered to remove triethylamine hydrochloride. To the filtrate is added 3.68 g of 1-butylamine and the mixture is heated to 60 °C for 6 h. After cooling the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate and concentrated to provide 13.28 g of the amidine as a yellow oil. 1H NMR (CDCly) 7.55 (m, 2H), 7.4 (m, 3H), 3.37 (bm, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 0.95 (t,
J = 7 Hz, 3H). 2-Bromo-3-methoxycyclopentenone (131) is prepared via the method of
Curran et al JACS, vol 112, page 5601. To a suspension of 1,3-cyclopentanedione (10 g) in chloroform (700 ml) is added a N-bromosuccinimide (18.2 g). The mixture is refluxed for 2 h, cooled and concentrated. Methanol (700 mL} and p-toluenesulfonic acid (1 g) are added and the solution is refluxed overnight. The mixture is concentrated to 100 ml, diluted with methylene chloride (500 mL) and poured into water. The aqueous layer is discarded and the organic layer is washed with water (3
X 100 mL), dried (NazS04) and concentrated. The residue is crystallized from ethyl acetate to give 131 as tan crystals (1.67 g). 1-Butyl-2-phenyl-4,5-dihydrocyclopenty|1,2-d]imidazol-6-one {Compound 132). To a } mixture of amidine 130 (3.52 g, 20 mmol} and enone 13 (4.58 g, 24 mmol} in chloroform (40 mL) and water (5 mL) was added solid potassium carbonate (3.32 g, 24 mmol). The resulting mixture is refluxed overnight. After cooling, the mixture is washed with water, dried (Na»SOs) and concentrated. Purification on silica gel eluting with 25% ethyl acetate/hexane gives the desired product 132 (3.0 gj LC-MS
{M*+1): 255. H-NMR (6, CDCl3): 0.84 (t, J = 7.6 Hz, 3H), 1.23 (dt, J = 7.0, 7.6 Hz, 2H), 1.81 (m, 2H), 2.95 (m, 4H), 4.13 {t, J = 7.6 Hz, 2H) 7.5-7.45 (m, 3H), 7.76-7.6 (m, 2H) ppm. 1-Butyl-2-phenyl-4,5-dihydrocyclopenty[1,2-d|imidazol-6-ol (Compound 133). To a solution of 132 (2.68 g) in methanol (20 mL) is added sodium borohydride {1.5 equiv) and the mixture stirred overnight. The mixture is concentrated, diluted with chloroform and washed with 0.5 N NH4Cl solution. The organic layer is dried (Na>S04) and concentrated to provide the desired product 133. LC-MS (M + 1) 257.
Butyl(1-butyl-2-phenyl-4,5.6-trihydrocyclopentyl|3,2-d]imidazol-6-yl))amine (Compound 135). Compound 133 (2 g) is dissolved in chloroform (20 mL) and thionyl! chloride (5 ml) and the resulting solution is stirred at room temperature overnight. The solvent and excess thionyl chloride are evaporated and the crude chloride 134 was dissolved in n-butylamine (10 mL). After 2 h, the excess butylamine was evaporated, the residue dissolved in ethyl acetate and the organic solution washed with 5% NaOH solution and water. The organic layer was dried and concentrated. The organic residue is purified by column chromatography on silaica gel eluting with 10% CH30H in CHCl; to provide the desired secondary amine 138 in 82% yield. LC-MS (M+1) 312 !H-NMR (chemical shift, CDCl3): 0.83 (t, J = 7.2 Hz, 3H), 0.9 (t, J = 7.2 Hz, 3H), 1.23 (q, J = 7.2 Hz, 2H), 1.35 (gq, J = 7.2 Hz, 2H), 1.46 (m, 2H), 1.70 (m, 2H), 2.24 (m, 1H), 2.55-2.66 (m, 4H), 2.73-2.80 (m, 2H), 3.97-4.04 (m, 2H), 4.30 (d, J = 5.6 Hz, 1H), 7.37-7.44 (m, 3H), 7.55-7.57 (m, 2H). 4-{[Butyl(1-butyl-2-phenyl(4,5,6-trihydrocyclopenta[3,2-d}imidazol-6- yl))amino]methyl}-3-chlorophenol (Compound 5, Table 1). To a solution of compound 135 (50 mg) in 1,2-dichloroethane (2 ml) and 2-chloro-4- hydroxybenzaldehyde (30 mg) is added sodium triacetoxyborohydride (100 mg). The resulting mixture is allowed to stir overnight. After washing with 0.5 ammonium chloride solution, the organic layer is dried (Na>SO4) and concentrated. Purification using preparative thin layer chromatography eluting with 5% CHsOH/CHCly provides the desired product 136 as an oil (21 mg). LC-MS (M+1) 452, (M-1) 450.
IH-NMR (chemical shift, CDCl3): 0.74 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 7.2 Hz, 3H), 1.11 (g, J = 7.2 Hz, 2H), 1.21-1.33 (m, 2H), 1.41-1.51 (m, 4H), 2.34-2.44 (m, 3H}, . 2.51-2.57 (m, 1Hj, 2.60-2.67 (m, 1H}, 2.69-2.75 (m, 1H), 3.38 (d, J = 7.6 Hz, 1H], 3.47 (d,J = 13.6 Hz, 1H), 3.65 (d, J = 13.6 Hz, 1H), 3.78-3.96 (m, 1H), 6.62 (dd, J = 8.2 Hz. 1H), 6.78 (d, J = 2 Hz, 1H), 7.07 (d, J = 8 Hz, 1H), 7.35-7.41 (m. 3H), 7.45- 7.48 (m, 2H).
Preparation of 4-{[Butyl(1-butyl-2-phenyi(4.5.6-trihydrocyclopenta [3.2-d]imidazol-6-yl}))amino]methyl}-3-chlorophenol
NH
MeO
NH +
Je 0
Br 130 | 131 rH 0]
N
Jt 132
N
Compound 133 X = OH
N X Compound 134 X =ClI / Compound 135 X = HNBu
OH
~y oa
Je ; Compound 136
Example 6. Preparation of 2-phenyl-4-(N,N-di{2H-Benzo[3.4-d]-1,3-dioxolan-5- ylmethyllamino)methyl-3-butylpyndine 4-Phenyl-5-butyloxazole (140). A mixture of a-bromohexanophenone (25.5 g, 0.1 mole), ammonium formate (22 g, 0.35 mole) and formic acid (110 mL) was refluxed with stirring for 3 h. The reaction mixture was poured onto ice and made basic with 10 N NaOH and extracted with ether. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acctate in hexane. To provide the desired compound as an oil (8.3 g, 41 %); 'H NMR (6, CDCl, 400 MHz) 7.55 (m, 2H), 7.40 (s, 1H), 7.34 (dd. J= 7.7 Hz, 2H). 7.22 (dd, J = 7, 7 Hz, 1H), 2.74 (m, 2H), 1.6 (m, 2H), 1.30 (m, 2H), 0.84 (t, J = 7 Hz, 3H) ppm. 2-Phenyl-3-butylisonicotinic acid (141). A mixture of 4-phenyl-5-butyloxazole (12, 5 g, 25 mmol) and maleic acid (3.5 g, 30 mmol) is heated at 100 °C for 30 min.
After cooling, the semisolid mass is triturated with ether and the solid collected by filtration . !H NMR (6, CDCl, 400 MHz) 11.68 (brs, 1H), 8.72 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.48-7.51 (m, 2H), 7.42-7.44 (m, 2H), 6.25 (s, 1H), 2.86 (4,
J= 7.6 Hz, 2H), 1.36 (m, 2H), 1.11 (dt, J= 7.6, 7.2 Hz, 2H), 0.68 (t, J = 7.6 Hz, 3H).
MS (M+1): 256, (M - 1) 254. 2-Phenyl-4-hydroxymethyl-3-butylpyridine (142). 4 mL of a 1M solution of lithium aluminum hydride in tetrahydrofuran is added to a solution of 2-phenyl- 3-butylisonicotinic acid (13, 510 mg, 2 mmol) in tetrahydrofuran (20 mL). The reaction is stirred overnight and then quenched with 5 mL of 15% aqueous NaOH.
The resulting mixture is extracted with ether, dried (Na;SO4} and concentrated to provide the desired hydroxymethylpyridine as an oil (470 mg). LC-MS (M+1): 242; 'H
NMR ( , CDCL3) 8.35 (1H, d, J = 5.2 Hz), 7.30-7.39 (6H, m), 4.59 (2H, s), 2.43 (2H, t, J = 8.0 Hz), 1.23 (2H, m), 1.13 (2H, m), 0.70 (3H, t, J = 7.2 Hz). } 2-Phenyl-4-(N-{2H-benzo[3,4-d}-1,3-dioxolan-5-ylmethyl})aminomethyl-3- butylpyridine (143). Thionyl chloride (200 mg, 1.67 mmol) is added to a solution of 2-phenyl-4-hydroxymethyl-3-butylpyridine (400 mg, 1.66 mmol) in pentene stabilized chloroform (8 mL) and the mixture is heated to 50 °C for 2 h. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (Na:S0:) and concentrated. | The resulting crude chloride is taken up in dimethylformamide (10 ml) and added dropwise to a refluxing solution of piperonylamine (1.0 g, 4 equiv) in dimethylformamide {30 mL) containing 3 g of powdered potassium carbonate. After the addition is complete, the resulting mixture is refluxed for an additional 3 h, cooled and partitioned between water (200 mL) and ether (100 mL}. The ethereal layer is washed 2 times with water, dried (Na2S04) and concentrated. The resulting material is purified by chromatography on silica cluting with 10% CH3OH/CHCI; to give the desired secondary amine 15. LC-
MS (M+1): 375.3; H-NMR (§, CDCla): 0.73 (3H, t, J = 7.2 Hz), 1.15 2H, m J = 7.2
Hz), 1.30 (2H, mj}, 2.58 (2H, t, J = 8.0 Hz), 3.79 (2H, s), 3.83 (2H, sj}, 5.93 (2H, s)}, 6.75-6.82 (2H, m), 6.89 (1H, d, J = 1.2 Hz), 7.36-7.42 (6H, m)}, 8.45 (1H, d, J = 4.8
Hz) ppm. 2-Phenyl-4-(N,N-di{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl})Jaminomethyl-3- butylpyridine (144). To a solution of 14 (38 mg) in dichloroethane (5 mL) was added piperonal (30 mg). The resulting mixture was stirred for 3 h after which time sodium triacetoxyborohydride (150 mg) is added in one portion and the resulting mixture is stirred overnight. The reaction mixture was quenched with 10% ammonium hydroxide solution (5 ml). The organic layer is washed with water and extracted with 1N HCI solution. The acidic extract is made basic with 1N NaOH solution and extracted with chloroform. The organic extract is dried (Na>SQ4) and concentrated. The resulting oil is purified on preparative thin layer chromatography eluting with 10% CH30H/CHCIs to give the desired tertiary amine 144 as an oil (18 mg). LC-MS (M+1): 509.4; H-NMR (8, CDCl3): 0.71 (3H, t, J = 7.2 Hz), 1.10 (2H, m, J = 7.2 Hz), 2.60 (2H, t, J = 8.0 Hz), 3.48 (4H, s), 3.58 (2H, s), 5.94 (4H, s), 6.75 (1H, : d, J = 8.0 H2),6.80 (1H, dd, J = 0.8, 8.0 Hz), 6.91 (1H, d, J = 0.8 Hz), 7.36-7.43 (5H, m), 7.56 (1H, d, J = 5.2 Hz), 8.47 (1H, 4, J = 5.2 Hz) ppm.
Preparation of 2-Phenyl-4-(N,N-di{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}) aminomethyl-3-butylpyridine
COOH ——>» 140 141 0 0)
NZ
A OH NZ
1.thionyl chloride Nn NH —— 2. piperonylamine
K,CO; 142 143 0—\ 0 0 (0) (0)
NZ
—_— reduction 144 fo) o—/
Example 7. Preparation of an Arylpyrazole;
1,3-diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N-butylaminojmethvl-
S-propylpyrazole
N’-Phenyl-N-phenylhydrazone (150). Benzaldehyde (9.81 g, 9.25 mmol) is added at 0-5 °C to a solution of phenyl hydrazine (10 g, 9.25 mmol) in ethanol (100 ] ml). A cream colored solid forms and the reaction mixture is allowed to stand for 2h. The solid is collected by filtration, washed with ice-cold ethanol and dried under vacuum to provide the desired compound, compound 150 (14.92 g);LC-MS m/z 197.2, 1H NMR (6, CDCl3, 400 MHz) ppm.
Ethyl 1,3-diphenyl-5-propylpyrazole-4-carboxylate (152). A mixture of 150 (5 g, 25.5 mmol) and ethyl butyrylacetate (20.2 g, 128 mmol) and a catalytic amount of zinc chloride is heated at 125 °C under an air atmosphere for 3h. The reaction vessel is fitted with a short path distillation head and excess ethyl butyrylacetate iss distilled away under vacuum. The resulting material is purified by column chromatography on silica eluting with 10% ethyl acetate in hexanes to provide the desired ester 152 as a yellow oil (6.39 g) which crystallizes upon standing. Recrystallization from diisopropyl ether provides a white solid. 'H NMR (6, CDCl, 400 MHz} MS (M+1): 335.2 1,3-Diphenyl-4-hydroxymethyl-5-propylpyrazole (153). To a solution of ester 153 (670 mg, 2 mmol) in tetrahydrofuran (20 ml) is added 4 mL of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The reaction is stirred overnight and then quenched with 5 mL of 15% aqueous NaOH. The resulting mixture is extracted with ether, dried (Na;SO4) and concentrated to provide the desired hydroxymethylpyrazole as an oil (505 mg). LC-MS (M+1): 293.3; 'H NMR (6,
CDCL3) 7.86 (dd, J = 8.4 Hz, 2H), 7.34-7.52 (m, 8H), 4.65 (s, 2H), 2.72 (t, J = 8.0 Hz, 2H), 1.52 (m, 2Hj, 0.87 (t, J = 7.6 Hz, 3H). [(1,3-Diphenyl-5-propylpyrazol-4-yljmethyllbutylamine (154). To a solution of 18 (289 mg) in pentene stabilized chloroform (8 mL) is added thionyl chloride (1 mL) and the mixture heated to 60 °C for 2 h. The resulting mixture is cooled, washed with saturated sodium bicarbonate solution, dried (NaxSO.) and concentrated. The resulting crude chloride is taken up in dimethylformamide (3 mL)
and added dropwise to a solution of butylamine {1.0 g) in dimethylformamide (10 mL) containing 2 g of powdered potassium carbonate. After the addition is complete, the resulting mixture is stirred for an additional 3 h and partitioned between water (20 mL) and ether (10 mL). The cthereal layer is washed 2 times with water, dried (Na:SOs) and concentrated. The resulting material is purified by chromatography on silica eluting with 10% CH;OH/CHCIl; to give the desired secondary amine 1585 (190 mg). LC-MS (M+1): 348.3; H-NMR (5, CDCl3): 7.87 (dd,
J= 8.0, 1.6 Hz, 2H), 7.32-7.48 (m, 8H), 3.77 (s, 2H), 2.70 (m, 4H), 1.48 (m, 4H), 1.34 {m, 2H), 0.91 {t, J= 7.6 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H) ppm. 1,3-Diphenyl-4-(N-{2H-benzo[3,4-d]-1,3-dioxolan-5-ylmethyl}-N- butylamino)methyl-5-propylpyrazole (Compound 155). To a solution of 154 (35 mg) in dichloroethane (5 ml) is added piperonal (30 mg). The resulting mixture is stirred for 3 h after which time sodium triacetoxyborohydride (150 mg) is added in one portion and the resulting mixture is stirred overnight. The reaction mixture is quenched with 10% ammonium hydroxide solution (5 ml). The organic layer is washed with water and extracted with 1N HCI solution. The acidic extract is made basic with IN NaOH solution and extracted with chloroform. The organic extract is dried (Na;S04) and concentrated. The resulting oil is purified on preparative thin layer chromatography eluting with 10% CHsOH/CHCIs to give the desired tertiary amine (Compound 155) as an oil (24 mg). LC-MS (M+1): 482.5; H-NMR (6, CDCl): 7.87 (d, J= 7.2 Hz, 2H), 7.47 (d, J = 4.4 Hz, 4H), 7.33-7.43 (m, 4H), 6.77 (s, 1H), 6.70 (s, 2H), 5.92 (s, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 2.74 (t, J = 8.0 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H}, 1.42 (m, 4H), 1.21 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H) ppm.
Preparation of 1.3-Diphenyl-4-(N-{2H-benzo[3.4-d]-1,3-dioxolan-5-yimethyl} -N-butylamino)methyl-5-propylpyrazole
Ph
H 0 0 N= O—gt¢
N_ A ghee og 151 ) _ 192 : Ph v= O—H
N—/ 153
Ph
N= NH ~_- \/ of 154
Ph o \ Ne ~~
Nw /
CY 155
Example 8. Synthesis of N-(1-fluorobenzyl)-N-indan-2-v1-2-(6, 7-dimethoxy-1- phenyl-1,2 3 4-tetrahydroisoquinglin-1-vl) acetamide (162). A mixture of 6, 7- dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (160, 153 mg, 0.5 ’ mmol), N-(1-fluorobenzyl)-N-indan-2-yl-2-bromoacetamide (161, 180 mg, 0.5 mmol) and potassium carbonate (500 mg) in acetonitrile is heated at 80 °C overnight. After cooling, the mixture is filtered and concentrated. The resulting residue is purified by column chromatography eluting with 5% methanol in chloroform to provide the title product (162) as a thick oil (215 mg, 78%). 'H NMR (CDCls) 6.8-7.3 (m, 14H), 6.60(s, 1H), 6.05 (s, 1H),
MeO ( MeO. ~ @
C] 0 F | 0 F
MeO NH + NN, —_— a MeO ~ NALS
HCI O) ie 5 160 161 162
Example 9. Preparation of 4’Trifluoromethyl-biphenyl-2-carboxylic acid benzo{1,3]dioxol-5-ylmethyl-benzyl-amide (174). 1,1’-carbonyldiimidazole (175 mg) is added to a solution of 2-iodobenzoic acid (248 mg, 1 mmol)(170) in tetrahydrofuran (THF, 5 ml). The resulting mixture is stirred overnight at room temperature. A solution of N-3,4-methylenedioxybenzyl-N-benzylamine (241 mg, 1 equiv)(171) in THF (2 ml) is added and the resulting solution is stirred for 1 h, quenched with water and extracted with diethyl ether. The organic extracts are dried (Na2SOs) and concentrated. The residual material is taken up in dimethoxyethane (10 ml) and a catalytic amount (20 mg of ’ tetrakis(triphenylphosphine)palladium(0) is added. The resulting mixture is stirred under an argon atmosphere for 10 min and solid 4-trifluoromethyllphenylboronic acid (150 mg) is added in one portion. A second phase of 1N aqueous Na;SOs is added and the mixture is warmed to 80 °C for 6 h under a argon atmosphere. The solution is cooled, diluted with water and ethyl acetate and filtered through a pad of celite. The organic phase is dried over sodium sulfate and concentrated.
Purification on silica eluting with 20% ethyl acetate in hexane provided the desired biphenylamide product (174)(410 mg). The proton NMR displays a doubled pattern commonly observed for amides which possess some rotational restriction about the } amide nitrogen at room temperature. The ratio of the rotomers is approximately equal. 'H NMR (CDCI3) 3.50 and 3.62 (two doublets, J = X Hz, 1H), 3.72 and 3.83 {two doublets, J = X Hz, 1H), 4.10 and 4.18 (two doublets, J = X Hz, 1H), 5.09 and 5.16 (two doublets, J = x Hz, 1H}, 5.95 (d, J = X Hz, 2H, OCH:0), 6.30 (m, 1.5 H), 6.46 (d, J = 1 Hz, 0.5 Hz), 6.60 and 6.66 {two doublets, J = X Hz, 1H), 6.80 (bd, J =
X Hz, 1H), 6.86 (m, 1H), 7.16-7.62 (m, 11 H). 1. CDI, THF es _—_— ° l oO
NH 172
Ls B(OH),
[0] 1. b_/
CF; 2. Pd(PPh;), @® J 3. Na;COs;, dimethoxyethane
N o [o] o—/ 174
CF; 4'-Trifluoromethyl-biphenyl-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-benzyl-amide
Example 10. Preparation of N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-vl- benzamide . 2-Pyrazol-1-yl-benzonitrile, Compound 177. A solution of 20 mmol of 2- fluorobezonitrile and 40 mmol of pyrrazole is mixed together in dimethylformaide with 1 equivalent of potassium hydroxide and a catalytic amount of 18-crown-6.
The mixture is stirred at room temperature overnight, quenched with water and ethyl acetate and extracted with ethyl acetate. The organic extract is washed repeatedly with 1 N NaOH solution. The organic layer is then diluted with ether and washed with 1N HCI solution, dried and concentrated. 1H NMR (CDCl3) 6.55 (t, J = 2 Hz, 1H), 7.42 (M, 1H}, 7.65-7.82 m, 4H), 8.15 (d, J = 1 Hz, 1H). 2-Pyrazol-1-yl-benzoic acid, Compound 178. A solution of compound 177 in conc HCl is refluxed overnight, cooled and concentrated. The product is precipitated by addition of 1 N NaOH until pH of 5-6, filtered and dried. 1H (CDCl3) 6.52 (t, J = 3
Hz, 1H), 7.40 (d, J = 8 Hz, 1H), 7.50 (t, J = 8 Hz, 1H) 7.62 (t, J = 8 hz, 1H), 7.81 (m, 2H), 8.12 (d, J = 8 Hz, 1H).
N-Benzo[1,3]dioxol-5-ylmethyl-N-benzyl-2-pyrazol-1-yl-benzamide, Compound 179. 1.1 equiv of carbonyl diimidazole is added to a solution of benzoic acid 178 (200 mg) in tetrahydrofuran (5 mL); the reaction is stirred at room temperaturte for 3 h. After this time N-piperonyl-N-benzylamine (0.25 g) is added in one portion.
After 30 min, the reaction is filtered, diluted with ether and washed with water. The organic layer is dried (Na2SO4) and purified over column chromatography to provide the desired product (390 mg). The proton NMR displays a typically doubled pattern.
IH (CDCl3) 3.83 and 4.32 (two doublets, J = 16 Hz, 1H), 3.91 (two doublets, J = 8
Hz, 1H), 4.18 two doublets (J = 6 Hz, 1H), 5.0 and 5.1 (two doublets, J = 14 Hz, 1H), 5.93 and 5.98 (s and doublet, J = 2 Hz, 2H, OCH0), 6.35-6.40 (m, 2H), 6.51 (d, J = 4 Hz, 0.5 H), 6.4 (m, 1.5 H), 7.0-7.88 m, 15H). LC-MS 412.3
J
F NY
CN CN
_—
H
N
TT) 177 175 176
HCI
BR 'S)
No NN
N 0
COOH
-
N
0 > - 179 0
Example 11. Preparation of _N-benzoyl-N-(4-methoxybenzyl)-N-(1-propyl-2- methyleno-7-azabenzimidazole 2-aminopropyl-3-nitropyridine
NH, or OO
JH
Ne CH3CN NZ ON 180 181 N 2-chloro-3-nitroaminopyridine (180) (5.5 g, 35 mmol} is dissolved in 150 mL acetonitrile at room temperature. Propylamine (21 g, 350 mmol} is added dropwise ) and the reaction mixture is stirred for 5 hours at room temperature. The solvent and excess propylamine are removed in vacuo. The residue is dissolved in 150 mL ethyl acetate and washed once with 100 mL saturated NaHCO3 solution and once with 100 mL brine. The organic layer is dried over MgSO, filtered, and the solvent removed in vacuo to afford 6.3 g of 2-aminopropyl-3-nitropyridine (181). 2-aminopropyl-3-aminopyridine.
H2 xo NO2 Pd/C Or
CL 40 psi Ni C H 181 ) 182 2-aminopropyl-3-nitropyridine (171)(6.3 g, 35 mmol) is dissolved in 100 mL 1/1 ethyl acetate / ethanol in a Parr shaker bottle. Nitrogen is bubbled through the solution for 2 minutes followed by the addition of 10% Pd/C (500 mg). The suspension is hydrogenated on a Parr apparatus under 40 psi of Hz until hydrogen uptake ceased. The suspension is filtered through Celite and the solvent evaporated in vacuo to afford 5.3 g of the 2-aminopropyl-3-aminopyridine (182). 1-propyl-2-chloromethyl-7-azabenzimidazole
NH, NH cl (Lo + wo —
N™ N° N~ N 182 N 183 ( 2-aminopropyl-3-aminopyridine (172) (5.3 g, 35 mmol} is dissolved in 100 mL CHCl3 at room temperature. Ethyl chloromethylimidate hydrochloride (14 g, 89 mmol) is added followed by KoCOs3 (25 g, 180 mmol). The suspension was stirred vigorously at room temperature for 3 hours. The reaction mixture is filtered through Celite and the solvent removed in vacuo. The residue is passed through a short plug of silica gel eluting with ethyl acetate to afford 3.7 g of 1-propyl-2-chloromethyl-7- azabenzimidazole (183). 1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole.
JOR
HN
Pu adi yy
N \ CH3CN NTN ( 183 o OMe : 4-Methoxybenzylamine (3.8 g, 27 mmol) is dissolved in 20 mL dry acetonitrile. 1- propyl-2-chloromethyl-7-azabenzimidazole (173)(940 mg, 4.5 mmol) dissolved in 4.5 mL acetonitrile is added dropwise. The mixture is stirred 10 hours at room temperature. The solvent is removed in vacuo and the residue dissolved in 20 mL ethyl acetate. This solution is washed once with 20 mL 1 N NaOH, once with 20 mL water, once with 20 mL 5% HOAc in water, then once with 5 N NaOIi. The organic phase was dried over MgSO, filtered, then concentrated in vacuo. The product mixture is purified by flash chromatography eluting with ethyl acetate followed by 95/5/1 ethyl acetate / methanol / triethylamine to afford 850 mg of the 1-propyl-2- (4-methoxybenzylaminojmethyl-7-azabenzimidazole (184).
N-benzoyl-N-(4-methoxybenzyl}-N-(1-propyl-2-methyleno-7-azabenzimidazole i _
NHN Os oN 7 N \ / OMe ¢ OMe 184 185 1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (174)(19 mg, 0.06 mmol) is dissolved in 0.6 mL toluene. Saturated sodium bicarbonate solution in water (0.3 ml) is added followed by benzoyl chloride (11 mg, 0.08 mmol). The reaction mixture is stirred at room temperature for 10 hours. It is then diluted with mL ethyl acetate and transferred to a separatory funnel. The aqueous layer is : removed and the organic phase washed once with 1N NaOH, once with 5 mL water, then and once with mL brine. The organic phase is dried over MgSO, filtered and the solvent removed in vacuo. The product is purified by preparatory tlc eluting with
1/1 ethyl acetate / hexanes to afford 20 mg of the desired compound (185). NMR 400 MHz (CDCls) 8.39 ppm (br d, 1 Hj, 8.15 ppm (br d, 1 H), 7.52 ppm (m, 1.5 H), 7.40 ppm (s, 1.5 H), 7.22 (m, 1 H), 7.18 ppm (br d, 1 H), 6.83 ppm, (d, J = 4 Hz, 2
H), 4.93 ppm (br s, 2 H), 4.71 ppm ( br s, 1 H), 4.39 ppm (br s, 1 H), 3.79 ppm (s, 3 . H), 1.89 ppm (br m, 2 Hj), 0.98 pp, (br t, 3 H).
Example 12
Assay for C5a Receptor Mediated Chemotaxis
This assay is a standard assay of C5a receptor mediated chemotaxis.
Human promonocytic U937 cells or purified human or non-human neutrophilis are treated with dibutyryl cAMP for 48 hours prior to performing the assay. Human neutrophils or those from another mammalian species are used directly after isolation. The cells are pelleted and resuspended in culture media containing 0.1% fetal bovine serum (FBS) and 10 ug/ml calcein AM (a fluorescent dye). This suspension is then incubated at 37 °C for 30 minutes such that the cells take up the fluorescent dye. The suspension is then centrifuged briefly to pellet the cells, which are then resuspended in culture media containing 0.1% FBS at a concentration of approximately 3 x 106 cells/mL. Aliquots of this cell suspension are transferred to clean test tubes, which contain vehicle (1% DMSO) or varying concentrations of a compound of interest, and incubated at room temperature for at least 30 minutes. The chemotaxis assay is performed in ChemoTx™ 101-8, 96 well plates (Neuro Probe, Inc. Gaitherburg, MD). The bottom wells of the plate are filled with medium containing 0-10 nM of C5a, preferably derived from the same species of mammal as are the neutrophils or other cells (e.g., human CS5a for the human
U937 cells). The top wells of the plate are filled with cell suspensions (compound or vehicle-treated). The plate is then placed in a tissue culture incubator for 60 minutes. The top surface of the plate is washed with PBS to remove excess cell suspension. The number of cells that have migrated into the bottom well is then determined using a fluorescence reader. Chemotaxis index (the ratio of migrated cells to total number of cells loaded) is then calculated for each compound concentration to determine an ICs value.
As a control to ensure that cells retain chemotactic ability in the presence of the compound of interest, the bottom wells of the plate may be filled with varying concentrations chemo-attractants that do not mediate chemotaxis via the CSa receptor, e.g. zymosan-activated serum (ZAS), N-formylmethionyl-leucyl- . phenylalanine (FMLP) or leukotriene B4 (LTB4}, rather than Cb5a, under which conditions the compounds of the invention preferably do not inhibit chemotaxis.
Preferred compounds of the invention exhibit ICsq values of less than 1 pM in the above assay for C5a mediated chemotaxis.
Example 13
Determination of dopamine D4 receptor binding activity
The following assay is a standard assay for determining the binding affinity of compounds to dopamine Ds receptors.
Pellets of Chinese hamster ovary (CHO) cells containing recombinantly expressing primate dopamine Dg receptors are used for the assays. The dopamine
D. receptor expression vector may be the pCD-PS vector described by Van Tol et al. (Nature (1991) 358: 149-152). The sample is homogenized in 100 volumes (w/vol} of 0.05 M Tris HCI buffer containing 120 mM NaCl, 5S mM MgCl, and 1 mM EDTA at 4°C and pH 7.4. The sample is then centrifuged at 30,000 x g and resuspended and rehomogenized. The sample is then centrifuged as described and the final tissue sample is frozen until use. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris
HCI buffer containing 120 mM NaCl.
Incubations for dopaminergic binding are carried out at 25°C and contain 0.4 ml of tissue sample, 0.1 nM 3H-YM 09151-2 (Nemonapride, cis-5-Chloro-2- methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide) and the compound of interest in a total incubation of 1.0 ml. Nonspecific binding is defined as that binding found in the presence of 1 uM spiperone; without further additions, nonspecific binding is less than 20% of total binding.
Example 14. Preparation of radiolabeled probe compounds of the invention
The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 3°S), or iodine (preferably 125]). Such radiolabeled probes are conveniently synthesized by a radioisotope . supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope
Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard
Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American
Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek Biochemicals Inc., Brea,
CA.
Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas.
Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium- halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
Example 15: Baculoviral Preparations (For CSa Expression)
The human C5a (hC5a) receptor baculoviral expression vector was co- transfected along with BACULOGOLD DNA (BD PharMingen, San Diego, CA) into Sf9 cells. The S/O cell culture supernatant was harvested three days post-transfection.
The recombinant virus-containing supernatant was serially diluted in Hink’ s TNM-
FH insect medium (JRH Biosciences, Kansas City) supplemented Grace’s salts and with 4.1mM L-GIn, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat- inactivated fetal bovine serum (hereinafter “insect medium”) and plaque assayed for recombinant plaques. After four days, recombinant plaques were selected and harvested into 1 ml of insect medium for amplification. Each 1 ml volume of recombinant baculovirus (at passage 0) was used to infect a separate T25 flask containing 2 x 100 S/O cells in 5 mls of insect medium. After five days of incubation at 279C, supernatant medium was harvested from each of the T25 infections for use as passage 1 inoculum.
Two of seven recombinant baculoviral clones were then chosen for a second round of ! amplification, using 1 ml of passage 1 stock to infect 1 x 108 cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eight hours post infection, passage 2 medium from each 100ml prep was harvested and plaque assayed for titer. The cell pellets from the second round of amplification were assayed by affinity binding as described below to verify recombinant receptor expression. A third round of amplification was then initiated using a multiplicity of infection of 0.1 to infect a liter of Sf9 cells. Forty hours post-infection the supernatant medium was harvested to vield passage 3 baculoviral stock.
