JP2006502095A - Substituted biaryl amides as C5a receptor modulators - Google Patents

Abstract

Substituted biaryl amides of formula I are provided. Such compounds are ligands that can be used to modulate C5a receptor activity in vivo or in vitro, and treat diseases associated with pathological C5a receptor activation in humans, domestic pets and livestock animals. Is particularly useful. Pharmaceutical compositions and methods for using them to treat the above disorders and methods for using the ligands in receptor localization experiments are provided.

Description

The present invention includes substituted biaryl amides that modulate mammalian complement C5a receptors. Certain biaryl amides provided herein act as high affinity C5a receptor ligands and / or antagonists of complement C5a receptors, preferably human C5a receptors (including inverse agonists). The invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds to treat various inflammatory and immune system disorders. In addition, the present invention relates to the use of such compounds as probes for locating C5a receptors.

Background of the Invention
The C5a, a74 amino acid peptide is generated in the complement cascade by cleavage of complement protein C5 by the complement C5 convertase enzyme. C5a has both anaphylatoxins (eg bronchoconstriction and vascular spasmogen) and chemotaxis effects. It is therefore active in producing both the vascular and cellular phases of the inflammatory response. Since it is a plasma protein and is therefore generally available almost instantaneously at the site of provoking stimulants, it is key in initiating a complex series of events leading to an increase and amplification of early inflammatory stimulators. Is a mediator. The anaphylatoxin and chemotaxis effects of C5a peptides are believed to be mediated through interaction with the C5a receptor (CD88 antigen), a 52 kD membrane-bound G protein coupled receptor (GPCR). C5a is an excellent chemoattractant for polymorphonuclear leukocytes and carries neutrophils, basophils, eosinophils, and monocytes to sites of inflammation and / or cell injury. C5a is one of the best chemotactic agents known for a wide variety of inflammatory cell types. C5a also “activates” or prepares neutrophils for various antibacterial functions (eg, phagocytosis). In addition, C5a releases inflammatory mediators such as histamine, TNF-α, IL-1, IL-6, IL-8, prostaglandins and leukotrienes, and lysosomal enzymes and other cytotoxicity from granulocytes Stimulates the release of ingredients. Among its actions, C5a promotes the production of activated oxygen radicals and smooth muscle contraction.

  Considerable experimental evidence indicates elevated levels of C5a in a number of autoimmune diseases and inflammatory and related disorders.

  Agents that block the binding of C5a to other agents of that receptor, including inverse agonists, that modulate signal transduction associated with C5a-receptor interactions may contribute to such inflammation and autoimmune diseases. Pathological events related to toxin activity, including chemotaxis, can be inhibited.

SUMMARY OF THE INVENTION The present invention provides the following substituted biaryl amides of formula I: Such compounds are useful as modulators of the C5a receptor and preferably inhibit C5a receptor activation and / or C5a receptor-mediated signal transduction.

の化合物またはその薬学的に許容される塩を提供する。 Accordingly, in one aspect of the invention, Formula I:

Or a pharmaceutically acceptable salt thereof.

Ar ¹ in formula I
i) a selectively substituted phenyl having at least one selectively substituted phenyl or a selectively substituted heterocyclic substituent attached thereto,
ii) 2 to about 4 partially unsaturated or aromatic rings, 3-8 membered selectively substituted carbocycles in each ring, or
iii) optionally substituted heteroaryl;
It is.
R ¹ is an optionally substituted cycloalkyl, an optionally substituted (cycloalkyl) alkyl, an optionally substituted (heteroaryl) alkyl, an optionally substituted (aryl) alkyl, optionally Substituted aryl, optionally substituted heteroaryl having about 5-7 ring atoms and between 1 and 3 ring heteroatoms selected from N, O and S, or optionally substituted Wherein the aryl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, with the remaining ring atoms being carbon. And (b) fused to a 5-7 membered saturated or partially unsaturated ring independently substituted with 0-2 substituents selected from halogen, alkyl and alkoxyl.
R ² is each optionally substituted alkyl, cycloalkyl, (cycloalkyl) alkyl, heteroaryl, (heteroaryl) alkyl, aryl, (aryl) alkyl, indanyl or tetrahydronaphthyl, or R 2 ² is an optionally substituted phenyl (C ₀ -C ₂ alkyl), wherein the phenyl moiety is (a) 0, 1 or 2 rings independently selected from N, O and S; 5-7 membered having atoms, the remaining ring atoms are carbon, and (b) independently substituted with 0-3 substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy Of a saturated or partially unsaturated ring.

In certain aspects, the compounds described above have an IC ₅₀ value of 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM or less in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, or calcium mobilization assay. Presents. A preferred C5a is a mammalian receptor which can be either a cloned, recombinant expression receptor or a naturally expressed receptor. In some embodiments, the C5a receptor is a primate C5a receptor, including a human C5a receptor. In some embodiments, the C5a receptor modulators described herein exhibit a higher affinity for the human C5a receptor than for non-primate C5a receptors; for example, in some embodiments, the compounds of Formula I It exhibits a 5- or 10-fold greater affinity for human C5a receptor than for all or all non-primate C5a receptors.

Certain aspects of the invention specifically bind to the C5a receptor, preferably 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM in standard C5a receptor-mediated chemotaxis assays, radioligand binding assays, calcium mobilization assays. , Directed to compounds of the above formula I that exhibit IC ₅₀ values of 10 nM or 5 nM or less.

  The invention further provides, in certain embodiments, compounds of formula I that exhibit less than 5% agonist activity in a GTP binding assay.

  The present invention, in another aspect, further comprises a pharmaceutical composition comprising at least one of the aforementioned compounds or salts (or prodrugs or hydrates thereof) in combination with a physiologically acceptable carrier or excipient. I will provide a.

  In a further aspect, the present invention provides a method for treating a patient suffering from a disease responsive to C5a receptor modulation. (For example, human or non-human animals such as domesticated pets or livestock animals). Such methods generally comprise administering to the patient a C5a receptor modulating amount of at least one of the compounds or salts. For example, the present invention is sufficient to produce an effective amount of a compound of the present invention, e.g., a plasma concentration of a compound (or its active metabolite if prodrug) or in vitro white blood cells (e.g., neutrophils) Spheres) including methods of treating patients in need of anti-inflammatory or immunotherapy with a sufficient amount of a compound of the invention to inhibit chemotaxis. Treatment of humans, domesticated companion animals (pets) or livestock animals with such diseases with an effective amount of a compound of the invention is contemplated by the present invention. To treat any particular species of non-human animal, compounds that exhibit high affinity for the C5a receptor of that particular species are preferred.

  In a further aspect, a method is provided for inhibiting signal transduction activity of cellular C5a receptor comprising contacting a cell expressing C5a receptor with an effective amount of at least one of the compounds or salts. Such contacting can be done in vivo or in vitro. In some embodiments, the signal transduction activity that is inhibited is calcium conductance. In other embodiments, the signal transduction activity that is inhibited is C5a receptor-mediated cytochemistry, and the method comprises contacting mammalian white blood cells with a C5a receptor modulating amount of the compound or salt.

  In another aspect, there is further provided a method of inhibiting the binding of C5a to the C5a receptor. Within certain such aspects, inhibition occurs in vitro. Such a method contacts a C5a receptor with at least one of said compounds or salts under conditions that detectably inhibit C5a binding to the receptor and in an amount sufficient to inhibit it. Including that. Within other such aspects, the C5a receptor is in a patient. Such a method comprises at least one of the above-mentioned compounds in a patient at a concentration sufficient to detectably inhibit C5a binding to cells expressing the C5a receptor in vitro. Contacting with a compound or salt.

  Also, in certain aspects, the compound is labeled with a detectable marker (eg, a radioactive label or a fluorescein conjugate). The invention can be performed, for example, in a tissue piece (e.g., via autoradiography) or (e.g., via positron emission tomography, PET, or simple positron emission computed tomography, SPECT, scanning and imaging). Methods are provided for using appropriately labeled compounds of the present invention as probes to locate receptors, particularly C5a receptors, in vivo.

  In another aspect, the invention provides methods of using the compounds of the invention as positive controls in assays for receptor activity, such as radioligand binding, calcium mobilization, and C5a-mediated chemotaxis assays.

  The present invention further includes (a) a pharmaceutical composition as described herein in a container; and (b) said composition to treat one or more diseases responsive to C5a receptor modulation. A packaged pharmaceutical formulation comprising instructions for using the is provided.

  In yet another aspect, the invention provides a process for making the compounds disclosed herein, including intermediates.

  These and other aspects of the invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION Chemical Description and Terminology Compounds of the invention are generally described using standard nomenclature.

  As used herein, the term “substituted biarylamide” refers to all compounds satisfying one or more of formulas I, IA and II-XIV herein as well as the pharmaceutically acceptable of such compounds. Salts, prodrugs and hydrates.

  Certain compounds described herein may include one or more asymmetric elements (e.g., stereogenic centers, stereogenic axes, etc.) such that the compounds can exist in different stereoisomeric forms. Asymmetric carbon atoms). These compounds can be, for example, racemates or optically active forms. For compounds having two or more asymmetric elements, these compounds may additionally be a mixture of diastereomers. Unless otherwise specified, all optical isomers and mixtures thereof are included as compounds having asymmetric centers. In addition, compounds having carbon-carbon double bonds can occur in Z- and E-forms, and all isomeric forms of the compounds are included in the present invention unless otherwise indicated. Where the compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.

The present invention is meant to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. In general examples, without limitation, isotopes of hydrogen include tritium and deuterium, and carbon isotopes include ¹¹ C, ¹³ C, and ¹⁴ C.

Certain compounds are described herein using a general formula such as Formula I that includes variables such as Ar ¹ , R ¹ and R ² . Unless otherwise noted, each variable in such an expression is defined independently of other variables. Thus, for example, if it represented the group is substituted with 0-2 R ^*, then said group can be optionally substituted with up to two R ^* groups, R2 in each occurrence ^* is Selected independently of the definition of R2 ^* . Also, combinations of substituents and / or variables are allowed only if such a combination results in a stable compound.

  As used herein, “substituent” refers to a molecular moiety covalently bonded to an atom within a molecule of interest. For example, a “ring substituent” is a halogen, alkyl group, haloalkyl group, or other substituent described herein, covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of the ring. Can be a site. As used herein, the term “substituent” means that any one or more hydrogens on a named atom are replaced by selection from the indicated substituent, provided that the designated The normal valence of the selected atom is not exceeded, and substitution results in a stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity). To do. If the substituent is oxo (ie, ═O), then two hydrogens on the atom are replaced. If the aromatic moiety is replaced by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example, a pyridyl group substituted by oxo is tetrahydropyridone.

The phrase “optionally substituted” means that the group is either at one or more available positions, typically by one or more suitable substituents such as those disclosed herein. Means that it may or may not be substituted at position 1, 2, 3, 4 or 5. The compounds and various groups within the formulas described herein are “optionally substituted” including, for example, R ¹ , R ² and Ar ¹ . Optional substitution can also be indicated by the phrase “substituted with 0 to X substituents,” where X is the maximum number of substitutions.

Suitable substituents are, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, -COOH, SO ₂ NH _2, alkyl (e.g., C ₁ -C ₈ alkyl), alkenyl (e.g., C ₂ - C ₈ alkenyl), alkynyl (e.g., C ₂ -C ₈ alkynyl), alkoxy (e.g., C ₁ -C ₈ alkoxy), alkyl ether (e.g., C ₂ -C ₈ alkyl ether), alkylthio (e.g., C ₁ - C ₈ alkylthio), mono - or di - (C ₁ -C ₈ alkyl) amino, haloalkyl (e.g., C ₁ -C ₆ haloalkyl), hydroxyalkyl (e.g., C ₁ -C ₆ hydroxyalkyl), aminoalkyl (e.g. , C ₁ -C ₆ aminoalkyl), haloalkoxy (e.g., C ₁ -C ₆ haloalkoxy), alkanoyl (e.g., C ₁ -C ₈ alkanoyl), alkanone (e.g., C ₁ -C ₈ alkanone), alkanoyloxy (For example, C ₁ -C ₈ alkanoyloxy), alkoxycarbonyl (e.g., C ₁ -C ₈ alkoxycarbonyl), mono- - and di - (C ₁ -C ₈ alkyl) amino, mono- - and di - (C ₁ -C ₈ alkyl) amino C ₁ -C ₈ alkyl, mono- and di- (C ₁ -C ₈ alkyl) carboxylamide, mono- and di- (C ₁ -C ₈ alkyl) sulfonamide, alkylsulfinyl (eg C ₁ -C ₈ alkyl) sulfinyl), alkylsulfonyl (e.g., C ₁ -C ₈ alkylsulfonyl), aryl (e.g., phenyl), arylalkyl (e.g., such as benzyl and phenethyl (C ₆ -C ₁₈ aryl) C ₁ -C ₈ alkyl) , aryloxy (e.g., C ₆ -C ₁₈ aryloxy, such as phenoxy), arylalkoxy (e.g., (C ₆ -C ₁₈ aryl) C ₁ -C ₈ alkoxy) and / or 3-to 8-membered heterocyclic group including. Certain groups within the formulas provided herein are optionally substituted with 1-3, 1-4, or 1-5 independently selected substituents.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH ₂ is bonded through the carbon atom.

As used herein, “alkyl” is specifically intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Accordingly, the term C ₁ -C ₆ alkyl as used herein refers to an alkyl group having 1 to 6 carbon atoms. “C ₀ -C ₄ alkyl” refers to a bond or a C ₁ -C ₄ alkyl group. Alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylphenyl 1 to 8 carbon atoms (C ₁ -C ₈ alkyl), 1-6 carbon atoms (C ₁ -C ₆ alkyl), and 1 to 4 carbon atoms (C ₁ -C ₄ alkyl, such as ). “Aminoalkyl” is an alkyl group, as defined herein, substituted with one or more —NH ₂ groups. “Hydroxyalkyl” is a hydroxy group as defined herein substituted with one or more —OH groups.

“Alkenyl” refers to a straight or branched hydrocarbon chain containing one or more unsaturated carbon-carbon bonds, such as ethenyl and propenyl. Alkenyl groups are C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkenyl, and C ₂ -C ₄ alkenyl groups such as ethenyl, allyl or isopropenyl (which are 2-8, 2-6, respectively) Or having 2 to 4 carbon atoms).

“Alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple carbon carbon bonds. Alkynyl groups include C ₂ -C ₈ alkynyl, C ₂ -C ₆ alkynyl and C ₂ -C ₄ alkynyl groups, which have from ₂ to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. Alkynyl groups include, for example, groups such as ethynyl and propynyl.

  “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.

The term “alkanoyl” refers to an acyl group in a linear or branched arrangement (eg, — (C═O) -alkyl). Alkanoyl groups include C ₂ -C ₈ alkanoyl, C ₂ -C ₆ alkanoyl and C ₂ -C ₄ alkanoyl groups, which have from ₂ to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. “C ₁ alkanoyl” refers to — (C═O) —H, which is included in the term “C ₁ -C ₈ alkanoyl” (along with C ₂ -C ₈ alkanoyl).

The term “alkyl ether” refers to a linear or branched ether substituent linked via a carbon-carbon bond. The alkyl ether groups are C ₂ -C ₈ alkyl ethers, C ₂ -C ₆ alkyl ethers and C ₂ -C ₆ alkyl ethers having ₂ to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. Contains groups. As an example, a C ₂ alkyl ether group has the structure —CH ₂ —O—CH ₃ .

The term “alkoxycarbonyl” refers to an alkoxy group attached through a carbonyl (ie, a group having the general structure —C (═O) —O-alkyl). Alkoxycarbonyl groups each contain 2-8, 2-6, or 2-4 _{C 2 -C 8, C 2 -C} 6, and C ₂ -C ₄ alkoxycarbonyl group having carbon atoms . “C ₁ alkoxycarbonyl” refers to —C (═O) OH, which is included in “C ₁ -C ₈ alkoxycarbonyl”.

As used herein, “alkanoyloxy” refers to an alkanoyl group attached through an oxygen bridge (ie, a group having the general structure —OC (═O) -alkyl). Alkanoyloxy groups each contain 2-8, 2-6, or 2-4 _{C 2 -C 8, C 2 -C} 6, and C ₂ -C ₄ alkanoyloxy group having a carbon atom .

As used herein, the term “alkylthio” refers to an alkyl group bonded through a thioether bond. Alkylthio groups include C ₁ -C ₈ alkylthio, C ₁ -C ₆ alkylthio and C ₁ -C ₄ alkylthio, each having 1 to 8, 1 to 6, or 1 to 4 carbon atoms.

As used herein, “alkylsulfinyl” refers to an alkyl group bonded through a sulfinyl bond. Alkylsulfinyl groups are C ₁ -C ₈ alkyl sulfinyl, C ₁ -C ₆ alkyl sulfinyl, and C ₁ -C ₄ alkyl having 1-8, 1-6, and 1-4 carbon atoms, respectively. Contains sulfinyl.

As used herein, “alkylsulfonyl” means an alkyl group bonded through a sulfonyl bond. Alkylsulfonyl groups are C ₁ -C ₈ alkylsulfonyl, C ₁ -C ₆ alkylsulfonyl, and C ₁ -C ₄ alkyl having ₁ to 8, 1 to 6, and 1 to 4 carbon atoms, respectively. Contains sulfonyl.