The remaining cell pellet is assayed for affinity binding using the “Binding Assays” described by DeMartino et al., 1994, J. Biol. Chem. 269 #20, pp.14446-14450 at page 14447, adapted as follows. Radioligand is 0.005-0.500nM [1251jc5a (human recombinant), New England Nuclear Corp., Boston, MA; the hC5a receptor- expressing baculoviral cells are used instead of 293 cells; the assay buffer contains 50 mM Hepes pH. 7.6, 1 mM CaCl,, 5 mM MgCly, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and 100 KIU/ml aprotinin; filtration is carried out using GF/C
WHATMAN filters (presoaked in 1.0% polyethyeneimine for 2 hours prior to use); and the filters are washed twice with 5 mLs cold binding buffer without BSA, bacitracin, or aprotinin.
Titer of the passage 3 baculoviral stock is determined by plaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression.
A multiplicity of infection of 0.1 and a 72-hour incubation were the best infection ‘ parameters found for hC5a receptor expression in up to 1l-liter Sf9 cell infection cultures.
Example 16: Baculoviral Infections
Log-phase Sf9 cells (INVITROGEN Corp., Carlsbad CA), are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27°C. Infections are carried out either only with virus directing the expression of ’ the hC5a receptor or with this virus in combination with three G-protein subunit- expression virus stocks: 1) rat Gajg G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2) bovine bl G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3) human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), which may be obtained from BIOSIGNAL Inc., Montreal.
The infections are conveniently carried out at a multiplicity of infection of 0.1:1.0:0.5:0.5. At 72 hours post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining S/O cells are harvested via centrifugation (3000 rpm/ 10 minutes; 4°C).
Example 17: Purified Recombinant Insect Cell Membranes
Sf9 cell pellets are resuspended in homogenization buffer (10 mM
HEPES, 250 mM sucrose, 0.5 yg/ml leupeptin, 2 yg/ml Aprotinin, 200 yM PMSF, and 2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds). The homogenate is centrifuged (536 x g/ 10 minutes/ 40C) to pellet the nuclei. The supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000 X g/ 30 minutes, 4°C) and the resulting pellet resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice. The final pellet is resuspended in ice cold Dulbecco’s PBS containing S mM EDTA and stored in frozen aliquots at -80°C until needed. The protein concentration of the resulting membrane preparation (hereinafter “P2 membranes”) is conveniently measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, CA). By this measure, a 1-liter culture of cells typically yields 100-150 mg of total membrane protein.
Example 18: Agonist-Induced GTP Binding
Agonist-stimulated GTP-gamma’S binding (“GTP binding”) activity can be used to identify agonist and antagonist compounds and to differentiate neutral antagonist compounds from those that possess inverse agonist activity. This activity . can also be used to detect partial agonism mediated by antagonist compounds. A compound being analyzed in this assay is referred to herein as a “test compound.”
Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of the hC5a receptor and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of SfO cells as described in Example 16.
Agonist-stimulated GTP binding on purified membranes (prepared as described in Example 17) is assessed using hCSa (Sigma Chemical Co., St. Louis,
Missouri, USA) as agonist in order to ascertain that the receptor/G-protein-alpha- beta-gamma combination(s) yield a functional response as measured by GTP binding.
P2 membranes are resuspended by Dounce homogenization (tight pestle) in
GTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2 mM
EGTA, 0.1% BSA, 0.1 mM bacitracin, 100KIU/mL aprotinin, 5 uM GDP) and added to reaction tubes at a concentration of 30 ug protein/reaction tube. After adding increasing doses of the agonist hCSa at concentrations ranging from 10-12 M to 10°
M, reactions are initiated by the addition of 100 pM GTP gamma>’S. In competition experiments, non-radiolabeled test compounds (e.g., compounds of the invention) are added to separate assays at concentrations ranging from 10-10 M to 10->M along with 10 nM hC5a to yield a final volume of 0.25 mL.
Neutral antagonists are those test compounds that reduce the CSa- stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added C5a or other agonist and in the further absence of any test compound).
In contrast, in the absence of added C5a certain preferred compounds of the invention will reduce the GTP binding activity of the receptor-containing membranes below baseline, and are thus characterized as inverse agonists. If a test compound that displays antagonist activity does not reduce the GTP binding activity below i baseline in the absence of the C5a agonist, it is characterized as a neutral antagonist.
An antagonist test compound elevates GTP binding activity above baseline in the absence of added hC5a in this GTP binding assay is characterized as having partial agonist activity. Preferred antagonist compounds of the invention do not elevate GTP binding activity under such conditions more than 10% above baseline, preferably not more than 5% above baseline, and most preferably not more than 2% above baseline.
Following a 60-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1%
BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120mM
NaCl). The amount of receptor-bound (and thereby membrane-bound)
GTP gamma’’S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 mM GTP gamma 35S and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments may be conveniently analyzed using
SIGMAPLOT software (SPSS Inc., Chicago, Illinois, USA).
EXAMPLE 19 Calcium Mobilization Assays
A. Response to C5a
U937 cells are grown in differentiation media (1 mM dibutyrl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37 C then reseeded onto 96-well plates suitable for use in a FLIPR™ Plate Reader (Molecular Devices
Corp., Sunnyvale CA). Cells are grown an additional 24 hours (to 70-90%
confluence) before the assay. The cells are then washed once with Krebs Ringer solution. Fluo-3 calcium sensitive dye (Molecular Probes, Inc. Eugene, OR} is added to 10 ug/mL and incubated with the cells at room temperature for 1 to 2 hours. The 96 well plates are then washed to remove cxcess dye. Fluorescence responses, . measured by excitation at 480 nM and emission at 530 nM, are monitored upon the addition of human C5a to the cells to a final concentration of 0.01-30.0 nM, using the FLIPR™ device (Molecular Devices). Differentiated U937 cells typically exhibit signals of 5,000-50,000 Arbitrary Fluorescent Light Units in response to agonist stimulation.
B. Assavs for Determination of ATP Responses
Differentiated U937 cells (prepared and tested as described above under “A.
Response to C5a”) are stimulated by the addition of ATP (rather than C5a) to a final concentration of 0.01 to 30 uM. This stimulation typically triggers a signal of 1,000 to 12,000 arbitrary fluorescence light units. Certain preferred compounds of the invention produce less than a 10%, preferably less than a 5%, and most preferably less than a 2% alteration of this calcium mobilization signal when this control assay is carried out in the presence or absence of the compounds.
C. Assays for the Identification of Receptor Modulatory Agents: Antagonists and Agonists
Those of skill in the art will recognize that the calcium mobilization assay described above may be readily adapted for identifying test compounds as having agonist or antagonist activity, at the human Cb5a receptor.
For example, in order to identify antagonist compounds, differentiated U937 cells are washed and incubated with Fluo-3 dye as described above. One hour prior : to measuring the fluorescence signal, a subset of the cells is incubated witha 1 M concentration of at least one compound to be tested. The fluorescence response upon the subsequent addition of 0.3 nM (final concentration) human recombinant
C5a is monitored using the FLIPR™ plate reader. Antagonist compounds elicit at least a 2-fold decrease in the fluorescence response relative to that measured in the presence of human C5a alone. Preferred antagonist compounds elicit at least a 5- fold, preferably at least a 10-fold, and more preferably at least a 20-fold decrease in ; the fluorescence response relative to that measured in the presence of human C5a alone. Agonist compounds elicit an increase in fluorescence without the addition of
C5a, which increase will be at least partially blocked by a known C35a receptor antagonist.
Example 20. Assays to evaluate agonist activity of small molecule CS5a receptor antagonists
Preferred compounds of the invention are C5a receptor antagonists that do not possess significant (e.g., greater than 5%) agonist activity in any of the CSa mediated functional assays discussed herein. Specifically, this undesired agonist activity can be evaluated, for example, in the GTP binding assay of Example 18, by measuring small molecule mediated GTP binding in the absence of the natural agonist, C5a. Similarly, in a calcium mobilization assay e.g., that of Example 19, a small molecule compound can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist, C5a. The preferred extent of C5a agonist activity exhibited by compounds of the invention is less than 10%, more preferably less than 5% and most preferably less than 2% of the response elicited by the natural agonist, C5a.
EXAMPLE 21. Expression of a CSa receptor
A human C5a receptor cDNA was obtained by PCR using 1) a forward primer adding a Kozak ribosome binding site and 2) a reverse primer that added no : additional sequence, and 3) an aliquot of a Stratagene Human Fetal Brain cDNA library as template. The sequence of the resulting PCR product is set forth as SEQ
ID NO:1. The PCR product was subcloned into the cloning vector pCR-Script AMP (STRATAGENE, La Jolla,CA) at the SrfI site. It was then excised using the restriction enzymes EcoRI and Notl and subcloned in the appropriate orientation for expression into the baculoviral expression vector pBacPAK 9 (CLONTECH, Palo Alto,
CA) that had been digested with EcoRI and Notl.
As set forth in the tables appended hereto, R groups do not necessarily correlate with those R groups shown in the text of the specification or in the claims. , The following table 1 (204-313) is a list of preferred 1,2,5 substituted imidazoles of the present invention;
The following table 2 (314-419) is a list of preferred 1,2,4,5 substituted imidazoles of the present invention;
The following table 3 (420-421) is a list of preferred pyrazoles of the present invention;
The following table 4 (422-423) is another list of preferred 1,2,4,5 substituted imidazoles of the present invention;
The following table 5 (424-456) is a list of preferred amides of the present invention; and
The following table 6 (457-458) is a list of preferred amides of the present invention.
Additional Aspects of Preferred Compounds of the Invention
The most preferred compounds of the invention are suitable for pharmaceutical use in treating human patients. Accordingly, such preferred compounds do not exhibit single or multiple dose acute or long-term toxicity, mutagenicity (e.g., as determined in a bacterial reverse mutation assay such as an
Ames test), teratogenicity, tumorogenicity, or the like, and rarely trigger adverse effects (side effects) when administered at therapeutically effective dosages. For example, preferred compounds of the invention will not prolong heart QT intervals (e.g., as determined by electrocardiography, e.g., in guinea pigs, minipigs or dogs).
Therapeutically effective doses or concentrations of such compounds do not cause liver enlargement when fed to or injected into laboratory animals (e.g., mice or rats) and do not promote the release of liver enzymes (e.g., ALT, LDH, or AST) from hepatocytes in vitro or in vivo.
Because side effects are often due to undesirable receptor activation or antagonism, preferred compounds of the invention exert their receptor-modulatory effects with high specificity. This means that they only bind to, activate, or inhibit the activity of certain receptors other than CSa receptors with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 10 micromolar and most preferably greater than 100 micromolar. Such receptors preferably arc selected from neurotransmitter receptors such as alpha- or beta-adrenergic receptors, muscarinic receptors (particularly ml, m2, or m3 receptors), dopamine receptors, and metabotropic glutamate receptors; and also include histamine receptors and cytokine receptors, e.g., interleukin receptors, particularly IL-8 receptors. Such receptors may also include GABAA receptors, bioactive peptide receptors (other than CS5a receptors, including NPY or VIP receptors), neurokinin receptors, bradykinin receptors, hormone receptors (e.g., CRF receptors, thyrotropin releasing hormone receptors, or melanocyte-concentrating hormone receptors).
Additionally, preferred compounds of the invention do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity, or
CYP3A4 activity. Preferred compounds of the invention also do not exhibit cytotoxicity in vitro or in vivo, are not clastogenic, e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay, or the like and do not induce sister chromatid exchange, e.g., in Chinese hamster ovary cells.
Highly preferred C5a receptor antagonist compounds of the invention also inhibit the occurrence of C5a-induced oxidative burst (OB) in inflammatory cells, e.g., neutrophil, as can be conveniently determined using an in vitro neutrophil OB . assay.
Initial characterization of preferred compounds of the invention can be conveniently carried out using a C5a receptor binding assay or functional assay, such as set forth in the Examples, and may be expedited by applying such assays in a high throughput screening setting.
The following Tables depict further preferred compounds of the invention. In those Tables, the vriable X indicates the pouint of attachment of the specified moiety to the structure shown at the top of the Table. ’ :
= z g HY R31 z M 15 z me Jl) 9
Rom heer bh
CMpl fl faa dns [RIN Timo jemd Moss fils lon Obs sulk sl = == i N a a) &
H,C Xa 48,2627 w ww | tes | MER | aeos0s 3 ) X, X X, 7 [3 —- of ~ phe 2 =
PY X . | . 2 5 ig Fi
H.C x — I
ET I hat FE EN ION BELA RascU EXE] 5 xX. . fy
QL, es FO fg ee
Pe = — : z 202 X, H,C (J IST [4622784 \gyvaai 73 x X, X, = Xz
SE ~ os
X
2 HC ‘
ES 203 _ 2,09 | 459.2076 | 460.3052 a = cr. Com
2 ~X X, X; & = = 7 = X c H.C * g = VLE SUR . Cees le |. 2.0} 459.2675 | 460.2903
X X 0, al 2 2 \ x Lr p \ y / = ; 0
CH, X,
BUA ES SVSORUR UR SA I ome if 204 [467.2673 | 460.2008 —_ . wl = 7 \ 3 3 — cit, © <u
S26 |] A Cle el .._.|_.205 | 481.2729 | 402.3052 a =
X X %; =x 1 2 E > “3 E
Y ®
CH, X, 1 J @
L202 ne eb To}. 2 | 467.2573 | 466.2805 7
X X 4 @
DEES JA
= S ' YY
UU FOR NI ANURRR I CY | aes | 4832416 | 484.2005 = Cr pl i EN ==
EN \_/ = Ps Nai, < X c
X z 209 2 N Ll s 1.9 | 375.2075 | 376.2007 } . cae i = Cr X, je DY x = & x
I? Ma : CH, Xu o0 2 | 453.2416 454.2688
F 20 JD CT me] A ABR20IG A [93 moe ~ sak ay
EN pe [ \ 20) he & Hs 19 | 430247 [435.2709 —_—— a [ETN - - —- “ x, — a .
Cr |C jew bi g
No. = g ) OY 2
X, I 5
CH, Z 1.92 [492.2625 493.2012 x
AT J I BN - ef VOR ARREES | 490.20) = _— h - ’ pl 9 > X, CH, Wa } z w \_/ = z = o w 1,0 . 1S
X X [= ? hb 1.94 _ | 169.2729 | 470.2986 = 213 EE ER Ce 194 14G9.2729 1 4 [ ob X Xs 2 lg So : © > AL
X
21 ol ’ O° {17 | 4072814 | agn.2636
JURE Siok RU I PR . “ [TUT x Ci im en
Pat Xa s - | 2 z P ~
ES X, g Cl, 0.0 2.06 473.3042 | 474.3315 z 215 ER z
= X, ps — X; { : Cr J, 5 % ! N = CHi ’ £ EET I OC |. 203 [52729 | Me302
A I- X, Vi . Xe
Sp % 7 J = = . \_/ \
H,C X, =
ITA DE BS I coo | | a7n.250 | a7n2063 = X, —
J of ; ' = 7 NL ou
Q 35
Cr . 0, : 3 X
FIT I A IL OT | zon | assaare| asants i = r } X, a X; 8 I ep — w
Cs os | :
Z = E
I,C X I
A120 I HA A lL LOT | eer lane aza2cs a . — 2
X, CH, = en 7]
N \_/ cil,
X, X/ 20h te ee {18 | a302704 | 439.3110 = X, |cH, = oil, = x, = of 3 4 ps ~ z X, x; 22] ee 1.78 430.2784 1 439,313 z X, CH, == Om \ 7 oi, ; = X, x} 4 ~~ 2 ER EUR SA ot |.188_ | 452.204 {4533306 oC $ )
Pp
SR: Sale =
CH X can | UT | 208 | 459.200 4603148 ‘ —
SARI 0 :
Ww - = & > (Fs LL | 3 ci Xs 5% hg 22 J EO) INSTR I Sof 199. [459.1901] 450.200 x
X X ; x, & ~~ 1 2 [o A 5 : | N . >
X j—
CH 1 0.0 =
ZI I [185 [419.2573 | 420.2867 A
X, Xs Hs Xy a —
SHS A
Xa xy
CH a. _0
JS IN SU ES C1179 | 405.2416 | 406.2684 z = 2 [8] pd = 2 Cr A c cil X 0. 0 = 227 3 I ~ 2.08 | 521.1637 | 522.2009
= TTT TT en, Ik % Xi ( ) dh, zs “yO “J z { IY } I
E I A he) “ooo 0 Laer | stazees| sia2est xX;
X, X, 74 \ 5 — / = 7\_ 4
H co? X =
EJ DO RS I co |202 _|4ci2467 | 402.2794
Cr | ’ 8 = = \ = 7 \ ne X oa ot 2% A ! | R|f01.240) 462.2082 2 0 | :
X, cH, ‘ = I
N \_/ Sy S = - =
E
X @ 23] Xe CN ..|..205_ |A40652239] 466.267 x
RE PN eT = co. o 2
ES ’ 3 x or N 0
Lo
X X
232 EE RS CT 2d | 477.1739 478.2021 2 = x 2 x X, Xa {] 2 <= = z X, 11.C N= i 233 g oo 1.00 [462.2784 | 463.3135
= X, X, oo | | PES Ci LAN 8 Cr 204 = CH oO. = VI I I EE a I SR [-9 pl 8 JO
Ws = f Zz i .
X, 2
CH
4s ~ C1207 |s351793| 536.2415
X, X, fs Xe g
Cr [on g 2 3 ~ = cH Xs € 26 | } 9 | 210 _{4esz000 | age3085 . Bb
X, X, AO |X , = Y
A J n x, E
CH E
RETA I Mh 8 [ER ISON I IN A 2
H.C. ¥ 73 X; 2 cy )
DEN
= H.C x 3
J! EE Reh I Yl a |asaesez|4pagoer - X, 7) Xs } 2 « - =
OL
) = He X,
P3 239 : ee 1.87 _ {482.3046 | 483.3743
HyCu X, | Tg oy x x & 0 : \ ) 9 sata {58.2607 = | HC © L Xs 1.08 | Co c INEZ I NA I FR ———— = H.C X, | y y a
X, It = \_# I.g5 [18 veye[rganet
N-GH,
H,C 4 ! "ne Ln ae } :
Z| TO VERSUS Roo SUN UR SSSR UP rm _ or X, 5 @ = w "Po Has [yeIsy = ! \_/ 9 2
H,C X, O 2.00 ERE aod In] 202 re | me Fu 1 2 4 i. > non IT 0 Re, w . S
Hi-cH, E
H,C 4 Me 1.67 | 402,3046 | 403.3743
J FOUN SUSU [DS Bt cai 2 2
X, L X, X; bi 7.) iol 0S : : No¥
HC 0 Xs 190 | 510.222 | 616.2016 2:2: J OU FS DOU J — RENEE Ea 2 H, X, 5 3 SNR : c i _ 9 # HC Xa 0 2.01 | 467.2673 { 468.3038
= H, x, X; o— x 74 \ 0 a SPS = z 7 HG” 4 3 X = LG C 5 = 7 RE RE CY Ve 12 |st12471 512.300 a.
ADE i a & — = g It {3 247 he * ob 9 | 199 {4712922 a7n2030
TE X, X, X; 0 g 74 jo - 3d 4 \_/ Bi 3
HC 0 \ = 4 1.98 515.222 | 516.2795 on
ZI PU FE I . eee | oven | stszez sisares| ot
CHa X, J i Xz a
Oo X, - = . 5 \ i E
H.C X, 0 7 2A . C ee | 2.00 {403.2522 | 484.3008 2 i x, X, Yi i Xz = — = \ / 9
IE Lo “oo Lo 20s |soazen|sonaner g F X, Xa 2 \ X; 3 Ie _ ~~ — 3 ( 7 - 261 HC ‘ 208 | 477.258 | 478.3242 :
= cL TTT = NEN: z i XX x a 4 p ht Wa SE
EF Va oon 7 £ X, x = eke . . oy. |._.185_ | 496.2038} 497.3316
X, CH, , <5
N \ "a a an, 0) x3
Ad . a Ll. o_o | 393 496.2830) 497.3374 —
X, Ch, == Xe\ -O o 8 — w
Ly \{ 7 an, E x
Xs Xi ) - In
JT DO PER . . a] 198] 439.2624 1 440.3063 <i aX CH, = ol @ \_/ Xo = pw
P . = \_ 4 hi E
[2]
X, Xs 0 m
LS I I A | 208 | 487.2027 | 408.268 2
X, GH, X, cl
CY N an, oe
X
2 Le | Ls | 2a famines | aazme : aX GH, == Xs d \_/ —
Cc = — = 0 { % x H,C 27 SR 2 | 439.2624 | 440.0058
. X, X, X; 5 : > . B o~
IN oN = X 7 cH f 5 = BI ER FE oS | ras | sonases | sesaaie ¥ : Cr CH, == y Cl \ / 5 =
PZ AN _
N -\ OH
X, Xi
EE [NE BN Ce | 107 1 459.2077 | 460.287
X, CH, — cl a \_¢ Xo )= u pn \ ) 4
X x =
I I RR TE S| eos {477.1738 | areasg - ou ~~ ~ I
Cr CH, « Cl . @ ab! “OE =
X, Xx, \ 200 el . ee em | ee eeeaie|...2.06 } 461.2034 ) 462.2581 o . — X me [7] oN Xx, CM, 5 3
N \_/ { 2
X X
202 : [SUS EN DU RE ? DE PE TR EY ENN : SHS q oa < # X, X4 y 263 ee 1.76 | 400.3253 | 481.4043
2 GH, X, N= = g P N27 |\ = X, x! z SLC SN I EE ET eee | 075 [410.247 § 411.2961 - ~ -
X Chl == Cy, 0-Ci), im ' 3 X, = ait, z \_/ ()-d
X, x:
J ES ROT ome imine | 200 {603.2339 | 504.2063 _
X GH == F, 8 [oy 3 Xo = KF N \_¢ OI Eg $i S { O 5 &
X X ~- we |__|. Yo | 207 [4932001 | 4942970 £ i
X, CH, = X, : %
Cr N \_¢ or 5
N p=] : E @ x, xq [1]
LS I ES I ele em eee 1.88 | 425.2467 | 426.2948 p=] — [7]
UX, Ci, w= Xa DS ci 3 \_/
X, x; - S28 | SU eee | 205 443.2128 | 444.2672 2 UX, CH, F : Cl “= or * c \_/ z Xx X 260 OB oo a 2.04 | 461.2034 | 462.255 z X CH EE pm x, = x SM 3
Cr § | \_/ Ya z . _z z L cf = £ ao | a Ce 2a | a77.0738 | 4782420 cl X
X, Xs o 5
Y
271 oy 0% | 20s |san697| 522.208 R
TTT aX, x x, 2 1 2 y = 2 » 0 § 2
CH 00 x Ho" 272 3 ~ s 202 | 479.2573 | 480.2964 ou 2 20 DE ANU SRR BU A ob Te | 202 |479.2573 [480.2964 i
X x H LI “5 2 CH, > wi
Cr CH z E a J . 2 ch Xs 0.0 = 273 ? XT ]..208 [433.2729 434.3264 @ oH Xs W,C._CH, %g 3 7 > : X 274 Cs Cp |e | aszree| adnan = X, Ch, EN = : J N Wat ~l oS g 275 Xs ~ Xa 1.74 | 424.2627 | 425.208
IE
~~ x, |e, = X, 0 g Cy \_/ —( )N 2 = X X c ae fo lr I I | 198 {454.2368 | 456.2756 = X, | CH, = X,
PR HoH oc
F X, Xx) 27 WS IOUT ol tb _|..209 }495.1644 | 496.227 2% Ctl, Xs CH, @ =
Pr CH, 3 x
F X X = 2 NO ES EU bt | tmc._| 470.2848 | 471.3502 co
X CH Xs 9 oF
J 1 \ 4 4 J) w . = > = - r X, XJ 7)
Nee No bl ee |_207 | 496.3002 497.376 a
X, : [7] 0 I's 0
HG X
280 3 1 o/ 2.02 407.2027 | 408.2712 . 0 |) } UT |. 202 | 4o7.2027 | 488.2712 g x X, xX, xg
EN ei M ZZ i oS . z H.G X - 28} . oo ! © 2.02 | 501.2183 | 502.2874
Tw i , = X, x, Xa = 4 g AN = 0 z HC x o-/ ) = 282 [SPN RE a OT SIU) SO FOR = L282 4 & X, Xa a | X3
Oo" FOP ™
X [o] 209 HC ‘ o-/ 201_ | 459.2006 | 260.3366 <1 J IRN AR oe rm fr ns oJ Jol} : & w
He Xs © 2 473.3042 | 474.3661 x
La] LL. eT)? } 47330421 474.3661 z
AX, X, Xz * u : [a
Ie : w i | : ! 205 HC 4 21 {465.3144 | 466.3706 =
Pha JRO UU) PE pI — Po. . . FR ——— co —— rrr rem | rer | iim em en | ra fa
X
X, Xx, 1) 2
Is » ; =
HC Xs §
JLo ND oo SU [SEU] SUNT SN SA
X, X, x3 9% bd Is i 0 2 AA i 2 207 HC o-/ * 1.99 | 503.2784 | 504.3394 =
= x, X, Xs x
S a Cl
Z
= H.C X #
F Com | ee 4 X, Xs Xs
Cy \ 4g
Ie § ’ CH X 0.0 29 | Yo) | 1.99 | 459.2086 | 460.3446
X, X, HG ci, Xy _ ~~ H, @ = ©~N
X4 hd =
GH, 0.0 x 3, DE BO . yo |...207 447.2086 | 118.3367 pt
X, X, TR ou ~ | ' ~ z “Cl, w
X ) 5
CH 4 Q
RU MR A OO | 208 _|ast.2729 | 402.3204 E
X, X, PST Xg a x, 2 { 2 »
CH {0} 730 RE SR Cob 0 | 208 |a7soiee) 476.0039 of Xy Xs . 2 2 > o o CH X
S 293 A 00 211 | 473.3002 | 474.361 z x X, X, /\ Xs
Z CH % 7 = - 0.0 = 2 I RR - Co | Aas 41724161 418.2879 4 x X, X, XQ
P hl H,C ) “CH, X, 295 ee RR 5. .|.20s_]423.2675) 424.2075
Xx X Xs %s = > Ine “3 g
Tn wl
CH, x 0_0 = 2 J ES AU I . ol . [URI I |. 205 |A467.2673] 466.2819 B
Xy X, . —
[7]
CH, . w
N20 FE Rv EA FUORI FUE 413.2831 | 414.3154. =]
X X X =
CY 1 2 A BY @ ° ?
HG Se, 5
Caw |b TE eee | RO 467.2573 | 460.2849
X, CH, 2 N Xs 0 2 z X, X} ) 299 c 2.02 | 451.2624 | 452.2898
86EE BY | i6le ll] S02 oo TT ) fo [i < \ 1 X =
Rx 3 = : S = ol ile] $ ” ek af | ix he vooc ogy | 6Zvz sir | 102 00 hy to TVS ® $ 4 = [
HO
@ J ENN A AN DUNO GO SRNL INT AA HAG PA w ‘0 ‘ G’ - 2 ¥868°0¢5 | 22627685 | 66) 00 ) Ho £08 = N I m ) | = 0 € 4 - iY HO mB wT “x x | 'x mo RR [SSE ES IS Ce JEAN IAT Bh BU PE — 2B0E 06 | Z25E SEY | 96} Zoe = ay oo “HO 2 'S - m SF : - NINE = 1° x x |_X goezeiv|€esviv | toe | TT TG TT TT TTL TTT TTT ee
X x 4
AS a =/ x == wo "x - 6022'84b | EBEI'LLY | 202 vy 2 00g 3 10 . J z oh 0 i] =/ x = Ho | x ES
- x, low, nc N= : ie © OO & : ; L = F X, X/ z JC OR FE SO EN [USUI FROIN NSU EU = X, | CH, H.C, = X, on
Xq \_/
Cl
F X
307 | IT CU ]ltee ) 491214 | 4922748
NES CH, Lu ho, 8 lL CH, \ 7 © = «
EX OR Re I re esas aerst \ — xX, = ~ I
Xr CH, . 0 x
N \_¢ \_/
Z =
E
[= aw X, Xa 1.69 | 426.2579 | 426.3064 4
Caw |r a em | 189. | 426.2679 } 426.3064 a
Tr S Sell \ S > nn oO CZ] ad
CH xy Oo. o 310 ° Cob YL... _196 503.1079 504.2485
JL: NN FEN Fc ON I 3 £ = Re X, } z CH Xy 0._0 3 3 1.98 | 459.1981 | 460.2525
: ~ ns x, X
E Ns 4 z x x — = CH 4 [oo 0 3 IPI I HE SE BA _ op | 189 | 451.2293 | 452.2009
X, a, } jem 0
N \_/
F X, x3
LE I RUS fo |. _____| tes laeazs20|4r08111 _X, GH, 1,C, « 7)
X Y
3 5
N J y
E
X, x; c 1S FE ER ct) | _201 |4832686 | 484.3263 Jw
X CH H.C PANE TR 5 yy a — Can o 3 = . 5 = 3 =
F X, x: b
SA Ce] 1781 512.3316 | 513.4124 > y CH 2]
Cy CH, X, pr ) = 3 Nea \ nc 316 %a Xs - JEL RS SUS NE lm | a8t 432.3253 | 433.3902 £ Xs CH, X, oan ng ] A [a = 2 N )—CH, \ J 2 ! 3 H,C 37 ? Xs 1.83 | 450.3150 | 451.3883
Cr |¢ “) oy x Z : PEED SUEe un = ie 7 CH. 0._.0 X = B11 ON I TY | 187 [506.2602 | 507.3204 < AX, L oH [Xe i A < SA
CH X Cl
ITC A A CL | 10s |soat07e| s0a2502 wo Xr | Xa Xs OH |X a f ch, S
F = x \ 4
CH, X, © oN 2
EZ. FO NR ol | 197 | 535.2030 | 536.263 -
X, x, == 0 sg & mo] ry] ORE = g u
CH, X o 2 7S EE ER i ; coe | YT | 193 | 4932729 494.3287 E
NX | on = Sa WN a . — [72] \_/ Cn,
Kell
F X, Xx! 72 J I | 206 | 491.214 | 492.2753 _X, CH, 1,C, He Xo p=
EN : Ci = F X, . x! = 323 2.02 471.2453 | 472.317 -
X cH, | Inc x — - ENA a i) 5 3 | —\ y OH '
PS] = g cl z F X, x! = RST EE FE ee mee em] 182 442.214 | 444.2721
S) ~ 4 X CH HG H.C Xe
AN 1 3 aA fl] . NL y ~~ Cl
F X, x!