“Alkylamino” refers to a secondary or tertiary amine having the general structure —NH-aryl or —N (alkyl) (alkyl), wherein each alkyl may be the same or different. Such groups include, for example, mono- and di- (C ₁ -C ₈ alkyl) amino groups, where each alkyl may be the same or different and may contain 1 to 8 carbon atoms, and mono- and Includes di- (C ₁ -C ₆ alkyl) amino groups and mono- and di- (C ₁ -C ₄ alkyl) amino groups. Alkylaminoalkyl refers to an alkylamino group attached through an alkyl group (ie, a group having the general structure -alkyl-NH-alkyl or -alkyl-N (alkyl) (alkyl)). Such groups are, for example, mono- and di- (C ₁ -C ₈ alkyl) amino C ₁ -C ₈ alkyl, mono- and di- (C ₁ -C ₆ , wherein each alkyl may be the same or different. Alkyl) amino C ₁ -C ₆ alkyl, and mono- and di- (C ₁ -C ₄ alkyl) amino C ₁ -C ₄ alkyl.

The term “carboxyamido” or “amido” refers to an amide group (ie, — (C═O) NH ₂ ). “Alkylcarboxamido” refers to —NHC (═O) alkyl, preferably —NHC (═O) C ₁ -C ₂ alkyl.

The term “cycloalkyl” refers to a hydrocarbon ring group having the specified number of carbon atoms, usually 3 to about 8 ring carbon atoms. Cycloalkyl groups include C ₃ -C ₈ and C ₃ -C ₇ cycloalkyl groups having _{3 to 8} and 3 to 7 carbon atoms, respectively. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and bridged and caged saturated ring groups such as norbornane or adamantane.

  In the term “(cycloalkyl) alkyl”, “cycloalkyl” and “alkyl” are as defined above, and the point of attachment is on the alkyl group. This term includes, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylethyl.

  The term “halogen” refers to fluorine, chlorine, bromine or iodine.

  “Haloalkyl” refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

  “Haloalkoxy” refers to a haloalkyl group as defined above attached through an oxygen bridge.

  As used herein, the term “aryl” refers to an aromatic group that contains only carbon in the aromatic ring. Such aromatic groups may be further substituted with carbon or non-carbon atoms or groups. Typical aryl groups contain 1 to 3 separate or fused rings, at least one of which is aromatic, and 6 to 8 ring atoms, without heteroatoms as ring members. Particularly preferred carbocyclic aryl groups include phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. Where indicated, the carbon atoms present in the carbocycle may be optionally substituted with any of the various ring substituents as described above, or with the substituents specifically listed.

The term “arylalkyl” refers to an aryl group bonded through an alkyl group. Certain aryl alkyl group is bonded via a (C ₆ -C ₁₈ aryl) C ₁ -C ₈ alkyl group (i.e., 6-～18- membered aryl group C ₁ -C ₈ alkyl group Group). Such groups are, for example, phenyl or naphthyl bonded, or C ₁ -C ₈ alkyl, such as benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and 2-phenyl-ethyl, preferably C ₁ -C Includes groups attached through ₄ alkyls.

  The term “aryloxy” refers to an aryl group attached through a carbonyl (ie, a group having the general structure —C (═O) —O-aryl). Phenoxy is a typical aryloxy group.

  As used herein, the term “heteroaryl” includes 1 to 4 heteroatoms selected from N, O, and S, with the remaining 5 ring being stable 5 containing at least one aromatic ring that is carbon. It is intended to denote a -7 membered monocyclic or bicyclic ring or a 7- to 10-membered bicyclic heterocycle. If the total number of S and O atoms in the heteroaryl group exceeds 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 1, 2 or 3 or less, more typically 1 or 2. The total number of S and O atoms in the aromatic heterocycle is particularly preferably 1 or less. Examples of heteroaryl groups include pyridyl, furanyl, indolyl, pyrimidinyl, pyridinyl, pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.

  The term “heterocyclic group” or “heterocycle” refers to one or two rings, in each ring, and one selected from 3 to 8 atoms, N, O and S in at least one ring. Used to indicate saturated, partially unsaturated, or aromatic groups with between 3 heterogens. Any nitrogen or sulfur heteroatom may be selectively oxidized. A heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogen atom in the heterocycle may optionally be quaternized.

  Representative examples of heteroaryl and heterocyclic groups include, but are not limited to, acridinyl, azosinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl , Benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, Isochromanl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolinyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthyridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiimil, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl , Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazo , Pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2, 5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thieno Including imidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

  A “C5a receptor” is a G-binding protein receptor that specifically binds to a C5a protein.

  Preferably, the C5a receptor is a human C5a receptor, such as the protein product of the sequence of the resulting PCR product described by Gerard and Gerard ((1991) Nature 349: 614-17). The human C5a receptor may be that described by Boulay ((1991) Biochemistry, 30 (12): 2993-9) (GENBANK accession number M62505). Non-primate C5a receptor is rat C5a receptor, rat C5a receptor such as GENBANK accession number X65862, Y09613 and AB003042, canine C5a receptor, GENBANK accession number X65860, or guinea pig C5a receptor, GENBANK accession number It may be U86103.

A “C5a receptor modulator” refers to C5a receptor activation and / or activity (ie, C5a measured using the C5a receptor-mediated chemotaxis, radioligand binding assay, or calcium mobilization assay provided herein. Any compound that modulates receptor-mediated signal transduction). In certain embodiments, such modulators can exhibit an affinity constant or IC ₅₀ for binding to a C5a receptor of less than 1 micromolar. In other embodiments, the C5a receptor modulator is an affinity constant less than 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, or calcium mobilization assay. Or it can present an IC ₅₀ . For certain purposes described herein, the modulator preferably inhibits C5a activation resulting from C5a binding (i.e., the modulator is an antagonist), but the modulator is a C5a receptor agonist or antagonist. Good. Preferred antagonists are used in C5a receptor-mediated chemotaxis, radioligand binding and / or calcium mobilization assays of less than 1 micromolar, preferably less than 100 nanomolar (used interchangeably herein with EC _50). ) Exhibits antagonist IC ₅₀ . In addition, or alternatively, the modulator can act as an inverse agonist of the C5a receptor. In certain embodiments, a modulator provided herein has a primate C5a receptor, such as a human C5a receptor, which can be a cloned recombinantly expressed receptor or a naturally expressed receptor. Modulates body activation and / or activity. To treat any particular species of non-human animal, compounds that exhibit high affinity for the C5a receptor of that particular species are preferred.

  An “inverse agonist” of a C5a receptor is a compound that inhibits the activity of C5a at the C5a receptor and reduces the activity of the C5a receptor to below its basal activity level in the absence of added C5a. An inverse agonist of the C5a receptor can also inhibit C5a binding to the C5a receptor. The ability of a compound to inhibit C5a binding to the C5a receptor can be measured by a binding assay such as the radioligand binding assay listed in Example 19. The basal activity of the C5a receptor can be measured from a GTP binding assay such as the assay of Example 20. Reduction in C5a activity can also be measured from a GTP binding assay such as the assay of Example 20 or a calcium mobilization assay such as the assay of Example 21.

  A “neutral antagonist” of a C5a receptor is a compound that inhibits the activity of C5a at the C5a receptor but does not significantly alter the basal activity of the C5a receptor. Neutral antagonists of the C5a receptor can inhibit C5a binding to the C5a receptor.

  A “partial agonist” of the C5a receptor increases the activity of the C5a receptor beyond the level of basal activity of the receptor in the absence of C5a, but is achieved by saturating the level of the natural agonist C5a Does not increase C5a receptor activity. Partial agonist compounds can inhibit C5a binding to the C5a receptor. Partial agonists of the C5a receptor usually increase the activity of the C5a receptor from 5% to 90% of the level of activity achieved by the saturating concentration of the natural agonist C5a.

  A “C5a receptor modulating amount” of a compound is a compound (or pro) that is sufficiently high to detectably modify (modulate) C5a receptor activity and / or ligand binding when the concentration is used in an in vitro assay. A drug is sufficient to produce a plasma concentration of its active metabolite). A suitable in vitro assay is a standard in vitro C5 receptor-mediated chemotaxis assay (described in Example 14 herein); a C5a receptor-mediated calcium mobilization (described in Example 21 herein). Assays; and / or radioligand binding assays such as those provided in Example 19.

  A “therapeutically effective amount” of a compound is an amount sufficient to provide a discernible patient benefit. For example, a therapeutically effective amount can reduce the severity or frequency of symptoms. Alternatively, or in addition, a therapeutically effective amount can improve patient outcome and / or prevent or delay the onset of illness or symptoms.

As used herein, a “pharmaceutically acceptable salt” is suitable for use in contact with human or animal tissue without excessive toxicity, irritation, allergic reactions, or other problems or complications. The acid or base salts generally considered in the art. Such salts include mineral and organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methane Sulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, nitric acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid acid, such as fumaric acid, maleic acid, propionic acid, hydroxy maleic acid, hydroiodic acid, phenylacetic acid, alkanoic acids such as acetic, n is a 0~4 HOOC- (CH _{2) n} -COOH Contains acid salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonia. One skilled in the art will recognize additional pharmaceuticals for the compounds provided herein, including those listed by Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, P. 1418 (1985). Will be recognized as acceptable salts. Accordingly, this disclosure should be construed to include all pharmaceutically acceptable salts of the specifically cited compounds. A wide variety of synthetic techniques are available for the preparation of pharmaceutically acceptable salts. In general, pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts are obtained by reacting a stoichiometric amount of the appropriate base or acid with the free acid or base form of these compounds in water, an organic solvent, or a mixture of both. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

  A “prodrug” is a compound that does not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a patient to yield a substituted biarylamide. For example, a prodrug can be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxy, amine, or sulfhydryl group is attached to any group that is cleaved to form a free hydroxyl, amino, or sulfhydryl group, respectively, when administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate of alcohol and amine functional groups within the compounds provided herein. Preferred prodrugs include acylated derivatives. Prodrugs can be prepared by modifying functional groups present in the compound such that the modification is cleaved to the parent compound. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare prodrugs of the compounds provided herein.

  A “patient” is any individual treated with the C5a modulator provided herein. Patients include humans and other animals such as pets (eg, dogs and cats) and livestock. The patient may be experiencing one or more symptoms of a disease responsive to C5a receptor modulation, or may be free of such symptoms (ie, treatment may be prophylactic).

C5a Receptor Modulators As noted above, the present invention provides C5a receptor modulators (ie, compounds that modulate C5a receptor-mediated signal transduction; preferably compounds that detectably bind to C5a receptors). C5a receptor modulators are used to modulate C5a receptor activity in a variety of ways, including in the treatment of patients with diseases or disorders that are responsive to C5a receptor modulation, such as autoimmune and inflammatory diseases can do. C5a receptor modulators also serve as a variety of in vitro assays (e.g., assays for receptor activity) as probes for C5a receptor detection and localization and as standards in ligand binding and C5a receptor-mediated signal conversion assays. ) Can also be used.

  The C5a receptor modulators provided herein are substituted biaryl amides of formula I that detectably modify, preferably reduce, C5a receptor activation and / or signal transduction activity at concentrations below μm. (And pharmaceutically acceptable salts and prodrugs thereof). Such alterations in C5a receptor activity include standard in vitro C5a receptor-mediated chemotaxis assays (Example 14), C5a receptor-mediated calcium mobilization assays (Example 21) and / or radioligand binding assays. It can be measured using (Example 19). The present invention is based, in part, on the finding that small molecules of formula I act as antagonists and / or inverse agonists of the C5a receptor.

の化合物およびその薬学的に許容される塩に指向される。 Accordingly, an embodiment of the present invention is a compound of formula I:

And the pharmaceutically acceptable salts thereof.

In this embodiment of the invention, Ar ¹ is
i) at least one selectively substituted phenyl or a selectively substituted phenyl having a selectively substituted heterocyclic substituent attached thereto, or
ii) selectively substituted 9H-fluorenyl, optionally substituted heteroaryl, or substituted naphthyl;
It is.

In some embodiments, Ar ¹ is a selectively substituted phenyl or a selectively substituted phenyl having an optionally substituted heterocyclic substituent attached to it at the ortho position, or Ar ¹ is ortho. It is preferably a selectively substituted naphthyl group having a substituent at the position.

R ¹ in this aspect is optionally substituted cycloalkyl, optionally substituted (cycloalkyl) alkyl, optionally substituted (heteroaryl) alkyl, optionally substituted (aryl ) Alkyl, optionally substituted aryl, optionally substituted hetero having about 5-7 ring atoms and between 1 and 3 ring heteroatoms selected from N, O and S Aryl, or optionally substituted (aryl) alkyl, wherein said aryl moiety (a) has 0, 1 or 2 ring atoms independently selected from N, O and S. The remaining ring atoms are carbon, and (b) 5-7 membered saturated or partially unsaturated, substituted with 0-2 substituents independently selected from halogen, alkyl and alkoxy Fused to a ring.

R ² is in this embodiment each optionally substituted alkyl, cycloalkyl, (cycloalkyl) alkyl, heteroaryl, (heteroaryl) alkyl, aryl, (aryl) alkyl, indanyl, or tetrahydronaphthyl. Or R ² is an optionally substituted phenyl (C ₀ -C ₂ alkyl), wherein the phenyl moiety is (a) 0 independently selected from N, O and S, With 1 or 2 ring atoms, the remaining ring atoms are carbon, and (b) 0-3 substituents independently selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy Fused to a substituted 5-7 membered saturated or partially unsaturated ring.

In certain embodiments, the present invention includes compounds of Formula I and pharmaceutically acceptable salts, wherein R ² is selected from indanyl, (aryl) alkyl, and cycloalkyl, each of which is optionally substituted.

The present invention also provides that Ar ¹ is i) phenyl having at least one phenyl substituent or a heterocyclic substituent bonded thereto, wherein each phenyl, phenyl substituent, or heterocyclic substituent is independently halogen. Amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C Substituted with 0-4 substituents selected from _1- C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl; ii) independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono - and di -C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, -NHC (═O) C ₁ -C ₂ alkyl, optionally substituted phenyl, and optionally substituted thienyl. Naphthyl substituted with 1-3 substituents-option; iii) independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, 0 to 3 substitutions selected from C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, —NHC (═O) C ₁ -C ₂ alkyl 9H-fluorenyl substituted with groups; and iv) independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ halo Substituted with 0 to 3 substituents selected from alkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl Including compounds of formula I selected from heteroaryl and pharmaceutically acceptable salts.

R ¹ is in this embodiment i) each of which is independently halogen, hydroxy, nitro, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, mono- and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ (Heteroaryl) C ₀ -C ₄ alkyl or (aryl) substituted with 0 to 3 substituents selected from alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl ) C ₀ -C ₄ alkyl; or ii) independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy that 0-5 is substituted with a substituent (aryl) C ₁ -C ₄ alkyl, where the aryl moiety is independently (a) N, O Oyo Having 0, 1 or 2 ring atoms selected from S, the remaining ring atoms being carbon, and (b) independently from halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy Fused to a 5-7 membered saturated or partially unsaturated ring substituted with 0-2 substituents selected.

R ² is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (heteroaryl) C ₁ -C ₄ alkyl, (aryl) C ₁ -C ₄ alkyl, and indanyl Each of which is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ Substituted with 0-5 substituents selected from —C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl. Compounds and salts of this embodiment are referred to as compounds of formula IA.

In certain compounds and salts of Formula IA, R ² is (i) substituted with 0 to 2 substituents independently selected from halogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy 2-indanyl; and (ii) independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C Selected from ₁ -C ₂ haloalkyl, and phenyl (C ₁ -C ₂ alkyl) substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkoxy.

によって記載される式IAの化合物および塩を含む。 The present invention also relates to general formula II:

And compounds of formula IA and salts described by

Ar ¹ in formula II i) independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C _1- Substituted with 0 to 4 substituents selected from C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl, each of which is independently halogen, amino, cyano, hydroxy, C ₁ — C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, and -NHC ( = O) ₂ to the point of attachment with phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, naphthyl, thiazolyl, or pyrimidinyl, substituted with 0 to 3 substituents selected from C ₁ -C ₂ alkyl Phenyl substituted at the position, or ii) independently (a) halogen, amino, cyano, hydro Xi, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio , And —NHC (═O) C ₁ -C ₂ alkyl, and (b) each independently halogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C Phenyl substituted with 0 to 3 substituents selected from ₁ -C ₂ haloalkoxy and naphthyl substituted with 1 to 3 substituents selected from thienyl, iii) independently halogen, amino, Cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, and 9H-fluorenyl substituted with 0 to 3 substituents selected from —NHC (═O) C ₁ -C ₂ alkyl, or iv) independently halogen Amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C Heteroaryl substituted with 0 to 3 substituents selected from ₁ -C ₂ alkylthio and —NHC (═O) C ₁ -C ₂ alkyl.

Ar ² is independently selected from i) phenyl, ii) naphthyl, iii) 1 or 2 rings, 3 to 8 atoms in each ring, and N, O and S in formula II. A heterocycle having 1 to 3 heteroatoms; and iv) having 0, 1 or 2 ring atoms independently selected from N, O, and S, the remaining ring atoms being carbon Selected from phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring; wherein i), ii), iii) and iv) are each independently halogen, hydroxy, -COOH,- CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C Substituted with 0 to 5 substituents selected from ₂ alkyl.