EY NN FS Cee eee |_| .1.88 | 457.2206 | 450.2092
X cH 1G PIES —-
RNa | 3 a fo
Lo =
Cl 5 i [+4
X, x! } hag
E23 FE RI Alo. __|._v97 |4572206| 458.2043 . i
X CH, Te X, EE ha ’ "Nec, — a
Ps * ) w 2
F =
X, oH [23
Bd . } _ .- 1. Cet in mn |. 1.07 1 449.2042 | 450,3473 om 0.3473 Q
Xs H, HC, H,C X, a
TT x, oc
F X
2 X,
JZ. HN SA SN IO . FT | ce mem) 2 [475.1957 | 476.2632 g x AX X, *3 . z P TL HOw bd Ci, X, = 3 : I 4 202 {423.2675 | 424.3002
- CH, X, X, — 0 : a = +, x = i $ L830 [SR UU SUN SI FUN . xX or
X, CH, HC, = "_ on
X, \ / \ 7
Cl 1: N
Wm || “0 “| .1ss | 91214 | ass
X Cli, 1,6, == X, — 2
AS t a il X, \ / \ / Ol w = <. - 3
A ¢] 3 8 x = 3% I he Ct tee | 491.214 | 4922756 3 m
Cli '
SREP: . —{-" : . = = E ~GH 0 a [7]
I] =]
LCI UN SR o. a FER | _202 ]547.2635 540.3262 on oe rt § pr—{ — = X= o0-CHy 5 -
ES 334 \_/ 208 |577.1720| 578.25
Eo) oo EE A 3] z
X, x, Xa ZNO, Xs 2 CH, J J py pS I = X No = H.C 7] z EN BN 3 RE RT rr g _X, X, Xa X Ci OH
CH, 2 pe
No x
H.C . 5 rT [a I A me | 195 st72132 | 10.2701
Cr X, Pi X; cl OH g w ) pe} :
H.C Ine 5 pt
LA A Ba 1 Cee ce] 245 [621.3173 | 622.3606 ni
Cr f I % TE w = [ of 5
P . [=
H.C HG Xs =
SC EE SOA Slog me em | L205 [5153512 | 516.4240 a
X, X, Ft [o]] Xs 7
X] FN Nn _ A
H.C Xi o—/
CE I N Cee el ems) 188 | 483.2522 | 4p4.9056
X, X, H,C X, oH a H,C x! Xg a 310 or f 2.05_ | 487.3563 | 486.4303 =
X X, Clee TT 0 2 Da 3 : on % = 7 \ ) ) _ 7 H,C x! x = ELL EO A — i . . Bh eran [208 | 515.3512 | 516.4047 < X, X, 1,6 - OH
It S$
H,C Xx} X;
LP EA ’ . — oe |—205 _1501.3719 | 502.4088 —_
X, X, X, Q pel 5]
Cr 5 : 4 d = x
H,C = X; w I
CL I A Lo . } seme of 197] 467.2573 | 466.2054 a a
X X \ a oi a 7 N . 2 = o
HG Chl, *; 0
UR A - RE =| | 191 14332720] 434.297 2
X, X, X, Q pel
H,C X;
SE SP I -. oo OU semi [2207 | 473.3042 | 474.3316 - aX %, 1 q ol
I=) c H,C >) x = 346 a 5 2.01 | 459.2006 | 460.3174
Xi X, ’ ON £ [ 7 g 7 \ Sa 7 H,G — X; = FLV DE RE ~~ Smee ele Ll... 1.88_ [439.2624 ( 440.2939
Y X, X, 4 —OH
I a
H,C CH, X;
SL I DA ’ meee fom eee 17 | 405.278 | 406.3116 — [’:]
ENP X, 4 OH o = 7 N\ 3 = 3
H,C X; o
ES A [SER i : com | 1.96 | 445.3003 | 446.3387 84
X X H.C X Fon » i 2 a 4 — og 2a :
Xg- . . - { 7 \ E - [')]
H,C X = : a
SS LSE PE BR - I ee [2.07 15233199} 624,3464 2
X, X HG X, s oe °
Xg
H,G x cH,
SR: LE I SIT NN . ’ imeem ee [2.04 __| 489.3366 | 480.3575
X X H.G X 7 \ 0-CH, = 1 2 3 4 2 (0%, = f S Oy N a > H.C X{ - 352 i 2.45 529.3666 | 630.3951
= X, X, 1,6 X, a f& ( = lo]
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Ee X, X, H,G X, al == [o]
Xs
H,C X{
SE: SO SI . ; cee me ecm on |..2.08 [515.3512 | 516.3034 @
X, X, HG X, Oi oN or Jax - 2 7 \ X; hg . — - Ww
REN EE LS ba . ak
UO NU NN SR z
Cr §! M,C X, OO A w : I= 2 > =
A EO VI :
SRC RE A eS A RT I RA 2
Xi X, HG X, OH = x;
H,C X{
SST SE RE SS mere). 207 1 601.3719 | 502.3938 2 oi 2 Xo X, HG Xa o-ch, : i ax o = = 0 c 7 \ x z H,G x = 350 ee 2.08 | 539.3140 | 540.3187 x x, 0G X on = ! A 9 4 7 pon, x 4 z =" : N z sco M,C X; CH, = BE ES RA Lo | ...__.|_201_|s5053301 | 506.3531 & X, X, HG X on EE ol ate = 0
Xs
H.C X;
JE: (CV EE Ty I i | |. .2:16_ | 545.3618 | 546.3911 oil —
Cr | 2 xy j& Fi E & - 1) = 2
I ’ ) a 2
H,C — et 301 im
JENS) A RY RS — . i coe] ee mle} .214B3.2522 | 484.2723 Ww
X, X X, oil TT “Zz as o-all, . ©] faz | :
Xg h 2 ] = “0 H,C GH, a
Re el |. 1.93 | 449.2678 | 450.2099 g
X, X, X, ou : 2 a) o-GI,
C Boa xg
M,C
SX I ER BE FE - ceo ee mn]. 200_ | 489,2091 | 490.3192 2 ~X, xX, HG X, OH : O avs ol z = 0
S * z H,C x . 304 ? cr 2.06_ | 525.2091) 526.36
X x, iG X on
Cr 1 2 fi) 2] avs g x z H.C X/ z SS I TE en seme mele 2,12 1 631.3461 532.3955 = X, X, X, OH 4 Cr 7 OH 7 \ = 0
HC — X;
JR DR ee Soe eel] 195} 469.2365 ) 470.2061
X, X, X, ol I}
Cr Oi w - 0 z
H.C CH, X; LE
S72 I ER fe eee | 18 432022 4020s] 0 HW
X X X OH a 1 2 4 sally ade : ) = 0 =
H.C X3 a
ES I some eed | 203 | 475.2035) 476.9151 7
X, X, HG X, OH
OH
7
HC XJ X;
FE a comme | 0:04 1511.3189 | 512.3503 a X, X, HG X, OH on ol — < H.C X CI X = 370 i 3 ? s 1.72 | 477.3055] 470.3816
X, X, IG X, olf = OH : x a ) 7 M,C x X; = BL ER SE Coo ee [198 | 517.9668] 518.4061 & AX, X, 1,6 X, ne, - 49 == O-ClL. 7 \ x; h :
H,C X{ —
ST ER a — — — . — ef ...202 | 553.3304 | 564.3617 ©
P'S X, 1,G X, Wo, o 0 < = $4 =] =/ 0-cn, x
M,C N m - X Cl -
STN FE DT A ce | 18s |s190461 | soos SE ' »
X, X, ne X, ne a . 0 — rN 2 =/" o-cn, } 1 [= x5 [2]
M,C X; 2
ST SO AT SS Seem eee oo | 209 669.3774 | 560.4091 a 1] or p & “ [o]
SER: { 74 A Be en
H,C =
ULL HN FEU Ri em n en] 192 [497.2679 | 4p8.3000 [EX 4 bd Re Xs X, x4 "0
Ey 0 : og SUR a =/ o-c,
A ’ Xi
Z H,C - 376 2 503.3140 | 504.343 z X Tx 1 Gc X H.C 2 Cy | 2 ) 4 o . 7 784 = = On & H.C Xa Xs [E7200 (ER NURS I EE [US , ppom—— J, I
Or X, M,C X, WG, . . JN
SEF aR Re
H,C XJ so x5
JOELL: J SR SURPRISE FER [EE (ON 2 __ 625.955) 526.3682
X, X, HG X, We s ~N . =/ ol 3
H.C X/ Cit, : ~
TN ION AU I i eB aguasiefagzaora) 5 of X, 1G Xa a ~ I ) . . w ¢ { . [=
H.C x! we 0
JER. S NE EY) FE — oo. . [ITO FE — 205 [531.8025 532415 a
ZZ 7 N ( r y 2 H,C = %s 2 JN: FUR DRO (URS a UR [UU SUR (——
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H,C Xg 382 | 1.94 475.3199 | 176.3517
_X, X, ao x, z X; & = H C 07
Z Ea Le i EN JE 7 493.2522.) 484.2405 : %, & ~ x Xe Dos “ ~ Ju y he [High]
H,c dn,
SC SR I . Crees ef 194 | 617.2132 | 510.2035 % X, yen a 8 x; ’ . 0 2 : HC © 5 oy
BT A I : em eee [1.97 | 497.2678 498.2453 w, W
AAS X X, * ~0, (8 F< & wD w = 5 —
TY 2
H,C © hy "ae ~
LLL JO FOR RA EE EE 195 | 511.2471 | 512.2276 a
X X X Ih
Of \ 2 ! Ig 3 a,
H,C 4
CLT SN RA . . meee em ee [2.08 | 553.2041 | 554.2720
X X UN
X, . 2 - 4 4 20 () 2 x; Ra
E HC CH, o ci ang oo 2.05 519.3097 | 520.2906 = : pt .
X X, ” X cl, - Cr } 2 4 I - x he = oN 2 a,
Z H,C 5 = A SR Ba . . oo crn een ee. 2:03 |) 569.941 | 660.3246 < XN X, X, 5 oll Xg > Is Xi oe
HG _
BU LUN ER } a MOO | 178 | 469.2008 470.2381
X X X oH —_— > ! z ‘ ] = 4g X3 w cl 2
H.C x
J PRS Ba Ho” 0 lees | 288 503.1976 | 504.1985 tu w
X, Xs | D “a, a : 3 5
X; = = i o a =
H,C ) = : LZ PS DON I ome |" | 189 | 483.2522] 4p4.2435 7] 484.2435 a bE J : os a
X
Pe Je “I y (0) xy
H.C
BLN IE A A 1.89 [497.2314 498.207 x X, . X, all Xo
Is x = . : HC a 394 oo oil 1.71 | 455.2573 | 456.2579 4 1
= x X, X, X, {0 ]] x
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X35
R*
H,C
SEF SR . e185 [469.2720 | 470.2847 _
X, X, X, 0 8 x ) uy 1) (e] =) x [4
HC I~
SEZ SU RA RE remem | 1:85 {403.2622 | 4p4.24 So
X, X, Sh X, ol ~ 5 ' w
X3 ol . =
H,C Xs e
IN: °L SE EN RS UT DE commer]. 197 631.3826 | 532.3608 ©
X, X, HC y ANNO } 2
I> { X3 x0
H,C X3
JIA SU FS Ca 3 cman |. 2:07] 500.3042 | 510.2007 . X, X, 1, X, Of 2 X3 3 a z HC X; ° 40 ’ 1.99 | 401.3003 | 482.3098 -
< X, X, CH, X, NT
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C Is Xs all
H,C X;
SELLS NS SA ~ A mee meee] 2.01 | 481.3093 ( 482.3063 xg o} w - =
Is x
H,C X; =
SEE (SS AU ASR le a . 2.03 | 620.3199 | 524.3068 w cee }_203 623.3199 | 624.3068 w xX x, CH, X, Tv . hid I [o] . = = [> 2
H,C X Xx } = a ES HAI OR Koti BET TR Lr LT @
X, X, ba X, OS 2
HC A Gil dos 2 AT Te coo ee | L196 | 475.0199 | 476.3177
X, X, ft X, on z H.C » cl, = ) 406 } ) h } 1.79 447.325 | 448.3324 [= ! - =
X, X, CH, X, NO z Cr oA < Cl
H H.C X; GH, = I I w I —2.02 | 481.286 § 482.2677
In Xp ZZ at .
HC X; CH,
LS ES RA RR . Tome em e ee e of 188 | 447.326 | 440.326 -
X X oH X ny -On Cll, F- of FE PAN Cl : 3 : ec
TRON X. CH = a EG NLA he S A emf | 197 | 489.3355 | 490.3208 2 wu
X, X, CH, X, oe “E ry - ° =
AN =
HC X CH, xo A : = 410 e "a qe ~~ _|._2.01__ | 489.3355 | 400.3006 a
SA 2 woem ef WTI [201 | 489.3355 | 490.3206 Q
X, X, oH, X, og, 2
Xp
CZ]
H,C X; N
LLL I RE Eo DE em me | 2.08 | 495.326 | 496.9224
X, : xX, H, X, Cre
H,C X; CH, o A412 ) | 1.92 461.346 | 462.3352 o f ) >
X, X, GH, X, Non 2 Cr Is I N ~ xX : H,C X;
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X; =F
H,C X; CH,
ELL FE ELA ou coe] eee | 2 | 5153124 | st63120 =
X, X, CH, X, ~ N
K K | Ww jm} x
H.C X =
SL: A ie ee fe | _208 | 495.325 | 4s6.318) su 195.925 | 496.3101 5
X, X, SI, X, ® / J wn J a Cp j= } =
H.C X; CH : a
SCT SE NN 1 lh ee | 201 | ssr.0408 462.9989 2
X, X, I, X, ye! a
HC Xx
S170 IO NA a7 we ieee | 206 | 5013719 | s02382
X, CX, MH, X, gh ct, } Js . es 3 ao HG X; fo} 1 =
) X, X, H, X, fr = Son % J Xg & [a 7 alo H.C X; : CH, ,
EF CT x Tx CH, " TA I EE 9) [] 2 a3 L] x . Men,
Xa
H,C X;
LN EERE Cope = em) 208 | 614.4036) 516.423 a
X, Xx, H, X, % a
Xz (¢] 3 x
H.C X 5 a A MS I om 2M | 5163512 | 516.3070 5
Cr : X, Hy Xy an 0 . wh
X3 i
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H,C X; @
ZN RE Ee meme | 2141 521.3173 | 622.3266 | a
X, X, Cli, X, o. oH, 2
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HC : 5
F 3
ZN BO TU FT =~ ee 202 | 427.2424 | 428.2541 ~~, X Xs —_ 4
H,C 7)
F
X CH, 4
LAS Code. ...|. 206} 441.258 ) 442.2744 2 ~~ X, X, X; —
H,C =i ax
F ‘ 0 : w
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CLA oo cn L203] 455.2737 | 456.2899 a
F X 2 ~—~TK, X, B 7]
H,C
CH,
M : CH, 2A IE I Coe lol. ...|..208 [455.2737 | 456.2853 - X g ~~ XK X,|"s 3 H.C 2 SH ~ = F
Sor 3 X cH, 42g H.C 2.13 | 469.2893 | 470.3137 r —~X, Xo | X;
M,C ) - WP \ ® —— : I Bi : CC FA Lo 9 | 202 | 4852479) 486.2803 4 1
E ~CH, ~~ X, X, Xs:
C H,C ! CH,
H,C ao Lo ; CL ...|_ 215 [481.3093 462.332 ne ad " g 2 M,C oj 2 «
X, ij = 231 0 2m
SLI I SEE (0 NS NEY SSN N= J ~~, a _ x Xz 0
H,C I= a : . =
H,C = -
X, (0) 8 lo)
No «@ as Ce RE een oon]. 1:88 | 418.2573 | 420.2856 <
CY | a : - NG
Xs 0 = EF } Co me} 1.91 | 491.2573) 432.2898 2 ~TX, X, X3 > H.C and 2 re x, J 0) 434 1.92 | 433.2729 | 434.3079 we X, Xa 1 Xg
E 3 no g CH 9 = 3 7 . X, 0 = LS I BO Cm |e ee ee] 1:91] 433.2729 1 434.3078 y EN —~ TX, HG x, |X
H.C H cI
LZ 3
CH,
X, 4 o_o
No
ZA I 2.04 | 433.2729 | 434.3079 — — on]. 204 | 433.2729 434.3079 5 —~X a X ~ ® H.C ? { Mr s 4 =>
LA oT ]..204 | 401.2891] 402.3126 x
X =
X 4 X,
Qe ole Sad ¥ == n
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H,C a = - G Ral :
X, o
EO I (US Cn] 1.99 | 447.2886) 448.329
H,C X aN oo | ° 3 — g Xz H.C “ts X;
S 440 1.98 447.2866 | 148.3293
~TK, X, Xs
H.C
KE] - HC Ta bi 2 1 7 BC DO ES) co OT | 195 | 447.2088 | 440.3391 > ®] H,C X4 AN i & 0
X, iS 7 \
CH, —
X{ CH, x 442 5
SE RE SUD os ce ee o_|..206__ 1 447.2086 | 448.3315 — . [-] ne % NR % p - a H,C > %, GH, £
SS RU . a wo mee |. ..2:08 _ | 403.2987 | 404.3406 v W =
H ads H,C We X; . “& ¢ H,C Ww
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ELL EO Cen ma) 2:07 | 447.2886 { 448,3385 @ > H Read a Xs 3
Lael xy 0
Ey an “0
Z LAS coe fe ms]. 189 | 459.2886 | 460.3416 s ( ~TX, Xi Xs z pz H,C q 446 Xr 0 2.07 | 459.2886 | 460.3427
X, ~~ X, ‘ X35 = H,C z HC
H X 9 = 447 0 204 | 461.3042 | 462.362 = [EU A SEUSS OPE RE ee | eR AREER TPS 4 ~TX, X, Xz
HG
3
X
Cas | OT] Leet |7as0az| ara ~TX, w= Xs FH)
H.C £ u
JJ SO SN) FP ST OL [202 473.0042) 474.0605 2 ~~ XK, x4 X; =
H,C 5 i
[72] =
X
ENP ) = 450 2.05__| 473.3042 | 474.3627 e
CS J EN FR CL eer] .205_ 1 473.3042 | 474.36 @
X
~TX, X3 2
HG ne x bi 25) © 209 {475.3199 476.3831 . J) FS IU FO cl) 209 AT
ES ~~, o a .
ES HG 2 X; : 0 < 7 \
S
- 452 Xi _ — 2.09 |529.2729| 530.334
E
= ~~, o X, X3 = HC = X, c LASY e I BU vem | 2:00 __ | 545.2678 | 546.3349 < ~X, Xo |X; " &' Le)
X
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HC s us ~ Wu 4 x 7] 1 . w
JR TN. A GES IO ~ Co eee | 207 [459.2675] 460.326 5 => : X = { ~~, ’ 0 Xs . = 57 Xx \ V Q >
JL TL ST ce | |. 2. | 4D3.2416 454.3023 7 = ~TX, Xe Xs
Po «
CH.
X, 2 2 FN SER oo SL. erm | 206} 437.283] | 438.3368 3 ~~ x, X, Xs 3 H,C
S X, CH, 459 2.05 423.2675) 424.318
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BEC) EO Te UR Lr 8 | 204 [467.2573 468.3188 ~~ TX, Xe | Xs
H,C = ~N «
X, 2
CH, 3
Ae . . 2.06 | 437.2831 | 438.3386 im oo EE IT el Eli Sh IPR ~7X, X, [%5 iz
H,C a = ' p=] [= a | CH ) 2
JTC I FR FN ER RT REN UU SN NR a ~~ X, Xi Xq
H,C
X CH a 2 CL A DE N oT |._211 [473.2831 474.3485 = X; a ~~ TX, == — Xs g H,C \_/ { z 265 x, ~ ol, o 2.03 | 467.2573 468.3192
~~ TX X = (J {yr x 3 1 H,C 7 I LN SR BE ~ | 204 14232675] 424.3211 e » y Te X; 7 X, a 3
H.C x ox v ®
Aer SOEUR ce Co _ . f__21 | 473.2831] 474.3467 x Xx 3 H,c- [ )= ° x g \ [7-1
I ET A CNS 1700 | 202 | 467.2573] 468.9227 o
X =
J rad Rot ~ 2
X _ «
M \ /—F { =
BC SN NU oo 9 |e |47r2se2|dr2zet) og x ~~, Xe | Xs : © ®
H,C wi = . =) =
X, @ a = a
AO co} 2.02] 441.258 ) 442.3175 » = *: l t ads = Xs
Hy v) £
BRA TO TE ) Fy O oo |_18B_ 471.2022] 472.3026 2 BD no % Xoo Xs F 2 = 3 8 s 5 X
S 477 ! 2.03 441.258 | 442.3185
—~X, X, X3
H,C z F 2 X, g LAT Co CT ._. .|.201 |427.2424] 426.3031 z ~TX, Xi X : : (yn = F
X,
EV Fn I CL a e_.__|._207 | 477.258 | 478.3228
Qf Realises
H, = 4g @ r ~
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H.C pu = : o
X, m : 5
H.C -
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SEN Cat: =
X,
H.C
EL SE oo Co ._|_208_|437.2831 438.351 2 ~~ XK, Xi X 2 H.C $ z X, i1.c &
A783 A 2.14 487.2987 | 480.3652
Ny — ~ ~TX, ) ® H,C : I= pm Yr z ~ 479 3 a He Le 2 EE Co ee ee__.| 207 481.2729 | 482.3446 z X o -
BL: EL | CH lL Co ce 2.08_ | 451.2997 | 452.3621 ~TX x natant Eat TRY PERS Fibrin » He a kes
CH. © 3
J &
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Ce a ee 2.08 | 437.2831] 438.346 2 x, X; me] se TLL RIE LID. 000 "9
CH, & E
[7]
Cw | X, CH, CY . =
SE cede | 214 | a87.5987 | 488.3648 = “ 220) 487.2987 | 488.3646 [am
J adhd > ” 2 a : 483 x gon { 3
LAB on, ’ o] 2 ] eS | _ 206 |a81.2720( 482.3413 —~TX, xX x5 IE
HC {~ Ie!
CH, 484 x, H.C : = A84 SR 3 2.09 {437.2831 438.3447 2 fo a. . tL. LIER (Ep p-udy D Prbilied-godl NNT = H,C : ’ 8 / CH, {
X o ABS | ne 0 2 — 2.07 481.2729 | 482.3401
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H.C 3 z X, CH, o~ $ LI OE BR co ereens ona| .2:09 | 451.2987 | 452.3614 ph ~TK, X X; e H.C 4 o 3 = H,C
X,
H.C
A EY SE Co | 208 | 437.2031] 430.3099 ~~, a = Xs &
H,C nod) 4 w -
ILI CE SR nd ©. .| 208 |4sr2720| amesaer| 2 ~~, Xa | Xs CH, ~ om
H,C 3 v, Ww [2 Bi ut nN : =
X, H.C | =
EL ee . oe oo mere] 211 _ | 451.2987 452.3547 a ~X, X, Xs 2
H,C LZ
H.C 90 Xi ’ ik
CLS DR —— Comme {ee meee 2.09 437.2831 438.3419
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H,C > H,C~ cH, } I OO
El EL RE een |. 214] 487.2987 | 488.3654
E ~~, Xi Xs c H,C O z M : H,C- GH, C 492 | Oo 2.07 | 181.2729 | 482.3416
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HS H,C g 7 & : J = CH, 4 JE 2 J TS BU CL 0%) 21 | 451.2087 | 452.3654
Paar Xa Xx;
H.C
H,C
X,
CH, IN 2: J DE ROR Lo a CS l.e09 |437.2831) 438.3447 3] ~TX, “ CY " 3
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BT FR FR I ILE | 21a {487.0087 | ama3ss| TG x; w ~TX, wl Xe -
H.C ne 7 { . 2 x on, 0 —-
ELT FR SR a Soo, 9 }207 481.2729) 482.3421 a —~TX, X, Xs 2
HG = \_/9
IE Ie J oo CLO | a02 | 453278 | 450.3456
X
I) ~X, Xs § 2 H,C 3 qQ
Lan} 2 498 X Cty 201 | 439.2624 | 440.3276 =z
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JE J a IO ES |. 199. 4832522] 484.9252 ~~ K, X4 Xg
H,C — 7 \ \ / 5
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H,C 2
JE) SE CO I Cee of. 2. | 453.278 | 454.3479 hg w ~TX, X, Xg Zw
H,C —/ “z w -
X, : = 0 @
H,C Q
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X= —~TX, * X » HC ‘ _/E > OO - X, H,C
EN 503 ? eo. |. 2.06 | 489.278 | 490.3477 = _ X
EX H adi ke 0 72 N__/ Ss c Ce $ L )= = 504 X, Lo nd ) 1.97 | 483.2522] 484.3253
~~, Xa HG ; HC Xz 0 x 4 A : X, 8 _ z 505 UU BR . LC ._.._|_.198 | 453.278 | 454.3445 ~ M,C
A AN X X A
OO
= xy
J: I RR BR EE I 11.99) 439.2624) 440.3253 ~ H.C ~ ~ X. a X
He” Kyo | dS g ~~ o 3 s & J 807 i } oo Cm}. 207 | 489.278 } 490.3457 - . wv W
H Red o— X, X HG . i w 3 [ 5 0 7] 0) u . po
X, = 508 ~ 1.97 _|483.2522 | 484.3227 @
L808 I | 1.87 | 483.28 I @ > ~~, X, Xz 2
P H,C
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X x zu cares | cl ol, = 3 nr Th St Ey w . o- Xs
P . =) > “ 0 :
X X = 8 1 0 3 nd cll, <n 1756 ! se | _ _ o CV ]_=202_ 639.3512 |540.1099
Ny 1G x, wl % 2 | RHI PETE ne—~f_, _ “ J \ FO, 2 X, = 3 1757 * ? cl on, 8
© x
IS z [4 = o -%)
N re — . © a NE X, w _ oT a
P J A wl a hw}
Ig or, LL \, 2
X X, = hg ! - pu ] [17] 1750 oo ne Ch, « T i ne Cx Co ny - 3 EE 537.3719 | 638.4346 w
TS 2 BEAYY 2 ~x ma 1 s 7 1759 % : [M] . ite, 2 ee — oo : [7] -
Ey 3 ao [=] =
- R3 x N z N= MH > = N_/ a RI” H ne =
R2 RS [9
TABLE 3 .
CMP # RY R2 R3 R41 RS Ata, Time [Cinp. Mass [H+ lon Obs.
Xs Ye Ks 0
CH, ) o 0 ©
X . ~N 1800 Xa of s 19 | satzise | 532.2805 w
J
X, Ye * a x . XL 0 Xe 2° ou 1801 ) s ot no»
X, X, 0 x5 , S > ci 2 © In
CH, x X, Q 1602 ? "oo 188 | 565.2132 | 566.2751 7
Cr X; Xs
J Oo |x
CH,
X. Xs 1803 Co d 198 | 5152573 | 516.3182 yy 2 X, X, BI = = = 2 C © JN ° ° CH, i a To 1 : 1804 vo 0 i 196 | 559.2471 | 560.3251
N=] x &
ES Cr X, %; CH, [ad £ - @ J [-9
Hs X a X 1805 3 0 s 1.87 401.2729 | 402.34
X, X, x;
CH, x X = 1806 3 on » 2.01 521.2234 | 522.2003 3
X, X, X; cH, = 1. . & ~ 5
CH, = 0
X X, 1807 3 on s 1.91 487.239 | 408.3032 5
X, X, %; = - . [4]
Cr 2 =
CH, 77}
X 0% Non Xx, 1808 2 5 2.07 516.2573 | 516.2609 - a = = x a
Q
=
© R3 x RA 7 ~RS 4 N = Ri H H N 3 R2 RG
Bu 11ABLE 4 ,
CMP ¥ (RE R2 RI and R4 RH } Ro } Ati. Time [Cp Mass [H+ [an Obs
X, LN VER »
SalI 2 16s 1809 ne x i = | 204 | 493.2729 | 494.330
X, x, or Io =
X CN 8 ’ = ZB a 1810 fe x we = 202 | 499.239 | 500.3034 3 : Xy 0. 5 z
Xy xy 7 4b Ne) E
Xx Da a."
He 1811 To 3 i o ) , i 5 : 5 2 xy . He E ne i = 1812 : a x HH Xq oD
X : a oS rR 5
He Xa x © HC 1913 x an x,
X, : X 7 ; S bd x! . Na 2 nc 4 2 1814 ’ 201 | 485.2204 | 406.3 g x x " X o : S z x ~ "We ‘
z — — g } X, A Ia Fo ——1 - = xX J £ R11 To NE x” ne
ENR en, J $l > a LS
WO AN aes | sera 522.9520 1 0}
Cy” ¢ 5 § { Sr = ! 3 a ) ~
LIT ef (GR I. A A Xi 200 _ | 499.200 | 494.3401 od
X, ET nad GH, TT 2 = ci, ~ / = x 7 NL w
Yon yt” ; oT A LJ WAU A La 202 | 459.925 | 460.3719 2 x
X, » ne cil "oa
Leen, i / pu
Cr It of 5 2 / 2
LI SS SS RN. AN Rok FU _|_.201 | 450.325 | 460.9700 =
X, H, or TT [2]
SAC oN I Se : ==. . [7]
Sa fin LL FS. SSRN I TN Lana Br 527.2703 | 620.3104
He, x :
X, —] Cl =x Cl I, : or” Is x i “Oo ad ’ 5o1.335F [5va. 3303
See | LX ee et
N x om, LA ai, : CL [opel 3 102 "no PX A 1.99 [407.3189 | 480.3148 c > a < Ai Nw
XxX 3 Com hes |e bn 7 Teme IB n2 ik! Rin. Time. (Crp. Masa {11 lon Obs z Fe A 1: DUI | SUM SL Ey : \ CC 8 - 1032 NCA FSU NEB 2 Ee po t - % Jat \ LO eda) sams = = (el]) . ~N 1033 J se mee y 0) x | % z - 1 8 = iu
X—/ ke} zz ot CH w oda LO he pe 5 ’ - = ® | ) 7
PEIN =] <8 a ) aes | YN X“ |. 2m {awsome 42s . % CH, : @® 3 ES g g 98 336 X 2.33 439.2042 434.2509
X, CH, . @ z a
H X, : gg = - xg © 1837 2.33 433.2042 | 434.2613
Cl : OH x. ! 1838 3 2.22 419.1085 | 420.2401 @ x, L w 0" en, 3 ° x
X, [ol g 5 i 1839 A; 5.225 5 5 I ] ~ 23 505.2253 | 506.2785 “0
Gy x, = ® 6 2 b= . 12] x 1840 a 231 | 421.2042 | 422.2453 : X, H © g d =) x 4 1811 3 2.2 419.1885 | 420.2424
& = OH g g X; = 1842 } 2.27 419.1885 | 420.2401
SIPS
Ps o™ oO.
LS ¥ . cr” 1843 | 2.32 506.2253 | 506.2746 g ® I 4 4 o = o= [14 3 = x a."
E71 9g ; 1844 Co i 23 505.2253 | 506.2814 5
Xp = ® i i : 2 g 0 18456 o/ 3 2.27 421.1678 | 422.2155
C
LL
[ae] 2 @ g X a 1846 ? 2.4 427.1936 | 428.2449
Q z
Cl " x | A x g 0 2 X a 1847 Lo > 413.1991 | 414.2406 z 0, X3 ) & x 0 .
X,;
Q a 1848 oo N 0 465.1576 | 466.216 z
Th X ~ 3 Ww ® eo 5 x, a x @ 2 x w 1849 RE 420.2202 | 421.262 2 Zz > oy | : x, > =)
E
J © & @ [2 3 % 2 1850 oo ~ 489.1552 | 490.2146 @ (2 “ rr X. 1851 NU A 495.181 | 496.2438 ” *; g A 8 NE
Q [58 Td 2 X 4 1062 —/ 2 481.1865 | 482.2455
. NE
N
* “CH, 2 J & 4 F X z 1853 : 217 | 488.2076 | 489.2776
H z X
E ® " : 1854 [TI Ke 2.4 471.181 | 472.2344
X; g w
SP z
HG” A < 2
LL 249 | 457.2042 | 458.2641 re % 2 x
[72] ()
Cr
HC X f= 1856 | cad : 24 | 443.2097 | 444.2538 a y 444.25 g (JY a ~ ’ oP re
HCO x 1867 oo 3 242 | 433.2042 | 434.2522
Xx, or ) NX, } fac)
F) F : g pe 195 | "© Xi
2 Is 2 ® RAN 2 g " = ¢ 1859 , Xs
I
NX
F gg & 1860 Cl x3 wu
N
Co] : ) Sn N o & wv, Ww
CJ C *2 cn, = 1861 Xs 5
I 490.2369 | 491.2785 = = == N, X, CH. } %
R ie nL) [QI : :
CS ¢ ee . CH, 1862 Xs . 479.2321 | 480.2817
Pa X F
AN 2 ] w (YC 2 N : S 0 = : 1863 CH, X,
Zz .
=) | C—" g x | . = ! Sn : *£ = N X. oO = = 2 1665 cn, X, = = N, X, F F x CI 8 w ad
CY ¢ X 2 1866 oo oo B 2.15 | 485.2027 | 486.248 ag
BS Xx w ) 2 w
Lp w jm } re X = 1867 tL 3 2.29 472.4762 | 473.2223 E
X @ 8 HO ?
Bp @
N %,
Xi 0 \—o - 1868 1.78 411,1563 | 412.1952 2 xy = a f=) — x 1669 Ct i 2.44 443.1111 | 444.1614
X, . = z g = 3 S / X; - = CH X 2 1870 : i 24 423.1657 | 424.1971 -9 X,
SOP
He F g : 0
X ~N 1871 — : 2.11 504.2577 | 506.2372 uy @ I i x
Ne 5
F F ~ uw
I g x "oa w 1872 — . ? 2.08 508.2326 | 509.2144 =
X, = gg -
N [72] ~-% 2 cl F F] 9g X 1873 PE ? 221 | 5242031 | 525.1942 $ X, -
N X
F F SM
F
: ae 2 X 3 1874 3 24 558.2294 | 559.21 c
= z &
FH
= = 4 x; gg Ne ~% (A &
F w pa g b=] x 4 18756 ] . ? 2.01 490.242 | 491.2217 Im = ? w
Ho Xs | = : 5 > w -
F f= = x 0 . 1876 oo ? 2.11 524.2031 | 525.1987 fo] x =] 2 7]
CC.