R ² in formula II is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (heteroaryl) C ₁ -C ₄ alkyl, (aryl) C _1- Each selected from C ₄ alkyl, and indanyl; each independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, substituted with C ₁ -C ₂ haloalkoxy, 0-3 substituents selected thienyl, and phenyl.

R ³ and R ⁴ are independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, and C ₂ -C ₄ alkynyl.

The present invention also provides that R ¹ is i) independently halogen, hydroxy, nitro, cyano, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, mono- and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C Phenyl (C ₁ -C ₂ alkyl) substituted with 0 to 5 substituents selected from ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl Or ii) 0-3 substitutions independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy substituted with group (phenyl) C ₁ -C ₄ alkyl, wherein the said phenyl moiety 0, 1 or 2 ring atoms selected from N, O and S are independently (a) And, the remaining ring atoms being carbon, and (b) are independently halogen, C ₁ -C ₂ alkyl and C ₁ -C _2. 5 to substituted with 0-2 substituents selected from alkoxy A compound of formula IA, which is fused to a 7-membered saturated or partially unsaturated ring;

In other embodiments, the invention provides that R ¹ is i) independently halogen, hydroxy, nitro, cyano, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C _2- C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, mono- and di- (C ₁ -C ₂ alkyl) amino, C ₂ -C Benzyl substituted with 0 to 5 substituents selected from ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or ii Independently substituted with 0 to 3 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy phenyl -CH ₂ -, wherein the said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining The ring atom is carbon, and (b) a 5-7 membered saturated or partially unsaturated ring substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy Including compounds of formula IA and salts thereof.

The invention provides that R ² is i) 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy; or ii) each of which is independently halogen, Benzyl, piperonyl, substituted with 0 to 3 substituents selected from hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, Included are certain compounds and salts within this embodiment that are benzodioxanylmethyl and benzofuranylmethyl.

The present invention includes certain compounds or salts within this embodiment wherein R ² is 2-indanyl substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy.

The present invention further provides that R ² is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, Compounds and salts within this embodiment that are benzyl substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl.

の化合物および薬学的に許容される塩に関する。 In other embodiments, the present invention provides compounds of formula III:

And pharmaceutically acceptable salts thereof.

Ar ³ is, in these embodiments, each independently halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di- (C ₁ -C ₄ alkyl) Substituted with 0 to 3 substituents selected from amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl Phenyl, pyridyl, furanyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, naphthyl, thiazolyl or pyrimidinyl.

R ⁶ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and -NHC ( = O) represents 0 to 4 substituents selected from C ₁ -C ₂ alkyl.

R ¹ and R ² shown in Formula III bear the definitions given above for these variables in Formula I or (in some embodiments) Formula IA.

In other embodiments, the invention provides that R ² is i) each of which is independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C _{1- 2} -indanyl, C ₃ -C ₇ cycloalkyl, or C ₂ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with 0 to 2 substituents selected from C ₂ haloalkoxy; or ii ) halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-3 substituents selected from phenyl, piperonyl, benzodioxanyl methyl, and the compound of formula III is a benzofuranyl methyl including.

In other embodiments, R ² is i) 2-indanyl substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy; or ii) each of which is independently halogen Benzyl, piperonyl substituted with 0 to 3 substituents selected from: hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy , Benzodioxanylmethyl, or benzofuranylmethyl.

Another embodiment of the present invention is that R ¹ is i) independently halogen, hydroxy, nitro, cyano, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, mono- and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyl Benzyl substituted with 0 to 5 substituents selected from oxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl and phenyl; or ii) independently Phenyl substituted with 0 to 3 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy -CH ₂ -, wherein the said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms And (b) fused to a 5-7 membered saturated or partially unsaturated ring independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy. Relates to a compound of formula III which is

The present invention provides that R ¹ is i) independently halogen, hydroxy, nitro, cyano, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and 0-5 benzyl substituted with a substituent selected from phenyl; or (ii) independently, Phenyl-substituted with 0 to 3 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy CH ₂ -, wherein the said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms carbon And (b) independently fused to a 5-7 membered saturated or partially unsaturated ring substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy Including compounds of formula III and salts thereof.

In yet another embodiment of the present invention, R ¹ is (i) independently halogen, hydroxy, nitro, cyano, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di (C ₁ -C ₂ alkyl) amino, C ₂ -C Benzyl substituted with 0 to 5 substituents selected from ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or ( ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Substituted phenyl-CH _2- , wherein the phenyl moiety (a) has 0, 1 or 2 ring atoms independently selected from N, O and S, and the remaining The ring atom is carbon, and (b) a 5-7 membered saturated or partially unsaturated ring substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy Relates to compounds of formula III and salts thereof.

Further included in the present invention is Ar ³ , each independently of halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di-C ₁ -C 0 to 3 substituents selected from ₄ alkylamino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl In particular embodiments relating to compounds and salts of formula III which are 2-thienyl or 3-thienyl substituted with

In some of these embodiments, R ² is further:
(A) i) 0 to each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, and C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with two substituents; or ii) each independently halogen, hydroxy , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -NC (= O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, Defined as benzyl, piperonyl, benzodioxanylmethyl, and benzofuranylmethyl substituted with 0-3 substituents selected from thienyl and phenyl; or R ² is
(B) R ² is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl Benzyl, piperonyl, benzodioxanylmethyl, or benzofuranylmethyl substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl and phenyl Or R ² is defined as
(C) R ² is independently defined as 2-indanyl substituted with 0 to 2 substituents selected from chloro, fluoro, methyl and methoxy.

In addition, in some embodiments where R ² is defined as (A), (B) or (C) above,
R ¹ is i) independently halogen, hydroxy, nitro, cyano, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ Benzyl substituted with 0 to 5 substituents selected from alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or ii) independently halogen, hydroxy, C (Phenyl) C ₁ -C ₄ alkyl substituted with 0 to 3 substituents selected from ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, haloalkyl, and C ₁ -C ₂ haloalkoxy, wherein The phenyl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and And (b) fused to a 5-7 membered saturated or partially unsaturated ring independently substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy; is there.

In other embodiments where R ² is defined as (A), (B) or (C) above, R ¹ is (i) independently halogen, hydroxy, nitro, cyano, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and Selected from di- (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl Benzyl substituted with 0 to 5 substituents; or (ii) independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C _1- C ₂ phenyl -CH ₂ substituted with 0-3 substituents selected from haloalkoxy - 0, here, the phenyl moiety being selected from (a) independently, N, O and S 5 having 1 or 2 ring atoms, the remaining ring atoms being carbon, and (b) independently substituted with 0 to 2 substituents selected from chloro, fluoro, methyl and methoxy Fused to a 7-membered saturated or partially unsaturated ring;

In yet other embodiments where R ² is defined as (A), (B) or (C) above,
R ¹ is independently halogen, hydroxy, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl Benzyl optionally substituted with 0 to 3 substituents selected from mono- or di (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and phenyl It is.

Further, the present invention, R ¹ is chloro each is independently fluoro, been piperonyl or benzofuranyl methyl substituted with 0-3 substituents selected from methyl and methoxy, R ² is It relates to compounds and salts defined as (A), (B) or (C) above.

In another embodiment, the invention provides that Ar ³ is independently halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di-C ₁ -C ₄ alkylamino, Substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl Relates to compounds of formula III and salts which are phenyl.

In some aspects of this type,
R ² is
(D) i) each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, and C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with two substituents; or ii) each independently halogen, hydroxy , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, Benzyl, piperonyl, benzodioxanylmethyl, and benzofuranylmethyl substituted with 0-3 substituents selected from thienyl and phenyl; or R ² is
(E) halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ - C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-3 substituents selected from phenyl, piperonyl, be benzodioxanyl methyl or benzofuranyl methyl; or R ² is
(F) 2-Indanyl independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy.

In still other embodiments of this type where R ² is defined as (D), (E) or (F) above, R ¹ is i) independently halogen, hydroxy, nitro, cyano, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -NC (= O) C ₁ -C ₂ alkyl, Mono- and di- (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl Benzyl substituted with 0 to 5 substituents selected from: or ii) independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, haloalkyl, and C ₁ -C ₂ halo substituted with 0-3 substituents selected from alkoxy (phenyl) C ₁ -C ₄ alkyl, where the phenyl moiety is independently (a) N, O Contact And 0, 1 or 2 ring atoms selected from S, the remaining ring atoms are carbon, and (b) 0-2 independently selected from chloro, fluoro, methyl and methoxy Fused to a 5-7 membered saturated or partially unsaturated ring substituted with a substituent of

Other embodiments of this type in which R ² is defined as (D), (E) or (F) are those in which R ¹ is (i) independently halogen, hydroxy, nitro, cyano, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -NC (═O) C ₁ -C ₂ alkyl, mono From-and di- (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl Benzyl substituted with 0 to 5 substituents selected; or (ii) independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ phenyl substituted with 0-3 substituents selected from haloalkoxy -CH ₂ -, wherein the said phenyl moiety is selected from N, O and S are independently (a) Having 0, 1 or 2 ring atoms, the remaining ring atoms are carbon, and (b) substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy In particular fused to 5- to 7-membered saturated or partially unsaturated rings.

In certain embodiments of this type, wherein R ² is defined as (D), (E) or (F); R ¹ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - or di (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and phenyl Benzyl optionally substituted with 0 to 3 substituents selected from

In still other embodiments of this type, the invention provides that R ² is defined as (D), (E) or (F); and R ¹ is each independently chloro, fluoro, methyl, and methoxy. And compounds and salts that are piperonyl or benzofuranylmethyl substituted with 0 to 3 substituents selected from:

の化合物および塩を含む。 In yet another embodiment, the present invention provides a compound of formula IV:

And the compounds and salts thereof.

The substituents R ¹ and R ² shown in formula IV bear the definition given in formula IA.

Z ¹ in this embodiment is carbon or nitrogen; Z ² , Z ³ , and each occurrence of Z ⁴ , each S or O ring atom, if any, is located between two CR ⁷ groups Independently selected from CR ⁷ , NR ⁸ , S and O, and p is an integer in the range of 1-2.

R ⁶ in formula IV is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and Represents 0 to 4 substituents selected from —NHC (═O) C ₁ -C ₂ alkyl;

R ⁷ is independently in each occurrence of formula IV hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, mono- - and di - (C ₁ -C ₆ alkyl) amino, cyano, nitro, and C ₁ -C Selected from ₆ alkanoyl.

R ⁸ is independently at each occurrence hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C, in Formula IV. Selected from ₈ cycloalkyl, and C ₁ -C ₆ alkanoyl.

が1〜4個の窒素環原子を含み、独立して水素、ハロゲン、ヒドロキシ、アミノ、C₁-C₆アルキル、C₁-C₆アルコキシ、C₁-C₆ハロアルキル、C₁-C₆ハロアルコキシ、モノ-およびジ-C₁-C₆アルキルアミノ、およびC₁-C₆アルカノイルから選択される0〜3個の置換基で置換されており；およびpが1または2である式IVの化合物および塩に関する。 In certain embodiments, the present invention provides a group:

There comprises 1-4 nitrogen ring atoms independently hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ halo Of formula IV, substituted with 0 to 3 substituents selected from alkoxy, mono- and di-C ₁ -C ₆ alkylamino, and C ₁ -C ₆ alkanoyl; and p is 1 or 2 Relates to compounds and salts.

の化合物および薬学的に許容される塩に関する。 Another aspect of the invention is a compound of formula V:

And pharmaceutically acceptable salts thereof.

The variables R ¹ and R ² shown in equation V bear the definition given in equation IA.

R ⁶ bears the definition given in Formula IV.

In Formula V, one of Z ² or Z ³ is sulfur or oxygen; and R ⁹ is independently hydrogen, fluoro, chloro, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, Represents 0 to 3 substituents selected from C ₁ -C ₂ haloalkyl and C ₁ -C ₆ haloalkoxy;

の化合物および薬学的に許容される塩を含む。 A further embodiment of the invention is a compound of formula VI:

And a pharmaceutically acceptable salt.

The variables R ¹ and R ² shown in formula VI bear the definition given in formula IA.

R ⁶ bears the definition given in Formula IV.

In formula VI, Z ³ is nitrogen or CR ⁹ ; and R ⁹ is independently hydrogen, fluoro, chloro, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₂ haloalkyl, And 0 to 3 substituents selected from C ₁ -C ₆ haloalkoxy.

In addition, the present invention provides that R ² is i) each of which is independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ substituted with 0-2 substituents selected from haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, and C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl); and ii) the each independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, 0-3-benzyl substituted with a substituent selected from thienyl and phenyl, piperonyl, benzodioxanyl methyl, and benzofuranyl methyl; formula is selected from IV~VI And a pharmaceutically acceptable salt.

In the present invention, each R ² is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -NC (═O) C _1- Benzyl, piperonyl, benzodioxanylmethyl, or benzo, substituted with 0 to 3 substituents selected from C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl Including compounds of formula IV-VI that are furanylmethyl and pharmaceutically acceptable salts.

In other embodiments, the present invention relates to compounds of formulas IV to VI and pharmaceutics, wherein R ² is 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy. A chemically acceptable salt.

The present invention further, R ¹ is, i) independently a halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkynyl, C ₂ -C ₄ alkynyl , C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, mono- and di- (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy (Phenyl) C ₁ -C substituted with 0 to 5 substituents selected from C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl ₂ alkyl; or ii) 0-3 independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy (Phenyl) C ₁ -C ₄ alkyl substituted with a substituent of the above, wherein the phenyl moiety is (a) independently selected from 0, 1 or 2 ring sources selected from N, O and S And the remaining ring atoms are carbon, and (b) 5-7 membered saturated or independently substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy Including compounds and salts of Formulas IV-VI that are fused to a partially unsaturated ring;

The present invention, R ¹ is, i) independently a halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-5 substituents selected from phenyl; or ii) independently a halogen Phenyl-CH substituted with 0 to 3 substituents selected from: hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy ₂ -, wherein the said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms carbon der And (b) fused to a 5-7 membered saturated or partially unsaturated ring substituted with 0-2 substituents independently selected from chloro, fluoro, methyl and methoxy; Including compounds of formulas IV-VI and salts thereof.

In certain embodiments, the invention provides that R ¹ is independently halogen, hydroxy, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -NC (= O) 0 to 3 selected from C ₁ -C ₂ alkyl, mono- and di- (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and phenyl It relates to compounds of formula IV to VI and salts which are benzyl substituted with substituents.

In another embodiment, the invention is R ¹ is piperonyl or benzofuranylmethyl, each of which is independently substituted with 0-2 substituents selected from chloro, fluoro, methyl, and methoxy Relates to compounds and salts of formulas IV to VI.

の化合物および薬学的に許容される塩を含む。 A further embodiment of the invention is a compound of formula VII:

And a pharmaceutically acceptable salt.

The variables R ² , R ³ and R ⁴ shown in formula VII bear the definitions given in formula II.

Z ¹ is carbon or nitrogen in formula VII;
Z ² , Z ³ , and each occurrence of Z ⁴ are from CR ⁷ , NR ⁸ , S and O such that each S or O ring atom, if any, is located between two CR ⁷ groups. Independently selected, p is an integer ranging from 1 to 2; R ⁷ is independently in each occurrence hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C, in formula VII ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, mono- and di - (C ₁ -C ₆ alkyl) amino, cyano, nitro, and C ₁ -C ₆ alkanoyl; and R ⁸ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl at each occurrence , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, and C ₁ -C ₆ alkanoyl.

R ⁶ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio in formula VII And 0 to 4 substituents selected from —NHC (═O) C ₁ -C ₂ alkyl.

In certain embodiments, the invention provides that Ar ² has 0, 1 or 2 ring atoms independently selected from i) phenyl; or ii) independently N, O and S, with the remaining ring atoms being carbon A phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring; wherein i) and ii) are each independently halogen, hydroxy, —COOH, —CONH ₂ , C ₁ It relates to compounds of formula VII substituted with 0 to 2 substituents selected from —C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy.

R ² in this embodiment of the invention is i) 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy; or ii) each of which is independently Benzyl substituted with 0 to 3 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, Piperonyl, benzodioxanylmethyl, or benzofuranylmethyl.

R ³ and R ⁴ in this embodiment are hydrogen.

は、その各々が独立してハロゲン、ヒドロキシ、C₁-C₂アルキル、C₁-C₂アルコキシ、C₁-C₂ハロアルキル、およびC₁-C₂ハロアルコキシから選択される0〜3個の置換基で置換されたフェニルまたはチエニルである。 Said group:

0 to 3 each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy It is phenyl or thienyl substituted with a substituent.

R ⁶ in this embodiment is independently 0 to 2 selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy Represents a substituent.

の化合物および薬学的に許容される塩に関する。 An embodiment of the present invention is represented by formula VIII:

And pharmaceutically acceptable salts thereof.

R in formula VIII is (i) halogen, hydroxy, C ₁ -C ₃ haloalkyl, or C ₁ -C ₃ haloalkoxy, or (ii) each independently halogen, hydroxy, amino, oxo, cyano, 0-4 and di (C ₁ -C ₄₎ is selected from alkylamino - C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆ alkyl) amino substituted with ₁ substituent Or C ₃ -C ₇ cycloalkyl (C ₀ -C ₄ alkyl), (iii) phenyl, or (iv) 4-8 ring atoms, and independently selected from N, O and S A heterocycle having 3 heteroatoms; wherein (iii) and (iv) are each independently hydroxy, halogen, amino, cyano, nitro, C ₁ -C ₆ alkyl Kill, C ₁ -C ₆ alkoxy, mono- and di-C ₁ -C ₆ alkylamino, mono- and di-C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ Substituted with 0 to 3 substituents selected from —C ₆ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl.

R ² in formula VIII is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (heteroaryl) C ₀ -C ₂ alkyl, (aryl) C ₀ -C is ₂ alkyl or indanyl; halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, COOH, -NC (= O) C 1 - Is substituted with 0 to 3 groups selected from C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy; or R ² is (phenyl) C ₀ -C ₂ alkyl Wherein the phenyl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently 0 to 3 selected from halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Fused to a 5-7 membered saturated or partially unsaturated ring substituted with 1 substituent.

R ³ and R ⁴ are independently hydrogen, methyl or ethyl.

R ⁵ and R ⁶ are each independently halogen, hydroxy, cyano, nitro, amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, Mono- and di- (C ₁ -C ₆ ) alkylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl Represents 0 or more substituents selected from

Ar ² is i) phenyl, ii) naphthyl, iii) 1 or 2 rings, 3 to 8 atoms in each ring, and 1 to 3 heteroaryls independently selected from N, O and S A heterocycle having atoms; or iv) a 5-7 membered saturated or moiety having 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being carbon Each of i), ii), iii) and iv) is independently a) halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₃ haloalkyl, and C ₁ -C ₃ haloalkoxy, b) each independently halogen, hydroxy, amino, oxo, cyano, -COOH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy , mono - and di (C ₁ -C ₄₎ alkylamino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ alkyl carboxamide, C ₁ -C ₄ Arukirusurufu Alkylsulfonyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkyl sulfonates, C ₂ -C ₄ alkyl esters, and C ₁ -C ₄ alkoxy C substituted with 0-5 substituents selected from carbonyl ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, mono- - and di - (C ₁ -C ₆ alkyl) amino, and (C ₃ -C ₇ cycloalkyl Alkyl) C ₀ -C ₄ alkyl, c) C ₁ -C ₄ alkyl carboxamide, C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl sulfinyl, C ₁ -C ₄ alkyl sulfonyl, C ₁ -C ₄ alkyl sulfonate C, C ₂ -C ₄ alkyl ester, C ₁ -C ₄ alkoxycarbonyl, and heterocycloalkyl (C ₀ -C ₄ alkyl), and d) independently halogen, hydroxy, nitro, amino, C ₁ -C ₄ alkyl , C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and 5-7 membered het 1 or 2 rings, 3 to 8 atoms in each ring, and independently selected from N, O and S, substituted with 0 to 3 groups selected from cycloalkyl substituents Substituted with 0 to 5 substituents selected from (heterocyclic) C ₀ -C ₄ alkyl having 1 to 3 heteroatoms.

In certain other embodiments, the invention relates to compounds of formula VIII and salts, wherein R ³ , R ⁴ , R ⁵ and R ⁶ bear the values given for these variables in formula VIII.

R is (i) halogen, hydroxy, C ₁ -C ₃ haloalkyl, and C ₁ -C ₃ haloalkoxy, (ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl 0 to 4 substituents selected from C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- and di- (C ₁ -C ₄ alkyl) amino Substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl ₁ -O-, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆ alkyl) amino or C ₃ -C ₇ cycloalkyl, (C ₀ -C ₄ alkyl), (iii) phenyl, and (iv) pyridinyl, pyrimidinyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl , Thiazolyl, isoxazolyl, pyrrolidinyl, morpholinyl, piperazinyl, and Selected from peridinyl, wherein each of (iii) and (iv) is independently hydroxy, halogen, amino, cyano, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- and di- C ₁ -C ₆ alkylamino, mono- and di-C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₂ alkylthio, and Substituted with 0 to 3 substituents selected from —NHC (═O) C ₁ -C ₂ alkyl.

R ² is in this embodiment C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, thienylmethyl, quinazolinylmethyl, benzothia Zolylmethyl, indolylmethyl, benzimidazolylmethyl, phenyl, benzyl, phenethyl or indanyl; each of which is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C Substituted with 0 to 3 groups selected from ₄ alkylthio, —COOH, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy; Or R ² (a) has 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ 5- to 7-membered substituted with 0-3 substituents selected from haloalkoxy saturated or partially unsaturated Benzyl fused to the ring.

Ar ² is i) phenyl, ii) naphthyl, iii) pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl, or benzimidazolyl, iv) (a) independently selected from N, O and S Represents phenyl fused to a 5-7 membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms, the remaining ring atoms being carbon, where i), ii) , each independently a) halogen iii) and iv), hydroxy, cyano, amino, -COOH, -CONH _2, C ₁ -C ₃ haloalkyl, and C ₁ -C ₃ haloalkoxy, b) is each Independently halogen, hydroxy, amino, oxo, cyano, —COOH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di- (C ₁ -C ₄ ) alkylamino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy C ₁ -C ₄ alkyl carboxamidine de, C ₁ -C ₄ Ruki Rusuru alkylsulfonyl, substituted by C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkyl sulfonates, C ₂ -C ₄ alkyl esters 0-5 substituents selected, and from C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, mono- and di- (C ₁ -C ₆ alkyl) amino, and (C ₃ -C ₇ Cycloalkyl) C ₀ -C ₄ alkyl, and c) C ₁ -C ₄ alkylcarboxamide, C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ Alkyl sulfonates, C ₂ -C ₄ alkyl esters, C ₁ -C ₄ alkoxycarbonyls, and d) each independently halogen, hydroxy, nitro, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy , C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, pyrrolidinyl, morpholinyl (Pyrrolidinyl) C ₀ -C ₄ alkyl, (morpholinyl) C ₀ -C ₄ alkyl, (thiomorpholinyl) C ₀ -C ₄ alkyl substituted with 0 to 3 groups selected from R, thiomorpholinyl, piperazinyl, and piperidinyl , (Piperazinyl) C ₀ -C ₄ alkyl, and (piperidinyl) C ₀ -C ₄ alkyl, and (thiazolyl) C ₀ -C ₄ alkyl, (piperidyl) C ₀ -C ₄ alkyl, (morpholinyl) C ₀ -C Substituted with 0 to 5 groups selected from ₄ alkyl, (pyrrolidinyl) C ₀ -C ₄ alkyl, (piperidinyl) C ₀ -C ₄ alkyl, and (piperazinyl) C ₀ -C ₄ alkyl.

の化合物および塩に関する。 Yet another embodiment of the invention is a compound of formula IX:

And compounds and salts thereof.

The variables Ar ² , R, R ³ , R ⁴ , R ⁵ and R ⁶ bear the above definition for Formula VIII.

R ⁷ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- and di- (C ₁ -C It represents a _2-alkyl) 0-3 substituents selected from amino.

In certain embodiments, the invention provides that R ⁵ and R ⁶ are independently halogen, cyano, nitro, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C Including compounds and salts of formula IX selected from ₂ haloalkoxy and mono- and di- (C ₁ -C ₂ alkyl) amino.

The present invention also provides that R is (A) (i) halogen and hydroxy, and (ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- - and di - (C ₁ -C ₄ alkyl) C ₁ substituted with 0-4 substituents selected from amino Selected from -C ₆ alkyl and C ₁ -C ₆ alkoxy, or in other embodiments, (B) R is C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy, or in yet other embodiments, ( C) R is each independently hydroxy, halogen, amino, cyano, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkylamino, (C ₁ -C ₂ alkyl) Amino) substituted with 0 to 3 substituents selected from C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy It relates to compounds of formula IX and salts which are substituted phenyl, thienyl or pyridyl.

In the present invention, R is defined as (A), (B) or (C), and Ar ² is independently halogen, hydroxy, cyano, amino, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, and independent Formula IX, which is phenyl substituted with 0-5 groups selected from 5-7 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O and S And the compounds and salts thereof.

In another embodiment, the invention provides that R is defined as (A), (B) or (C), wherein Ar ² is independently halogen, hydroxy, cyano, amino, —COOH , -CONH _2, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl, or benze substituted with 0-5 groups selected from C ₀ -C ₂ alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl and piperidinyl Including compounds and salts of formula IX that are imidazolyl.

In yet another embodiment, the invention provides O wherein R is defined as (A), (B) or (C) above, wherein Ar ² is (a) independently selected from N, O and S. , Having 1 or 2 ring atoms, the remaining ring atoms being carbon, and (b) independently halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, is C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy of 5-7 membered substituted with 0-3 substituents selected from saturated or partially fused phenyl unsaturated ring Also included are compounds and salts of Formula IX.

The invention relates to R ² , each independently of halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₂ haloalkyl, and C _1- including a special class of compounds of formula IX is the benzyl or phenethyl substituted with 0-3 groups selected from C ₂ haloalkoxy.

R ₅ and R ₆ are independently in certain embodiments of this type halogen, cyano, nitro, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, mono- and di- (C ₁ -C ₂ Alkyl) amino, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy.

In still other embodiments of this type, R is (D) (i) halogen and hydroxy, and (ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C substituted with (C ₁ -C ₄ alkyl) 0-4 substituents selected from amino - ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono - and di C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, (E) R is C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy, and (F) R are each independently hydroxy, halogen, amino, cyano, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkylamino, (C ₁ -C ₂ alkylamino) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl And phenyl, thienyl, or pyridyl substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkoxy Selected.

In the present invention, R is defined as (D), (E) or (F), wherein Ar ² is independently halogen, hydroxy, cyano, amino, -COOH, -CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C _0- C ₂ alkyl, pyrrolidinyl, is morpholinyl, thiomorpholinyl, piperazinyl, and phenyl substituted with 0-5 group selected from piperidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl or benzimidazolyl Including compounds of formula IX and salts.

The invention further provides that R is defined as (D), (E) or (F) above, wherein Ar ² is (a) independently selected from N, O and S. And the remaining ring atoms are carbon, and (b) independently halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy of 5-7 membered substituted with 0-3 substituents selected from saturated or partially compound of formula IX is a phenyl fused to unsaturated rings And salt.

In yet another embodiment, the invention provides that R is defined as (D), (E) or (F) above, wherein R ² is (a) independently selected from N, O and S. , Having 1 or 2 ring atoms, the remaining ring atoms being carbon, and (b) independently halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, is C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ saturated 5- to 7-membered substituted with 0-3 substituents selected from haloalkoxy or partially condensed benzyl unsaturated ring Relates to compounds and salts of formula IX.

In some embodiments of this type, R ₅ and R ₆ are independently halogen, cyano, nitro, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, mono- and di- (C ₁ -C ₂ Alkyl) amino, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy.

Also, the present invention provides that R is defined as (D), (E) or (F) and the variables Ar ² , R, R ³ , R ⁴ , R ⁵ , R ⁶ are responsible for the definition of formula VIII. Relates to compounds and salts of formula IX.

In some embodiments of this type, Ar ² has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and ( b) independently halogen, hydroxy, cyano, 0-3 groups selected amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Phenyl fused to a 5 to 3 membered saturated or partially unsaturated ring substituted with a substituent of

The present invention provides that Ar ¹ is independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di -C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, -NHC (= O) formula II is C ₁ -C heteroaryl substituted with ₂ 0-3 substituents selected from alkyl And the compounds and salts thereof. For example, the present invention relates to Ar ¹ , each of which is independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ It relates to compounds and salts of formula II which are indolyl or indazolyl substituted with 0 to 3 substituents selected from haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino.

［式XおよびXI中、R⁵は独立してハロゲン、アミノ、シアノ、ヒドロキシ、C₁-C₄アルキル、C₁-C₄アルコキシ、C₁-C₂ハロアルキル、C₁-C₂ハロアルコキシ、モノ-およびジ-C₁-C₄アルキルアミノ、C₁-C₂アルキルチオ、-NHC(＝O)C₁-C₂アルキルから選択される二環式ヘテロアリール基のいずれかの環に存在する0〜3個の置換基を表わす］
である式XIIの化合物および塩に関する。 Thus, the present invention relates to formulas X and XI (within the scope of formula II):

[Wherein R ⁵ is independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, Present in any ring of a bicyclic heteroaryl group selected from mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, —NHC (═O) C ₁ -C ₂ alkyl Represents 0 to 3 substituents]
Relates to compounds of formula XII and salts thereof.

R ³ and R ⁴ are independently selected from hydrogen, methyl and ethyl in some embodiments of this type.

Ar ² is, in this type of embodiment, (A) independently halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ 1, 2 or selected from haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, and independently N, O and S Phenyl substituted with 0-5 groups selected from 5-7 membered heterocycloalkyl groups containing 3 heteroatoms; or (B) each independently halogen, hydroxy, cyano, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ Phenyl substituted with 0 to 5 groups selected from alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl and piperidinyl. Is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl or benzimidazolyl; or Ar ² is (C) (a) 0, 1 or 2 independently selected from N, O and S And the remaining ring atoms are carbon, and (b) independently halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ Haloalkyl and phenyl fused to a 5-7 membered saturated or partially unsaturated ring substituted with 0-3 substituents selected from C ₁ -C ₂ haloalkoxy.

In some of these embodiments, Ar ² bears the definition given immediately preceding (A), (B) or (C) and R ² is i) independently selected from chloro, fluoro, methyl and methoxy. 2-indanyl substituted with 0 to 2 substituents; or ii) each independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C benzyl substituted by _two 0-3 substituents selected from haloalkoxy, piperonyl, benzodioxanyl methyl, and benzofuranyl methyl.

In other embodiments of this type, Ar ² bears the definition given immediately above (A), (B) or (C) and R ² is independently selected from chloro, fluoro, methyl and methoxy. 2-Indanyl substituted with ~ 2 substituents.

In yet other embodiments within this class, Ar ² bears the definition given immediately preceding (A), (B), or (C), and R ² is independently halogen, hydroxy, C ₁ -C ₄ alkyl C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl and phenyl Benzyl substituted with 0 to 3 substituents.

The invention further relates to compounds of formula II and pharmaceutically acceptable salts, wherein Ar ¹ is tetrahydronaphthyl.

［式中、変数R²、R³、R⁴およびAr²は式IIの化合物について前記した定義を担い、および式XII中のR⁵は独立してハロゲン、アミノ、シアノ、ヒドロキシ、C₁-C₄アルキル、C₁-C₄アルコキシ、C₁-C₂ハロアルキル、C₁-C₂ハロアルコキシ、モノ-およびジ-C₁-C₄アルキルアミノ、C₁-C₂アルキルチオ、-NHC(＝O)C₁-C₂アルキルから選択される二環式ヘテロアリール基のいずれかの環に存在する0〜3個の置換基を表わす］
の化合物および塩に関する。 For example, the present invention provides compounds of formula XII:

[Wherein the variables R ² , R ³ , R ⁴ and Ar ² bear the definitions given above for the compound of formula II, and R ^{5 in} formula XII is independently halogen, amino, cyano, hydroxy, C ₁ − C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, -NHC (= O) represents 0 to 3 substituents present on any ring of a bicyclic heteroaryl group selected from C ₁ -C ₂ alkyl]
And compounds and salts thereof.

［式中、R⁶は独立してハロゲン、アミノ、C₁-C₂アルキル、およびC₁-C₂アルコキシから選択されるインダニル基のいずれかの環に存在する0〜3個の置換基を表わす］
の化合物および塩に関する。 The present invention specifically relates to Formulas XIII and XIV:

[Wherein R ⁶ independently represents 0 to 3 substituents present in any ring of an indanyl group selected from halogen, amino, C ₁ -C ₂ alkyl, and C ₁ -C ₂ alkoxy. Represent]
And compounds and salts thereof.

A specific embodiment of this invention is that 0 to 3 substitutions are present in any ring of indanyl groups wherein R ⁵ is independently selected from halogen, C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy And R ⁶ is methyl, if present, and includes compounds of formula XIII and XIV where R ³ and R ⁴ are independently hydrogen, methyl or ethyl.

［式中、Gは窒素または酸素であり、R¹⁰は独立してハロゲン、アミノ、C₁-C₂アルキル、およびC₁-C₂アルコキシから選択される2つの環系のいずれかの環に存在する0〜3個の置換基を表わす］
の基である。 Ar ² is, in this type of embodiment, (D) independently halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ Haloalkyl and phenyl substituted with 0 to 3 groups selected from C ₁ -C ₂ haloalkoxy; or Ar ² is (E) (a) independently selected from N, O and S Has 0, 1 or 2 ring atoms, the remaining ring atoms are carbon, and (b) independently halogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ Phenyl fused to a 5-7 membered saturated or partially unsaturated ring substituted with 0-3 substituents selected from haloalkoxy; or (F) Ar ² is each independently halogen, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ 0 to 4 substituents selected from haloalkoxy Naphthyl or tetrahydronaphthyl optionally substituted by: or (G) Ar ² is represented by the formula:

Wherein G is nitrogen or oxygen and R ¹⁰ is independently on any ring of two ring systems selected from halogen, amino, C ₁ -C ₂ alkyl, and C ₁ -C ₂ alkoxy Represents 0 to 3 substituents present]
It is the basis of.