CJ "
X
1877 3 2.04 508.2326 | 509.2227 2 2 x a e =
PY R2
R1 NT ® i 2 RABE 5 g CMP # IR R2 R3 Rtn. Time (Cmp. Mass (H+ lon Obs = © gg he 1878 ~~ ] %a 243 | 417.2093 | 418.20 g x, X; ' g : ) 2 1879 oo oh % 242 | 417.2003 | 418.2941 hy x, X; n,c 3 &e -
J X w 1880 li » 24 417.2093 | 418.2959 g u
SSE CE
. w - =) 9 7) 2 1881 i » 2.35 421.1842 422.275 - re
Cay ” | : > 7]
CH,
CO
1882 i * 253 | 411.2562 | 412.3455 oN " ” g 7 1883 } & 5 257 | 423.2562 | 424.3530
SURE “1 2 = J ° 1884 * 242 __ | 437.1546 | 438.1642 g x, X; SN x : 9g = 3
H 1885 2.37 417.2093 | 418.2095 -— X : = [] “J . : gg ) 1886 Xi Xs 2.41 417.2093 | 418.2095 ( x; 3 © 1887 * 2.42 431.2249 | 432.2221 ~ x X or \ w ) 3 “7 > =, 3 ! o 1888 ch, x 2.49 517.0803 | 518.1107 wi : . . zg 4
X, “ow!
Sad on : =)
X E
1889 ' Xs 2.46 | 429.2093 | 430.2187 9
H ’ a ae 1890 Co 2 2.48 429.2093 | 430.2192 es We Ib - cy a 2 x x : : 1891 ; 2.41 433.1042 | 434.2012 g Br X, x a 2 ? » > oN 1892 | cH, x, 2.46 469.1041 | 470.13
= a i Ct.
CD omy : " ESA ot z 1893 By * 2.21 549.1182 | 550.13 z [ X = HC. =
Ss [9 X X 1894 | ' TL 249 | 393.2126 | 391.2145 ?
X, CH, X; . bry 1895 oo oo 2.39 407.246 | 408.2380 ~ ct | : ul oP hg 1896 ne x 2.75 | 477.1837 | 478.2005 a - Ww x, 5
FE 1 iu 1897 % x3 = a 3 = } ne : @ 1898 { 26 525.1529 | 526.1517 (An (I - re
X X — 1899 ! 2 2.47 409.2406 | 410.245 a a : " : 1900 2.58 437.2719 | 438.2745 .
x, X3 o % & — cn, x g 1901 » 5 230 | 433.2042 | 434.2162 : wy yo | ~ b= o 720 a ¢ ine 1902 = *, 2.44 | 413.2355 | 414.2371 “Ly |, © 1903 oh % 242 | 413.2355 | 414.239 o = "SY oo z
I> 5 ew Ww
X, AB 1904 . 239 | 413.2355 | 414.2406 @ hx X; 5 0 E eg ;
HG. o 1905 | * To “ho 227 | 401.1991 | 402.2075 | p= x X; [x 7
SIN
RD, 1906 “ih CL * 228 | 401.1991 | 402.2055 x, X; Ci g, en wo g 1907 noo % 23 | 421.1445 | 422.163
EN r ) 2X X;
I |e x, : ! SN z Xx 1908 : 228 | 411.1446 | 412.1578
! i = ort rs : | A s z = Xi ? | I i 4 | CH, | i 1909 Co 247 | 407.246 | 408.2634 []
[7]
On, . I [ Vy i 2 1910 | 2.45 | 407.246 | onan = 2 2 [o@! oo z & [| X; ! E
F——F i | E : @
F | : ! a 1911 | Co 2.46 | s152123 416.2204 2
Ss Xa = i [} - X,
HC
1912 2 2.16 500.2281 | 500,2342 i % 2 2 f = SPR g ” pd ! rr" ; H 3 : <= 1913 | x, Cl i 3S 1.99! 524.2231 | 525.2072 >
Xs = x z [ol] - Xy z 1914 A © 219 | 528.1735 | 529.1874 £ LN X, = g i _.
Nn
HN. *s [ ci 1915 * oo ~ 238 | 562.1999 | 563.214
Ce n ~N cr = $® X 4 to 1918 - 23 (er >
F E
@ 2
F X . o a 1917 NB ’ We,
Xy “LY
Xi
J
= 1910 i Co Ll 2.13 494.2482 | 495.2661
ES HC. CH, HC NR | %5 : pa L L- =] = x — 2 nC i 1919 x F
X
He 2 3 < as L 0 = 2 N | > \_/
Z 1920 * 213 | 449.2216 | 450.2522 c CH, HN X; FE , x | C
N =
N =N
J
X
1921 3 ph 2.41 | 467.2121 | 468.2447
Hc o Ny |X g x, RW = u \ 3 " x a) \ — 1922 ~ : F 2.14 | 467.2121 | 468.2424 « 3 - N ) gu ne N Ru q ~ 0 x, LA w - : 2 . \ 2 oO -
I % ne’ “a 1923 oo Ch i 2.41 | 479.2321 | 460.2563 a 9 x, Pa 0 x;
N X, . Cy 2 8 1924 252 | 400.2515 | 401.2748 a — x, : oe O z= JN 1925 x, = 252 | 412.2515 | 413.2605 xy
Ed N = x , z 1926 | ) eh 228 | 346.2045 | 347.2321
EF X
/ 2 :
N
Xa — 1927 BN = 225 | 366.1732 | 367.2062
CH, tN tHe = ( baa &
H,C OD x, 3» [4] Wy x = a LD 3 1928 Ca Lee " 241 | 531.3007 | 532.9127 E * on, Xs 2 w
Q and 2 I "eg i EN 73 ie HC = 3 : §— -— 1929 . as oo oo 1.96 503.2243 | 504.2599 [= we, 1,6 . a s ", 7 ~{ Dd L d 1930 neo : 2 517.2399 | 518.2693
F ne ne, fn 2 ls} X, \ [+] 3 = : NLD) ~~ = 1931 ne-o * 1.96 | 519.2534 | 520.2534
ES x 7 cn Xs = 0" and i p! i) {He : CH, * Li : > z cl \, 2 1932 » Co 202 | 505.2132 | 506.2226 3 ne 0 a — nd) = 0 cn, ne s d
Xx; = - ey 1933 Lo med % 205 | 529.2941 | 530.2949 = oH ne g ne * LO cn, w ne h q 5 x; =
ND x - 1934 nN _meme ’ 203 | 529.2841 | 530.2936 eo oh H,c 2 5
Ls) « = 2 “JN :
[2] 1935 oo thee 192 | 531.2733 | 532.2859 a
H,C—0 xy [74
CH, 4 X "He ' = t) wr NLD H,C ue—o CH, 1936 } Cm 1.91 531.2733 | 532.2828 i Re x, ’ ) f =H 8 Ch —
EX 7 NN, *; LD oo ' = . s 1937 ef 1% 227 | 520203 | 521.2229
ES x X3
Cy \ — ci = oo) 3 z Om 7D ue g 1938 ~ Lo 225 520.203 | 521.2301 = He
ES EY z (x (A
F Br 1939 oo * 2.32 | 534.2186 | 535.2426 x, Ss H,C
Ci—¢/ A oN
SEN gn 8
HeC—p ° X ~~) w 2 x 1940 he cf 3 219 | 640.1695 | 541.1906 3
FS Xy Pg
Br ie =H © fr 2 I
BE CE
! cH 1941 Co ci > 223 | 560.0978 | 561.14 5
FS X, =
Br Be =H . 8 = CH ! 7)
Che [0 [en 1942 EE 223 | 560.0978 | 561.14 mS ne }
CY) X, 5 =N _
Ch = 1943 oa » 228 | 574.1135 | 675.16 3 < & & a / ZN 5 g \ ps oe [Po 1944 of cit,
= i = X, aE vg . ° CH _ i — 3
Ce [0 ue s 1945 .© 2.19 | 497.1982 | 490.2381 z TB ne = X oz. © ' \ [9 N x;
J
1946 | of a 2.26 511.2139 | 512.2437 = iS < \ 4 ZN © ee :
Te 0 : 1947 of et 225 | 511.2139 | 512.2631 Z » SINEe ; = MN ct i [ ie 23 1948 CO k a ci, = oe . 2.3 520.203 | 521.2333 5 7 N 3) =
CS- DES 3 \_ x x; : 1949 to oo “ 225 | 497.1982 | 498.2341 @ “ = X; : N CH 1950 Ch Xr va H,c ’ oo 225 | 497.1982 | 498.2305 7 oN "e - Cn () Jo] : ao HG
EN Ne
N x 2 1951 = | x 23 511.2139 | 512.2459 x, —
N =H [ol — . \ He = Ch, es iS oh z 1952 2.3 511.2139 | 512.2452 o
Ss x X g — 3 z ( : O
He F
Xz 1853 207 | 504.2577 | 505.2028
X, X =O) g o~N uw - 2
HC X | od 1954 : 207 | 504.2577 | 505.2755 w
X, X ZI ep k] . + © <r 5 —_ =) = oS : :
F X, oQ 1955 205 | 508.2326 | 509.2624 2
INN Xa 7 oN 9 ’ — F nec—-o x 1966 ? 203 | 520.2526 | 521.2631 2 -. = Xs
EN \_4 g g c— 2 F 1957 "a
ANG, - Xs . \_/ z ue hb X, = 1958 2.05 486.2671 | 487.2196 x X ; Foy [oF ne x, 1959 B 206 | 486.2671 | 487.2379 x, Xx Im
No 3 ~ », J &, 2 : 3 ne—o -
X, i 1960 LL _ 2.02 502.262 | 503.2366 z ¥ wn x “2 3 w = o
N . [= f= os 0 z o
Ch BS cH, 7 x 1961 — wu 256 | 507.098 | 508.09
C7 ”
N
2 z g X, = cH, 8 X; Ct o 1962 2.49 449.1329 450.125 v }
N $e = H,C z X ci 2 1963 ATT 249 {449.1329 | 450.1363 ¥ X ) ,
N
P H,C
S w—
X, 37 CH, &
X; cl w 1964 ] 2.55 463.1485 | 464.155 3 == . = : oe 7 cl - =
CO —J p TN i
J a Ww se XxX
I]
N 2 1965 . 25 | 461.1329 | 462.152 =
Xs xX [10] . ) Sen, 2 x ) oo (C0
N [) . 1966 Xi BN 213 | 508.115 | 509.1421 e Ra) ) 1967 2.39 | 437.1546 | 438.191 a = o
X, Xx
SNe,
AS
< 1 »
Xx = g 1968 |X NE 21 | 520.1011 | 521.1198
JQ ) an, : © 0 i
A he = x; > 1969 2.16 | 486.2307 | 487.2447
Ky IN 3 l — o-CHh Ci Po 2 ae =
Xi 3 1970 EE 201 | 424.2151 | 425.2368 z
X, X — "cn, a
Br CI Di 2 $
NZ - 7) ” ® g 1971 BN 208 | 472.115 | 473.1456 ) ® E g E -
Ra re :
XN, = [2] 1972 | \ Co = \ 238 | 437.1546 | 436.1952 . * 1973 RB oh 2.37 431.2249 | 432.2486 x; . : g & _ = : os $2
S 1974 - ci 2.38 | 437.1546 | 430.1897
& &, X z 1975 LL : 233 | 403.1936 | 404.224 = 3 : 0
Was 1976 A 236 | 415.1936 | 416.2279 &
X; x, 4 el IRE ; 3 [= ® - zs X
I w 1977 CL 23 | 421.1842 | 422218 5
X 2 E (J) : g [23 g S : os $1 : 1978 Lo ~ med 229 | 433.2042 | 434.2361
Dal ¢ 1979 x B hed 232 | 447.2198 | 448.251
X; : & iN g ogy A a [o}] — © 0 = 1980 : the 1 08 | 547.2026 | 548.3105
IIIS
F Rr Xj \ © ~ . « Co % — g F 0 i \ ne
IE 1981 : 19 549.2220 | 550.3254
F © X; : & =
Oe — ,
F
1982 » 1.97 525.2692 | 526.3528 _ ct x |X & _ w
Xi Cr \ z a) — »L ry u
HC ne ¢ 1983 } Co 4 1.94 577.2132 | 578.3243 Fw ct x; =] . =) [od = 9
N py [7]
H.C 1984 a : 2.01 553.2496 | 554.3531
X;
X, C0 =
F Co, XN \ VY 2 F — 2 F 0
EN HC ag 1985 ! 1.92 581.220 | 582.3329
Ci = X; AN
Lo — «| Co \ x Xx g Np /
ES ct 0 g 1986 1.95 551.1531 | 552.2697 < of] > X; a Co Ll cl »
H,C 1987 : 1.95 581.1637 | 562.2848 _ [of] x, | X ~ ! J ! 0 = x, AS x ee | od . w
Cl [¢ 2 u 1988 d 2.03 557.2001 | 558.311 A]
Ca o
X; [= & 2
X, E
RD @
Br — 2
Lo «” \ H.C , 1989 ] oo oh 1.9 501.1522 | 592.27 . x; @ X, Re . On 2 =
I 0 a H,C po 1990 : ’ 2.02 617.3042 | 618.4236
X;
X, : Co - = s 0 z Hye 4] 1991 mE a 1.92 639.1383 | 640.2621
HG X; a 0 on [C0
Ci 0 > 0 —_ / ©
H.C M,C 1992 5 Co Sk 195 | 607.2238 | 608.3556 o
H,C—0 X; 3 3 f— * Cro \ mT _/ S I r fo) -+ 7)
HC” w 1993 1 : 192 | 621.1627 | 622.29 =
HG X35 . = 0 0
Co 3
X, No ar ho’ H oo 1994 a os 3 1.96 | 651.1733 | 652.31
F > X; = CS 20 x Re
Ey 2 _/ 3 ! 0 a HC
S 1995 ’ 1.93 657.1288 | 658.2678
H,C xy | X45 re hd
Br ie [923 5 1996 I : ? 1.95 605.1670 | 606.29 3 H.C te X; [-9 r < @ 1997 202 | 581.2042 | 58232 o h ¢ ) : xe
HOW
— zg 2 cl 0 a
He w 1998 oo A : : 1.96 | 503.1904 | 504.3127 5
Cl X; = . = 2
X, =]
F = [72] - b
OF HC
1999 DE oe 187 | 615.1901 | 616.3185
Ci : X;
F 2 “NS 2 — g FF
S 2000 ’ 2.04 | 591.2264 | 592.3466 = yy (Xd AN x, () _ = & AA \_ 7 : 8 N i = z 9g 14 o >
S 200 * = 1 RE d ’ 193 | 578.2682 | 579.3848 £ - 379. 9 N 4 N ~~ >
Re ’ 2002 .
Re. oD : ~ 2003 *5 u : «
RK) ~ x X, 2 i - w [ 2 2004 oH E .- @
X 2 ne K x, 2005 on . . he aS) = : &, = x, a a~ci, . o & = 2006 Xz 247 | 475.2511 | 476.2856 a asa % J : &, ’
FH 2007 oo 236 | 403.1936 | 404.2317 = x x 2008 ? 242 | 427.1936 | 428.2387 as
Xa a - ~~ :
Ch =]
X, 4 -
CO y x = 2009 BN ? 243 | 437.1546 | 438.2044 > 5
X, oo = =~ Do
IO) E
Xs : ” ao =)
[7]
X
2010 : 2.39 433.45 | 434.1996 x,
Cy COO belay = 2011 ? 2.39 445.1842 | 446.226 2 2 a 2) z
: 2) ol | ~ 2 {) x g 2012 ? 241 | 455.1452 | 456.196 = Ss X,
L4 a0
D . : v. ; 2013 2.41 43315 | 434.1984 4 oo 3 3 75 fo 4 . ol
X, - i
CE x = 2014 oo 242 | 443.1111 | 444.1632 2 ~ Cl Xs % \_4 a x, a
X2 2015 Co 247 | 443.0111 | 444.1649 ~~! x, = a = 2) =
I X
2 2016 : 2.53 477.0721 | 478.137 = x
NS ao bh = f=
[7] 4 0 ~ w 3 ~ CH, X, €
X, )—s i ~ Wd 58 w 2017 *s 2 2.41 423.1657 | 424.2055 E
[2] [re] >
[7] 2 a
EN x o 4
= ~ g Rl re : H £ NN f= 4 HN
R"' R2 Re
TABLE ©
CMP ¢ [RiorRiandR2 |R3 RA RS R6 Rin. time [Cmp. Mass [i+ lon Obs.
X _
Ce OU x” "cu, LX pi
X ° = 1824 ZN I x Lo | 181 | 424.2151 | 425.2364 &
X a 0 = =x, 3 xT", (9 1 >
ZX — 1825 x, x; } 247 | 558.2518 | 559.2742 o
X o nn 4 =X, 3 xg T~""gu, 7 pi Qa -+ 5 =% = X e 1826 *; © 22 | 514.262 | 515.266 2
X 0 =
ROLE y ; 0 2 0
Xg
Xy 1827 oo WL N 209 | 508.2362 | 509.2629
X 0
UO x7 "en, i] SN = : 0 2 3 X Xq °o 5 z 1828 2.1 464.2464 | 465.2729 x &
Z
2 — g . - [o] Cl OH
Xs x7 T~""en, { Ir 0 *s
Xg 2.04 514.2023 | 515.2661 g 1829 ) » g
Xs Xa £) 3 =
Cr ° 2 i ) HC Xg 2 :
OH 1.98 436.2281 | 437.2896 a 1830 1- ee . . ae . E
Xs X, Xs =
Cr c z a
H,C X, oh 2.05 470.2125 | 471.2745 1831 2 = =H = a © =
2 i no Xe X, X; } ] a
E X, 0 $ rer RE os Cee eee [L204 [491.2948 | 492.3288 . F ~TX, Xs xX;
HC a nc 0 &
X, 0 » ra | FR . . Co em i |_2.08_ 493.3105 | 494.3472 3
CH, X, aN Z . w,
X Xe on, Oe X 55 _.729 EEE . } ? so - = ]-.208__ 465.2791 | 466.3023 w
F ~TX, H,C X, Xs 2
He Hc : E a . CH, Bi 2
X, :
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Bp ~ LX cH, h Xs - } ne X, —_ 2 3 =" cH ~ w \_¢ ? u
X : 2 944 ? x 1.77 | 495.3362 | 496.4057 x
X, cH, X35 Lo “— i re Ww, fi | li J - vu \_/ CH, +t @ : w
X [= sas | ILI RE I SE NS J __ 374 | 481.3206 | 482.3854, 2
X, CH, X; "oy X ~~ ) MU : 2 os CH, 2 4 0 a (I I IO FN Sr 16 _ | 525.467 | 526.4145 x, X, Xs ry So ro
H,C X Xs Hs
SS LA I A SE DU I _ 198 | 4812729 } 4823188 = X, Xy X, had d « OH
Qe H.C 3 X = 948 ’ * 201 501.278 | 502.3374
Xs
X Xs aH 2 ¢ g = | H,C b ’ % 199 1 501.278 | 602.3323 = 948 ee ET E— EL Beto B 4 Cr x; s § on eH
H,0 i Xs ’ 188 | 467.2037 | 468.3504 ®eld — SA HC LU Beil oy lo OIE : 3 cH
JS b * ’ 1.88 | 467.2037 | 468.352 a
See ea fee ENTS Br A— al =
X, X, o " u
Cr a iz = w x] Lh = ne | 204 | s43zmss | saa3sis, 5
SLL ENSURE AVES FUP A SR ar E
Xx, X, d i > p= @ x %; "ae ] EH 203 | 509.3042 | 510.364 8 ee ee a AA [ > AX X, Mu LJ
S$
Xs
X
2 He ' 183 | 636.204 | 537.3635 2 cL. SY IS Sa UN RS RE —_—— 3 X, Xy HN L] : > OC 2 x *s CH,
He ’ 1.94 502.3097 | 503.3694
. X, g ¢ " " 543.4108 : He ee |_20s_ | sn2ou | st3ai08
H SL NP UUNUSIUUUY FSUDNURRRG SVS Wa prvi las & X, X, = - g N 6 CH, 1.92 481.3093 | 482.3674
H,C © sz | asia 4823 957 | ee ee ef NC REE ba a ©
H Ss * %; 199 | 520.2729 | 530.3309 ~
EE Fn ifs mand 3309. s a * on 2
Cr 7 N = x ~ cH 324 g ¥ he 5 |S rer ssame | ase | gE 8s i . 5: @ * * oH E : = x 7)
He ] 5 | _200 | 6353199 | 536.3663 Q 86 eo 20 SIT 2
X, Xy 3 7 N —=N he : ® oH, toy | so2300r | swyasn {LO FON SANUS NURS NIN FU, — 8 oT i X, X . e : 1 ~
Ey ==N 2 x Xs 2 He 206 | 542.3409 | 543.387 pe 962 4 z
° x GH, X5 “5 Xy ’ z N §. % " [3 om s ho
F X ¢ = 963 : : mr | sean | soos
X, GH, X; 5) X,
Be I! i. wv, 964 % +f 177 | 5203208 | 530373
X, Xx, Bre Xo . or I & z o~
H,C X3 u 965 3 % > 98S ee ee 2 x x we P x ! i Y—ch, ‘ —- w 7 N ® 4
H x{ w= Tw 966 iC *s 194 | 528.3253 | 620.3721 w 8 lf 184 | 5283263 | 520.3721
X X. Whe X 2
ON ; Yen, ‘ E ft a
JG Ee g 3} CH. esr | we bhp | es) sea | aesasar @
X, X, HE, Xs
Cr —ch, 7 \
H x = - mee | Me Li | zos | suum | san 2 X, X, *; CH, 2
EA
[=] . ( cH X X 2 969 » 3 nf . 1.77) 491.9048 | 492.3542
X X mn X
SEIN IC o 7 ON ) 2 H.C x3 =
S LL-H FN RASS NURSE ST a 3 203_ | seo.2661 | 569.3215
ZF X X —Tr pI Tr EE = 2 Cy ] 2 WW . [= 4 ZA
X. =
H,C E see | sae | sasanes oP 21 ¢
H,C Xs Im) 8 1 214 | 574313) 57538 o
Cy X, 9, on, Xo pl . LN po] [4
S fe o ; x —_ wl
H.C : w seme Ease | sae [sina $F OX
X, X ©, Fah Xe @
N [17] [= 2
H.C % Ba
X, CH a ee ei tS 1 18s | 5083202 | 509.3457 a
N
\ cu,
H 5 x fas
X,
SLL) DU hi NAR EU A ha 11 | 5223389 | 23.3574
Cy Xy Q, Ln Xa nN ~y § £0 zx x = g 376 H.C ’ x pS 203. 562.3672 561.3868 =
X, x, O [8 Xa - — = Ie x3 Xx g 977 "e = | iss | sez | stesz0n
Z Cr Xx, O Of . = = ¢ Ie .
HC ? *3 CH _st8 4 ot oJ) 386] 481.3093) 482423
X, X, 0 fas 5 } ( ] 7 \
H s 3 Xg _
SLL FU SN SO JT | 205 | 521.3408 | 5223715 8 x, x . Ee; X, 3 ® = «
Ie x o—cH, &*
HC 3 jm 8. fT) 206 | 615.2036 | 616.3033 zg 4
Cr X, BS o | A} ¢ ) w —-
Ie X; 'o—ch, : 2
Hye % CH =
SLL IV (AR A DR _ } ! 189 | 481.3003 } 482.3204 a
X; a—cit oS Xs
LL. DE RU FU I oi |) 202 | 820.3406 | 522.3559
X, X, —0 Xo [id “on, g X a He : a 983 206 | 5152936 | 5163141 = } =
Baal \ == cH, = . z x4 ~ HC
S sss | mE oo CH, 199 | 481.3093 | 482.3264
H ee [189 | 481.3093 ) 4823204 fe = on 4 Ie x
H,C *s
SL J A SN SURO A SU 215 | 521.3406 | 622.3507
X X Hn x FARE a a —=
X, _
CH ° X & 6 SE ISU DA 3 NE DA .203 | 489.3366 | 490.3545 w
X X cn xs = ¥ : He. tH, CH, =] «
Xy 5
CH X : Ww er | Ton ® 1.93 461.3406 | 462.3651 - I
Xx X Tm TTT I HE te wv, [72] ' 7 od Xa ’ Tow cH, = 7 =
He * = e
JEL (RN i - JU SS Hh 21 | 5493355 | 550.355 a
X, X, Son ° »
Oo
Cs 55 x - 989 H.C ’ ;
JPL OPS SS SUT FR deo |. 183 4 853.2835 | 560.3169 % y . = 1s §58.2835 | 560.3169
Cr Se - _ g () = H.C X3 . *
Ia] 990 2 g 206 { 5653304 | 566.3608 [=]
Zz
= X, X, oS Xe x — ; f Se = x rom sz He ? . = BELL FR AA EE eT | 198 | cas3042 | 545332 o x, x, a , i] Ie ) D, Be es2 | We ol 1. I Mk. 182 | 5113199 | 5123402.
X, X, oS" Xq _
[7] 7 N ~ — . w
HC i B 3
SA oT) 205 | 551.3512 | 5520806 4
X, X, H x CH = or pe | :
I
X, no»
Tow
CH. . X
LLL I Ets oe ee 1 tot! amsasis | 480.3748 = 4
N [1] § . =" | 3
H,C ? x; we Ne Ne Tl 202 | s4eae3t | 547.2886
Cr Xx, OH X, [s] /” x Q
Ho ’ x cH - ee | 2 | st2.2707 | S¥33031 2 Xs X, on X, £ 2 +» g AY [=] X = H,C ? Xs 997 2.141 552.3101 651.335
Xx Xx 0, X,
Cr ) FN Jeo = = 7 Non % x4 = & H,C g JULI DS MR Vo Tl |._202 | 562631 | 5472680 z * * %Nymo * - & oH x
H,C 2 — —see go Ne | 203 | steer | srazote
Cy Xy ES Xa =0 ¢ OM & no x4 ~N ee ETT | ann | ssaator | 5533454 4
X, X, oily Xo 0 : x wa [ad $ ro
X.
H.C 3 ja I eo A Bh 2.06 578.4349 | 579.501 7 A
Xy x, & Xa = or - Lr p— a E x4 $ 7) 1002 H,C ) g
See ee 214 618.4661 | 619.54 2
X, X, ne, X EE SE SE « pa )
SJ “ (§
H.C x i x CH oes ee Ss tn | ss23828 __ 553.43
X, X, een, Je a wl 2 45 x - a H,C 2 re ' = 1004. 3
S 192 | 5924141 | s9347
X X cH x, CH
SHEE
4 Xy
X
2 coos | Tee re | amass | asa = X, X, X,
[72] = Cr 0) = 7 ON
SS a [-9
X, }
IN EN A NC SN Mc A NETS Poy pn
X X. CH ¥ CH.
Cr ' op E 3 xy _
X [7 ew de A | aa | aoa | asraoes ~
X, X, 7 Xs = = x xg “0 —- x [+] CH, w
H,C 2 fv} de me fT 203 | seaomes | sai | z
X, Xx, 7 \ . - w = pus J
Ag 9 [=
X [+} cH, : -
H,C ? “| om [7] 1009 2 bd 1.95 _ | 509.3042 | 510.3276 a
Cro £ $2 y ’ . LS a } x! o cH, ove oe EN ae | seas | soon
Cr Xz = Xe = Ie Ay OH - g ) -* H.C
IN] 101} H 1.96 615.2936 | 516.3184 = [= = : : ) mttintiaied
I) == 2 Ie x on 3 X ol ¢] s 1012 HC oH, 184 | 481.3093 | 482.3309
F LALLY FO EUS [FI SUA NSN F LS Ws: LAA lh =] X, X, A Xo = A & Ed -9
Xs on : H,C Xs 1013 i 198 | 521.3406 | 522.3765
SRI [® 2 ooo g
ELIT or , x 108 | 504.2659 | 565.0013 Y xX, x, x CH, =) e [- mr] o=y=0 tors ] SA ISS INS HN. NN Mo wor | swans | sae | gE x X - ’ eT cH ’ Tow 1 2 we, 7 N EF) = o = == E -
X3 X wn
RC ne” ° a toe ! 1.88 | 511.3199 | 512.3484 3 ee _J._l88 | 511.3199 | 512.3484 a
X, X, HC, ] A x CH,
It x! .
He X ove fe uo | 19a | 547.301 | 648.3231
I
EN
I x a HC 3 o 1018 . 1.96 523.3199 | 524.3481 = .
X, X, a 5 . . < Ie = ; = : g 10 Hse * oH = __1qt9 I Se [TE DU NS 3 1.82 489.3355 | 490.3575
H eft] %82 | 480.3055 | 4503575
S Cr & Non = : Ie [-9 xg
H.C x
LN SE Ma I Co 19 | 509.3042 | 510.3383
X, X, cme Tx al A EE
Ie x x! © 1021 H,C : o vom Me wes | ausazs | seuss uy x, x, oH xX — rr =
JN ad ) [4 — . =
H.C x i
CH
_vez2 (Vt | 461.3406 | 462.3634 7 » __L77 | 461.3406 | 4
X, 2 x5 °y = : 2 0 ©
HC Xs J
Meas | Tb 203 | 513.2628 | 574.0027 a
X, Xx, °y x on
Ie 9 J o
He Xy X Hh
Jozef ef 203 f seared | sesoss or i Sr pq oO : He x ’ 3 > x > dors ET eT aes | sraaszs | s74.3038
Oo | EA 7 0, dh J 1026 HC % nea & “h X,
= 2 r hf & 1027 "ue % ge Xe 185 | 514.2872 | 545.3213 £ El EET ET I eT Ie Be Ran : “x OL 3 *
X
H.C ? 1028 3 203 | 543.2686 { 544.3122
DE x, xX, : - _ o0—CH, Xe 7 N
SalI SH x 7) 1029 He cH 203 | 509.3042 | 5103173 uj
X, X, o-CH, 5 3 x x; =
H,C Xi w 1030 ? 212 | 549.3385 | 650.3542 CE
X, X, oH " ’ - w :) jo] x; E
H,C Xs 17}
JL.E TN NUNS (ASN RSSOUR SAN |. 198 | 5202720 | 630.2039 g
X, X, al Xe 7 = Qo x5 x
HC ? vos te ee fe _}..208 |} 5353159 | 536.3453 2 Ie =
EN * z H.C % g 1033 3 197 | 515.2036 { 516.3203 =} 3 atl
. B N * . [751 o~ [] - <I
X, X, on \ : id
P= © Lh - [=] 2 x = { . 2 1034 He CH, i = $ ef ee fe ES 1.87 401.3083 |" 402.3204 wt 3 X, X, an x I ER En Re x o 4 x ¥ [rr] 1035 H,C ’ = = NUS I FS NE 2.06 559.2835 | 560.311 wi
X x A EE I ! i a oc, Xe = -= o - . . : * x © 1036 HC CH, &
I Eno] RCE [NSN ISIS SS Ih 2.03 625.2994 | 526.3195 w
X, X, ou < TT ~ o-an, J pu} an 4 * im x . 1037 He : : : T re fe fe meee | T4207 | oss04 | sens 2 w
X, X, . on j DE Tow nH = . D ne % % 2
NULL I RA >
X, X, A Banta dd ee ad Ton TTT Tx —_— . [72] . LJ] oH a x x ° | c 3 1039 He ’ ' = urn ES) [SSSR TRN SUSU FE Hee NT 551.3148 | 5523455 x
X, x, oN - EE A bY] 8 [=] 2 : rN < b=) «© @ x! = n
Ey x — s 1040 He ’ ’ a =~ 1.93 531.2880 | 532.3201
S ~— - 4 - N } pe
Claims (163)
1. A compound of the formula: Rs Rg 8 oa SH Yo TR Rs Ras ~ Ar, Rg or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: the ring system represented by HET is any optionally substituted heterocycle comprising a nitrogen or oxygen that can act as a hydorgen bond acceptor, Y is N or CH; miso, 1, or 2; Ra, R3a, Rs, and Rs are independently selected from hydrogen, hydroxy, halogen, ‘ amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyi; R4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or 459 AMENDED SHEET 2004 -04- 26 s WO 02/49993 PCT/USOO/26816 Rs is optionally substituted carbocyclic aryl; optionally substituted arylalkyl, - optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 : rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and : Ar, and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms. Rs and Ro are independently chosen from H or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally : substituted cycloalkyl, (cycloalkyljalkyl, haloalkyl, or the like. :
2. A compound of the formula: : y Ps 0) - . y SYN X4 2 a Sh Ry ~ R, Rs Raa Ara Rg or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: mis 0, 1, or 2; nisOorl, X and X, are independently chosen from C and N, Xs is C-R; or N, Xj3is C-R or N, : R and R, are independently chosen from hydrogen, hydroxy, halogen, amino, cyano, * nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyljalkyl, 460 AMENDED SHEE? 2004 -04- 26
: : optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R2, Rs, Raa, Rs, and Re are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyt; when n is 0, R; and Rs may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted; when n is 1, R and R3 may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted; Rs is alkyl. alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl each of which may be optionally substituted; or : Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings. 3 to 8 members in each ring and from 1 to 3 heteroatoms. Rs and Ry are independently chosen from H or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, (cycloalkyl)alkyl, haloalkyl, &r the like.