In other embodiments, the invention relates to compounds and salts of Formulas XIII and XIV, wherein R ³ and R ⁴ are combined to form an oxo group.

  Exemplary substituted biaryl amides provided herein include, but are not limited to, those specifically described in Examples 1-10. It will be apparent that the specific compounds cited therein are merely representative and are not intended to limit the scope of the invention. Furthermore, as noted above, all compounds of the present invention can exist as hydrates, free bases or pharmaceutically acceptable acid addition salts.

  Certain substituted biaryl amides according to Formulas I, IA, II-XIV have one or more stereocenters. In certain embodiments, such compounds may be enantiomers and have an enantiomeric excess of at least 55%. Within that further embodiment, such compounds have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, 98% or 99%. Certain compounds having one or more stereocenters have an enantiomeric excess of at least 99%.

  Certain substituted biaryl amides according to formulas I, IA and II-XIV have two or more stereogenic centers. In certain such embodiments, such compounds have a diastereomeric excess of at least 55%. In other embodiments, such compounds have a diastereomeric excess of 60%, 70%, 80%, 85%, 90%, 95% or 98%. Certain compounds having two or more stereogenic centers have a diastereomeric excess of at least 99%.

The substituted biarylamides provided herein are standard in vitro C5 receptor-mediated chemotaxis assays (described in Example 14), radioligand binding (described in Example 19), or Detectably modify (modulate) C5a receptor activity and / or ligand binding as measured using the C5a receptor-mediated calcium mobilization assay (described in Example 21). Preferred compounds are such standard C5a receptor - mediated chemotaxis, radioligand binding, and / or calcium mobilization assay at approximately 500nM IC ₅₀ less than or equal, about 250nM or less an IC ₅₀ and more preferably in such an assay, Even more preferably, such an assay exhibits an IC ₅₀ of about 200, 150, ₁₀₀ , ₅₀ , 25, 10 or 5 nM or less.

  Initial characterization of compounds can be conveniently performed using C5a receptor binding assays or functional assays as described in the Examples, and applying such assays in high throughput screening settings. Can be promoted by. Additional assays suitable for measuring the effects of small molecule compounds on C5a receptor binding and receptor modulating activity, as well as assays suitable for measuring their effects on C5a-induced neutropenia in vivo are available Published publications, for example, with respect to its disclosure in this regard in Examples 6-9, columns 19-23, and for its discussion of complement and inflammation in columns 1-2, see here for reference. It can be found in incorporated US Pat. No. 5,807,824. One skilled in the art will recognize that such assays can be readily adapted for use with different types of cells or animals deemed appropriate.

  In certain embodiments, preferred compounds are (such as reduced lethal or preferably pharmaceutically acceptable oral doses, preferably less than 2 grams, more preferably less than 1 gram as reduced C5a-induced neutropenia. Oral bioavailability, capable of providing a detectable in vivo effect), the ability to inhibit leukocyte chemotaxis at nanomolar concentrations, preferably at sub-nanomolar concentrations, low toxicity (preferred compounds are C5a Non-toxic when administered to a subject with a receptor-modulating amount), minimal side effects (preferred compounds produce side effects comparable to placebo when administered to a subject with a C5a receptor-modulating amount), low serum Protein binding and appropriate in vitro and in vivo half-life (preferred compounds are QID administered, preferably TID administered, more preferably BLD administered, most preferably administered once a day) With favorable pharmacological properties, including an in vitro half-life equal to the in vivo half-life Distribution in the body relative to the site of complement activity is also desirable (e.g., compounds used to treat CNS disorders preferably penetrate the blood brain barrier, while low brain levels used to treat peripheral disorders). Compounds are typically preferred).

  Routine assays well known in the art can be used to evaluate these properties and identify superior compounds for a particular application. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, such as Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans can be predicted from the brain level of the compound in laboratory animals to which the compound is administered (eg, intravenously). Serum protein binding can be predicted from albumin binding assays such as those described by Oravcova et al. (1996) Journal of Chromatography B 677: 1-27. The compound half-life is inversely proportional to the frequency of administration of the compound necessary to achieve an effective amount. The in vitro half-life of the compounds can be predicted from the microsomal half-life assay described by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition 26: 1120-27.

  Toxicity and side effects can be assessed using any standard method. In general, the term “non-toxic” as used herein must be understood in a related sense and is approved by the US Food and Drug Administration (“FDA”) for administration to mammals (preferably humans). Any substance that is intended or in accordance with FDA approval for administration to mammals (preferably humans) in maintaining established standards. Toxicity can also be assessed using assays that detect effects on cellular ATP production. Other assays that can be used include bacterial back mutation assays such as the Ames test, and standard teratogenic and tumorigenesis assays. Preferably, as a result of administration of a compound provided herein at a dose (i.e., a dose that produces an effective in vivo concentration), the cardiac QT interval (as measured by electrocardiography in guinea pigs, minipigs or dogs) There is no extension. When administered daily for 5 days, or preferably 10 days, such doses do not cause liver enlargement, resulting in more than 100% over matched controls in laboratory rodents (e.g. mice or rats), Preferably, an increase in the liver to body weight ratio of 75% or less and more preferably 50% or less is provided. Such a dose also preferably does not cause liver enlargement, so that it is more than 50%, preferably not more than 25%, than matched untreated controls in dogs or other non-rodent mammals, and More preferably, an increase in liver ratio to body weight of 10% or less results.

  Certain preferred compounds do not promote substantial release of liver enzymes (eg, ALT, LDH or AST) from hepatocytes in vivo. Preferably, the dose is greater than 100%, preferably no more than 75%, and more preferably no more than 50% serum levels of such enzymes in vivo in laboratory rodents compared to untreated subjects. Does not raise. Similarly, the concentration (in medium or other such solution that is contacted with and incubated with cells in vitro) equal to 2 times, preferably 5 times, and most preferably 10 times the minimum in vivo therapeutic concentration. It does not cause detectable release of any such liver enzyme from hepatocytes in vitro beyond the baseline levels observed in the medium from the treated cells.

In some embodiments, preferred compounds exhibit their receptor-modulating effects with high specificity. This binds to and activates certain receptors other than the C5a receptor with an affinity constant greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar. Or only inhibits its activity. The invention also includes highly specific C5a receptor modulating compounds that exhibit 200-fold greater affinity for the C5a receptor than for other cellular receptors. Such receptors include α- or β-adrenergic receptors, muscarinic receptors (especially m1, m2 or m3 receptors), dopamine receptors, and metabotropic glutamate receptors; and histamine receptors and cytokines Includes neurotransmitter receptors such as receptors (eg, interleukin receptors, particularly IL-8 receptors). Such receptors also include GABA _A receptors, bioactive peptide receptors (other than C5a and C3a receptors, including NPY or VIP receptors), neurokinin receptors, bradykinin receptors, and hormones Receptors (eg, CRF receptors, thyroid stimulating hormone releasing hormone receptors or melanin-concentrating hormone receptors) are also included. Compounds that act with high specificity generally exhibit fewer undesirable side effects.

Within certain embodiments, modulators provided herein have GABA receptors, MCH receptors, NPY receptors, dopamine receptors, serotonin receptors and VR1 receptors, even with high or moderate affinity. Does not detectably bind to receptors that do not mediate inflammatory responses, such as Additionally or alternatively, certain preferred C5a receptor modulators are substantially higher (eg, at least 5 times higher, at least 10 times higher, or at least 100 times higher) than for receptors that do not mediate inflammatory responses. Exhibits affinity for the body. Assays for assessing binding to receptors that do not mediate inflammatory responses are described, for example, in US Patents incorporated herein by reference for their disclosure of GABA _A receptor binding assays in Example 14, columns 16-17. US Patent Application No. 10 / 152,189, Example 19, columns 45-46, incorporated herein by reference for its disclosure of the MCH receptor binding assay at 6,310,212, Example 2, pages 104-105. U.S. Pat.No. 6,362,182, incorporated herein by reference for its disclosure of CRF1 and NPY receptor binding assays in U.S. Patent No. 6,362,182, incorporated herein by reference for its disclosure of dopamine receptor binding assays in column 10. No. 6,355,644, Examples 4-5, US Pat. No. 6,482,611, incorporated herein by reference for its disclosure of VR1 receptor binding assay in column 14. Including those that have been mounting. C5a receptor modulators provided herein, such as C3a receptor and / or A _S receptors, to one or more other receptors known to mediate inflammatory responses It will be clear that they can be combined, but not necessarily.

  Certain preferred embodiments are C5a receptor antagonists that do not possess significant (eg, greater than 5%) agonist activity in any of the C5a receptor-mediated functional assays discussed herein. Specifically, unwanted agonist activity can be assessed, for example, in the GTP binding assay of Example 20, by measuring small molecule-mediated GTP binding in the absence of the natural agonist C5a. Similarly, in a calcium mobilization assay (eg, of Example 21), small molecule compounds can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist C5a. The preferred degree of C5a agonist activity exhibited by the compounds provided herein is less than 10%, 5% or 2% of the response induced by the natural agonist C5a.

  In addition, preferred C5a receptor modulators do not inhibit or induce microsomal cytochrome P450 enzyme activity such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity. Also, preferred C5a receptor modulators do not exhibit cytotoxicity in vitro or in vivo, such as chromosomes (measured using, for example, mouse erythroid progenitor cell micromicronucleus assay, Ames micronucleus assay, spiral micronucleus assay, etc.) It is not aberrant and does not induce sister chromatid exchange (eg, in Chinese hamster ovary cells). Also preferred is a C5a receptor that inhibits the development of C5a-induced oxidative burst (OB) in inflammatory cells (e.g., neutrophils), as can be conveniently measured using an in vitro neutrophil OB assay. Modulator.

For detection purposes, the compounds provided herein can be isotopically or radiolabeled. Thus, a compound cited in Formula I (or any other formula specifically recited herein) has an atomic mass or mass number that is different from the atomic mass or mass number normally found in nature. It can have one or more atoms replaced by atoms of the same element. Examples of isotopes that can be present in the compounds provided herein are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P , Including hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine isotopes such as ³⁵ S, ¹⁸ F and ³⁶ Cl. In addition, heavier isotopes such as deuterium (i.e., ² H) greater metabolic stability, for example, can provide certain therapeutic advantages resulting from increased in vivo half-life or reduced dosage requirements, Therefore, it is preferable in some situations.

Methods of Use The C5a modulators provided herein can be used as agonists or (preferably) antagonists of the C5a receptor in a variety of contexts, both in vitro and in vivo. Within certain aspects, C5a antagonists can be used to inhibit the binding of a C5a receptor ligand (eg, C5a) to a C5a receptor in vitro or in vivo. In general, such methods involve the use of a sufficient amount of C5a receptor herein in the presence of a C5a receptor ligand in an aqueous solution and under conditions suitable for binding of the ligand to the C5a receptor. Contacting with one or more substituted biarylamides provided therein. The C5a receptor can be present in suspension (eg, in an isolated membrane or cell preparation) or in cultured or isolated cells. Within certain embodiments, the C5a receptor is expressed by cells present in the patient and the aqueous solution is a body fluid. In general, the amount of C5a receptor modulator in contact with the receptor is, for example, the radioligand binding assay described in Example 19, the calcium mobilization assay described in Example 21, or the chemistry described in Example 14. It should produce a concentration in aqueous solution sufficient to inhibit C5a binding to the C5a receptor in vitro, as measured using a chemotaxis assay. Preferably, the concentration is such that the level of chemotaxis observed in a control assay (e.g., where the compound provided herein is not added) is added by the compound described herein. In vitro chemotaxis as significantly higher than the level observed in the assay performed (here, significance measured as p ≦ 0.05 using conventional parameter statistical analysis methods such as Student's T-test) It is sufficient to inhibit chemotaxis of white blood cells in the assay.

  Also provided herein are methods for modulating, preferably inhibiting, the signal-transducing activity of the C5a receptor. Such modulation can result in Ca receptor (either in vitro or in vivo) in an effective amount of one or more C5a receptors provided herein under conditions suitable for binding of the modulator to the receptor. This can be achieved by contacting with a modulator. The receptor may be present in a cell preparation cultured or isolated in solution or suspension, or in a patient. Modulation of signal transduction activity can be assessed by detecting a calcium ion conductance effect (also referred to as calcium mobilization or flux) or by detecting an effect on C5a receptor-mediated cytochemistry. In general, an effective amount of C5a modulator is C5a receptor signal transduction activity in vitro within the calcium mobilization assay described in Example 21, or C5a receptor-mediated cell chemotaxis within the assay described in Example 14. An amount sufficient to produce a concentration (in an aqueous solution in contact with the receptor) that modulates. A C5a receptor modulator provided herein is preferably administered orally or topically to a patient (e.g., a person) and modulates C5a receptor signal-transducing activity while at least one body fluid of the animal. Make it exist.

  The present invention further provides a method of treating a patient suffering from a disease responsive to C5a receptor modulation. As used herein, the term “treatment” includes both disease-modifying treatments and symptomatic treatments, either of which is prophylactic (ie, before onset of symptoms, preventing, delaying or reducing the severity of symptoms. Or therapeutic (ie, before the onset of the sign, to reduce the severity of the sign and / or the duration of the sign). The disease is dependent on the amount of locally present C5a receptor ligand and / or in the alleviation of the disease or its symptoms, modulation of C5a receptor activity leads to an inappropriate decrease in C5a receptor activity. When it happens, it is “responsive to C5a receptor modulation”. Patients can include primates (especially humans), domesticated companion animals (such as dogs, cats, horses) and livestock (such as cows, pigs, sheep), and dosages are as described above. is there.

  Diseases that are responsive to C5a receptor modulation include:

Autoimmune diseases -e.g. rheumatoid arthritis, systemic lupus erythematosus (and associated glomerulonephritis), psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus Acupuncture, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic conditions, Good Pasteur syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immunovasculitis, tissue graft rejection , And hyperacute rejection of transplanted organs.

Inflammatory disorders and related diseases --e.g., Neutropenia, sepsis, septic shock, Alzheimer's disease, seizures, severe burns, lung injury and ischemia-inflammation related to reperfusion, osteoarthritis, and acute ( Adult) respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS). Also, such as insulin-dependent diabetes mellitus (including diabetic retinopathy), nephropathy lupus, Hayman nephritis, membranous nephritis and other forms of glomerulonephritis, contact-sensitive responses, and post-external dialysis syndrome Compensation as occurs during extracorporeal circulation of blood (e.g., during hemodialysis or associated with vascular surgical procedures such as coronary artery bypass grafting or heart valve replacement via the heart-lung machine) Derived from blood contact with an artificial surface that can cause body activation, or other artificial blood vessels or container surfaces (e.g., ventricular assist devices, artificial heart machines, transfusion tubing, blood storage bags, plasmapheresis, plateletpheresis, etc.) Also included are pathological sequelae associated with inflammation associated with contact.

Cardiovascular and cerebrovascular disorders -such as myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease.

  In a further aspect, the C5a receptor modulator can be used to perfuse a donor organ prior to transplantation of the organ into a recipient patient. Such perfusion is preferably performed using a solution (eg, a pharmaceutical composition) containing a modulator at a concentration sufficient to inhibit C5a receptor-mediated effects in vitro and / or in vivo. Such perfusion is preferably compared to that occurring in a controlled transplant recipient (including limited, no history control) that has received a transplant of a donor organ that has never been so perfused. Reduce the severity or frequency of one or more inflammatory sequelae after transplantation.

  The therapeutic methods provided herein generally comprise administering to a patient an effective amount of one or more compounds of the invention. Suitable patients include patients suffering from or susceptible to (ie, prophylactic treatment) the disorders or illnesses identified herein. Typical patients for treatment according to the invention include mammals, especially primates, especially humans. Other suitable patients include domesticated companion animals such as dogs, cats, horses, etc., or livestock animals such as cows, pigs, sheep and the like.

  In general, the therapeutic methods provided herein comprise administering to a patient an effective amount of a compound (one or more compounds provided herein). The effective amount can be an amount sufficient to modulate C5a receptor activity and / or an amount sufficient to reduce or alleviate the symptoms presented by the patient. Preferably, the amount administered is sufficiently high to detect leukocyte (e.g., neutrophil) chemotaxis sufficiently in vitro to detect the compound (or, if a prodrug, its active metabolite). ) Is sufficient to produce a plasma concentration. The method of treatment can vary depending on the compound used and the particular disease to be treated; for the treatment of most disorders, a frequency of administration no more than 4 times daily is preferred. In general, the administration method twice daily is more preferred, with administration once a day being particularly preferred. However, the specific dose and method of treatment for any particular patient will depend on the activity, age, weight, general health, sex, diet, time of administration, route of administration, secretion rate, drug of the particular compound used. It will be appreciated that the combination (i.e. other drugs to be administered to the patient) and the severity of the particular illness being treated will depend on various factors, including the judgment of the attending physician. Let's go. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients can generally be monitored for the effectiveness of treatment using medical or veterinary standards appropriate to the disease to be treated or prevented.

  As noted above, the compounds and compositions provided herein are useful as inhibitors of C5a receptor-mediated chemotaxis (e.g., they are used as standards in such chemotaxis assays). be able to). Accordingly, provided herein are methods for inhibiting C5a receptor-mediated cell chemotaxis, preferably leukocyte (eg, neutrophil) chemotaxis. Such methods include contacting white blood cells (especially primate white blood cells, especially human white blood cells) with one or more compounds provided herein. Preferably, the concentration is such that, as described above, the level of chemotaxis observed in the control assay is significantly higher than the level observed in the assay to which the compound described herein is added. In vitro chemotaxis assays are sufficient to inhibit chemotaxis of white blood cells.

  Within another aspect, the present invention provides various non-pharmaceutical in vitro and in vivo uses for the compounds provided herein. For example, such compounds can be labeled and used as probes for detection and localization of C5a receptors (in samples such as cell preparations or tissue pieces, preparations or fractions thereof). Compounds can also be used as positive controls in assays for C5a receptor activity, as standards for measuring the ability of candidate agents to bind to C5a receptor, or as positron emission tomography (PET) imaging or single photon emission. It can also be used as a radioactive tracer for scanning computed tomography (SPECT). Such methods can be used to characterize C5a receptors in living subjects. For example, C5a receptor modulators can be labeled using any of a variety of well-known techniques (e.g., radiolabeled with a radionuclide such as tritium as described above) and with the sample for an appropriate incubation time. Incubation (eg, binding is first measured by assaying over time). Following incubation, unbound compound is removed (eg, by washing) and any method suitable for the label used (eg, autoradiography or scintillation counting for radiolabeled compounds; using spectroscopic methods) The luminescent group and the fluorescent group can be detected. As a control, matched samples containing a labeled compound and a large (eg, 10-fold greater) amount of unlabeled compound can be treated similarly. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of the C5a receptor in the sample. Detection assays, including receptor autoradiography (receptor mapping) of C5a receptors in cultured cell or tissue samples, are described in Section 8.1.1 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York. This can be done as described by Kuhar in 8.1.9.

  The modulators provided herein can also be used in various well-known cell separation methods. For example, the modulator can be used as an affinity ligand to immobilize and thereby isolate C5a receptors in vitro (e.g., to isolate receptor-expressing cells) or tissue culture dishes or other supports. Can be connected to the inner surface of the. Within one preferred embodiment, a modulator linked to a fluorescent marker such as fluorescein is contacted with the cells, which are then analyzed (or isolated) by fluorescence activated cell sorting (FACS).

Pharmaceutical formulations The present invention also provides a pharmaceutical composition comprising one or more C5a receptor modulators provided herein together with at least one physiologically acceptable carrier or excipient. To do. The pharmaceutical composition can be, for example, water, buffer (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrate (e.g., glucose, mannose, sucrose). Or dextran), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and / or preservatives. As noted above, other active ingredients can be included in the pharmaceutical compositions provided herein, but are not necessarily required).

  A carrier is often a substance that can be combined with an active compound prior to administration to a patient for the purpose of controlling the stability or bioavailability of the compound. Carriers used within such formulations are generally biocompatible and can be biodegradable. Carriers include monovalent or polyvalent molecules such as, for example, serum albumin (eg, human or bovine), ovalbumin, peptides, polylysine, and polysaccharides such as aminodextran and polyamidoamine. The carrier also includes solid support materials such as beads and microparticles comprising, for example, polylactate polyglycolate, poly (lactide-co-glycolide), polyacrylate, latex, starch, cellulose or dextran. The carrier can bear the compound in a variety of ways, including covalent bonds (directly or via a linker group), non-covalent interactions or mixing.

  The pharmaceutical composition can be formulated for any suitable method of administration, including, for example, topical, oral, nasal, rectal or parenteral administration. In certain embodiments, a composition in a form suitable for oral use is preferred. Such forms include, for example, pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, the compositions provided herein can be formulated as a lyophilizate. The term parenteral as used herein refers to subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, and any similar injection or infusion technique. Including.

  Compositions intended for oral use can be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and include one or more agents: suspending agents, flavoring agents, coloring agents An agent and a preservative can be included to provide an attractive and palatable formulation. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granules and disintegrants (e.g. corn starch or alginic acid), binders (e.g. , Starch, gelatin or acacia), and lubricants (eg, 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 monostearate or glyceryl distearate may be employed.

  Formulations for oral use can also be presented as hard capsules, where the active ingredient can be mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin) and presented as a soft capsule. Here, the active ingredient is mixed with water or an oil medium (eg 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 include suspending agents (eg, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic); and dispersants or wetting agents (eg, natural lectins such as lectins). Condensation products of alkylene oxides and fatty acids such as phosphatides, polyoxyethylene stearates, condensation products of ethylene oxides and long chain fatty alcohols such as heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate Condensation products of ethylene oxide with fatty acid-derived partial esters and hexitol, or ethylene oxide and fatty acid-derived moieties such as polyethylene sorbitan monooleate Including ester and condensation products of hexose Cistercian Ruan hydride). An aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more Sweetening agents such as sucrose or saccharin can be included. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain one or more demulcents, preservatives, flavoring agents and / or coloring agents.

  Oily suspensions may be formulated by suspending the active ingredient in a mineral oil, such as vegetable oil (eg, arachis oil, olive oil, sesame oil or coconut oil) or liquid paraffin. The oily suspensions can contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those described above and / or flavoring agents can be added to provide a palatable oral preparation. Such a suspension can 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, can also be present.

  The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil (eg olive oil or peanut oil), a mineral oil (eg liquid paraffin) or a mixture of these. Suitable emulsifiers include naturally occurring gums (e.g. gum arabic or tragacanth), naturally occurring phosphatides (e.g. soy, lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g. sorbitan monooles). Acid), and condensation products of fatty acid and hexitol-derived partial esters with ethylene oxide (eg, polyoxyethylene sorbitan monooleate). The emulsion may also contain one or more sweetening and / or flavoring agents.

  The pharmaceutical compositions can be prepared as sterile injectable aqueous or oleaginous suspensions in which the modulator is suspended or dissolved in a solvent, depending on the solvent and concentration used. Such compositions can be formulated according to the known art using suitable dispersing, wetting agents and / or suspending agents such as those mentioned above. Among the acceptable solvents and solvents that can be used are water, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectable compositions, and adjuvants such as local anesthetics, preservatives and / or buffering agents can be dissolved in the solvent.

  C5a receptor modulators can also be administered in the form of suppositories (eg, for rectal administration). Such compositions are prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. be able to. Such materials are cocoa butter and polyethylene glycol.

  The pharmaceutical composition can be formulated as a sustained release formulation (ie, a capsule-like formulation that provides slow release of the modulator after administration). Such formulations can generally be prepared using well-known techniques, eg, administered by oral, rectal or subcutaneous implantation, or by implantation at the desired target site. The carriers used in such formulations are biocompatible and can also be biodegradable; preferably, the formulations provide a relatively constant level of modulator release. The amount of modulator included in the sustained release formulation depends, for example, on the site of implantation, the rate and expected duration of release, and the nature of the disease to be treated or prevented.

  In addition to or in conjunction with the above forms of administration, the modulator is conveniently added to food or drinking water (e.g., for administration to non-human animals, including companion animals and livestock (such as dogs and cats)) can do. Animal samples and drinking water compositions can be formulated so that the animal takes an appropriate amount of the composition with its diet. It may also be convenient to provide the composition as a premix for addition to the sample or drinking water.

  The C5a receptor modulators provided herein generally have sufficient body fluid (e.g., blood, plasma, serum, CSF) to detectably inhibit C5a binding to the C5a receptor when assayed in vitro. , Synovial fluid, lymph fluid, interstitial fluid, tears or urine). A dose is considered effective if it provides a discernible patient benefit as described herein. Preferred systemic doses range from about 0.1 mg to about 140 mg per kilogram body weight per day (about 0.5 mg to about 7 g per patient per day), with oral doses generally being about 5 to 20 times higher than intravenous doses. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular form of administration. Dosage unit forms will generally contain between about 1 mg to about 500 mg of an active ingredient.

  The pharmaceutical composition is a disease responsive to C5a receptor modulation (e.g., rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, bronchial asthma, Alzheimer's disease, stroke, myocardial infarction, atherosclerosis, ischemic Can be packaged to treat heart disease or ischemia-reperfusion injury). The packaged pharmaceutical composition comprises an effective amount of at least one C5a receptor modulator as described herein and a composition contained for treating a disease responsive to C5a receptor modulation in a patient Can include a container that holds instructions (eg, labeling) indicating that should be used.

Compound Preparation The substituted biaryl amides provided herein can generally be prepared using standard synthetic methods. In general, starting materials are commercially available from suppliers such as Sigma-Aldrich Corp. (St. Louis, MO) or synthesized from commercially available precursors using established protocols. can do. By way of example, a synthetic route similar to that shown in the scheme below can be used with synthetic methods known in the art of synthetic organic chemistry, or variations thereof recognized by those skilled in the art. Each variable in the following schemes such as “R” or “Ar” refers to any group compatible with the description of the compounds provided herein. Individuals skilled in the art can find one or several modifications of the synthetic steps described herein without significant addition from the total synthetic scheme.

  The orthobiaryl amides described herein can be prepared through a series of chemical transformations similar to those shown graphically in Scheme I.

Scheme 1 Preparation of orthobiaryl amide

As indicated, the synthetic pathway begins with a benzoic acid of general structure A having a group X in the ortho position. The X group can be iodine, bromine, chlorine, sulfonate ester or polyfluoroalkyl sulfonate ester. The benzoic acid may be substituted by up to four independently selected substituents represented by the variable R ⁶ . Examples of suitable substituents include, but are not limited to, chlorine, fluorine, cyano, C ₁ -C ₆ straight or branched alkyl, C ₁ -C ₆ straight or branched alkoxy, trifluoromethyl, Trifluoromethoxy, nitro, amino, mono- and di-alkylamino, sulfonamido, mono- and di-alkylsulfonamide, alkylthio (e.g. methylthio), alkyl sulfoxide, alkyl sulfone, acetyl, acetoxy, alkylcarbonyl (-C = OO (alkyl)), or dialkylaminocarbonyl (-C = ON (alkyl) ₂ ). In addition, two adjacent R ⁶ groups can be combined with a 3-5 methylene carbon chain to form a 5-7 carbon alkyl ring fused to a benzoic acid moiety. In addition, two adjacent R ⁶ groups together with an alkyloxy chain, such as -OCH ₂ O- or -OCH ₂ CH ₂ O-, are combined with oxygen-containing moieties fused to benzoic acid (in this example, each , Methylenedioxy or ethylenedioxy).

  The benzoic acid is then activated by conversion to the acid chloride with thionyl chloride, oxalyl chloride, and the like. Alternatively, it can be activated by treatment with carbonyldiimidazole or similar agents. The activated benzoic acid is then treated with a suitable secondary amine in the presence of a base to give a tertiary amide of general structural formula B.

  The amide B is then converted to the biaryl structure C through the use of aryl coupling reactions known in the chemical literature. Examples of such reactions are Stille reactions in which an aryltrialkyltin reagent is coupled to a suitable aryl in the presence of a catalyst such as palladium or nickel; or an arylboronic acid in the presence of a base or nickel or Suzuki reaction coupling to an appropriate aryl in the presence of a palladium catalyst.

The group “Ar ³ ” of the general structural formula C can be phenyl, naphthyl or other aromatic groups, which can contain up to 5 further independently selected substituents (eg, hydrogen, halogen, cyano, C ₁ -C ₆ linear or branched alkyl, C ₁ -C ₆ linear or branched alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino, mono- or di-alkylamino, sulfonamide, mono or dialkyl sulfonamide, alkylthio (e.g., methylthio), alkyl sulfoxide, alkyl sulfone, acetyl, acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl (-C = OO (alkyl)), aminocarbonyl (-CONH _2), mono alkylaminocarbonyl (-C = ONH (alkyl)), dialkylaminocarbonyl (-C = ON (alkyl) _2), methylenedioxy or ethylene, Njiokishi) selectively may be substituted with.

Ar ^{3 in the} general structural formula C may also represent a heteroaryl group such as 1- or 2-thienyl or 1- or 2-furanyl. Such heteroaryl groups are halogen, cyano, C ₁ -C ₆ straight or branched alkyl, C ₁ -C ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, mono- or di-alkyl. Amino, sulfonamide, mono- and di-alkylsulfonamide, alkylthio (eg methylthio), alkylsulfoxide, alkylsulfone, acetyl, acetoxy, hydroxycarbonyl, —COOH, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, or dialkyl It may be further substituted with up to 3 independently selected substituents such as aminocarbonyl.

Scheme 2

  In scheme 2, the variable X is halogen, preferably chlorine or bromine.

  As shown in Scheme 2, condensation of an appropriately substituted 1-naphthoyl halide (D) with an appropriately substituted amine (E) in the presence of a base such as triethylamine or calcium carbonate, A compound of formula F is obtained. Compounds of general formula D and E can be prepared by one of several methods described in the chemical literature.

  Certain compounds provided herein contain one or more stereogenic centers. In these situations, single enantiomers (ie, optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of racemates. Racemic resolution 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 following examples are given for illustrative purposes and are not intended to be limiting. Unless otherwise noted, all reagents and solvents are of standard commercial grade and are used without further purification or are readily prepared from such materials by routine methods. One skilled in the art of organic synthesis will recognize that the starting materials and reaction conditions can be varied to achieve the desired target product.

Scheme 3

Examples Abbreviations used:
The following abbreviations are used in Examples 1-5.
PyBroP Bromotris (pyrrolidino) phosphonium hexafluorophosphate
DMA dimethylacetamide
NMM N-methylmorpholine
t-BuOH tert-butanol
CDI 1,1'-carbonyldiimidazole
DMF Dimethylformamide
SOCl ₂ thionyl chloride
Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) palladium (0)
Na ₂ SO ₄ sodium sulfate
CDCl ₃ deuterochloroform
THF tetrahydrofuran
¹ H NMR proton nuclear magnetic resonance
SiO ₂ silica
SPE solid phase extraction
LCMS liquid chromatography / mass spectrometry
HPLC high pressure liquid chromatography
MHz megahertz
Hz hertz
MS mass spectrometry
m / z mass / charge ratio
(M + 1) Mass + 1

Example 1
Preparation of 4'-trifluoromethyl-biphenyl-2-carboxylic acid benzo [1,3] dioxol-5-ylmethyl-benzyl-amide

1,1′-carbonyldiimidazole (175 mg) is added to a solution of 2-iodobenzoic acid (248 mg, 1 mmol) 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 eq) (2) in THF (2 mL) was added and the resulting solution was stirred for 1 h and quenched with water. Extract with diethyl ether. The organic extract is dried (Na ₂ SO ₄ ) and concentrated. The remaining 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 for 10 minutes under an argon atmosphere and solid 4-trifluoromethylphenylboronic acid (150 mg) is added in one portion. A second phase of 1N aqueous Na ₂ SO ₄ is added and the mixture is warmed to 80 ° C. under argon for 6 hours. 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 gives the desired biphenylamide product (4). Proton NMR exhibits the double pattern normally observed with amides that have some rotational limitations around the amide nitrogen at room temperature. The ratio of rotomers is almost equal.

Example 2
Preparation A of 3-methyl-biphenyl-2-carboxylic acid benzyl-indan-2-yl-amide

  Thionyl chloride (1 ml) is added to a suspension of 2-iodo-6-methylbenzoic acid (665 mg, 2.5 mmol) (5) in 10 ml of toluene. The mixture is stirred at 80 ° C. for 2 hours; the solvent and the remaining thionyl chloride are then evaporated. The residue is dissolved in 5 ml of anhydrous tetrahydrofuran and added at 0 ° C. to a solution of benzyl-indan-2-yl-amine (557 mg, 2.5 mmol) in 10 ml of tetrahydrofuran containing 506 mg of triethylamine. The resulting mixture is stirred at room temperature overnight, diluted with 20 ml of ethyl acetate, washed with water and brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography gives compound 6. MS (+ VE) m / z 467 (M +).

Process B

A solution of phenylboronic acid (40 mg, 0.325 mmol) in aqueous sodium carbonate (2.0 N 1.0 ml) and 0.3 ml ethanol was added 6 (117 mg, 0.25 mmol) and Pd (PPh _{3 in} 2 ml of compound under N _2. ) ₄ (13 mg, 0.015 mmol) in solution. The resulting mixture is stirred at 80 ° C. overnight. The mixture is cooled to room temperature, diluted with 20 ml of ethyl acetate, washed with water and brine, dried and concentrated. The crude product is purified by silica gel chromatography to give 97 mg of product 7.