3. A compound of the formula: 461 AMENDED SHEET 2004 -04- 26
N X3 Rs Rs Rg ; PY AA Y Ry Ar, Re or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: mis 0, 1, or 2; X2is C-Rj or N, | : Xais C-R or N, E ji R and R; are independently chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; Rz2, R3, Raa, Rs, and Rg are independently selected from hydrogen, hydroxy, halogen, amino, cyano. nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally - substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl: nL R and Ri may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted; R, is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, Bh : optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 : rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and 462 pS AMENDED SHEET 2884 -84- 2¢
: Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally a - substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic : group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms. Rs and Ro are independently chosen from H or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, (cycloalkylalkyl, haloalkyl, or the like.
4. A compound of the formula: R, R FO Var Ary” XC Y R, RiRaa ar, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: the ring system represented by 0 xX" is a 5 to 7 membered heterocycle that may be either aromatic or partially unsaturated, XisNorC; } Y is N or CH; : ‘nis 0, 1, or 2; mis 0, 1, or 2; : R and R, are independently chosen from hydrogen, hydroxy, halogen, amino, cyano, _ nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkylalkyl, 463 AMENDED SHEE 2004 -04- 26
: optionally substituted carbocyclic aryl, optionally substituted arylalkyl, : optionally substituted heteroaryl or heterealicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R2, Rs, Raa, Rs, and Re are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino. optionally : substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkylalkyl; when n is 0, R; and R3 may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted; : : when nis 1, R and Ra may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl each of which may be optionally substituted; or
R. is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 : : rings, 3 to 8 members in each ring and from 1 to3 heteroatoms; and Ar; and Ar» are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
5. A compound according to Claimé4, wherein R and R; are independendently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and : ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may : be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, : 464 AMENDED SHEF™ 2004 -04- 26
: iii} phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, : isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, : pyrimidyl, pyrazinyl, each of which may be optionally substituted or : substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl. alkynyl, alkoxy, amino, and mono- or dialkylamino; Rais hydrogen, hydroxy, halogen, amino. cyano, nitro, or haloalkyl, or R,is alkoxy, mono- or dialkylamino, alkyl, alkenyl, alkynyl or (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, : nitro, cyano, trifluoromethyl, trifluoromethoxy. haloalkyl, hydroxy, acetoxy, : alkoxy, amino, and mono- or dialkylamino; ; Rs, Raa, Rs. and Rs are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyljalkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifftuoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino; when n is 0, R; and Riz may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino; . when n is 1, R and Rs3may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy. acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; ‘ Rs is alkyl, alkenyl, alkynyl, cycloalkyl, {cycloalkyl)alkyl, each of which may be unsubstituted or substituted with 465 AMENDED SHEET 2004 -04-'26 one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; or
Rs is phenyl, ethylenedioxyphenyl, methylenedioxypheny!, phenylalkyl, chromanyl, : pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected i from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy. amino, mono- or dialkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; or Rais a bicyclic oxygen-containing group of the formula: 2%,
wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; and
Ar; and Ar. are independently chosen from i) phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
SEE pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, : benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, 466 AMENDED SHEET 2004 -04- 2 §
. cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally - substituted or substituted with up to four groups independently selected : from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, : hydroxy, -acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, and ii) bicyclic oxygen-containing groups of the formula: 0 NE Rg } wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy. alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino.
6. A compound according to Claimé, wherein R and R, are independently selected from i) hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, mono- or di{Ci- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C2-Ce alkenyl, C,-Cs alkynyl, Ca-Cs cycloalkyl, and (Cs- Cs)cycloalkyl) C1-Cj alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di{Cs- . Cs)alkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl. triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or So substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, 467 AMENDED SHEET 2004 -04- 26
C,;-Cs alkyl, C,-Cs alkenyl, Ca-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Cs)alkylamino; when n is 0, R; and R; may be joined to form a Cz-Cg cycloalkyl or C3-Cs " heterocycloalkyl! ring, each of which may be-unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C-Cs alkyl, C2-Cg alkenyl, C2-Ce alkynyl, C,-C; alkoxy, amino, mono- or di(C;- Ce)alkylamino; when n is 1, R and Rymay be joined to form a C3-Cg cycloalkyl or C3-Cs heterocycloalky! ring, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, : trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C:- Cs)alkylamino; R2 is hydrogen, hydroxy, halogen, amino, cyano, nitro, or haloalkyl, Raz is alkoxy, mono- or di{C;-Ce¢)alkylamino, C,-Cs alkyl, C2-Csalkenyl, C2-Cs alkynyl or (C3-Cscycloalkyl) Ci-Cjalkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkoxy, amino, and mono- or di{C,-Cslalkylamino; Rs, Raa, Rs, and Rg are independently selected from i) hydrogen, halogen, hydroxy, amino, Ci-Cs alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and i1) C1-Cs alkyl, C2-Cs alkenyl, C»-Cs alkynyl, C3-Cg cycloalkyl, and (C3-Cs cycloalkyl) C,-C3 alkyl, each of which may be unsubstituted or substituted by : one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkoxy, amino, mono- or di(C,- Cs)alkylamino; Rs 1s C1-Cg alkyl, C2-Cg allcenyl, Ca-Ce alkynyl, C3-Cg cycloalkyl, (C3-Cs cycloalkyl) Ci- Cs alkyl, each of which may be unsubstituted or substituted with 468 AMENDED SHEET 2004 -04- 26
. one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, : C2-Cs alkenyl, C,-Cs alkynyl, C,-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino; or Ra is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C;-Cialkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz(d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Cs)alkylaminocarbonyl, N-( Ci-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1- piperidyl; or Rs is a bicyclic oxygen-containing group of the formula: : on >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy.
C;-Cs alkyl, Co-Cs alkenyl, Ca-Cs alkynyl, Ci-Cs alkoxy, amino, and mono- or di(Ci- Cs)alkylamino; and : : Ar; and Ar; are independently chosen from phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C,-Cs)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, 1soxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidy!, pyrazinyl, benzimidazolyl, 469 AMENDED SHEET 2004 -04- 26
- naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, “ benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl. . : benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or . quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, Ca-Cs alkenyl, C2-Ce alkynyl, C1-Ce alkoxy, amino, mono- or di(Ci- Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di{C;-Cs)alkylaminocarbonyl, N-(C,-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl; and : ii) bicyclic oxygen-containing groups of the formula: >%, wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C,-Cs alkenyl, Co-Ce alkynyl, C1-Cs alkoxy, amino, and mono- or di{C)- Ce)alkylamino.
7. A compound according to Claim 4 of the formula: ya TEX, rR, Re San PY Ra Ry; Raa ju Ary Rg wherein: oo X and X, are independently chosen from C and N; oo Xa is C-Ry or N; m, Ary, Ara, Ri, Ro, Rs, Raa, Rs, Rs, and Rs are as defined in Claim 4; 470 AMENDED SHEET 2004 -04- 26
: Rs and Ro are independently chosen from H or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, (cycloalkylalkyl, haloalkyl, or the like.
8. A compound of the formula: R, Re - 3m Ary N Ar L RsR 2 R, 3A wherein: mis 0, 1, or 2; . R; is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl! or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R; is chosen from optionally substituted C;-Cs alkyl, optionally substituted C3-Cs cycloalkyl, optionally substituted Cs-Cas cycloalkyl(C:-Cs)alkyl, optionally substituted C,-Cs alkenyl, optionally substituted Ca-Cs alkynyl, haloalkyl, aminoalkyl, each of which may be unsubstituted or substituted, Rs, Ria, Rs, and Rs are independently selected from hydrogen, hydroxy, halogen, } : amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted allcynyl, optionally substituted cycloalkyl, and optionally substituted : {cycloallyl)alkyl; 471 AMENDED SHEET 2004 -04- 26
: . R; and Rs may be joined to form a cycloalkyl or heterocycloalkyl ring, each of which may be optionally substituted; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl each of which may be optionally substituted; or R Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Ar, and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms. !
9. A compound according to claim 8 wherein R; is substituted with one or more substituents selected from oxo, hydroxyl, alkoxy, amide, ester, cyano, acetoxy or nitro.
10. A compound according to claim 9 wherein the oxo is carbonyl.
11. A compound according to Claim 8 of the formula: R4 Ra N 4 7 \_ N
- . \ R Ar, . Ry 3 . wherein m, Ari, Are, Ri, Re, Ra, and Rs are as defined in Claim 8,
12. A compound according to Claim 8 . of the formula: R4 Rs on T rN aL, \ herei | Rj Ara wherein: R, R, is hydrogen, C;-C; alkyl, halogen or phenyl optionally substituted with Ci-Cs alkyl, C1-Ce alkoxy, halogen, hydroxy, amino, or mono- or di(C1-Cs)alkylamino; . Rais C;-Cs alkyl or C3-Cg cycloalkyl; and Rj is hydrogen or Ci-C7 alkyl. 472 AMENDED SHEET 2004-04 20
13. A compound according to Claim 8 of the formula: R, Ry —~ C N AS 1 l R Ary R, 3 wherein: Ar) is phenyl, ethylenediosyphenyl, methylenedioxyphenyl!, phenylalkyl, thienyl, imidazolyl, pyridyl, pyrimidyl, benzodioxinyl, benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, : trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C.-Cs alkenyl, Co- Cs alkynyl, C,-Cs alkoxy, amino, mono- or di(Ci-Ce)alkylamino; Arg is defined as in Claim 8; R; is hydrogen, Ci-C7 alkyl, halogen or phenyl optionally substituted with C;-Cs alkyl, C1-Cs alkoxy, halogen, hydroxy, amino, or mono- or di(C;-Ce)alkylamino; Ra» is C;-Cs alkyl or C3-Cs cycloalkyl; and Rj is hydrogen or C,-C7 alkyl; and Rs is C1-Cg alkyl, C3-Cs cycloalkyl, or (C3-Cs cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected ‘ from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Cs}alkylamino.
14. A compound according to Claim g of the formula: Ry R4 N r N : WAS 1 R Ar, R, 3 wherein: 473 : AMENDED SHEET 2004 -04- 26
Ar, is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, thienyl], imidazolyl, pyridyl, pyrimidyl, benzodioxinyl, benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C»-Cs alkenyl, Co- Ce alkynyl, C,-Ce alkoxy, amino, mono- or di(Ci-Cs)alkylamino; Aris defined as in Claim 8; R; is hydrogen, C,-C7 alkyl, halogen or phenyl optionally substituted with Ci1-GCs allyl, C,-Cs alkoxy, halogen, hydroxy, amino, or mono- or di(C:-Ce)alkylamino; Ro is C;-Cs alkyl or C3-Cs cycloalkyl; and : Rj; is hydrogen or C)-C7 alkyl; and R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl{Ci-Cs)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl. benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Ce alkenyl, Co-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-C¢)alkylamino; or Rs is a bicyclic oxygen-containing group of the formula: . 2 wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca-Cs alkenyl, C2-Cg alkynyl, C1-Cs alkoxy, amino, and mono- or di(Cy- Ce)alkylamino. 474 AMENDED SHEET 2004 -04- 26
15. A compound according to Claim 8 of the formula: : Ri Rs v— ; N AS DY I R r2 . R, 3 wherein: Ar; is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, : C2-Cs alkenyl, C2-Cq alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci- Cs)alkylamino; Ars is defined as in Claim 8; R; is hydrogen, methyl, ethyl, or phenyl; Rs is Ca-Cs alkyl or C3-Cs cycloalkyl; and Rs is hydrogen or methyl; and Rs is C1-Cs alkyl, C3-Cs cycloalkyl, or (C3-Cs cycloalkyl) C1-Cj alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, triflucromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di{C;-Cs)alkylamino.
16. A compound according to Claim 8 of the formula: R; R4 N f rN N AS hy I R 2 R, 3 wherein: 475 AMENDED SHEET 2004 -04- 26
. Ar, is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up r to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di{Ci- Cs)alkylamino; : Ara is defined as in Claim 8: R; is hydrogen, methyl, ethyl, or phenyl; Ra is C3-Cs alkyl or C3-Cy cycloalkyl; and R; is hydrogen or methyl; and : Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl{C;-Cq)alky], . thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d}isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, : haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C-Cs alkenyl, Co-Cs alkynyl, C1-Ce alkoxy, amino, mono- or di(Ci-Cs)alkylamino; or Rs is a bicyclic oxygen-containing group of the formula: ge Ra wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, C»-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C,- : Cs)alkylamino.
17. A compound according to Claim 8 of the formula: 476 AMENDED SHEET 2004 -04- 26
R, _Rs N g N WAS BY R r2 Ro 3 . wherein: : Ar) is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci- Cs)alkylamino; Ar, is chosen from phenyl, phenyl(Ci-Cq)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indany!, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, k benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, . trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Ce alkenyl, C»- Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:- Cs)alkylaminocarbonyl, N-(C,-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl; or Ar, is a bicyclic oxygen-containing groups of the formula: ol NHK CI Ra wherein Rg represents.0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, hydroxy, acetoxy, C.-C alkyl, C»-Cs alkenyl, C»-Cg alkynyl, C,-Cg alkoxy, amino, and mono- or di{C- Ce)alkylamino; R, is hydrogen, methyl, ethyl, or phenyl:
Ra is C3-Cg alkyl or C3-Cs cycloalkyl; and Rs is hydrogen or methyl; and Ry is C1-Cg alkyl, C3-Cg cycloalkyl, or (C3-Cs cycloalkyl) C1-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, Ca-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di{C,-Cs)alkylamino.
18. A compound according to Claim 8 of the formula: Ri Ra4 nv [ N WAS A R 2 R» 3 wherein: Ar, is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C:-Ci)alkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-Ce)alkylamino; Ars is chosen from phenyl, phenyl(C1-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo|bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinelinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, Co- : Ce alkynyl, C,-Cs alkoxy, amino, mono- or di(Ci-Ce)alkylamino, carboxylic - acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;- Ces)alkylaminocarbonyl, N-(C1-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl; or 478 AMENDED SHEET 2004 -04- 26
} Ar; is a bicyclic oxygen-containing groups of the formula: 0 NE . : Re : wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, triftucromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C»-Cp alkenyl, Ca-Cs alkynyl, C,-Cs alkoxy, amino, and mono- or di{C;- Cs)alkylamino; R, is hydrogen, methyl, ethyl, or phenyl; : : R; is C3-Cs alkyl or Cs-Cs cycloalkyl; and ] R; is hydrogen or methyl; and i R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C:-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo{b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d}isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, - haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, C2-Cs alkenyl, Ca-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci-Cslalkylamino; or R: is a bicyclic oxygen-containing group of the formula: os) >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C-Cs alkoxy, amino, and mono- or di(C- Cs)alkylamino.
19. A compound according to Claim 8 of the formula: 479 AMENDED SHEET 2004 -04- 26
R; Re n— [ WAS R Ar R, 3 or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: Ar, is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(Ci-Cs)alkyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Co-Cs alkenyl, Ca-Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C1-Ce)alkylamino;
Ara is a bicyclic oxygen-containing groups of the formula:
NH Rg wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Ca-Cs alkenyl, Ca-Ce alkynyl, C1-Cs alkoxy, amino, and mono- or di(C,- Cs)alkylamino;
R: is selected from i) hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, mono- or di(Ci- Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C;-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (Cs- Cg)cycloalkyl) C1-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(Ci-
Cs)alkylamino; or
R, is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
: pyrazinyl, each of which may be optionally substituted or substituted with : - up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino; R2 and Rj; are independently selected from i) hydrogen, halogen, hydroxy, amino, C;-Ce alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C;-Cs alkyl, Ca-Co alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (C3-Cs cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkoxy, amino, mono- or di(Ci- C¢)alkylamino; and R, is C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, (Cs-Cs cycloalkyl) Ci- Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, C,-Cs alkenyl, C2-Cg alkynyl, C1-Cs alkoxy, amino, and mono- or di(C- Cs)alkylamino; or Ra is phenyl, ethylenedioxyphenyl], methylenedioxyphenyl, phenyl(Ci-Cua)alkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy,
' amino, mono- or di(Ci-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Ce)alkylaminocarbonyl, N-{ C1-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1- piperidyl; or : Rais a bicyclic oxygen-containing group of the formula: on) . Ra wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy. C,-Cs alkyl, C2-Cs ] alkenyl, CoCo alkynyl, C1-Cs alkoxy, amino, and mono- or di(C:-Cs)alkylamino.
20. A compound according to Claim 19, wherein the compound exhibits an ICso of 1uM or less in an assay of CSa mediated chemotaxis or calcium mobilization.
21. A compound according to Claim 19, wherein: R, is hydrogen, methyl, ethyl, or phenyl; Rs is C3-Cs alkyl or C3-Cs cycloalkyl; Rs is hydrogen or methyl; and Rais Ci-Cs alkyl, C2-Cs alkenyl, C»-Cs alkynyl, C3-Cs cycloalkyl, (C3-Cg cycloalkyl) Ci- Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, C2-Cs alkenyl, Ca- Cs alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C;-Ce)alkylamino. : 22. A compound according to Claim 19, wherein: R; is hydrogen, methyl, ethyl, or phenyl, Ra is C3-Cs alkyl or C3-Cs cycloalkyl; Rs is hydrogen or methyl; and 482 AMENDED SHEET 2004 -04- 2 6
Rais Ci-Cs alkyl, C,-Cs alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, (C3-Cs cycloalkyl) Cy- Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, triftuoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, Ca- Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C,-Ce)alkylamino.
23. A compound according to Claim 19, wherein: R, is hydrogen, methyl, ethyl, or phenyl; Raz is C3-Cs alkyl or C3-Cg cycloalkyl, Rs; is hydrogen or methyl; and Ra is phenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl. quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2-Ce alkenyl, Ca- Cs alkynyl, C:-Cs alkoxy, amino, mono- or di(C,1-Cs)alkylamino.
24. A compound according to Claim 19, wherein: R) is hydrogen, methyl, ethyl, or phenyl, Ra» is C3-Cg alkyl or C3-Cg cycloalkyl, Rj; is hydrogen or methyl; and Rs is a bicyclic oxygen-containing group of the formula: - ge : Ra wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C»-Cs alkenyl, C2-Cs alkynyl, Ci1-Ce alkoxy, amino, and mono- or di(C,- Cs)alkylamino. 483 AMENDED SHEET 2004 -04- 2 6
25.A compound of the formula: Re Ria Rs . Rg N (CRsaRsa) n AS Ar, N N Rs Ar, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: n is an integer from 0 to 3; and R» is chosen from optionally substituted Ci-Cs alkyl, optionally substituted C3-Cs cycloalkyl, optionally substituted Cs-Cs cycloalkyl(C,-Cslalkyl, optionally substituted C»-Cs alkenyl, optionally substituted Cz-Cs alkynyl, haloalkyl, aminoalkyl, each of which may be unsubstituted or substitu ted, Rs is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl, haloalkyl, each or which may be substituted or unsubstituted; or Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms, Rs and R3a are the same or different and represent hydrogen or alkyl; or Rs and Raza, taken together with the carbon atom to which they are attached, form a cycloalkyl ring; Rs and Rs are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or 484 AMENDED SHEET 2004 -04- 26
} Rs and Rs, taken together with the carbon atom to which they are attached form a cycloalkyl ring; . Rsa and Rea are the same or different, and are independently selected at each
Co. occurrence from hydrogen, halogen, hydroxyalkyl and alkoxy; R7 represents hydrogen or alkyl; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar, are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic . group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.
26. A compound according to claim 25 wherein R; is substituted with one or ~ more substituents selected from oxo, hydroxyl, alkoxy, amide, ester, cyano, acetoxy or nitro.
27. A compound according to claim 26 wherein the oxo is carbonyl. :
28. A compound according to Claim 25,wherein: n, Rs, Rs, Raa, Rs, Re, Rsa, Rea, and R; are defined as in Claim 25, aad R4 is hydrogen or . alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino, : Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, : pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, 485 AMENDED SHEET 2004 -04- 26 benzodioxinyl, benzodioxolyl, benz(d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, 480 AMENDED SHEET 2084 94 76 aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and - XaRg, wherein Xs and Rp are as defined below; or
Rais a bicyclic oxygen-containing group of the formula:
>%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifftuoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or;
Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d}isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and — X4Rp, wherein Xs and Rg are as defined below;, and ii) bicyclic oxygen-containing groups of the formula:
0 2 gn wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, ” : trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; X,4 is independently selected at each occurrence from the group consisting of -CHa-, - CHRc-, -O-, -S(O)m-, -NH-, -NRc-, -C(=O)NH-, -C(=O)NRc-, -S(0)uNH-, -5(0)aNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)a-, -C(=O)NHS(O}a-, and ~NRcS(O)n- (where m is 0, 1, or 2); and Rs and Re, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH(alkyl), -N{alkyl)(alkyl), -NHC(O)(alkyl), -N(alkyl)C(O)(alkyl), -NHS(O)x(alkyl), -S(O)x(alkyl), ~ S(0)xNH{alkyl), _S(O)N(alkyl) ali), (where xis 0, 1, or 2).
29. A compound according to Claim 25, wherein: n and Rs are defined as in Claim 25, and R: and Risa are the same or different and represent hydrogen or C,-Cs alkyl; or R; and Rsa. taken together with the carbon atom to which they are attached, form a
Cs.s cycloalkyl ring; “ Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, C1-Ce alkyl, or C;-Cs alkoxy; or : Rs and Rs, taken together with the carbon atom to which they are attached form a
Cs.s cycloalkyl ring;
Rs. and Rg, are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, Ci-Ce alkyl, and C.-C alkoxy; R4 is hydrogen or 488 AMENDED SHEET 2004 -04- 26
Cis alkyl, Cag alkenyl, Ca. alkynyl, Ca-scycloalkyl, (Ci.s cycloalkyl)Ci.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, triflnoromethoxy, haloalkyl, hydroxy, acetoxy, C;1-Ce alkyl, Co. alkenyl, Cog alkynyl, C;-Cs alkoxy, amino and mono- or di(C;-Ce)alkylamino,
R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, Co. alkenyl, C26 alkynyl, C,-Cs alkoxy, amino,
mono- or di(C1-Ce)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Ce)alkylaminocarbonyl, N-{ Ci-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, — X4RB, wherein Xs and Rg are as defined below; or ) Rs is a bicyclic oxygen-containing group of the formula: ON >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2 alkenyl, C2. alkynyl, C,-Cs alkoxy, amino, and mono- or di(Cs- Ce)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl; Ary and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo|b|thiophenyl, benzodioxanyl,
benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyi, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Caz.6 alkenyl, C26 alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-Ce)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-C¢)alkylaminocarbonyl, N-( Ci1-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —X4Rg, wherein X; and Rp are as defined below; and il) bicyclic oxygen-containing groups of the formula:
on) Re wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C26 alkenyl, Ca. alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino;
X4 is independently selected at each occurrence from the group consisting of -CHa-, - CHRc¢-, -O-, -5(O)w-, -NH-, -NRc-, -C(=0)NH-, -C(=O)NR¢-, -S(O)nNH-, -S(0)uNRc-, -NHC(=0)-,
-NRcC(=0}-, -NHS(O})w-, -C(=O)NHS(O)m-, and ~NRcS(O)u- (Where m is 0, 1, or 2); ; and Re and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or
: substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C1-Cs alkyl), -NH(C1-Cs alkyl), -N(C1-Cs alkyl)(C1-Cs alkyl), -NHC(0)(Ci-Cs alkyl), -N(Ci-Cs alkyl)C(O)(C1.s alkyl}, -NHS(O)x(C1-Cs alkyl), -S(0)x(C1-Ce alkyl), - : S(0)xNH(C1-Cs alkyl), -S(O}xN(C1-Cs alkyl)( Ci-Cs alkyl), (where x is 0, 1, or 2).
30. A compound according to Claim 25, wherein n, R2, R3, Raa, Rs, Re, Rsa, Rea, and Ry are as defined in Claim 25, Rs is hydrogen or C1-Cs alkyl, Co-Cq alkenyl, C-Cs alkynyl, Ca-Cscycloalkyl, (C3-Cacycloalkyl) C1-Caalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca-Cs alkenyl, C2-C¢ alkynyl, Ci-C¢ alkoxy, amino and mono- or di(Ci- Ce)alkylamino, Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Ce alkenyl, Ca- Ce alkynyl, C:-Cs alkoxy, amino, mono- or di(Ci-Cs)alkylamino, amino(C;- Cg)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-C¢)alkylaminocarbonyl, N-( C1-Ces)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl, -XaRs, wherein Xa and Rp are as defined below; or : R4is a bicyclic oxygen-containing group of the formula: OT >%, 91 : AMENDED SHEET 2004 -04- 26 wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C»-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C- Ce)alkylamino;
Ar; is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, thienyl, or pyridyl, : pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or substituted with up to four substituents independently selected from:
halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,- Cs)alkylaminocarbonyl, N-( C,-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —X4Rs, wherein X4 and Rg are as defined below;
Ar; is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cg alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-( C;- Co)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and - X4Rg, wherein X; and Rp are as defined below; or
Ars is a bicyclic oxygen-containing group of the formula:
CL Ra’
wherein Ry’ represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-C¢ alkenyl, C2-Cs alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; X4 is independently selected at each occurrence from the group consisting of -CHz-, - CHRc-, -O-, -8(O)n-, -NH-, -NRc-, -C(=0O)NH-, -C(=O)NRc-, -S(O)uNH-, -S(O)mNRc-, -NHC(=0}-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)a-, and -NRcS(O)n- (where m is 0, 1, or 2); and Rp and Re, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C,1-Cs alkyl), -NH(C1-Cs alkyl), -N(C1-Cs alkyl)(C:-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Ce alkyl)C(O)(C1-Ce¢ alkyl), -NHS(O)«(C1-Cs alkyl), -S(0)«(C1-Cs alkyl), - S(O)xNH(C1-Cs alkyl), -S(O)xN(C1-Cs alkyl)(Ci-Ce alkyl), (where x is 0, 1, or 2).
31. A compound according to Claim 30 wherein: Rs and R4 are the same or different and represent hydrogen or methyl; Rs and Rs are the same or different and represent hydrogen or methyl; and Rss and Rea are the same or different, and are independently selected at each occurrence from hydrogen and methyl.
32. A compound according to Claim 30 wherein: R3 and R4 are hydrogen; Rs and Rg are the same or different and represent hydrogen or methyl; and Rsa and Rsa are the same or different, and are independently selected at each occurrence from hydrogen and methyl.
33. A compound according to Claim 30 of the formula: Rs Re I Res) n oe N R; i N yA = Rs Ar, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: Ra, Rs, Arg, and n are as defined for Claim 30; Rs and Rs are the same or different and represent hydrogen or methyl; Rsa and Rea are the same or different, and are independently chosen at each occurrence from hydrogen and methyl; and Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C»-Cs alkenyl, C2-Cs¢ alkynyl, C;-C¢ alkoxy, amino, mono- or di(C,-Ce)alkylamino, and amino(C;-Ce)alkoxy.
34. A compound according to Claim 32, of the formula: Rs Re I sae) n or N R2 é ™ . 4 A Rs Ar, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: R4, Arp, and n are as defined for Claim 30; R: is C3-Cs straight or branched chain alkyl, C2-Cs alkenyl, or C2-Cg alkynyl;
Rs and Rs are the same or different and represent hydrogen or methy Rsa and Re. are the same or different, and are independently chosen at each occurrence from hydrogen and methyl; and Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, C,-Cs alkenyl, C2-Cs alkynyl, Ci-Cs¢ alkoxy, amino, mono- or di(C-Ce)alkylamino, and amino(C,;-Ce)alkoxy.
35. A compound according to Claim 33, ora pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: Arz, Rx, and n are as defined for Claim 30 R2 is C3-Cg straight or branched chain alkyl, C»-Cs alkenyl, or C2-Cs alkynyl; and Rs is C:1-Cg straight or branched chain alkyl, C3-Cs alkenyl, or C2-Cg alkynyl.
36. A compound according to Claim 33, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: R: is C3-Cs straight or branched chain alkyl, C,-Cg alkenyl, or C»-Cg alkynyl; Rs is phenyl, which may be unsubstituted or substituted with: Ci1-Cs alkyl, C2-Cs alkenyl, Cz-Cs alkynyl, C3-Cs cycloalkyl, (Cs-Cs cycloalkyl)C,-C4 alkyl, haloalkyl, C;-Cs alkoxy, halogen, hydroxy, amino, or mono- or di(C,-Ce)alkylamino; or R4 is a bicyclic oxygen containing group of the formula: 0 ie ° 2 o-oo Ra 0 Ra wherein Ra is hydrogen, Ci-Cs alkyl, C2-Cs alkenyl, C,-Cg alkynyl, Cs-Cg cycloalkyl, (Cs-Cscycloalkyl) C1-Cs alkyl, haloalkyl, alkoxy, halogen, hydroxy, amino, or mono- or di(C1-Cs)alkylamino; Ar; is phenyl which is unsubstituted or optionally substituted or substituted with up to four groups independently selected from:
halogen, Ci-C7 alkyl, C;-C; alkoxy, cyano, amino, mono- or di(C;- Ce)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, 1-morpholino, nitro, hydroxy, acetoxy, trifluoromethyl, and . trifluoromethoxy or —X4Rg, wherein X4 and Rp are as defined for Claim 33; or Ar; is a bicyclic oxygen-containing group of the formula:
o . 0 Sr oor - Od lo) Ra 0 Ra wherein Rj, Ra’, and n are as defined in Claim 33.
37. A compound according to Claim 33, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: R; is C3-Cs straight or branched chain alkyl, C2-Cs alkenyl, or C,-Cs alkynyl; Rs is C1-Cs straight or branched chain alkyl, C2-Cs alkenyl, or Ca2-Cs alkynyl; Ar; is a bicyclic oxygen containing group of the formula: 0 je © Jd - C 0 Ra 0 Ra wherein Ra’ and n are as defined for Claim 33.
38. A compound of the formula: Rs; R3A%s : MeO Rsa io Br 0 wherein: n is an integer from O to 3; R3 and Rasa are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or R3 and Raa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring; Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or Rs and Re, taken together with the carbon atom to which they are attached form a cycloalkyl ring; and Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy.
39. A compound according to Claim 38, wherein: R3 and Rasa are the same or different and represent hydrogen or C;-Cs alkyl; or Rj; and Ria, taken together with the carbon atom to which they are attached, form a cycloalkyl ring of from three to six carbon atoms; Rs and Rs are the same or different and represent hydrogen, halogen, hydroxy, C,-Cs alkyl, or C;-C¢ alkoxy; or Rs and Re, taken together with the carbon atom to which they are attached form a cycloalkyl ring of from three to six carbon atoms; and Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, Ci- Cs alkyl, or C,-Cs alkoxy.
40. A compound according to Claim 38, wherein: : Rj; and Rs are hydrogen; and Rs, Re, Rsa, and Rea are the same or different and represent hydrogen or methyl.
41. A compound of the formula:
Rs RaaRq Re N Rsa Pres Ary N \ 0] Ro wherein:
n is an integer from 0 to 3;
R; is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each of which may be substituted or unsubstituted;
R3; and Ry are the same or different and represent hydrogen or alkyl; or
Rs and Rasa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or
Rs and Rg, taken together with the carbon atom to which they are attached, form a cycloalkyl ring;
Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; and
Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or;
Ar; is unsubstituted or substituted carbocyclic aryl, unsubstituted or substituted arylalkyl, or a unsubstituted or substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.
42, A compound according to Claim 41 in which:
R2 is C1-Cs straight or branched chain alkyl, C.-Cs alkenyl, C>-Cg alkynyl, C3-Cs cycloalkyl, C2-Cg (cycloalkyl)Ci-Cs4 alkyl, or C:-Cs haloalkyl;
: R3 and Rasa are the same or different and represent hydrogen or C:-Cg alkyl; or Ra and Ra,, taken together with the carbon atom to which they are attached, form a cycloalkyl ring of from three to six carbon atoms; and
Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, Ci-Cs alkyl, or C;-Ce alkoxy; or
Rs and Rs, taken together with the carbon atom to which they are attached form a cycloalkyl ring of from three to six carbon atoms;
Rsa and Rea are the same or different and represent hydrogen, halogen, hydroxy, Ci- : Cs alkyl, or C;-Cs alkoxy;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, phenyl, thienyl, or pyridyl, pyrimidyl, dihydrobenzofuranyl, furanyl, benzodioxanyl, indolyl, each of which is unsubstituted or substituted with up to four substituents independently selected from:
halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,
hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cg alkynyl, C;-Cs alkoxy, amino, mono- or di(C,;-Cs)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;- Ce)alkylaminocarbonyl, N-( C,-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidiny}, 1-piperidyl, and -X4Ra, wherein X4 and Rg are as defined below;
Xs is independently selected at each occurrence from the group consisting of -CH»-, - CHRc-, -O-, -S(O)n-, -NH-, -NR¢-, -C(=0O)NH-, -C(=O)NRc¢-, -S(O)uNH-, - S(0)mNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)m-, and — NRcS(O)m- (Where m is 0, 1, or 2); and
Rs and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted : with one or more substituent(s) selected from: oxo, hydroxy, -O(C,-Cs alkyl), -NH(C1-Cs alkyl), -N(C1-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C;-Cs alkyl)C(0)(C1-Cs alkyl), -NHS(0)x(C1-Cs alkyl), -S(0)x(C1-Cs alkyl), -
S(0)xNH(C1-Cs alkyl), -S{O)xN(Ci-Ce alkyl)(C1-Cs alkyl), (Where x is 0, 1,o0r 2).
43. A compound according to Claim 41 of the formula: R ®> Rs N 5A / \ Rea AN fn N KK = | © Rx Ra wherein: nis 0, 1, or 2: Rs is C3-Cg straight or branched chain alkyl, C2-Cs alkenyl, or C2-Csg alkynyl; Rs, Rs, Rsa, and Rea are the same or different and represent hydrogen or methyl; and Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, C»-Cg alkenyl, C»2-Cs alkynyl, C;-C¢ alkoxy, amino, mono- or di(C,-Cs)alkylamino, and amino(C;-Cs)alkoxy.
44. A compound of the formula: R3aRs Rj Rg R N a PE ) Ry Arq N HO R2 wherein: n is an integer from O to 3; and R; is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl, haloalkyl, each or which may be substituted or unsubstituted; S00
Rs and Raza are the same or different and represent hydrogen or alkyl; or Rs; and Rasa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring; Rs and Re are the same or different and represent hydrogen or alkyl; or Rs and Rs, taken together with the carbon atom to which they are attached, form a cycloalkyl ring; Rsa and Rea are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy; Ry; represents hydrogen or alkyl; and Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms.
45. A compound according to Claim 44, of the formula: Rs Re N Rsa AEG AN " 4 OH RY NF R2 wherein: n is an integer from 0 to 3; R: is C3-Cg straight or branched chain alkyl, C,-Cg alkenyl, or C»-Cg alkynyl; Rs, Re, Rsa, and Rea are the same or different and represent hydrogen or methyl; and Rx represents up to four substituents independently chosen from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C,-Cs alkenyl, C»-Cg alkynyl, Ci-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, and amino(C:-C¢)alkoxy. S01
46. A process for preparing a compound of the formula: R, R;A Rs Re 0 A =" R; Ar, N N SE Rs Ar, wherein: n is an integer from O to 3; and R2 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, or haloalkyl, each or which may be substituted or unsubstituted; R4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be substituted or unsubstituted; or R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaromatic or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms, R3 and Ria are the same or different and represent hydrogen or alkyl; or R3 and Raa, taken together with the carbon atom to which they are attached, form a cycloalkyl ring; Rs and Rg are the same or different and represent hydrogen, halogen, hydroxy, alkyl, or alkoxy; or Rs and Rs, taken together with the carbon atom to which they are attached form a cycloalkyl ring; Rs, and Resa are the same or different, and are independently selected at each occurrence from hydrogen, halogen, hydroxy, alkyl, and alkoxy; R7 represents hydrogen or alkyl; Ar, is ethylenedioxyphenyl, methylenedioxypheny], or;
Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, or an optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 hetero atoms. : the process comprising: reacting a compound of the formula: Rs foals, ge A o Arq N Y Ry Ry wherein Y is halogen or sulfonate ester, in a suitable solvent in the presence of a suitable base, with a secondary amine of the formula: HN [1 Ry Arp
47. A process according to Claim 46, wherein n and Y are as defined in Claim 46; Rs and Ria are the same or different and represent hydrogen or C1-Ce alkyl; or R3 and Raia, taken together with the carbon atom to which they are attached, form a
Cs.s cycloalkyl ring; Rs and Re are the same or different and represent hydrogen, halogen, hydroxy, Ci-Cs . alkyl, or C,-Cs alkoxy; or Rs and Rs, taken together with the carbon atom to which they are attached form a Cis cycloalkyl! ring; Rsa and Rea are the same or different, and are independently selected at each ~ occurrence from hydrogen, halogen, hydroxy, Ci1-Cs alkyl, and C,-Cs alkoxy;
R2 is hydrogen or
Cis alkyl, Cas alkenyl, Cas alkynyl, Cs.g cycloalkyl, (Css cycloalkyl) Ci.3 alkyl, or Ci-
Cs haloalkyl, each or which unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluormethyl, trifluoromethoxy, Ciz haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C:-C¢)alkylamino;
Ra is hydrogen or Cis alkyl, Cas alkenyl, Cag alkynyl, Cs.scycloalkyl, (Cs.g cycloalkyl)Ci aalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce¢ alkyl, Cae alkenyl, Coa.¢ alkynyl, C;-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino,
Rs is phenyl], ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl], benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cs.¢ alkenyl, Ca. alkynyl, C1-Cs alkoxy, amino, mono- or di{C1-Cg)alkylamino, amino(C;-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs)alkylaminocarbonyl, N-( Ci1-Cg)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, — X4Rp, wherein X4 and Rp are as defined below; or
Rs is a bicyclic oxygen-containing group of the formula: 2%,
wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl,
C26 alkenyl, Ca.6 alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or;
Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,
thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluioromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.6 alkenyl, Ca.¢ alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-Cg)alkylamino, amino(C;-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( C1-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —X4Rg, wherein X4 and Rp are as defined below; and ii) bicyclic oxygen-containing groups of the formula:
0 x oN wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, ' Ca.¢ alkenyl, C2. alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino;
X4 is independently selected at each occurrence from the group consisting of -CHa-, - CHRc-, -O-, -5(0)w-, -NH-, -NR¢-, -C(=O)NH-, -C(=O)NRc-, -S(O)uNH-, -S(O)mNRc-, -NHC(=0}-,
SS
-NRcC(=0}-, -NHS(O)n-, -C(=O)NHS(O)n-, and —NRcS(O)n- (Where m is 0, 1, or 2); and Rp and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: : hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(Ci1-Cs alkyl), -NH(C:-Cs alkyl), -N(C1-C¢ alkyl)(Ci1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-C¢ alkyl)C(O)(Ci-6 alkyl), -NHS(O}x(C1-Cs alkyl), -S(O)x(C1-Cs alkyl), - S(O)«NH(C,-C¢ alkyl), -S(O)xN(C1-Ce alkyl) C1-Cs alkyl), (where x is 0, 1, or 2).
48. A compound of the formula: Rq Xr" rere Re J Arq ZZ mN R2 R3R3a Ara or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: mis 0, 1, or 2; R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally : substituted (cycloalkylalkyl; or R is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; S06
Ri, R2, Rs, Raa, Rs, ‘and Re are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally : substituted (cycloalkylalkyl; Raq is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
49. A compound according to Claim 48, wherein the compound exhibits an ICs0 of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
50. A compound according to Claim 48 of the formula R1 R N XX I. Ry ! Ar ZF N R2 Rj Ara wherein Ar, Ara, R, Rj, R2, R3, and R4 are as defined in Claim 48.
51. A compound according to Claim 50, wherein R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino; or
: R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; and
Ri, R2, and Rs; are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
R4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,
Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinoliny},
cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or ’ dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, —-X4Rs, wherein X4 and Rg are as defined below; or Rais a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from i} phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b}thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d}isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or } dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —- XaRg, wherein X; and Rg are as defined below; and il) bicyclic oxygen-containing groups of the formula: oe NT Rp wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; Xa is independently selected at each occurrence from the group consisting of -CHa-, - CHRc-, -O-, -S(0)n-, -NH-, -NR¢-, -C(=O)NH-, -C(=O)NRc-, -S{O)uNH-, -S(O)uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)m-, -C(=O)NHS(O)w-, and -NRcS(O)n- (Where m is 0, 1, or 2); and Rp and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH(alkyl), -N(alkyl)(alkyl), -NHC(O)(alkyl), -N(alky])C(O)(alkyl), -NHS(O)«(C1-Cs alkyl), -S(O)«(alkyl), -S(O)xNH(alkyl), -S(O):N(alkyl)(alkyl), (where x is 0, 1, or 2).
52. A compound according to Claim 50, wherein Ri, R2, and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(C;- Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C,-C¢ alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (Cs-Cs cycloalkyl) C,-C; alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, Ci1-Cs alkoxy, amino, mono- or di(Ci- Ce)alkylamino;
Ris selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(Ci-
’ Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C2-Cs alkenyl, C»-Cs alkynyl, Cs-Cs cycloalkyl, and (Ca- Cs)cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;- C¢)alkylamino; or
R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Co-Cs alkenyl, C2-Ce alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino;
Rs is hydrogen or Cis alkyl, Cz.s alkenyl, Cas alkynyl, Ca.scycloalkyl, (Css cycloalkyl)Ci-4alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca.¢ alkenyl, Ca.6 alkynyl, C:-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino,
Rs4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl,
pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
‘ oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl,
sn cinnolinyl, quinazolinyl,.or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C26 alkenyl, C2.¢ alkynyl, C;-Ce alkoxy, amino, mono- or di(C,-Ce)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C,1-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, — X4Rg, wherein X4 and Rg are as defined below; or Ris a bicyclic oxygen-containing group of the formula: on) >%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
Ca.6 alkenyl, Cz alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino; and Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazoly], thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cz2.6 alkenyl, Ca.s alkynyl, C1-Ce alkoxy, amino, mono- or di(Ci-Cs)alkylamino, amino(C:-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-C¢)alkylaminocarbonyl, N-( S12
C:-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and —X4Rp, wherein X4 and Rg are as defined below; and ii} bicyclic oxygen-containing groups of the formula: 0 x oN wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl,
Ca. alkenyl, Cas alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;- C¢)alkylamino; Xs is independently selected at each occurrence from the group consisting of -CHaz-, - CHRc-, -O-, -S(O)m-, -NH-, -NR¢-, -C(=0O)NH-, -C(=O}NRc-, -S(O}uNH-, -S(O)uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)m-, -C(=O)NHS(O)n-, and -NRcS(O)n- (Where m is 0, 1, or 2); and Rs and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C1-Cs alkyl), -NH(C,-Cs alkyl), -N(C1-C¢ alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Cs alkyl)C(O)(C1-6 alkyl), -NHS(O)«(C1-Cs alkyl), -S(O)«(C:-Cs alkyl), - S(O)xNH(C,-Cs alkyl), -S(O)xN(C1-Cs alkyl)( C1-Cs alkyl), (Where x is 0, 1, or 2). }
53. A compound according to Claim 50, wherein: R is hydrogen, halogen, C;-Cs alkyl, C;-Cs alkenyl, C2-Cs alkynyl, C;-Cs cycloalkyl, (Ca-Cgcycloalkyl)Ci-Caalkyl, C;-Cs alkoxy, or C;-Cg haloalkyl, or
R is a phenyl which may be substituted by up to five substituents independently chosen from C;-Cg alkyl, C,-Cs alkenyl, C,-Cs alkynyl, C:-Cs alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy, nitro, amino, mono or di(Ci- Ce)alkylamino, aminocarbonyl, sulfonamido, mono or di(C,-Cs)alkylsulfonamido, 3,4-methylenedioxy, 3,4-(1,2-ethylene)dioxy, trifluoromethyl or trifluoromethoxy;
R; is hydrogen, C;-Cs alkyl, C2-Cg alkenyl, C;-Cg alkynyl, C3-Cg cycloalkyl (Cs- Cscycloalkyl)C,-Csalkyl or C;-Cg haloalkyl;
Ry is C;-Cs alkyl, C2-Cs alkenyl, C;-Cs alkynyl, C;-Cs cycloalkyl or (Cs- Cscycloalkyl)C,-Csalkyl or C1-Cg haloalkyl;
R; is hydrogen, C;-Cg alkyl, C2-Cg alkenyl, or C,-Cg alkynyl;
R4 is C;-Cs alkyl, C3-Cs cycloalkyl, or {(C3-Cg cycloalkyl) C,-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, triftuoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C,-Cs alkenyl, C2-C¢ alkynyl, C:-Cs alkoxy, amino, and mono- or di(C,-Cg)alkylamino; or
Rs is phenyl, phenyl(C:-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl,
indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C3-C¢ alkenyl, Co- Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino; or
Rs is a bicyclic oxygen-containing group of the formula:
2% wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce¢ alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C;-C¢ alkoxy, amino, and mono- or di(C;-Cs)alkylamino; and S14
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar: are independently chosen from phenyl, phenyl(C:-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d)isoxazolyl, quinolinyl, : isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C,-Ce alkenyl, C2-Cg alkynyl, C,-C¢ alkoxy, amino, mono- or di(C,-Cs)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs)alkylaminocarbonyl, N-(C;- Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl, and bicyclic oxygen-containing groups of the formula: 0 2 GN wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino.
54. A compound according to Claim 50, wherein: R is hydrogen, halogen, C,-Cs alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C,-Cs cycloalkyl, (C3-Cgcycloalkyl)Ci-Caalkyl, Ci-Cg alkoxy, or C;-Cg haloalkyl, or Ris a phenyl which may be substituted by up to five substituents independently chosen from C,-Cs alkyl, C,-Cs alkenyl, C>-Cs alkynyl, C,-Cs alkoxy, halogen, cyano, carboxylic acid, hydroxy, acetoxy, nitro, amino, mono or di(Ci- Ce)alkylamino, aminocarbonyl, sulfonamido, mono or di(C;-Ce)alkylsulfonamido, 3,4-methylenedioxy, 3,4-(1,2-ethylenejdioxy, trifluoromethyl or trifluoromethoxy; S18
R, is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, C»-Cs alkynyl, C3-Cs cycloalkyl (Cs- Cscycloalkyl)Ci-Csalkyl or Ci-Cg haloalkyl;
Ry is Ci-Cg alkyl, C,-Cs alkenyl, C»-Cs alkynyl, Ci-Cs cycloalkyl or (C3-Cs cycloalkyl) Ci-Caalky! or C1-Cg haloalkyl;
Rs is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, or C2-Cg alkynyl;
Rs is C1-Cs alkyl, C3-Cs cycloalkyl, or (C3-Cs cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Cj;-C¢ alkyl, C2-C¢ alkenyl, C2-Ce alkynyl, C,-C¢ alkoxy, amino, and mono- or di(C1-Ce)alkylamino; or
Rs is phenyl, pheny](C1-Cas)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl,
indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz|[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, Co- Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino; or Rs is a bicyclic oxygen-containing group of the formula: >%,
wherein Ra represents O to 3 groups selected from halogen, nitro, cyano,
trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Ce alkenyl, C»-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Ce)alkylamino;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C,-Cs alkenyl, C2-Ce alkynyl, C,-Cs alkoxy, amino, mono- or di(C:-Cs)alkylamino; and
Ar; is phenyl, phenyl(Ci-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four : groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-Cs alkenyl, Co- Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:- Cs)alkylaminocarbonyl, N-(Ci-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl, or Ar; is a bicyclic oxygen-containing group of the formula: oN) Rp wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C,-Cg alkynyl, Ci1-Cs alkoxy, amino, and mono- or di(Ci- Ce)alkylamino.
55. A compound according to Claim S50, wherein R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or phenyl; R; is hydrogen, methyl or ethyl; Rz is C3-Cs alkyl; Riis hydrogen, methyl or ethyl; Rs is C)-Cs alkyl, C3-Cs cycloalkyl, or (C3-Cs cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-C¢ alkenyl, C»-Cs alkynyl, C:-Cs alkoxy, amino, and mono- or di(C,-Ce)alkylamino; or
Rs is phenyl, phenyl(Ci1-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four : groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-Cs alkenyl, Co- Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino; or Rs is a bicyclic oxygen-containing group of the formula: oe) 2%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;-Ce)alkylamino; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino; and Ar; is phenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benzjd]isoxazolyl, quinolinyl, isoquinolinyl, and quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl, C2o-Cs alkenyl, Co- Cs alkynyl, C,-Cs alkoxy, amino, mono- or di(C,-Ce)alkylamino; Ar is a bicyclic oxygen-containing group of the formula: on] gS ZZ Re wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2-Ce alkenyl, C2-Cs alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C:-Cs)alkylamino. )
56. A compound of the formula: R4 Xr? RRs Re J Ar = mN R2 R3 Ria Arp wherein:
mis O, 1, or 2;
R is hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl; or
R is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
Ri, Ra, Rs, Raa, Rs, and Rg are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;
} Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl each of which may be optionally substituted; or R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar: are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
57. A compound of the formula: Rq NX R R4 Lo Ar FZ NH R: Rs wherein Ari, R, Ri, Rs, R3, R4 are as defined in Claim 56.
58. A compound according to Claim 56, wherein: Ri, Re, and Rj; are independently selected from i) hydrogen, halogen, hydroxy, amino, C,-Ce alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C;-Cg alkyl, C2-Cs alkenyl, C»-Cg alkynyl, C3-Cs cycloalkyl, and (C3-Cs cycloalkyl) C;-C; alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkoxy, amino, mono- or di(Ci- Ce)alkylamino; Ris selected from i) hydrogen, halogen, hydroxy, amino, C:-Cs alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and : ii} C,-Cs alkyl, C2-Cs alkenyl, C,-Cg alkynyl, C3-Cs cycloalkyl, and (Ca- Csg)cycloalkyl) Ci-C3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(Ci- Cs)alkylamino; or
R is selected from phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
} oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl, C2-Cs alkenyl, C2-C¢ alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino;
R4 is hydrogen or Cis alkyl, Cas alkenyl, Ca.s alkynyl, Ca.gcycloalkyl, (Cs.s cycloalkyl)Ci.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2 alkenyl, Cas alkynyl, C,-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino,
Ra is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indoly], indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cz.6 alkenyl, C26 alkynyl, C:-Ce alkoxy, amino, mono- or di(Ci1-Ce)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Cy-Cs)alkylaminocarbonyl, N-( . Ci-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, — X4Rp, wherein X,; and Rp are as defined below; or Rais a bicyclic oxygen-containing group of the formula:
>%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl,
Ca. alkenyl, Cs.¢ alkynyl, C1-Cs alkoxy, amino, and mono- or di(Ci- Ce)alkylamino; and Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; : Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Ca.¢ alkenyl, Cae alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce¢)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C:-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -X4Rp, wherein X4 and Rg are as defined below; and il) bicyclic oxygen-containing groups of the formula: 0 2 (J wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C26 alkenyl, Ca.6 alkynyl, C1-Cs alkoxy, amino, and mono- or di(Ci- Cs)alkylamino; :
X. is independently selected at each occurrence from the group consisting of -CHa-, - CHRc-, -O-, -S(O)w-, -NH-, -NRc-, -C(=O)NH-, -C(=O)NRc-, -S(O})uNH-, -S(O})uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)m-, -C(=O)NHS(O)-, and -NRc¢S(O)u- (where mis 0, 1, or 2); and Rs and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: : hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C1-Cs alkyl), -NH(C,-Cs alkyl), -N(C1-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Cs alkyl)C(O)(Ci16 alkyl), - NHS(O)x(C1-Ce alkyl), -S(O}x(C1-Cs alkyl), -S(O)xNH(C:-Ce¢ alkyl), -S(O)xN(Ci-Ce alkyl)( C1-Ce¢ alkyl), (where xis 0, 1, or 2).
59. A compound according to Claim 56, wherein: R is hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, or phenyl; Ri is hydrogen, methyl or ethyl; R: is C3-Ce alkyl; Rs is hydrogen, methyl or ethyl; R4 is C;-Cg alkyl, C3-Cg cycloalkyl, or (Cs-Cs cycloalkyl) Ci-Cs alkyl, each of which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, triftuoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C;-C¢ alkenyl, C2-Cs alkynyl, Ci;-C¢ alkoxy, amino, and mono- or di(C,-Cs)alkylamino; or Rs is phenyl, phenyl(C;-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl,
. indolyl, indanyl, benzo[b]thiophenyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Ce alkenyl, Ca Cs alkynyl, C;-Ce alkoxy, amino, mono- or di(Ci-Cs)alkylamino; or Rais a bicyclic oxygen-containing group of the formula: OF >%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C:-Cs alkoxy, amino, and mono- or di(Ci-Ce)alkylamino; and Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, phenyl, thienyl, or pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-C¢ alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C:-Cs alkoxy, amino, mono- or di(C:-Cs)alkylamino.
60. A compound of the formula: N R = PEN m N Ry Roz R; Ri Ara or pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: misO, 1, or 2; R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted ‘ alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl,
optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; Ra, Rs, Raa, Rs, and Re are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyljalky); R and R3; may be joined to form an optionally substituted saturated carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ringof from to 8 members; R4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
61. A compound according to Claim 60, wherein the compound exhibits an ICso of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
62. A compound according of the formula: . R Pv a ads Ry Rs Ar or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, i mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, ’ optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R: and Rj; are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl; R and R; may be joined to form an optionally substituted carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ring of from S ro 8 members; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkylalkyl each of which may be optionally substituted; or Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
63. A compound according to Claim 62, wherein R and Rj are not joined.
64. A compound according to Claim 62, wherein: R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, ’ trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazoly], isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; R2 and Rj; are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino; R4 is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino, R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{b]thiophenyl, benzodioxanyl,
benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,
: hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and — Xa4Rs, wherein X43 and Rg are as defined below; or
Rs is a bicyclic oxygen-containing group of the formula:
oe) 2%,
wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or;
Ar) and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazoly}, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl,
hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N-
alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and - X4Rp, wherein X4 and Rg are as defined below;, and ii) bicyclic oxygen-containing groups of the formula: CL Rg wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; X4 is independently selected at each occurrence from the group consisting of -CHo-, - CHRc-, -O-, -S(O)m-, -NH-, -NR¢-, -C(=0)NH-, -C(=0)NRc-, -S(O)uNH-, -S(O)mNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)w-, and ~NRcS(O)n- (Where m is 0, 1, or 2); and Rp and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH{alkyl), -N{alkyl)(alkyl), -NHC(O) (alkyl), -N(alkyl)C(O)(alkyl), -NHS(O)«(alkyl), -S(O)x(alky)), - S(O)xNH(alkyl), -S(O)«N{alkyl)(alkyl), (where x is 0, 1, or 2).
65. A compound according to Claim 62, wherein: R is selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(C;- Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C2-C¢ alkenyl, C2-Cg alkynyl, Ci-Cs cycloalkyl, and (Cs- Cs)cycloalkyl) C,-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(Ci- Cs)alkylamino,
iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl,
’ pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2-Ce alkenyl, C2-Cs alkynyl, C1-Ce alkoxy, amino, and mono- or di(C;-Cs)alkylamino;
R2 and R; are independently selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cg cycloalkyl, and (C3-Cs cycloalkyl) C:-C3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkoxy, amino, mono- or di(Ci- Cs)alkylamino;
R4 is hydrogen or Ci-s alkyl, C23 alkenyl, Cag alkynyl, Ca.scycloalkyl, (Cs.s cycloalkyl)Ci.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl, Ca. alkenyl, Cas alkynyl, C1-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino,
Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromany], pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,
; pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C26 alkenyl, C2.6 alkynyl, C1-Ce alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C:-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-( C,-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, - X4Rs, wherein X4 and Rg are as defined below; or R: is a bicyclic oxygen-containing group of the formula: 2%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
Cs.¢ alkenyl, Ca.6 alkynyl, C,-Cs alkoxy, amino, and mono- or di(C;- Cs)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C26 alkenyl, C2.6 alkynyl, Ci-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C;-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( Ci1-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -X4Rs, wherein X; and Rg are as defined below; and ii) bicyclic oxygen-containing groups of the formula: oe NH , Re wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
Ca.6 alkenyl, Cas alkynyl, C,-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; Xa is independently selected at each occurrence from the group consisting of -CHa-, - CHRc-, -O-, -S(O)m-, -NH-, -NR¢-, -C(=0)NH-, -C(=O)NRc-, -S(O)uNH-, -S(O)nNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)n-, -C(=O)NHS(O)m-, and —-NRcS(O)w- (where m is 0, 1, or 2); and Re and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C1-Cs alkyl), -NH(C1-Cs alkyl), -N(C,-Cs alkyl)(C1-Cs alkyl), -NHC{O)(C:1-Cs alkyl), -N(C;-Cs alkyl)C(O)(Ci-s alkyl}, -NHS(0)x(C1-Cs alkyl), -S(0)x(C1-Cs alkyl), - S(O)xNH(C1-Cs alkyl), -S(0)xN(C1-Cs alkyl)( C1-Ce alkyl), (where x is 0, 1, or 2).
66. A compound according to Claim 62, wherein: Ris hydrogen, halogen, hydroxy, C;-C¢ alkoxy, haloalkyl, C,-Csg alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-Cg cycloalkyl, and (Cs-Cs)cycloalkyl) Ci-Cs alkyl, or R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-C¢ alkenyl, C2-Cs alkynyl, C;-Ce alkoxy, amino, and mono- or di(C,-Cs)alkylamino, aminocarbonyl, sufonamido, mono or di(C;- Cs)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy; Ra: is selected from C;-Cs alkyl, C2-Cg alkenyl, C2-C¢ alkynyl, C3-Cs cycloalkyl, (C3-Cs cycloalkyl) C;-C3 alkyl and haloalkyl; : Rs is hydrogen C;-Cs alkyl, Ca2-Cs alkenyl, C2-Cs alkynyl; Rs is Cig alkyl, C..s alkenyl, C2 alkynyl, Csscycloalkyl, (C3.s cycloalkyl)C,.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C25 alkenyl, Cz alkynyl, C,-Cs alkoxy, amino and mono- or di(C,-Cs)alkylamino, Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(Ci-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl,
C2.6 alkenyl, Ca.6 alkynyl, C,-Cs alkoxy, amino, mono- or di{C,-Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, Rais a bicyclic oxygen-containing group of the formula: 2%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C26 alkenyl, Ca. alkynyl, C,-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from i) phenyl, pheny)(C;-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, and benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups ‘ independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.6 alkenyl, Ca.6 alkynyl, C,-Cg alkoxy, amino, mono- or di(Ci-Ce)alkylamino, amino(C,- Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C1-Cs)alkylaminocarbonyl, N-( C:-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or ii) bicyclic oxygen-containing groups of the formula: 0 2 on wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C26 alkenyl, C26 alkynyl, C,-Cs alkoxy, amino, and mono- or di(C;-Ce)alkylamino.
67. A compound according to Claim 66, wherein R, Ry, R3, Rs, and Ar; are as defined in Claim 66; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkyl, Ca. alkenyl, Ca6 alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(C:- Ce)alkoxy.
68. A compound according to Claim 66, wherein: R, R2, and R3 are as defined in Claim 66; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C26 alkenyl, Ca. alkynyl, C;-C¢ alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(C- Ce)alkoxy; Rs is C3.Cs alkyl, C,.Cs alkenyl, C2.Cs alkynyl, Cs.Cscycloalkyl, (Cs.s cycloalkyl)Ci. Caalkyl, C1-Cg haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl,
Ci.6 alkenyl, C26 alkynyl, Ci1-C¢ alkoxy, amino and mono- or di(C;- Cs)alkylamino, Rs4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C;-Ca)alkyl, - thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cz. alkenyl, Ca.¢ alkynyl, Ci-Cs alkoxy, amino, mono- or di(C;- Cs)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Cs)alkylaminocarbonyl, N-( C;- Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; Ar; is phenyl, phenyl(C;-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo{b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Co. alkenyl, Ca alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-Ce)alkylamino, amino(C;-
. Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or Ar» is bicyclic oxygen-containing groups of the formula:
0 > (IS wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, ‘ trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca6 alkenyl, C2.¢ alkynyl, C:-Cs alkoxy, amino, and mono- or di(C:-Cs)alkylamino.
69. A compound according to Claim 66, wherein: R is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Cs-Cs cycloalkyl, or (Cs- Cg)cycloalkyl) C;-Cj; alkyl, or R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C:-Ce)alkylamino, aminocarbonyl, sufonamido, mono or di(Ci- Ce)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy; Rais C3-Cs alkyl; Rj is hydrogen, methyl, or ethyl; Rs is C3.Cs alkyl, C2.Cs alkenyl, C2.Cs alkynyl, Cs.Cscycloalkyl, (Cs.s cycloalkyl)Ci- Csalkyl, C1-Cs haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl, C6 alkenyl, C26 alkynyl, C;-C¢ alkoxy, amino and mono- or di(Ci- Cs)alkylamino, R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidy], pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca.6 alkenyl, Ca.6 alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci-
Cs)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Cs)alkylaminocarbonyl, N-( C,- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups ’ independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-C¢ alkyl, C2.¢ alkenyl, C26 alkynyl, C;-C¢ alkoxy, amino, mono- or di(C1-Ce)alkylamino, and amino(C:- Ce)alkoxy; Ar; is phenyl, phenyl(C;-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiopheny], benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d)isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.¢ alkenyl, Cz.6 alkynyl, C;-C¢ alkoxy, amino, mono- or di(C,-Ce)alkylamino, amino(C;- Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Ce)alkylaminocarbonyl, N-( C1-Ce)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or Ar; is bicyclic oxygen-containing groups of the formula: 0 XN . Re wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-C¢ alkyl, Ca¢ alkenyl, Ca.¢ alkynyl, C,-Cs alkoxy, amino, and mono- or di(C:-Ce}alkylamino.
70. A compound according to Claim 66, wherein: R is hydrogen, C,-Cs alkyl, C,-C¢ alkenyl, C2-C¢ alkynyl, Cs-Cs cycloalkyl, or (Cs- Cs)cycloalkyl) Ci-Cjs alkyl, or phenyl; Ry is C3-Cs alkyl;
Rs; is hydrogen, methyl, or ethyl;
Rs is C3.Cs alkyl, C,.Cs alkenyl, C2.Cs alkynyl, Ci.Cscycloalkyl, (Cs-s cycloalkyl)C,. Csalkyl, C;-Cg haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl, Ca¢ alkenyl, C26 alkynyl, C;-Cs alkoxy, amino and mono- or di(C;- Ce)alkylamino;
Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl, Cz.¢ alkenyl, Cas alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(C;- Ce)alkoxy; and
Ar; is phenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, C2.Cs alkenyl, Co.
Cs alkynyl, C,-C alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(Ci- Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cg)alkylaminocarbonyl, N-( C1-Cg)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar; is bicyclic oxygen-containing groups of the formula:
on) Re wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Ca.6 alkenyl, C2.¢ alkynyl, C:1-Cs alkoxy, amino, and mono- or di{C,-Cs)alkylamino.
71. A compound according to Claim 66, wherein:
R is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, or (Cs- Cs)cycloalkyl) C;-Cs alkyl, or phenyl;
R2 is Ca-C¢ alkyl;
g Rs is hydrogen, methyl, or ethyl;
R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(Ci-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl}, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca alkenyl, C26 alkynyl, C1-Cs alkoxy, amino, mono- or di(Ci- Ce)alkylamino, amino(C,-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs)alkylaminocarbonyl, N-( C;- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Ce alkyl, Ca.¢ alkenyl, Ca6 alkynyl, C,-C¢ alkoxy, amino, mono- or di(C:-Cejalkylamino, and amino(Ci- Ce)alkoxy;
Ar, is phenyl, pheny)(C:-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
: trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cg alkyl, Ca. alkenyl, Ca . alkynyl, C;-Cs alkoxy, amino, mono- or di(C:-Cg)alkylamino, amino(C;- Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar, is bicyclic oxygen-containing groups of the formula: NH (OS Re : wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca.6 alkenyl, Cs.¢ alkynyl, C;-Cs alkoxy, amino, and mono- or di(C,-Cs)alkylamino.