Example 3
Preparation of N-benzyl-N- (2-methyl-benzyl) -2-pyrrol-1-yl-benzamide

2-Pyrrole-1-yl-benzoic acid (3.7 mg; 1 eq) 8 is dissolved to 0.2 M in DMA containing triethylamine (5% v / v). A solution of benzylamine (0.2 M in toluene containing NMM (5% v / v); 0.10 ml; 1 eq) is added followed by a solution of PyBroP (0.2 M in THF; 0.12 ml; 1.2 eq) To do. The resulting solution containing intermediate (9) is shaken at room temperature for 3 hours. Then a solution of 2-methylbenzyl bromide (0.2 M in toluene; 0.15 ml; 1.5 eq) was added followed by 0.5 M in potassium tert-butoxide (THF / t-BuOH (1: 1, v / v)). 0.16 ml; 4 equivalents). The solution is heated to 50 ° C. for 3 hours, then cooled to room temperature and treated with saturated ammonium chloride (0.35 ml). The reaction is extracted with isopropyl ether (0.5 ml) and the upper organic layer is deposited on a silica gel SPE cartridge (0.5 g SiO ₂ ). The cartridge is eluted with 25% ethyl acetate in hexane (4 ml) and the eluted solution is concentrated under reduced pressure to give the desired product (10). LCMS: target mass 381.20 (M + H) ⁺ ; observed mass 381.15 (M + H) ⁺ ; 92% spectral purity.

Example 4
Preparation of N-indan-2-yl-N- (3-methyl-benzyl) -2-pyrrol-1-yl-benzamide
2-Pyrrole-1-yl-benzoic acid (3.7 mg; 1 eq) (8) is dissolved to 0.2 M in DMA containing triethylamine (5% v / v). A solution of indan-2-ylamine (0.2 M in toluene containing NMM (5% v / v); 0.10 ml; 1 eq) was added; followed by PyBroP (0.2 M in THF; 0.12 ml; 1.2 eq). Added. The resulting solution is shaken at room temperature for 3 hours. The solution was then added to potassium tert-butoxide (THF / t-BuOH (1: 1, 0.5 M in v / v; 0.15 ml; 3.75 eq) and 3-methylbenzyl bromide (0.2 M in toluene; 0.125 ml; 1.25 The reaction is shaken at room temperature for 20 minutes, then 3-methylbenzyl bromide (0.2 M in toluene; 0.15 ml; 0.5 eq) and potassium tert-butoxide (THF / t-BuOH (1: 1) , v / v) 0.5M; 0.025 ml; 1.25 equivalents) The reaction is shaken again at room temperature for 20 minutes, and 3-methylbenzyl bromide (0.2 M in toluene; 0.05 ml; 0.5 equivalents) and Treat again with potassium tert-butoxide (0.5 M in THF / t-BuOH (1: 1, v / v); 0.025 ml; 1.25 eq.) The reaction is then heated to 50 ° C. for 2 hours and then at room temperature. The reaction is extracted with isopropyl ether (0.5 ml) and the upper organic layer is deposited on a silica gel SPE cartridge (0.5 g SiO ₂ ). Is eluted with 25% ethyl acetate in hexane (4 ml) and the eluted solution is concentrated under reduced pressure to give the title compound (11) LCMS: target mass 407.21 (M + H) ⁺ ; ) ⁺ ; 92% spectral purity.

Example 5
Preparation of 2-methoxy-naphthalene-1-carboxylic acid benzyl-indan-2-yl-amide

3.87ppmにおけるメトキシ基を有する従たるアミド回転異性体も観察される。 2-Methoxynaphthoic acid (202 mg, 1 mmol) is dissolved in thionyl chloride (1 ml). The resulting solution is refluxed for 2 hours. The thionyl chloride is evaporated on a rotary evaporator, the residue is taken up in toluene (5 ml) and concentrated again. The resulting 2-methoxynaphthoyl chloride (12) is dissolved in dry tetrahydrofuran (5 ml) containing triethylamine (278 microliters, 2 mmol) and dimethylaminopyridine (DMAP, 20 mg). A solution of N-benzyl-N-indan-2-ylamine (179 mg, 0.8 mmol) (13) is added to the 2-methoxynaphthoyl chloride solution and the resulting solution is stirred overnight. A solution of sodium bicarbonate (3N, 5 ml) is added and the mixture is extracted with ethyl acetate (3 × 20 ml). The organic extract is then washed with water and brine, dried over sodium sulfate and concentrated. The crude product is purified by silica gel chromatography to give the desired compound (14) as an oil. LC-MS 408 (M + 1),

A secondary amide rotamer with a methoxy group at 3.87 ppm is also observed.

Example 6
Preparation of 2- (5-methyl-thiophen-2-yl) -naphthalene-1-carboxylic acid indan-2-yl- (2-fluoro-benzyl)-

上記化合物(16)は実施例5に記載された方法によって調製する。 Step A Synthesis of 2-methoxy-naphthalene-1-carboxylic acid indan-2-yl- (2-fluoro-benzyl) -amide

Compound (16) above is prepared by the method described in Example 5.

Step B Synthesis of 2-hydroxy-naphthalene-1-carboxylic acid idaran-2-yl- (2-fluoro-benzyl) -amide

Boron tribromide (1n in dichloromethane, 1 mL) was added at -78 ° C under nitrogen under anhydrous 2-methoxy-naphthalen-1-carboxylic acid indan-2-yl- (2-fluoro-) in nitrogen (5 mL). Add to a solution of (benzyl) -amide (16) (421 mg; 1 mmol). The mixture is then stirred overnight at room temperature. After cooling to 0 ° C., water is added to quench the reaction. The organic phase is separated, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography to give the title compound (17) as a white solid (365 mg, 90%). LC-MS [MH +] 412;

Step C Synthesis of 1- [Indan-2-yl- (2-fluoro-benzyl) -carbamoyl] -naphthalen-2-yl ester of trifluoro-methanesulfonic acid

  At 0 ° C. under nitrogen, trifluoromethanesulfonic anhydride (0.27 mL, 1.6 mmol) was added 2-hydroxy-naphthalen-1-carboxylic acid indan-2-yl- (2-fluoro-benzyl) in anhydrous pyridine (5 mL). ) -Amide (17) (323 mg, 0.8 mmol) is added dropwise in 10 minutes. The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue (18) is dried in vacuo and used in the next step without further purification.

Step D 2- (5-Methyl-thiophen-2-yl) -naphthalene-1-carboxylic acid indan-2-yl- (2-fluoro-benzyl) -amide

1- [Indan-2-yl- (2-fluoro-benzyl) -carbamoyl] -naphthalene trifluoromethanesulfonate in 2 mL 1N sodium carbonate and toluene (v / v = 1/1) in a sealed tube under nitrogen A mixture of 2-yl ester (18), 5-methyl-2-thiopheneboronic acid (19) (142 mg, 1 mmol) and Pd (PPh) ₄ (50 mg) was heated at 90 ° C. for 16 hours. After cooling to room temperature, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with 1N HCl, saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography to give the desired product (20) (72 mg, 19% over 2 steps). LC-MS [MH +] 492.

Example 7
Synthesis of 1,5-dimethyl-1H-indole-4-carboxylic acid indan-2-yl- (4-methyl-benzyl) -amide

Step A Synthesis of 4-bromo-5-methylindole

Fuming nitric acid (> 90% yellow fuming HNO ₃ ) is slowly added to a solution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 ml) cooled in an ice bath (above freezing point). . Allow the mixture to warm to room temperature and stir for 1 hour, then heat at 80 ° C. for 2 hours or until GC / MS analysis indicates that the reaction is complete after microscale base workup . Cool the reaction mixture to room temperature and pour into ice / water with stirring. The resulting yellow precipitate is collected by suction filtration and air dried to give 2,6-dimethyl-3-nitrobromobenzene.

  Bredereck reagent (tert-butoxybis (dimethylamino) methane-16 g, 91 mmol) is added to a solution of 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120 ml) at room temperature. . The reaction mixture is heated at 120-125 ° C. under nitrogen for 5 hours or until the starting material is almost consumed according to TLC. The reaction mixture is cooled to room temperature, poured into water (300 ml) and extracted with dichloromethane (100 ml × 3). The combined extracts are dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture of enamines as a dark brown oil. This material is taken to the next step without further purification. The crude mixture is dissolved in acetic acid / water (250 ml of 4: 1), cooled to 0 ° C. and treated with slowly added zinc dust (57 g, 870 mmol) in several portions. After the addition is complete, the reaction mixture is heated at 110 ° C. for 4 hours. The zinc is removed by filtration through a celite pad and the filtrate is extracted with dichloromethane (100 ml × 3). The combined extracts were dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel (EtOAc / hexane 1:20) to give 4-bromo-5-methylindole (5.3 g) (21). Obtain as a light purple oil.

Step B Preparation of 4-bromo-1,5-dimethyl-1H-indole of 4-bromo-5-methylindole (3.55 g, 16.9 mmol) (21) in 10 ml anhydrous DMF at 0 ° C. under nitrogen The solution is added to a suspension of sodium hydride (1.01 g, 60% in mineral oil, 25.3 mmol, 1.5 equiv) in 10 ml DMF. The resulting mixture is stirred at 0 ° C. for 30 minutes and then warmed to room temperature. After stirring for another 2 hours at room temperature, the reaction mixture is cooled to 0 ° C. Iodomethane (2.40 g, 18.6 mmol, 1.1 eq) is added dropwise and the mixture is stirred at 0 ° C. for 2 hours, then warmed to 50 ° C. and stirred for another 2 hours. The reaction mixture is poured into 100 ml ice-water, extracted with ethyl acetate (30 ml × 3), washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the product (22) is dried to dryness under high vacuum to give 3.75 g of pure compound.

Step C Preparation of 1,5-dimethyl-1H-indole-4-carboxylic acid Under nitrogen, N-BuLi (1.6 M in hexane, 3.45 ml, 5.5 mmol, 1.1 equiv) was cooled to −78 ° C. To a solution of 4-bromo-1,5-dimethylindole (1.12 g, 5 mmol) (22) in anhydrous tetrahydrofuran. The resulting solution is stirred at −78 ° C. for 30 minutes and then quenched by introducing anhydrous carbon dioxide gas. The reaction mixture is slowly warmed to room temperature, 20 ml of water is added to the flask and the tetrahydrofuran is evaporated under reduced pressure. The resulting aqueous solution is adjusted to pH 5-6 with 1.0N hydrochloric acid. The product was extracted with ethyl acetate (25 ml × 3), washed with water and brine, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under high vacuum to 927 mg of 1,5-dimethyl-1H-indole -4-carboxylic acid (23) is obtained.

Step D Preparation of 1,5-dimethyl-1H-indole-4-carboxylic acid indan-2-yl- (4-methyl-benzyl) -amide
1,5-Dimethyl-1H-indole-4-carboxylic acid (23) (189 mg, 1.0 mmol) in 10 ml anhydrous 1,2-dichloromethane with EDCI (2 eq), HOBT (1 eq), and 2.0 eq triethylamine ) And (4-Tolyl) -indan-2-ylamine (237 mg, 1.0 mmol, 1.0 equiv) in a solution of (24). The resulting solution is stirred at room temperature for 5 hours and heated at reflux overnight. The reaction mixture is diluted with dichloromethane (20 ml) and extracted with saturated sodium bicarbonate solution (10 ml × 2), water (10 ml × 2), and brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and purified by reverse phase preparative HPLC to give indan-2-yl-1,5-dimethyl-1H-indole-4-carboxylate (4-Methyl-benzyl) -amide (25) is obtained.

Example 7A
Preparation of 1,5-dimethyl-1H-indole-4-carboxylic acid (4-di-methylamino-benzyl)-(4-isopropyl-phenyl) -amide This compound (26) was prepared from 4-carboxy- It can be prepared by the procedure described in the previous examples using 1,5-dimethylindole and (4-isopropylphenyl)-(4′-dimethylamino) benzylamine.

Example 8
Preparation of 5-isopropyl-1-methyl-1H-indazole-4-carboxylic acid indan-2-yl- (4-methyl-benzyl) -amide

Step A Preparation of 4-bromo-5-isopropyl-1-methylindazole (28)
A solution of 4-bromo-5-isopropylindazole (27) (488 mg, 2.04 mmol) in 5 ml anhydrous DMF under nitrogen at 0 ° C. was added sodium hydride (122 mg, 60% in mineral oil, 3.06 mmol) in 5 ml DMF. Mmol, 1.5 eq) suspension. The resulting mixture is stirred at 0 ° C. for 30 minutes and then warmed to room temperature. After stirring for another 2 hours at room temperature, the reaction mixture was cooled to 0 ° C., iodomethane (318 mg, 2.24 mmol, 1.1 eq) was added dropwise and the mixture was stirred at 0 ° C. for 2 hours and then warmed to room temperature. Stir overnight. The reaction mixture is poured into 30 ml ice-water, extracted with ethyl acetate (30 ml × 3), washed with water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the product is purified via flash column chromatography to give 340 mg of 4-bromo-5-isopropyl-1-methylindazole.

Step B Preparation of 5-Isopropyl-1-methyl-1H-indazole-4-carboxylic acid Of 4-bromo-5-isopropyl-1-methylindazole (340 mg, 1.34 mmol) (28). The resulting solution is stirred at −78 ° C. for 30 minutes. The anion is quenched by introducing anhydrous carbon dioxide gas and the flask is slowly warmed to room temperature. Water (20 ml) is added to the flask, the tetrahydrofuran is evaporated and the aqueous solution is prepared with 1.0 N hydrochloric acid to pH 5-6. The product is extracted with ethyl acetate (15 ml × 3), washed with water and brine, dried over anhydrous sodium sulfate, concentrated and dried under high vacuum to give 270 mg of pure product (29) . MS (+ VE) m / z 219 (M ⁺ +1).

Step C Preparation of Isopropyl-1-methyl-1H-indazole-4-carbonyl chloride
A 2.0N oxalyl chloride-dichloromethane solution (3.0 ml, 6.2 mmol, 5 eq) was added to 5-isopropyl-1-methyl-1H-indazolecarboxyl in a mixture of 5 ml cyclohexane and 5 ml aqueous THF containing a drop of DMF. Add to a solution of acid (270 mg, 1.24 mmol). The resulting solution is stirred overnight at room temperature. The solvent is evaporated; 10 ml of toluene is added and the mixture is evaporated again to dryness to give 5-isopropyl-1-methyl-1H-indazole-4-carbonyl (30) chloride as a brown foam.

Step D Preparation of 5-isopropyl-1-methyl-1H-indazole-4-carboxylic acid indan-2-yl- (4-methyl-benzyl) -amide
At 0 ° C., 5-isopropyl-1-methyl-1H-indazole-4-carbonyl chloride (0.618 mmol, 1.0 eq) (30) in 5 ml THF was added to (4) in 5 ml tetrahydrofuran containing 250 mg triethylamine. -Tolyl) -indan-2-yl-amine (147 mg, 0.618 mmol) is added to a solution of (31). The resulting mixture is stirred at room temperature overnight, diluted with 20 ml of ethyl acetate, washed with water and brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography give 168 mg of 5-isopropyl-1-methyl-1H-indazole-4-carboxylic acid indan-2-yl (4-methyl-benzyl) -amide (32).

Example 8A
Preparation of 5-Isoproyl-1-methyl-1H-indazole-4-carboxylic acid (4-dimethylamino-benzyl)-(4-isopropyl-phenyl) -amide
At 0 ° C., 5-isopropyl-1-methyl-1H-indazole-4-carbonyl chloride (0.618 mmol, 1.0 eq) in 5 ml of THF was added to (4-isopropyl in 5 ml of tetrahydrofuran containing 250 mg of triethylamine. Add to a solution of phenyl)-(4′-dimethylamino) benzylamine (165 mg, 0.618 mmol). The resulting mixture is stirred at room temperature overnight, diluted with 20 ml of ethyl acetate, washed with water and brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography gives 157 mg of 5-isopropyl-1-methyl-1H-indazole-4-carboxylic acid (4-dimethylamino-benzyl)-(4-isopropyl-phenyl) -amide (32A) .

Example 9
Synthesis of 5-isopropyl-1-methyl-1H-benzimidazole-4-carboxylic acid (4-dimethylamino-benzyl)-(4-isopropyl-phenyl) -amide

Acyl chloride (0.618 mmol, 1.0 equiv) (30) in 5 ml THF at 0 ° C. was added (4-isopropylphenyl)-(4′-dimethylamino) benzyl in 5 ml tetrahydrofuran containing 250 mg triethylamine. Add to a solution of amine (33) (165 mg, 0.618 mmol). The resulting mixture is stirred at room temperature overnight, diluted with 20 ml of ethyl acetate, washed with water and brine, and dried over sodium sulfate. Concentration and purification by silica gel chromatography gives 157 mg of the amide compound (34) (54% yield).

Example 10
Additional compounds Additional substituted biaryl amides are shown in Tables 1-3. The compounds shown in Table 1 are provided in Scheme 1 and are further prepared via the methods described in Examples 1 and 2. The compounds shown in Table 2 are prepared via the methods provided in Examples 3 and 4. The compounds in Table 2 are provided in Scheme 2 and are further prepared via the methods described in Examples 5 and 6. Compounds with an asterisk in the column marked “Ca ²⁺ Mob” were tested in the standard assay for C5a mode-mediated calcium mobilization listed in Example 18 and found to exhibit a Ki of less than 1 μM.

  All compounds in Table 2 were tested in a radioligand binding assay (Example 17) and found to inhibit C5a binding to the human C5a receptor by more than 95%.

  The LC / MS data shown in Tables 1, 2 and 3 were obtained using the following apparatus and method. MS analysis data was obtained in positive ion mode at 15V Cone voltage using a WATERS ZMD 2000 Mass Spec detector with a WATERS 600 pump, WATERS 2487 dual wavelength detector, GILSON 215 autosampler, and GILSON 841 microinjector. It is a spray MS. MassLynx version 3.4 software was used for data collection and analysis.