72. A compound of the formula: ~~ ' ) R Rs IW — vy Re Re Rs Ra — Arp Ro or pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: mis 0, 1, or 2; R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkylalkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; Ra, Rs, R3a, Rs, and Rs are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;
R and R; may be joined to form an optionally substituted saturated carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ringof from ) 5 to 8 members; Rs, is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be * optionally substituted; or Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Rs and Ry are independently chosen from H or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, (cycloalkyl)alkyl, haloalkyl, or the like. Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
73. A compound according to Claim 72, wherein the compound exhibits an ICso of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
74. A compound according of the formula: y~" A Arp = ~~" . R, R, . or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: R is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyljalkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, ) optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 : rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; R» and R; are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl; R and R3 may be joined to form an optionally substituted carbocylic ring of from 5 to 8 members or an optionally substituted heterocyclic ring of from 5 ro 8 members; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted; or R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
75. A compound according to Claim 74, wherein R and R3 are not joined. .
76. A compound according to Claim 74, wherein: . R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and S42 ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino,
iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
R2 and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino;
Rj is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino,
R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
a oxazolyl, isoxazolyl, oxadiazoly, triazolyl, tetrazolyl, pyridyl, pyrimidy},
) pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids,
: aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and - X4Rg, wherein Xs and Rg are as defined below; or Rais a bicyclic oxygen-containing group of the formula: OF 2%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar: are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo{b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or ) dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, } aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and - XsRp, wherein X4 and Rg are as defined below;, and ii) bicyclic oxygen-containing groups of the formula:
0 1 wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, . trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; Xa4 is independently selected at each occurrence from the group consisting of -CHa-, - CHRc-, -O-, -S(O)a-, -NH-, -NRc-, -C(=O)NH-, -C(=0)NRc-, -S5(0)uNH-, -S(O)uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(Q)m-, -C(=O)NHS(O)n-, and -NRcS{O)m- (where m is 0, 1, or 2); and Rg and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH(alkyl), -N(alkyl)(alkyl), -NHC(O)(alkyl), -N(alkyl)C(O) (alkyl), -NHS(O)x(alkyl), -S(O)x(alkyl), - S(0O)xNH(alkyl), -S(O)«N(alkyl)(alkyl), (where x is O, 1, or 2).
77. A compound according to Claim 74, wherein: R is selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (Cs- ) Cs)cycloalkyl) C,-C; alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, triflueromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(C;- Cs)alkylamino, S45 iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, : nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C»-Cs alkenyl, C2-Cs alkynyl, C;-Cs alkoxy, amino, and mono- or di{C,-C¢)alkylamino; R; and R; are independently selected from i) hydrogen, halogen, hydroxy, amino, C;-C¢ alkoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C3-Cs cycloalkyl, and (C3-Cs cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkoxy, amino, mono- or di(C;- Cs)alkylamino; Ra is hydrogen or Cis alkyl, Caz.s alkenyl, Cys alkynyl, Csgcycloalkyl, (Css cycloalkyl)Ci.salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Ca.¢ alkenyl, C2.6 alkynyl, C,-C¢ alkoxy, amino and mono- or di(C;-Ce)alkylamino, R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bthiophenyl, benzodioxanyl,
. benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, S46 hydroxy, acetoxy, C1-Cs alkyl, Ca. alkenyl, Ca.¢ alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Ce)alkylaminocarbonyl, N-( C1-Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, — . XsRg, wherein Xs and Rp are as defined below; or R4is a bicyclic oxygen-containing group of the formula: on) 2%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
Cs.¢ alkenyl, Cas alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazoly], thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cs.6 alkenyl, Cz.¢ alkynyl, C,-C¢ alkoxy, amino, mono- or di(C1-Ce¢)alkylamino, amino(C:-Ce)alkoxy, carboxylic acid, esters of : carboxylic acids, aminocarbonyl, mono or di(Ci-Ces)alkylaminocarbonyl, N-( Ci1-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidy], and -X4Rg, wherein X4 and Rp are as defined below; and ii) bicyclic oxygen-containing groups of the formula: S47 oe) Rs wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, . trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl,
Ca2.6 alkenyl, Ca. alkynyl, C1-Cs alkoxy, amino, and mono- or di(Ci- Ce)alkylamino; Xa4 is independently selected at each occurrence from the group consisting of -CHz-, - CHRc-, -O-, -S(O)m-, -NH-, -NRc-, -C(=O)NH-, -C(=0)NRc-, -S(O)nNH-, -5(O)uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)m-, -C(=O)NHS(O)m-, and -NRcS(O)m- (where m is 0, 1, or 2); and Rg and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C,-Cs alkyl), -NH(C:1-Cs alkyl), -N(C;-Cs alkyl)(C1-Cs alkyl), -NHC(O)(C1-Cs alkyl), -N(C1-Ce alkyl)C(0)(C1-6 alkyl), -NHS(O)x(C1-Cs alkyl), -S(O)x(C1-Cs alkyl), - S(O)xNH(C,-Cs alkyl), -S(O)xN(C1-Cs alkyl)( Ci-Cs alkyl), (where x is 0, 1, or 2).
78. A compound according to Claim 74, wherein: Ris hydrogen, halogen, hydroxy, Ci-Cs alkoxy, haloalkyl, C1-Cs alkyl, C2-Cs alkenyl, ’ C;-Cs alkynyl, C3-Cg cycloalkyl, and (C3-Cs)cycloalkyl) C1-Cs alkyl, or R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C1-Ce alkoxy, amino, and mono- or di(C,-C¢)alkylamino, aminocarbonyl, sufonamido, mono or di(Ci- Cs)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy; R: is selected from C,-Cs alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, (Cs-Cs cycloalkyl) C;-Cs alkyl and haloalkyl; : Rs is hydrogen C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl; Rs is Cis alkyl, Cas alkenyl, C2.s alkynyl, Cs.scycloalkyl, (Cs.s cycloalkyl)Ci.4alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C26 alkenyl, Cas alkynyl, C;-Cg alkoxy, amino and mono- or di(Ci-Ce)alkylamino, R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C,-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl, C26 alkenyl, C2 alkynyl, C;-Cs alkoxy, amino, mono- or di(Ci-Ce)alkylamino, amino(C,;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-C¢)alkylaminocarbonyl, N-( C:- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, Rs is a bicyclic oxygen-containing group of the formula: OF >%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, ) trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl,
C..6 alkenyl, Ca. alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar: and Ar; are independently chosen from i) phenyl, phenyl(C,-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, and benz|d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups . independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2.6 alkenyl, Ca.¢ alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;- Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-C¢)alkylaminocarbonyl, N-( Ci-Ce)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or il) bicyclic oxygen-containing groups of the formula: oe) Rp wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Co.6 alkenyl, Ca.6 alkynyl, C:-Cs alkoxy, amino, and mono- or di(C;-Ce)alkylamino.
79. A compound according to Claim 78, wherein R, R2, Ra, R4, and Ar; are as defined in Claim 78; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca alkenyl, Cz.s alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(C;- Ces)alkoxy.
80. A compound according to Claim 78, wherein: R, R2, and Rj are as defined in Claim 78; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2 alkenyl, Cae alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, and amino(C;- Ce)alkoxy; Rs is C3.Cg alkyl, C..Cs alkenyl, C2.Cs alkynyl, Cs.Cscycloalkyl, (Cas cycloalkyl)Ci. ) Caalkyl, C,-Cs haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl, C26 alkenyl, C26 alkynyl, C;-Cs¢ alkoxy, amino and mono- or di(Ci- Ce)alkylamino, Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(Ci-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxiny], benzodioxolyl, benz|d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C26 alkenyl, Ca.6 alkynyl, C;-Cs alkoxy, amino, mono- or di(Ci- Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; Ar, is phenyl, phenyl(C;-Cas)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cg alkyl, Ca alkenyl, Ca alkynyl, C.-C alkoxy, amino, mono- or di(C:-Ce)alkylamino, amino(Ci-
. Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C1-Cs)alkylaminocarbonyl, N-( C1-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or Ar; is bicyclic oxygen-containing groups of the formula:
0 x (OS wherein Rg represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl, C26 alkenyl, Cz.¢ alkynyl, C1-Cs alkoxy, amino, and mono- or di(Ci-Ce)alkylamino.
81. A compound according to Claim 78, wherein: R is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, Cs-Cg cycloalkyl, or (Cs- Cs)cycloalkyl) Ci-Cs alkyl, or R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C)-Cs alkyl, C-Ce alkenyl, C»-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;-Cg)alkylamino, aminocarbonyl, sufonamido, mono or di(Ci- Cs)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy; Rz21is C3-Cg alkyl; Rj is hydrogen, methyl, or ethyl; Rs is C3.Cg alkyl, C2.Cs alkenyl, C».Cg alkynyl, Cz.Cscycloalkyl, (Css cycloalkyl)Ci. Casalkyl, C1-Cs haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce allyl, Cos alkenyl, Cae alkynyl, Ci-C¢ alkoxy, amino and mono- or di(Ci- Cs)alkylamino, Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(Ci-Csalkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b|thiophenyl, benzodioxanyl, benzodioxinyl, ] benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca.6 alkenyl, Ca.6 alkynyl, C;-Cs alkoxy, amino, mono- or di(Ci-
Cs)alkylamino, amino(C:-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;- Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; Ary is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups
. independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2. alkenyl, Cae alkynyl, C,-Cs alkoxy, amino, mono- or di(Ci-Cs)alkylamino, and amino(Ci- Ces)alkoxy; Ar; is phenyl, phenyl(Ci-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz{d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cz.¢ alkenyl, Cz. alkynyl, C,-Cs alkoxy, amino, mono- or di{C;-Cs)alkylamino, amino(C;- Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di{C,-Ce)alkylaminocarbonyl, N-( C;-Cg)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or Ar is bicyclic oxygen-containing groups of the formula: 0 2 (4 wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cz alkenyl, C26 alkynyl, Ci-Cs alkoxy, amino, and mono- or di(C,-Cs)alkylamino.
82. A compound according to Claim 78, wherein: R is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, or (Cs- Cs)cycloalkyl) C1-C3 alkyl, or phenyl; R2is C3-Cs alkyl;
Rs is hydrogen, methyl, or ethyl; Rs is C3.Cs alkyl, C,.Cs alkenyl, C2.Cs alkynyl, Cs.Cgscycloalkyl, (Cs.s cycloalkyl)C,. Caalkyl, C,-Cg haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano,
. trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cz¢ alkenyl, Ca. alkynyl, Ci-Cs alkoxy, amino and mono- or di(C;- Cs)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C26 alkenyl, Ca alkynyl, Ci-Cs alkoxy, amino, mono- or di(Ci-Ce)alkylamino, and amino(C;- Ce)alkoxy; and Ara is phenyl, phenyl(C;-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2.Cs alkenyl, Co. Cs alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;- Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( C,-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or Ar; is bicyclic oxygen-containing groups of the formula: oe) Rs wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, Ca.¢ alkenyl, C2.6 alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Cs)alkylamino. RAS
83. A compound according to Claim 78, wherein: R is hydrogen, C,-Cg alkyl, C2-Cs alkenyl, C»-Cs alkynyl, C3-Cg cycloalkyl, or (Cs- Cs)cycloalkyl) C,-Cs alkyl, or phenyl; R2is C3-Cs alkyl;
. R3 is hydrogen, methyl, or ethyl; Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C;-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca.¢ alkenyl, C26 alkynyl, C1-Cs alkoxy, amino, mono- or di(C- C¢)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Cs¢)alkylaminocarbonyl, N-( C;- Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2.¢ alkenyl, Ca alkynyl, C:-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(Ci- Ce)alkoxy; Ar is phenyl, phenyl(C;-Cs}alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz|[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2.6 alkenyl, Ca. alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C;- Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( C,-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar; is bicyclic oxygen-containing groups of the formula: 0 1 gn wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2.6 alkenyl, Cy alkynyl, C;-Cs alkoxy, amino, and mono- or di(Ci-Ce)alkylamino.
84. A compound of the formula: 74 a Rs Re fo ~<A T cH = Re Rs Raa ~ Ary Rg or pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: mis 0, 1, or 2; R2, Rs, R3a, Rs, and Rs are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkylalkyl; Ra is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl each of which may be optionally substituted; or Rs is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, ‘ optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and Rs and Rg are independently chosen from H or optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally ~ substituted cycloalkyl, (cycloalkyl)alkyl, haloalkyl, or the like.
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
85. A compound according to Claim 84, wherein the compound exhibits an ICso of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
86. A compound according of the formula: Ry a 4 Arq AA / R2 Rs or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: R2 and Rj; are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyljalkyl; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, {cycloalkyl)alkyl each of which may be optionally substituted; or R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and ' Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
87. A compound according to Claim 86, wherein: R is selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino, iii) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazoly], isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; R2 and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, alkoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, and ii) alkyl, alkenyl, alkynyl, cycloalkyl, and (cycloalkyl)alkyl, each of which may “be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or dialkylamino; R; is hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyljalkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, i hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino and mono- or dialkylamino, R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl and - X4Rs, wherein Xs and Rg are as defined below; or
Rs is a bicyclic oxygen-containing group of the formula: >%, wherein Ra represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazoly], isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl], triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{djisoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, mono- or dialkylamino, aminoalkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or dialkylaminocarbonyl, N- alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidy! and - X4Rp, wherein Xs and Rg are as defined below;, and ii) bicyclic oxygen-containing groups of the formula:
0 ie on wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, triffluoromethoxy, haloalkyl, hydroxy, acetoxy, alkyl, alkenyl, alkynyl, alkoxy, amino, and mono- or dialkylamino;
X,4 is independently selected at each occurrence from the group consisting of -CHo-, - CHRc-, -0O-, -S(O)m-, -NH-, -NRc-, -C(=0)NH-, -C(=O)NRc-, -S(O)uNH-, -S(O)uNR¢-, -NHC(=0}-,
-NRcC(=0)-, -NHS(O)a-, -C(=O)NHS(O)u-, and -NRcS(O)n- (where m is 0, 1, or 2); and
Re and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of:
hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(alkyl), -NH(alkyl}, -N(alkylj(alkyl), -NHC(O)(alkyl), -N(alkyl)C(O)(alkyl), -NHS(O)x(alkyl), -S(O)«(alky]), - S(0)xNH(alkyl), -S(O)xN(alkyl)(alkyl), (where x is O, 1, or 2). ’
88. A compound according to Claim 86, wherein: R is selected from i) hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, mono- or di(Ci- Ce)alkylamino, cyano, nitro, haloalkyl, and ii) C1-Cs alkyl, C,-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (Cs- Cs)cycloalkyl) C,-C3 alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, and mono- or di(Ci-
Cs)alkylamino, iti) phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazoly}, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, Co-Ce alkynyl, Ci-Cs alkoxy, amino, and mono- or di(Ci-Cs)alkylamino;
R2 and Rj are independently selected from i) hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, mono- or di(C:- Cs)alkylamino, cyano, nitro, haloalkyl, and ii) C;-Cs alkyl, C»-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (C3-Cs cycloalkyl) C;-Cs alkyl, each of which may be unsubstituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce alkoxy, amino, mono- or di(C;- Ce¢)alkylamino;
R4 is hydrogen or Cis alkyl, Cas alkenyl, Cs.s alkynyl, Ca.scycloalkyl, (Cs. cycloalkyl)C, alkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cae alkenyl, Cae alkynyl, Ci-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino,
Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenylalkyl, chromanyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl,
S61 benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz{d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Co alkenyl, Ca.6 alkynyl, C1-C¢ alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C,-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cs)alkylaminocarbonyl, N-( C1-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, - X4Rp, wherein Xs and Rg are as defined below; or R4 is a bicyclic oxygen-containing group of the formula: oe) 2%, wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl,
Ca.¢ alkenyl, Ca.¢ alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar2 are independently chosen from i) phenyl, phenylalkyl, chromanyl, pyrroly], furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, indanyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[bjthiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d}isoxazolyl, quinolinyl, isoquinolinyl, ’ cinnolinyl, quinazolinyl, or quinoxalinyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, C2.6 alkenyl, C2 alkynyl, C:-C¢ alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Ce)alkylaminocarbonyl, N-( Ci-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, and -X4Rg, wherein Xs and Rg are as defined below; and ii) bicyclic oxygen-containing groups of the formula:
. } o 5 oss wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, . C26 alkenyl, Ca.¢ alkynyl, C1-Cs alkoxy, amino, and mono- or di(C;- Ce)alkylamino; X, is independently selected at each occurrence from the group consisting of -CHaz-, - CHR¢-, -O-, -S(O)m-, -NH-, -NRc-, -C(=O)NH-, -C(=O)NRc-, -S(O)uNH-, -S(O}uNRc-, -NHC(=0)-, -NRcC(=0)-, -NHS(O)m-, -C(=O)NHS(O)m-, and -NRcS(O)m- (Where mis 0, 1, or 2); and Rg and Rc, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups, which may contain one or more double or triple bonds, each of which may unsubstituted or substituted with one or more substituent(s) selected from: oxo, hydroxy, -O(C1-Cs alkyl), -NH(C,-C¢ alkyl), -N(C,1-Cs alkyl)(C,-Cs alkyl), -NHC(O)(Ci1-Cs alkyl), -N(C1-Cs alkyl)C(O)(Ci-6 alkyl), -NHS(0)x(C1-Cs alkyl), -S(O}x(Ci1-Cs alkyl), - S(O)xNH(C)-Cs alkyl), -S(O)xN(C1-Cs alkyl){ C1-Ce alkyl), (where x is ) 0, 1,0r2).
89. A compound according to Claim 86, wherein: R is hydrogen, halogen, hydroxy, C;-Cs alkoxy, haloalkyl, C1-Cs alkyl, Cz-Co alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, and (C3-Cs)cycloalkyl) C1-Ca alkyl, or
R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C,-Cs alkoxy, amino, and mono- or di(C:-C¢)alkylamino, aminocarbonyl, sufonamido, mono or di(C:- Cs)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy; R; is selected from C;-Cs alkyl, C2-Cg alkenyl, C2-Cq alkynyl, C3-Cs cycloalkyl, (C3-Cs cycloalkyl) C,-C; alkyl and haloalkyl; Rs is hydrogen C;-Cs alkyl, C2-Cs alkenyl, C-Cs alkynyl; Rs is Cig alkyl, Cas alkenyl, C2s alkynyl, Cs.scycloalkyl, (Css cycloalkyl)Ci-salkyl, haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Cz.¢ alkenyl, Cas alkynyl, Ci-Cs alkoxy, amino and mono- or di(C:-Ce)alkylamino, R,4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl{(C:-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indoly], indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d]isoxazolyl, each of which may be substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl,
Ca.6 alkenyl, Ca alkynyl, C;-C¢ alkoxy, amino, mono- or di(C:-Cgjalkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs}jalkylaminocarbonyl, N-( Ci- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl, Rais a bicyclic oxygen-containing group of the formula: CI
2%. wherein Ra represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, S64
Ca.¢ alkenyl, Cs. alkynyl, C1-Cs alkoxy, amino, and mono- or di(Ci- Ce)alkylamino; Ar is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from . i} phenyl, phenyl(C,-Ca)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiopheny], benzodioxanyl, benzodioxinyl, benzodioxolyl, and benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, C2.6 alkenyl, Cz. alkynyl, C;-Cs alkoxy, amino, mono- or di(C:-Ce)alkylamino, amino(C:- Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C)-Ce)alkylaminocarbonyl, N-( C1-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or ii) bicyclic oxygen-containing groups of the formula: © x Ls Rg : wherein Rp represents O to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C-Cs alkyl, Cz. alkenyl, C2 alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Ce)alkylamino.
90. A compound according to Claim 89, wherein R, R2, Ra, R4, and Ar; are as defined in Claim 89; Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups ’ independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Cz.6 alkenyl, Cz. alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, and amino(C;- Ce)alkoxy. S68
91. A compound according to Claim 89, wherein:
R, Ry, and Rj; are as defined in Claim 89;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cac alkenyl, Cas alkynyl, C;-Ce alkoxy, amino, mono- or di(C,-CsJalkylamino, and amino(C;- Cs)alkoxy;
Rs is C3.Cs alkyl, C2.Cs alkenyl, C,.Cs alkynyl, Cs.Cscycloalkyl, (Cs-s cycloalkyl)Ci.
Caalkyl, C;-Cg haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Cae alkenyl, Cz alkynyl, Ci-C¢ alkoxy, amino and mono- or di(Ci- Cs)alkylamino,
Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C;-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo(b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz[d)isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Cy. alkenyl, Ca.¢ alkynyl, C,-Cs alkoxy, amino, mono- or di(Ci- Ce)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Ce)alkylaminocarbonyl, N-( C:- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;
Ar, is phenyl, phenyl(C,-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl,
benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of k which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:-Cs alkyl, Cas alkenyl, Ca.s alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(Ci-
Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci-Cg)alkylaminocarbonyl, N-( C1-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or Ar; is bicyclic oxygen-containing groups of the formula: 0 1 oN wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Ca.6 alkenyl, C..6 alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Cs}alkylamino.
92. A compound according to Claim 89, wherein: R is hydrogen, C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, or (Cs- Cs)cycloalkyl) C,-Cs alkyl, or R is phenyl substituted with up to five groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cs alkoxy, amino, and mono- or di(Ci-Ce¢)alkylamino, aminocarbonyl, sufonamido, mono or di(Ci-
. Ce)alkylsulfonamido, 3,4-methylenedioxy, and 3,4-(1,2-ethylene)dioxy; Ra is C3-Cs alkyl; Rs is hydrogen, methyl, or ethyl; R4 is C3.Cg alkyl, C2.Cg alkenyl, C2.Cs alkynyl, Cs.Cgcycloalkyl, (Cs.s cycloalkyl)Ci. Cialkyl, C;-Cs haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce¢ alkyl, C26 alkenyl, Cas alkynyl, C;-C¢ alkoxy, amino and mono- or di(Ci- CeJalkylamino, R4 is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C,-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofurany], naphthyl, indolyl, indany], benzo{b|thiophenyl, benzodioxanyl, benzodioxinyl,
benzodioxolyl, benz|d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Cs alkyl, Ca. alkenyl, C26 alkynyl, C;-Cs alkoxy, amino, mono- or di(Ci-
: Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;- Ces)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl;
Ar, is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2. alkenyl, Coa.6 alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, and amino(Ci- Ce)alkoxy;
Ar, is phenyl, phenyl(C,-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz|[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2.¢ alkenyl, Cz alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Cg)alkylamino, amino(C;- Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C,-Ce)alkylaminocarbonyl, N-( C:-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or
Ar; is bicyclic oxygen-containing groups of the formula:
oe) Re wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C26 alkenyl, Cz. alkynyl, C1-Cs alkoxy, amino, and mono- or di(C:-Cs)alkylamino.
93. A compound according to Claim 89, wherein: R is hydrogen, C;-Cs alkyl, C2-Cs alkenyl, Ca2-Cg alkynyl, C3-Cs cycloalkyl, or (Ca- Cs)cycloalkyl) Ci-C3 alkyl, or phenyl; Rais C3-Cs alkyl; Rj is hydrogen, methyl, or ethyl;
Ras is C3.Cg alkyl, C».Cs alkenyl, C1.Cs alkynyl, Cs.Cacycloalkyl, (Cs.s cycloalkyl)Ci.
Cialkyl, C,-Cs haloalkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca alkenyl, Cie alkynyl, C;-C¢ alkoxy, amino and mono- or di(C;- Ce)alkylamino;
Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Ci.¢ alkenyl, Cas alkynyl, Ci1-Cs alkoxy, amino, mono- or di(C:-Ce¢)alkylamino, and amino(C;- Cs)alkoxy; and
Ar; is phenyl, phenyl(C,-Cs)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b|thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C2.Cs alkenyl, Co.
Cs alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(C;- Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C,-Cejalkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidyl; or ; Ar: is bicyclic oxygen-containing groups of the formula: Cor Re wherein Rp represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, C2.6 alkenyl, Ca.s alkynyl, C;-Cs alkoxy, amino, and mono- or di(C;-Cs)alkylamino. :
94. A compound according to Claim 89, wherein:
R is hydrogen, Ci-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Csg cycloalkyl, or (Cs- Cs)cycloalkyl) C1-Cs alkyl, or phenyl;
R21s C3-Cg alkyl;
Rs is hydrogen, methyl, or ethyl;
Rs is phenyl, ethylenedioxyphenyl, methylenedioxyphenyl, phenyl(C,-Ca4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiophenyl, benzodioxanyl, benzodioxinyl, benzodioxolyl, benz|d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2 alkenyl, Cz.¢ alkynyl, C1-Cs alkoxy, amino, mono- or di(C;- Cs)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C:-Cs)alkylaminocarbonyl, N-( C;-
~ Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidyl; Ar) is ethylenedioxyphenyl, methylenedioxyphenyl, or phenyl with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, triflnoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Ce alkyl, C2.6 alkenyl, C2 alkynyl, C:-Cs alkoxy, amino, mono- or di(C;-Cs)alkylamino, and amino{C;- Ce)alkoxy; Ar, is phenyl, pheny}(C;-C4)alkyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, chromanyl, dihydrobenzofuranyl, naphthyl, indolyl, indanyl, benzo[b]thiopheny], benzodioxanyl, benzodioxinyl, benzodioxolyl, or benz|[d]isoxazolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, Ca alkenyl, Cog alkynyl, Ci-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, amino(C;- Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( C;-Cs)alkylsulfonylaminocarbonyl, 1- azetidinyl, 1-pyrrolidinyl, 1-piperidy]; or
. Ar; is bicyclic oxygen-containing groups of the formula: “LT Re wherein Rg represents 0 to 3 groups selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, Ca.6 alkenyl, C,.¢ alkynyl, C,-C¢ alkoxy, amino, and mono- or di(C;-Ces)alkylamino.
95. A compound according to Claim 1 of the formula 0 Xo Z>" (CHp)y Ar, ST —R; R2 or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein: Xs is C, N or CH; mis 0,1, 2, or 3; Ar; is chosen from optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and R) and R; are independently chosen from C;.s alkyl, Cz. alkenyl, C2.s alkynyl, Cs. scycloalkyl, (Cs.s cycloalkyl)Ci.4alkyl, each or which may be unsubstituted or : substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs SN alkyl, Ca alkenyl, Cz alkynyl, Ci-Cs alkoxy, amino and mono- or di(Ci- Cs)alkylamino, or R: and R; are independently chosen from phenyl, phenylalkyl, chromanyl, chromanylaikyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl, azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C2.¢ alkenyl, C26 alkynyl, C1-Ce alkoxy, amino, mono- or di(C:-Cs)alkylamino, amino(C,-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci- Ce)alkylaminocarbonyl, N-( C,-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl;
96. A compound according to Claim 95 of the formula: Arp \_/ R= N m \ SF Re Arq or a pharmaceutically acceptable salt thereof, wherein: R; is as defined in Claim 95; mis 1, 2, or 3; nis 1, 2, or 3; hy represents a carbon chain that may be substituted with hydrogen, halogen, cyano, nitro amino, mono or dialkyl amino, alkenyl, alkynyl, alkoxy,
trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl, or cycloalkyl; Ar; and Ar; independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic
. group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; and R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH,), mono or dialkylaminocarbonyl, sulfonamido, and mono or dialkylsulfonamido.
97. A compound according to Claim 96, wherein the compound exhibits an ICso of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
98. A compound according to Claim 96, wherein n, m, and R; are defined as in Claim 96; Ar, is independently chosen from phenyl, pyridyl, and pyrimidinyl each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(C,-Ce)alkylamino, cyano, nitro, C,-Cs haloalkyl, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, (Cz-Cscycloalkyl) Ci1-Csalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH,), mono or di(C1-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C;-Cs)alkylsulfonamido; and Ar; represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl, each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(C;-Ce)alkylamino, cyano, nitro, C,-Cs haloalkyl,
C1-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-Cg cycloalkyl, (C3-Cscycloalkyl) C1-Csalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONHz), mono or di(C,-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C;-Ce)alkylsulfonamido.
99. A compound according to Claim 95 of the formula — \ _\~Rs 0)
Pp. — N \ Ri XJ RN } Rs R, Rs, and Rs each represent up to 5 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(Ci- Cs)alkylamino, cyano, nitro, C1-Cs haloalkyl, C1-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C;3-Cs cycloalkyl, (Cs-Cscycloalkyl) Ci-Csalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONHj), mono or di(C:-Ce)alkylaminocarbonyl, sulfonamido, and mono or di(C;-Cs)alkylsulfonamido; and represents suberanyl, indanyl, tetrhydronaphtyl, or indolyl, each of which is optionally optionally substituted or substituted with up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, : mono- or di(C;-Cs)alkylamino, cyano, nitro, C;-Cs haloalkyl, C;-Cs alkyl, Cz- Ce alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, (Cs-Cscycloalkyl) C,-Csalkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH,, mono or di(C:-
Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C;-Ces)alkylsulfonamido. : R, is chosen from Cis alkyl, Cs alkenyl, Cag alkynyl, Cascycloalkyl, (Css cycloalkyl)C.4alkyl, each or which may be unsubstituted or substituted with
. one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C;-Ce¢ alkyl, C26 alkenyl, Ca. alkynyl, C;-Cs alkoxy, amino and mono- or di(Ci- Cs)alkylamino, or R; is chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl, azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl,
Ca.6 alkenyl, Cas alkynyl, C;-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Ce)alkylaminocarbonyl, N-( C;- Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidyl;
100. A compound according to Claim 95 of the formula: ZZ Rr, N EN Ng, Arq Oo or a pharmaceutically acceptable salt or prodrug, thereof, wherein: R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy carbonyl (COOH),
aminocarbonyl (CONH3), mono or di(Ci-Ce)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or dialkylsulfonamido; R; and R: are independently chosen from Ci.s alkyl, Ca.s alkenyl, C23 alkynyl, Ca. scycloalkyl, (Ca.s cycloalkyl)Ci.qalkyl, each or which may be unsubstituted or . substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca alkenyl, Ca. alkynyl, C;-Cs alkoxy, amino and mono- or di(C;- Cs)alkylamino, or R; and R; are independently chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl, azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C26 alkenyl, C2.¢ alkynyl, Ci-Ce alkoxy, amino, mono- or di(Ci-Ce)alkylamino, amino(C;-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(Ci- Ce)alkylaminocarbonyl, N-( C;-Cg)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl; Ar, is chosen from optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic, heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms, ethylenedioxyphenyl or methylenedioxyphenyl.
101. A compound according to Claim 100, wherein the compound exhibits an ICso of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
102. A compound according to Claim 100, wherein
R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-C¢ alkoxy, acetoxy, mono- or di(C;-Cs)alkylamino, cyano, nitro, C;- Cs haloalkyl, C1-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, (Cs- Cs cycloalkyl) C;-Cs alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH3), mono or di(C;-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C1-Ce)alkylsulfonamido;
R; and R: are independently chosen from C,s alkyl, Ca.s alkenyl, Cz.s alkynyl, Cs. scycloalkyl, (Cs.s cycloalkyl)Ci.salkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, C2.6 alkenyl, C26 alkynyl, Ci-C¢ alkoxy, amino and mono- or di(C- Ce)alkylamino, or
R: and Rz are independently chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl, azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, } haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, Ca. alkenyl, Cas alkynyl, C1-Ce alkoxy, amino, mono- or di(C;-Cs)alkylamino, amino(Ci-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;- Cs)alkylaminocarbonyl, N-( C;-Cg)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-
pyrrolidinyl, and 1-piperidyl;
Ar; is chosen from ethylenedioxyphenyl, methylenedioxyphenl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, and pyridyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,
haloalkyl, hydroxy, acetoxy, Ci;-Ce¢ alkyl, Ca alkenyl, Ci. alkynyl, Ci-Cs alkoxy, amino, mono- or di(C;1-Cs)alkylamino, amino(C,-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;- Cs)alkylaminocarbonyl, and N-(C;-Cs)alkylsulfonylaminocarbonyl; and
103. A compound according to Claim 102, of the formula N Sg, = © wl wherein: R; is as defined in Claim 102; Rx represents up to 5 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Ce alkoxy, acetoxy, mono- or di(C;-Cs)alkylamino, cyano, nitro, C;-Cs haloalkyl, C;-Ce alkyl, C2-Cs alkenyl, and C2-Cs alkynyl; and R; is C)-Csalkyl, Cs.Cscycloalkyl, (C3.Cs cycloalkyl)C,.Csalkyl, phenyl, phenylC;- Csalkyl, chromanyl, chromanylC,-Csalkyl, imidazolyl, imidazolylC,-Csalkyl ,pyridyl, pyridylC;-Csalkyl, pyrimidyl, pyrimidylC,-Csalkyl,pyrazinyl, pyrazinylC,-Cealkyl, indolyl, indolylC,-Csalkyl, indanyl, indanylC,;-Cealky}, benzodioxolyl, or benzodioxolylC;-Cealkyl each or which may be unsubstituted or substituted with up to 4 substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-Cs alkyl, C;.¢ alkenyl, Ca.¢ alkynyl, Ci1-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino.
104. A compound according to Claim 102, of the formula:
Ry N : Sg, 0) rR AN wherein:
Rx represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy substituted with 0-2 Rj, acetoxy, mono- or di(Ci-Ce)alkylamino, cyano, nitro, Ci-C¢ haloalkyl, C,-Ce alkyl, C2-Cg alkenyl, and C2-Cg alkynyl;
R) is phenyl, phenylC,-Cs alkyl, C3-Cs cycloalkyl, C3-Cs cycloalky(C:-Cs alkyl), naphthyl, napthylC,-Csalkyl, indanyl, indanylC;-Cs alkyl, benzodioxolanyl, or benzodioxolanylC1-Cs alkyl, each of which may be substituted by up to 4 groups chosen from halogen, hydroxy, amino, C1-Cs alkoxy, acetoxy, mono- or di(C,-Ce)alkylamino, cyano, nitro, C;-Cs haloalkyl, C;-Cs alkyl; and
Ry is chosen from Cis alkyl, Cis alkenyl, Cas alkynyl, Cs.scycloalkyl, (Css cycloalkyl) C,.4alkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Cs alkyl, C26 alkenyl, Cie alkynyl, Ci-Cs alkoxy, amino and mono- or di(C;- Cs)alkylamino, or
R2 is chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl,
pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl,
} azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl,
WO (12/49993 PCT/US00/26816
Ca.6 alkenyl, Cy. alkynyl, C1-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino, amino(C,-Ce)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-Cs)alkylaminocarbonyl, N-( Ci- Cs)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1-pyrrolidinyl, and 1-piperidy};
105. A compound according to Claim 102 wherein: Ry is as defined in Claim 102; R represents up to 4 groups independently chosen from hydrogen, halogen, amino, C,-Cs alkoxy, C)-Cs alkyl, trifluoromethyl, and trifluoromethoxy; Ri is phenyl, benzyl, C3-Cs cycloalkyl, C3-Cs cycloalkyl(Ci-Cs alkyl), naphthyl, naphthyl-CH»-, indanyl, indandyl-CHaz-, benzodioxolanyl-CH»-, or benzodioxolanyl, each of which may be substituted by up to 4 groups chosen from halogen, hydroxy, amino, C;-Ce alkoxy, acetoxy, mono- or di(C:- Ce)alkylamino, cyano, nitro, Ci-Ce haloalkyl, C1-Cs alkyl; and Ar; is chosen from ethylenedioxyphenyl, methylenedioxyphenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, Ci.Cs alkoxy, Ci-Ce alkyl, and amino.
106. A compound according to Claim 102 wherein: R represents up to 4 groups independently chosen from hydrogen, halogen, amino, C,-Cg alkoxy, C1-Ce alkyl, trifluoromethyl, and trifluoromethoxy; R; is benzyl which is unsubstituted or substituted by up to 4 groups chosen from halogen, hydroxy, amino, C;-Ce alkoxy, acetoxy, mono- or di(C;- Ce)alkylamino, cyano, nitro, Ci-Cs haloalkyl, C:-Ce alkyl; Ar, is chosen from ethylenedioxyphenyl, methylenedioxyphenyl, pyrrolyl, imidazolyl, . pyrazolyl, triazolyl, thiophenyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, trifluoromethyl, trifluoromethoxy, Ci.Cs alkoxy, C1-Cs alkyl, and amino; and
R:2 is chosen from phenyl, benzyl, indolyl, indolyl-CH»-, indanyl, indanyl-CHo-, chromanyl, chromanyi-CHs-, benzofuranyl, benzofuranyl-CHp-, benzodioxinyl, benzodioxinyl-CH2-, benzodioxolyl-CH,-, and benzodioxolyl, each of which may be optionally substituted or substituted with up to four . groups independently selected from: halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Ca.6 alkenyl, C2.6 alkynyl, C,-Cs alkoxy, amino, and mono- or di{C,;-C¢)alkylamino.
107. A compound according to Claim 102, of the Formula Rell \ Q N Oo R, 2061 ! m I 1 N ——/Ry wherein: misO, 1, 2, or 3, and AK represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydroxy, halogen, or amino; R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, Ci1-Csalkyl, C,-C¢ alkenyl, C;-Csalkynyl, C;-Cs alkoxy, acetoxy, mono- or di(C;-Cs)alkylamino; Rx and Ry each represent up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(C;- Ce)alkylamino, cyano, nitro, C;-C¢ haloalkyl, C;-Cs alkyl, C,-C¢ alkenyl, and
C.-C alkynyl; and Ri) and Rs are independently selected from C;-Csalkyl, C3.Cscycloalkyl, (C3.Cs cycloalkyl)Ci-Csalkyl, phenyl, phenylC;-Cealkyl, pyridyl, and pyridylC;-
Cealkyl, each or which may be unsubstituted or substituted with up to 4 substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C:1-Cs alkyl, C2.s alkenyl, Cz alkynyl, C;-Cs alkoxy, amino and mono- or di(C;-Cs)alkylamino.
108. A compound according to Claim 1 of the formula Ary ~ XX N N AN Im Re] a Ar = { 2 R4 or a pharmaceutically acceptable salt, prodrug or hydrate thereof, wherein; mis O, 1, 2, or 3, and A represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino; nis 0, 1, 2, or 3, and AN represents a carbon chain which is optionally substituted with methyl, ethyl, methoxy, ethoxy, hydoxy, halogen, or amino; Rz represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, and(cycloalkyljalkyl; Rs is chosen from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl and arylalkyl, each of which may be unsubstituted, optionally substituted or substituted by one or more of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, alkoxy, amino, mono- or : dialkylamino; and Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or;
Ar; and Ar; are independently optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic or heteroalicyclicalkyl group having ; from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms.
109. A compound according to Claim 108, wherein the compound exhibits an ICsp of 1uM or less in an assay of C5a mediated chemotaxis or calcium mobilization.
110. A compound according to Claim 108, wherein mis 1 and AA represents a carbon chain which is unsubstituted; nis 1 and AA represents a carbon chain which is unsubstituted; R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, acetoxy, mono- or di(C,-Cs)alkylamino, cyano, nitro, C;- Cs haloalkyl, C;-Cs alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C2-Cs cycloalkyl, and(Cs3-Cs cycloalkyl} Ci1-C4 alkyl; R; is C3-Cs alkyl or C3-Cs cycloalkyl; Ar; is ethylenedioxyphenyl, methylenedioxyphenyl, or; Ar; and Ar; are independently chosen from phenyl, phenyl(C:-Cs)alkyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl, and pyrazinyl, each of which may be unsubstituted or optionally substituted or substituted with up to four groups independently selected from halogen, ) nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C,-Cs alkoxy, amino, mono- or di(C;-Ce)alkylamino.
111. A compound according to Claim 95 of the formula
CY 0 R { PS PP N Ry Ary Ro wherein: Ari, R; and Ra» are as defined in Claim 95; and R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-C¢ alkoxy, acetoxy, mono- or di{Ci-Ce)alkylamino, cyano, nitro, Ci- Cs haloalkyl, C,-Cs alkyl, C2-Cs alkenyl, C,-Cs alkynyl, C3-Cs cycloalkyl, (Cs- Cs cycloalkyl) C;-Cs alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH2), mono or di(C,-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C,-Ces)alkylsulionamido;
112. A compound according to Claim 95 of the formula XX 0] PL "1 PF N Ry NT q wherein: Ar; and R) are as defined in Claim 95; and . R represents up to 4 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(C;-Cs)alkylamino, cyano, nitro, C;- Cs haloalkyl, C;i-Cs alkyl, C2-Cs alkenyl, C2-Ce alkynyl, Ca-Cs cycloalkyl, (Cs- Cs cycloalkyl) C,-C3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH3),
mono or di(C,-Ce)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C:-Ce)alkylsulfonamido;
113. A compound according to Claim 95 of the formula 0 R= MN PF N R, NT %
NS . N a wherein: R; is as defined in Claim 95; and R and Rj; represent up to 5 groups independently chosen from hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy, acetoxy, mono- or di(C:-Cs)alkylamino, cyano, nitro, C;1-Cs haloalkyl, C,-Cs alkyl, C2-Cs alkenyl, C2-Cs alkynyl, C3-Cs cycloalkyl, (C3-Cg cycloalkyl) C;-C3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH3), mono or di(C,-Cs)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C;-Ce)alkylsulfonamido;
114. A compound according to Claim 9S of the formula
2 0 R= PN PZ N R; . NT Ls TN = Rs wherein: Ri is as defined in Claim 95; and R, R3 and Ra represent up to 5 groups independently chosen from hydrogen, halogen, hydroxy, amino, C;-Cs alkoxy, acetoxy, mono- or di(C;- Cs)alkylamino, cyano, nitro, Ci-Cg¢ haloalkyl, C1-Cs alkyl, C»-Cs alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, (C3-Cs cycloalkyl) C,-Cj3 alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONH2}, mono or di(Ci-Ce)alkylaminocarbonyl, sulfonamido, 3,4-methylenedioxy, ethylenedioxy, and mono or di(C;- Cs)alkylsulfonamido;
115. A compound according to Claim 95 of the formula I N Ng, 0] NE ’ wherein: R) and R; are as defined in Claim 95.
116. A compound according to Claim 95 of the formula N 0) 7 ON wherein: R, is as defined in Claim 95.
117. A compound according to Claim 95 of the formula N Ng, 0) wherein: R; and R; are as defined in Claim 95.
118. A compound according to Claim 95 of the formula i N wherein: Rj is as defined in Claim 95.
119. A compound according to Claim 95 of the formula N Sg, 0) { wherein: Rj and R; are as defined in Claim 95.
120. A compound according to Claim 95 of the formula I N p i og » wherein: R, is as defined in Claim 95.
121. A compound according to Claim 95 of the formula
N Sg, = 0 Re wherein: R; and R; are as defined in Claim 95; and Rx represents up to 5 groups independently chosen from hydrogen, halogen, hydroxy, amino, C1-Cs alkoxy, acetoxy, mono- or di(C;-Cs)alkylamino, cyano, nitro, Ci-Cs haloalkyl, C;-Cs alkyl, C2-Cs alkenyl, and C2-Ce alkynyl.
122. A compound according to Claim 95 of the formula i) N Za ? Re | 8 wherein: R; is as defined in Claim 95; and Rx represents up to S groups independently chosen from hydrogen, halogen, hydroxy, amino, C,-Cs alkoxy, acetoxy, mono- or di(C,-Ce)alkylamino, cyano, nitro, C1-C¢ haloalkyl, Ci-Cs alkyl, Co-Cs alkenyl, and C2-Cs alkynyl.
123. A compound according to Claim 1 of the formula
0) wd, N—R; { wherein
R; and R; are independently chosen from C;.s alkyl, C23 alkenyl, C2.s alkynyl, Cs. scycloalkyl, (Cs.s cycloalkyl)Ci.4alkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, triflucromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Cas alkenyl, Cas alkynyl, C1-Cs alkoxy, amino and mono- or di(Ci- Cs)alkylamino, or
R; and R; are independently chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl, azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci1-Cs alkyl, C26 alkenyl, C25 alkynyl, C:-Cs alkoxy, amino, mono- or di(C:-Cs)alkylamino, amino(Ci-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;- Ce)alkylaminocarbonyl, N-( Ci-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl;
Ar, is chosen from optionally substituted carbocyclic aryl, optionally substituted
] arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, or an optionally substituted heteroalicyclic,
’ heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms, ethylenedioxyphenyl or methylenedioxyphenyl; and
124. A compound according to Claim 123 wherein R; and R; are connected to form a 5-8 member optionally substituted carbocyclic or heterocyclic ring.
125. A compound according to Claim 123 of the formula R 8 N—R; { wherein R: and R; are independently chosen from C,s alkyl, Cz alkenyl, C23 alkynyl, Cs. scycloalkyl, (Css cycloalkyl)C.4alkyl, each or which may be unsubstituted or substituted with one or more substituents selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, Ci-Ce alkyl, Cz. alkenyl, Cz.¢ alkynyl, Ci-C¢ alkoxy, amino and mono- or di(C;- Cs)alkylamino, or R; and R» are independently chosen from phenyl, phenylalkyl, chromanyl, chromanylalkyl, imidazolyl, imidazolylalkyl, pyridyl, pyridylalkyl, pyrimidyl, pyrimdylalkyl, pyrazinyl, pyrazinylalkyl, indolyl, indolylalkyl, indanyl, indanylalkyl, imidazopyridyl, azaimidazopyridyl, benzimidazoyl, benzimidazoylalkylbenzodioxolylalkyl, or benzodioxolyl, each of which may be optionally substituted or substituted with up to four groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C,-Cs alkyl, Cz.6 alkenyl, Ca.¢ alkynyl, C1-Cs alkoxy, amino, mono- or di(C,-Cs)alkylamino, amino(C:-Cs)alkoxy, carboxylic acid, esters of carboxylic acids, aminocarbonyl, mono or di(C;-
) Ce)alkylaminocarbonyl, N-( C,-Ce)alkylsulfonylaminocarbonyl, 1-azetidinyl, 1- pyrrolidinyl, and 1-piperidyl; R is chosen from hydrogen, halogen, hydroxy, amino, alkoxy, acetoxy, mono- or dialkylamino, cyano, nitro, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, . (cycloalkyl)alkyl, hydroxy carbonyl (COOH), aminocarbonyl (CONHz), mono or di(C1-Ce)alkylaminocarbonyl, sulfonamido, and mono or dialkylsulfonamido;
126. A compound according to Claim 125 wherein R; and R; are connected to form a 5-8 member optionally substituted carbocyclic or heterocyclic ring.
127. A compound according to Claim 95 wherein: Ar) is bound to the ring bearing Xs to form an optionally substituted heterocyclic 5-8 member ring.
128. A compound according to Claim 95 wherein: R; and R; are connected to form a 5-8 member optionally substituted carbocyclic or heterocyclic ring.
129. A compound according to Claim 95 wherein: Ar; is bound to the ring bearing Xs to form an optionally substituted heterocyclic 5-8 member ring; and R; and R; are connected to form a 5-8 member optionally substituted carbocyclic or heterocyclic ring.
130. A compound according to Claim 5 wherein: , Rs and Ar; are connected to form a 5-8 member optionally substituted carbocyclic or heterocyclic ring.
131. A compound according to Claim 8 wherein:
N
R. and Ar. are connected to form a 5-8 member optionally substituted carbocyclic or heterocyclic ring.
132. A compound according to Claim 3 wherein: . A has hydrogen bond acceptor ability.
133. A compound as set forth in any of Tables 1 through 6, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
134. A compound that is: 1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl methyl]Jaminomethylimidazole 1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxy phenylmethyl}-N- phenylmethyllamino)ethylimidazole 1 -Butyl-2-phenyl-4-bromo-5-(N -phenylmethyl-N-[1-butyl})amino- methylimidazole 1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl}-N- phenylmethyl)Jaminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yljmethyl-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl}-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[1,4-benzodioxan-6-yl|methyl-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole , 1-(1-Butyl)-2-(2-fluorophenyl)-5-(N-{1,4-benzodioxan-6-ylmethyl]-N- phenylmethyl)amino- methylimidazole 1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[naphtha-2-ylmethyl]-N- phenylmethyljamino-methylimidazole
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N -[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole . 1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-{4-dimethylaminophenylmethyl]-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4- methylenedioxyphenylmethyl])amino- methylimidazole 1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4- methylenedioxyphenylmethyl])amino- methylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl}-N- phenylmethyl)amino methylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-(3,4-methylenedioxyphenylmethyl}-N- phenylmethyl) aminomethylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4- methylenedioxyphenylmethyl])amino- methylimidazole 1-(1-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)- aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-{1-(N-[3,4-methylenedioxyphenylmethyl}-N- phenylmethyl)amino} ethylimidazole 1-(1-Pentyl}-2-phenyl-5-(N-{indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole 1-(1-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole ; 1-(1-Butyl)-2-phenyl-5-(N-{ 1-(S)-phenylethyl]-N- phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[1-(R)-phenylethyl}-N- phenylmethyl)aminomethylimidazole
1-(1-Butyl}-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dichlorophenyljmethyljaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl)) aminomethylimidazole . 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- methoxyphenylmethyl])-aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1- propyliphenylmethyl]jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-[3,4- dichlorophenylethyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyljmethyl-N-[4- nitrophenylmethyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1- propyloxy} phenylmethyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-[quinol-6- ylmethyl])- aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-[2,3- dichlorophenylmethyl])-aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4- dimethylphenylmethyl])-aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyllmethyl-N-[indan-2-yl})- aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- phenylethyl])amino-methylimidazole 1-(1-Propyl)-2-phenyl-5-(N-[1,4-benzodioxan-6-ylmethyl]-N- phenylmethyl)aminomethyl-imidazole } 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- ethyl)aminomethylimidazole
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-{1- propyl}jJaminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1- butyl])Jaminomethyl-imidazole ; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cycloheptylmethyl)amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N- isobutyljaminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- cyclopentylethyl])amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-{3- cyclopentylpropyl])amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-{1-n- octyl])aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N- cyclopropylmethyljamino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N- cyclopentylmethyl)amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N- cyclohexylmethyl)amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-{t- amyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{3- methyl}butyl)jJamino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2-~ dimethyl}butyl]) aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N- methyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2- thiophenylmethyl])amino-methylimidazole
1-(1-Butyl)-2-phenyl-5-(N-(3 ,4-methylenedioxyphenylmethyl]-N- [indoi-5- ylmethyl])amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl}-N-[{1- methylindol-5-yl}methyl})aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyljmethyl-N-[4-hydroxy-2- chlorophenyl}-methyljaminomethylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyljmethyl-N- phenylmethyl]) aminoethylimidazole 1-1 -Butyl)-2-phenyl-5-(N -[3,4-methylenedioxyphenyljmethyl-N-[2,3- dihydrobenzo[b)furan-5-yljmethyl)Jaminomethylimidazole 1-Butyl-2-(4-fluorophenyl)-5-(1-[N-{3,4-methylenedioxyphenyljmethyl-N- phenylmethyl]-amino)ethylimidazole 1-(1-Butyl)-2-(2-thienyl)-5-(N-[3,4-methylenedioxyphenyljmethyl-N- phenylmethyl] aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N- phenylmethyl)amino-methylimidazole 1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4- dimethoxyphenylmethylj)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl}-N- phenylmethyljaminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-{4-methylaminophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl}-N- phenylmethyl)aminomethyl-imidazole) 1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl}-N- phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenylmethyl]-N- phenylmethyljaminomethylimidazole 1-{1-Butyl)-2-phenyl-5-(N-[3,4-difluorophenylmethyl]-N- phenylmethyljaminomethylimidazole
1-(1-Butyl)-2-phenyl-5-(N-(benzo[b]thiophen-5-ylmethyl)-N- phenylmethyljaminomethyl-imidazole : 1-(1-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N- phenylmethyl)Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-4-bromo-5-{N-phenylmethyl-N-[1- butyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-{4-methoxyphenylmethyl]-N- phenylmethyl)Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-{6-chloro-3,4-methylenedioxyphenylmethyl]-N- phenylmethyl)-aminomethylimidazole 1-(1-Butyl}-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-[1- butyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3-methoxyphenylmethyl]-N- phenylmethyljaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-fluorophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-4-bromo-5-(N-[2,3-dichlorophenylmethyl]-N-{1- butyl])aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-|[2,6-dichlorophenylmethyl]-N- phenylmethyljaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N- phenylmethyl)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-4-chloro-5-(N-phenylmethyl-N-[1- butyl])Jaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[4-{1-pyrrolidinyl}phenylmethyl]-N- phenylmethyljaminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[4-diethylaminophenylmethyl]-N- phenylmethyl)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[pyridin-2-ylmethyl}-N- phenylmethyl)aminomethylimidazole
1-(1-Butyl)-2-phenyl-5-(N-[pyridin-3-ylmethyl]-N- phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[pyridin-4-ylmethyl}-N- phenylmethyl)aminomethylimidazole : 1-(1-Butyl)-2-phenyl-5-(N-[2-fluoro-6-chlorophenylmethyl}-N- phenylmethyl)aminomethyl-imidazole) 1-(1-Butyl)-2-phenyl-5-(N-[2,4-dichlorophenylmethyl}-N- phenylmethyl)aminomethyl-imidazole) 1-(1-Butyl)-2-phenyl-5-(N-[4-chlorophenylmethyl]-N- phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[{4-hydroxyphenylmethyl}-N- phenylmethyljaminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[4-trifluoromethoxyphenylmethyl]-N- phenylmethyl)aminomethyl-imidazole) 1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-3,4-dimethoxyphenylmethyl]-N- phenylmethyl)amino-methylimidazole) 1-(1-Butyl)-2-phenyl-5-(N-[4-nitrophenylmethyl]-N- phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[4-aminophenylmethyl]-N- phenylmethyl)aminomethylimidazole 1-(1-Buty))-2,4-diphenyl-5-(N-phenylmethyl-N-[1- butyl])aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[2-aminopyridin-S-ylmethyl]-N- phenylmethyl)aminomethyl-imidazole 1-(1-Butyl)-2-phenyl-5-(N-[2,3-dihydrobenzo[b]furan-5-ylmethyl]-N- phenylmethyl)amino-methylimidazole . 1-(1-Butyl)-2-phenyl-5-(N-[2-chloro-4-hydroxyphenylmethyl}-N-[1- butyl])aminomethyl-imidazole) ; Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4- ylmethyl)-amine; 599
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl- 3H-imidazol-4-ylmethyl]-amine; 4-({Benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl}-amino}-methyl)- benzamide; : 4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-3- chloro-phenol; 4-({11 _(3-Butyl-2-phenyl-3H-imidazol-4-yl) -pentyl]-cyclohexylmethyl-amino}- methyl)-phenol; 4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino}-methyl}- benzamide; 4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}-2- methyl-phenol; 4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl-aminoj- methyl}-2-methyl-phenol; (3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-difluoro-benzyl}-(4- methoxy-benzyl)-amine; Benzyl-(3-butyl-2 ,5-diphenyl-3H-imidazol-4-ylmethyl)-(2 ,3-dihydro- benzo[1,4}dioxin-6-ylmethyl)-amine; (3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,5-difluoro-benzyl)-(4- methoxy-benzyl)-amine; (3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(2,6-dichloro-benzyl)-(4- methoxy-benzyl)-amine; Benzo[1,3]dioxol-5-ylmethyl-butyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl- 3H-imidazol-4-ylmethylj-amine; 4-({Benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl)- amino}-methyl}-benzenesulfonamide; Benzo 1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl- 3H-imidazol-4-ylmethyl}-amine; 4-({Butyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]- amino}-methyl)-3-chloro-phenol;
4-{{(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-methoxy-benzyl)- amino]-methyl}-benzoic acid, 4-({Benzyl-[3-butyl-2-(3-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl]- amino}-methyl)-3-chloro-phenol; : Benzo|1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4- yl}-pentyl}-amine; Benzo] 1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4- yl)-ethyl}-amine; 4-{[Butyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}- benzamide; Benzo|1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-fluoro-phenyl)-2-phenyl-3H- imidazol-4-ylmethyl]-amine; 3-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino}-methyl}- phenol; 4-{{Butyl-(3-butyl-5-tert-butyl-2-phenyl-3H-imidazol-4-ylmethyl)-amino] - methyl}-benzamide; 4-{{Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-aminoj-methyl}- 2,6-dimethyl-phenol; 4-({|3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]- cyclohexylmethyl-amino}-methyl)-2,6-dimethyl-phenol; [3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]- cyclohexylmethyl-(2,3-dihydro-benzofuran-5-ylmethyl)-amine ; (4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-cyclohexylmethyl- amino|-methyl}-phenyl)-dimethyl-amine; 4-{5-[(Bis-benzo{ 1,3]dioxol-5-ylmethyl-amino}-methyl}-2,4-diphenyl-imidazol- 1-yl}-butan-1-ol; (4-{{(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl}-cyclohexylmethyl-aminoj- methyl}-phenyl}-dimethyl-amine; 4-{[Butyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino}-methyl}-2,6- dimethyl-phenol;
4-({Butyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl}-ethyl]-amino}-methyl)- 2,6-dimethyl-phenol; 4-{[(3-Butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-(4-dimethylamino-benzyl)- amino]-methyl}-benzoic acid 1-(1-Butyl)-2-phenyl-4-methyl-5-(N-phenyimethyl-N-[1- butyl})aminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl]-N- phenylmethyl}-aminomethylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[2-chloro-4-hydroxyphenylmethyl}-N- phenylmethyl)-aminomethylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[2,3-dichlorophenylmethyl]-N- phenylmethyl)amino-methylimidazole 1-(1 Butyl)-2-(3-fluorophenyl)-5-(N-[4-dimethylaminophenylmethyl}-N- phenylmethyljamino-methylimidazole 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[4-{1-pyrrolidinyl}phenylmethyl}-N- phenylmethyljamino-methylimidazole 1-(1-Butyl)-2-(3-chlorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenylmethyl}-N- phenylmethyl] amino)ethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-{indol-5-ylmethyl]-N- phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-(4-fluorophenyl)-5-{1-N,N-di[3,4- methylenedioxyphenylmethyljamino)ethylimidazole 2-{[5-({Butyl{(1-butyl-2,4-diphenylimidazol-5-yl)methyljamino}methyl)-2- pyridyljJaminojethan-1-ol, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
135. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICso of about 500 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
136. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICso of about 200 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
137. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICse of about 100 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
138. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICso of about 50 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
139. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICso of about 25 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
140. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICso of about 10 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
141. A compound of any one of claims 1 through 134 wherein the compound exhibits an ICso of about 5 nM or less in a standard in vitro C5a mediated chemotaxis or calcium mobilization assay.
142. A compound of any one of claims 1 through 134 wherein the
. compound exhibits less than 5% agonist activity in a GTP binding assay.
143. A compound of any one of claims 1 through 134 wherein the compound exhibits a 10-fold selectivity for the antagonist activity over the compound’s effects on ATP stimulated responses in a GTP binding assay.
144. A pharmaceutical composition comprising a compound of any one of claims 1 through 143 or a prodrug or hydrate thereof and a pharmaceutically acceptable carrier therefor.
145. A compound or composition of any one of claims 1 through 143 for use in a method for treating a patient suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors.
146. A compound or composition of any one of claims 1 through 143 for i use in a method for treating a patient suffering from or susceptible to an autoimmune disease or disorder.
147. A compound or composition of any one of claims 1 through 143 for use in a method for treating a patient suffering from or susceptible to rheumatoid arthritis, systemic lupus erythematosus, associated glomerulonephritis, psoriasis, Crohn’s disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome, glomerulonephritis, pulmonary hemorrhage, or immunovasculitis.
148. A compound or composition of any one of claims 1 through 143 for use in a method for treating a patient suffering from or susceptible to an inflammatory condition. 604 AMENDED SHEET 2004 -04- 26 i
149. A compound or composition of any one of claims 1 through 143 for use in a method for treating a patient suffering from or susceptible to neutropenia, sepsis, septic shock, Alzheimer’s disease, stroke, inflammation associated with burns, lung injury, myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, traumatic central nervous system injury, ischemic heart disease, and ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, tissue graft rejection, or hyperacute rej ection of transplanted organs.
150. A compound or composition of any one claims 1 through 143 for use in a method for treating a patient suffering from or susceptible to pathologic sequellae associated with insulin-dependent diabetes mellitus, lupus nephropathy, Heyman nephritis, membranous nephritis, glomerulonephritis, contact sensitivity responses, or inflammation resulting from contact of blood with artificial surfaces.
151. A compound or composition of any one of claims 145 through 150 wherein the patient is a mammal.
152. A compound or composition of any one of claims 145 through 150 wherein the patient is a human.
153. An in vitro method for inhibiting C5a-promoted cellular chemotaxis, comprising administering to mammalian white blood cells a chemotaxis or calcium mobilization-inhibitor effective amount of a compound or composition of any one of claims 1 through 143.
154. The method of claim 153 wherein the white blood cells are human. 603 AMENDED SHEET 2004 -04- 26 i }
155. An in vitro method of localizing C5a receptors in a tissue, comprising: contacting a tissue with a detectably labeled compound or composition of any one of claims 1 through 143 under conditions that permit binding of the compound to, the tissue; and detecting the bound compound.
156. A method of preparing a donor organ for organ transplantation comprising: - perfusing the donor organ, prior to transplantation of the organ into a recipient patient, with a liquid solution comprising a compound of Claim 1 ina - pharmaceutically acceptable carrier, wherein the solution comprises a concentration of the compound that is sufficient, to inhibit CS5a-mediated chemotaxis of cells expressing a CSa receptor in vitro, or to inhibit CSa-induced calcium mobilization in cells expressing the C5a receptor in vitro, or to inhibit C5a- induced GTP binding to the membranes of cells expressing the Ca receptor in vitro, or when present in vivo in an animal’s bloodstream when a neutropenia-induction- sufficient amount of CS5a is introduced into the bloodstream of the animal, to reduce the resulting C3a-induced neutropenia in vivo. . i 606 - w AMENDED SHEET 2004 -04- 26
157. A compound of any of claims 1 to 143 wherein the compound produces less than 10%, 5% or 2% reduction of ATP-induced calcium mobilization in a calcium mobilization assay.
158. The use of a compound or composition of any one of claims 1 to 143 in a method of making a medicament for use in a method for treating a patient suffering from or susceptible to a disease or disorder involving pathologic activation on C5a receptors.
159. The use of a compound or composition of any one of claims 1 to 143 in a method of making a medicament for use in a method for treating a patient suffering from or susceptible to an autoimmune disease or disorder.
160. The use of a compound or composition of any one of claims 1 to 143 in a method of manufacturing a medicament for use in the method for treating a patient suffering from or susceptible to rheumatoid arthritis, systemic lupus erythematosus, associated glomerulonephritis, psoriasis, Crohn’s disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome, glomerulonephritis, pulmonary hemorrhage, or immunovasculitis.
161. The use of a compound or composition of any one of claims 1 to 143 in a method of manufacturing a medicament for use in a method for treating a patient suffering from or susceptible to an inflammatory condition. 607 AMENDED SHEET 2004 -04- 26
162. A compound or composition of any one of claims 1 through 143 for use in a method for inhibiting C5a-promoted cellular chemotaxis comprising administering to mammalian white blood cells a chemotaxis or calcium mobilization-inhibitor an effective amount of said compound or composition.
163. A detectably labeled compound or composition of any one of claims 1 through 143 for use in a method of localizing C5a receptors in a tissue comprising contacting said tissue with said detectably labeled compound or composition under conditions that permit binding of the compound to the tissue, and detecting the bound compound. 608 AMENDED SHEET 2004 -04- 2 6
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200301160A ZA200301160B (en) | 2000-09-29 | 2000-09-29 | High affinity small molecule C5A receptor modulators. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200301160A ZA200301160B (en) | 2000-09-29 | 2000-09-29 | High affinity small molecule C5A receptor modulators. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200301160B true ZA200301160B (en) | 2004-04-28 |
Family
ID=32851448
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200301160A ZA200301160B (en) | 2000-09-29 | 2000-09-29 | High affinity small molecule C5A receptor modulators. |
Country Status (1)
| Country | Link |
|---|---|
| ZA (1) | ZA200301160B (en) |
-
2000
- 2000-09-29 ZA ZA200301160A patent/ZA200301160B/en unknown
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