グラジエントについての合計実行時間は4.0分であった。 Samples 2-20 microliters were injected onto a 33 x 4.6 mm YMC ProPack C18; 5 micron column and eluted using a 2-phase linear gradient at a liquid speed of 4 mL / min. Samples were detected at 220 and 254 nm. The elution conditions were as follows: mobile phase A-95 / 5 / 0.1 water / methanol / TFA, mobile phase B-5 / 95 / 0.1 water / methanol / TFA.

The total run time for the gradient was 4.0 minutes.

Example 11
Pharmaceutical formulations for oral and intravenous administration
A tablet containing an A C5a antagonist and an anti-arthritic agent that is not a C5a receptor antagonist can be prepared as described below:

B Tablets containing the C5a receptor antagonist as the only active ingredient can be prepared as described below:

Tablets containing a C C5a receptor antagonist and a C5a receptor inactive agent can be prepared as follows:

An intravenous formulation containing a D C5a receptor antagonist and a C5a receptor inactive agent can be prepared as follows:

An oral suspension containing an E C5a receptor antagonist and a C5a receptor inactive agent can be prepared as follows:

Example 12
Preparation of Radiolabeled Probe Compounds of the Invention The compounds of the invention are prepared as radiolabeled probes by performing their synthesis using a precursor containing at least one atom that is a radioisotope. The radioisotope is preferably selected from at least one of carbon (preferably ¹⁴ C), hydrogen (preferably ³ H), sulfur (preferably ³⁵ S), or iodine (preferably ¹²⁵ I). . Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in the conventional 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 Radiolabelled Chemicals , Inc., St. Louis, MO; and Moravek Biochemicals Inc., Brea, CA.

  For example, (American Radiolabelled Chemicals, St. Louis, MO, Product No. ARC-153) is used as a starting material to obtain the many biaryl amides provided herein using the method shown in Scheme 2. be able to.

  Tritium labeled probe compounds are conveniently prepared with a catalyst via platinum catalyst exchange in tritiated acetic acid, acid catalyst exchange in tritiated trifluoroacetic acid, or heterogeneous catalyst exchange with tritium gas. Such preparations are also conveniently carried out as conventional radiolabels by any of the suppliers listed in the previous paragraphs using the compounds of the invention as substrates. In addition, suitably some precursors can be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borolithiate.

Example 13
Receptor Autoradiography Receptor autoradiography (receptor mapping) uses the radiolabeled compounds of the present invention prepared as described in the previous examples and uses Current Protocols in Pharmacology (1998) John Wiley & Sons. , In New York, sections 8.1.1-8.1.9, as described by Kuhar.

Example 14
Assay for C5a receptor-mediated chemotaxis This assay is a standard assay for C5a receptor-mediated chemotaxis.
Prior to performing the assay, human promonocytes U937 cells or purified human or non-human neutrophils are treated with dibutivir Camp for 48 hours. Human neutrophils or neutrophils from another mammalian species are used directly after isolation. Cells are pelleted and resuspended in culture medium containing 0.1% fetal bovine serum (FBS) and 10 μg / ml calcein AM (fluorescent dye). This suspension is then incubated for 30 minutes at 37 ° C. so that the cells take up the fluorescent dye. The suspension is then lightly centrifuged to pellet the cells, which are then resuspended in culture medium containing 0.1% FBS at a concentration of approximately 3 × 10 ⁶ cells / mL. An aliquot of this cell suspension is transferred to a clear tube containing solvent (1% DMSO) or various concentrations of the compound of interest and incubated at room temperature for at least 30 minutes. Chemotaxis assays are performed in CHEMO TX 101-8, 96 well plates (Neuro Probe, Inc. Gaithersburg, MD). Fill the bottom well of the plate with medium containing 0-10 nM C5a, preferably from the same species of mammal, such as neutrophils or other cells (e.g. human C5a for human U937 cells) . Fill the top well of the plate with cell suspension (compound or solvent-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 to the bottom well is then measured using a fluorescence reader. The chemotaxis index (ratio of migrated cells to total number of labeled cells) is then calculated for each compound concentration to determine the IC ₅₀ value.

  As a control to confirm that the cells maintain chemotactic activity in the presence of the compound of interest, the compounds provided herein are preferred over C5a, preferably under conditions that do not inhibit chemotaxis. Rather, various concentrations of chemoattractants that do not mediate chemotaxis via the C5a receptor (e.g., thymosan-activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4 (LTB4 )) To fill the bottom well of the plate.

Preferred compounds exhibit IC ₅₀ values of less than 1 μM in the assay for C5a receptor-mediated chemotaxis.

Example 15
C5a receptor expression
Human C5a by PCR using 1) a forward primer to add a Kozak ribosome binding site and 2) a reverse primer without additional sequence, and 3) an aliquot of the Stratagene human fetal brain cDNA library as a template Receptor cDNA is obtained. The sequence of the resulting PCR product is as described by Gerard and Gerard, (1991) Nature 349: 614-17. The PCR product is subcloned into the cloning vector pCR-Script AMP (STRATAGENE, La Jolla, Calif.) At the Srf I site. It is then excised using the restriction enzymes EcoRI and NotI and cloned in a suitable orientation for expression into the baculovirus expression vector pBacPAK 9 (CLONTECH, Palo Alto, Calif.) That has been digested with EcoRI and NotI.

Example 16
Baculovirus preparation for C5a expression The human C5a (hC5a) receptor baculovirus expression vector is cotransfected into Sf9 cells with BACULOGOLD DNA (BD PharMingen, San Diego, Calif.). Sf9 cell culture supernatant is harvested 3 days after transfection. Hanks containing recombinant virus-containing supernatant supplemented with Grace's salt, 4.1 mM L-Gln, 3.3 g / L LAH, 3.3 g / L ultrafiltered yeast and 10% heat-inactivated fetal bovine serum Are serially diluted in TNM-FH insect medium (JRH Biosciences, Lenexa, KS) (hereinafter referred to as “insect medium”) and plaque assay is performed on the recombinant plaques. After 4 days, recombinant plaques are selected and harvested in 1 ml insect medium for amplification. Each 1 ml dose of recombinant baculovirus (passage 0) is used to infect another T25 flask containing 2 × 10 ⁶ Sf9 cells in 5 ml of insect medium. After 5 days incubation at 27 ° C., supernatant medium is harvested from each of the T25 infections used as passage 1 inoculum.

Then, using 1 ml of passage 1 stock, 2 out of 7 recombinant baculovirus clones were selected for the second round of amplification in 100 ml insect medium divided into 2 T175 flasks. Infect 1 × 10 ⁸ cells. Forty-eight hours after infection, passage 2 medium from each 100 ml preparation is harvested and plaque assayed for titer. The cell pellet from the second round of amplification is assayed by affinity binding as described below to confirm expression of the recombinant vector. A third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect 1 liter of Sf9 cells. Forty hours after infection, the supernatant medium is harvested to obtain passage 3 baculovirus stock.

For affinity binding using a “binding assay” substantially as described by DeMartino et al. (1994) J. Biol. Chem. 269: 14446-50 (page 14447), adapted as follows: Assay cell pellets. Radioligand is 0.005-0.500 nM [ ¹²⁵ I] C5a (human recombinant); New England Nuclear Corp., Boston, MA); hC5a receptor-expressing baculovirus cells are used instead of 293 cells; assay buffer is Contains 50 mM Hepes pH 7.6, 1 mM CaCl ₂ , 5 mM MgCl ₂ , 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and 100 KIU / ml aprotinin; GF (pre-soaked in 1.0% polyethyleneimine for 2 hours prior to use) Filter using / C WHATMAN filter paper; wash the filter paper twice with 5 mL cold binding buffer without BSA, bacitracin or aprotinin.

  The titer of the 3rd passage baculovirus stock is determined by plaque assay and multiplicity of infection, incubation time, and binding assay experiments are performed to determine conditions for optimal receptor expression. A multiplicity of infection of 0.1 and an incubation time of 72 hours were the best infection parameters found for hC5a receptor expression in Sf9 cell infection media up to 1-liter.

Example 17
Baculovirus infection Log phase Sf9 cells (INVITROGEN Corp., Carlspad CA) are infected with one or more stocks of recombinant baculovirus and subsequently cultured in insect medium at 27 ° C. Infection is only with viruses that direct the expression of the hC5a receptor, or three G-protein subunit-expressing virus stocks, all of which are available from BIOSIGNAL Inc. (Montreal, Canada), 1) rats G _i2 G-protein-coding virus stock (BIOSIGNAL # V5J008), 2) bovine b1 G-protein-coding virus stock (BIOSIGNAL # V5H012), and 3) human g2 G-protein-coding virus stock (BIOSIGNAL # V6B003) Do with this virus combined.

  For convenience, infection is performed at a multiplicity of infection of 0.1: 1.0: 0.5: 0.5. At 72 hours post infection, a sample of the cell suspension is analyzed for viability by trypan blue dye exclusion and the remaining Sf9 cells are harvested via centrifugation (3000 rpm / 10 min / 4 ° C.).

Example 18
Purified recombinant insect cell membrane
The Sf9 cell pellet is resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 μg / ml leupeptin, 2 μg / ml aprotinin, 200 uM PMSF, and 2.5 mM EDTA, pH 7.4) and the POLYTRON homogenizer (30 seconds) Homogenize using setting 5). The homogenate is centrifuged (536 × g / 10 min / 4 ° C.) to pellet the nuclei. The supernatant containing the isolated membrane is decanted into a clear centrifuge tube, centrifuged (48,000 × g / 30 min, 4 ° C.) and the resulting pellet is resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice. Resuspend the final pellet in ice-cold Dulbecco's PBS containing 5 mM EDTA and store in aliquots frozen at −80 ° C. until needed. The protein concentration of the resulting membrane preparation (hereinafter “P2 membrane”) is conveniently measured using the Bradford protein assay (Bio-Rad Laboratories, Hercules, Calif.). With this measurement, a 1-liter culture of cells typically yields 100-150 mg of total membrane protein.

Example 19
Radioligand binding assay Purified P2 membranes prepared by the method described above were combined with binding buffer (50 mM Hepes pH 7.6, 120 mM NaCl, 1 mM CaCl ₂ , 5 mM MgCl ₂ , 0.1% BSA, pH 7.4, 0.1 mM bacitracin, 100 KIU / ml Resuspend by Dounce homogenization (dense pestle) in (aprotinin).

For saturation binding analysis, membranes (5-50 μg) are added to polypropylene tubes containing 0.005-0.500 nM [ ¹²⁵ I] C5a (human (recombinant), New England Nuclear Corp., Boston, Mass.). Non-specific binding is measured in the presence of 300 nM hC5a (Sigma Chemical Co., St. Louis, MO) and accounts for less than 10% of the total binding. To assess the effect of guanine nucleotides on receptor affinity, GTPγS is added to the duplicate tube at a final concentration of 50 μM.

For competition analysis, membranes (5-50 μg) are added to polypropylene tubes containing 0.030 nM [ ¹²⁵ I] C5a (human). Non-radiolabeled displacer is added to separate assays at concentrations ranging from 10 ⁻¹⁰ M to 10 ⁻⁵ M to obtain a final dose of 0.250 mL. Non-specific binding is measured in the presence of 300 nM hC5a (Sigma Chemical Co., St. Louis, MO) and accounts for less than 10% of the total binding. Following a 2 hour incubation at room temperature, the reaction is terminated by rapid vacuum filtration. Samples are filtered through pre-soaked GF / C WHATMAN filter paper (in 1.0% polyethyleneimine for 2 hours prior to use) and rinsed twice with 5 mL cold binding buffer without BSA, bacitracin or aprotinin. The remaining bound radioactivity is quantified by gamma counting. K _I and Hill coefficient (“nH”) are determined by fitting the Hill equation to values measured with the help of SIGMA plot software (SPSS Inc., Chicago, IL).

Example 20
Agonist-induced GTP binding Agonist-stimulated GTP-gamma ³⁵ S binding ("GTP binding") activity can be used to identify agonist and antagonist compounds and to distinguish neutral antagonist compounds from those with inverse agonist activity. This activity can also be used to detect partial agonist effects mediated by antagonist compounds. A compound to be analyzed in this assay is referred to herein as a “test compound”. Agonist-stimulated GTP binding activity is measured as follows: four independent baculovirus stocks (one directs expression of the hC5a receptor and three each of the three subunits of the heterotrimeric G-protein Is used to infect cultures of Sf9 cells as described in Example 17.

  Receptor / G-protein was evaluated using agonist-stimulated GTP binding to purified membranes (prepared as described in Example 18) using hC5a (Sigma Chemical Co., St. Louis, MO) as an agonist. -Confirm that the alpha-beta-gamma combination produces a functional response as measured by GTP binding.

GTP binding assay buffer (50 mM Tris _{pH7.0,120mM NaCl, 2mM MgCl 2, 2mM} EDTA, 0.1% BSA, 0.1mM bacitracin, 100 KIU / mL aprotinin, 5 [mu] M GDP) in the dounce (Dounce) homogenization (tight Resuspend the P2 membrane with a pestle and add to the reaction tube at a concentration of 30 μg protein / reaction tube. Increasing volumes of agonist hC5a are added at concentrations ranging from 10 ⁻¹² M to 10 ⁻⁶ M, followed by addition of 100 pM GTP-gamma ³⁵ S. In competition experiments, non-radiolabeled test compounds are added to separate assays at concentrations ranging from 10 ⁻¹⁰ M to ^{10 −5} M with 10 nM hC5a to obtain a final volume of 0.25 mL.

  Neutral antagonists bind C5a-stimulated GTP binding activity by membranes in this assay in the absence of baseline (in the absence of added C5a or other agonist, and in the absence of any test compound). It is a test compound that decreases toward (but not lower than) the GTP level).

  In contrast, in the absence of added C5a, preferred compounds reduce the GTP binding activity of receptor-containing membranes below baseline and are therefore characterized as inverse agonists. If a test compound that exhibits antagonist activity does not reduce GTP binding activity below baseline in the absence of a C5a agonist, it is characterized as a neutral antagonist.

  Antagonist test compounds that increase GTP binding activity above baseline in the absence of hC5a added in this GTP binding assay are characterized as having partial agonist activity. Preferred antagonist compounds do not increase GTP binding activity by 10%, 5% or 2% above baseline under such conditions.

Following a 60 minute incubation at room temperature, the reaction was terminated by vacuum filtration on GF / C filter paper (presoaked in wash buffer 0.1% BSA) followed by ice-cold wash buffer (50 mM Tris pH 7. (0, 120 mM NaCl). The amount of receptor-bound (and thereby membrane-bound) GTP-gamma ³⁵ S is measured by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filter paper. Non-specific binding is measured using 10 mM GTP-gamma ³⁵ S, which typically represents less than 5 percent of total binding. Data is expressed as a percentage above the base (baseline). The results of these GTP binding experiments can be conveniently analyzed using SIGMAPLOP software.

Example 21
Calcium mobilization assay
A Response to C5a
U937 cells were grown for 48 hours at 37 ° C. in differentiation medium (1 mM dibutyl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) and then FLIPR ™ plate reader (Molecular Devices Corp., Sunnyvale CA) Re-inoculate a 96-well plate suitable for use in Cells are grown for an additional 24 hours (to 70-90% confluence) prior to assay. The cells are then washed once with Krebs Ringer's solution. FLUO-3 calcium sensitive dye (Molecular Probes, Inc. Eugene, OR) is added to 10 μg / mL and incubated with the cells for 1-2 hours at room temperature. The 96 well plate is then washed to remove excess dye. The fluorescence response measured by excitation at 480 nM and emission at 530 nM is monitored using FLIPR ™ devices (Molecular Devices) upon addition of human C5a cells to a final concentration of 0.01-30.0 nM. Differentiated U937 cells typically exhibit a signal of 5,000 to 50,000 arbitrary fluorescent units in response to agonist stimulation.

B Assay for measurement of ATP response
Differentiated U937 cells (prepared and tested as described above under “Response to A C5a”) are stimulated by the addition of ATP (rather than C5a) to a final concentration of 0.01-30 μM. This stimulation typically triggers a signal of 1,000 to 12,000 arbitrary fluorescent units. Certain preferred compounds show less than 10%, 5% of this calcium mobilization when this control assay is performed in the presence of compound, compared to the signal when the assay is performed in the absence of compound. Less than 2% or less than 2% modification is produced.

C Receptor Modulators: Assays for Identifying Antagonists and Agonists The calcium mobilization assay described above can be readily adapted to identify test compounds that have agonist or antagonist activity at the human C5a receptor.

  For example, to identify antagonist compounds, differentiated U937 cells are washed and incubated with Fluo3 dye as described above. One hour before measuring the fluorescent signal, incubate with a subset of cells, 1 μM of at least one compound to be tested. The fluorescence response upon subsequent addition of 0.3 nM (final concentration) human recombinant C5a is monitored using a FLIPI ™ plate reader. Antagonist compounds fuse at least a 2-fold decrease in fluorescence response to that measured in the presence of human C5a alone. Preferred antagonist compounds induce at least a 5-fold, preferably at least 10-fold, more preferably at least a 20-fold decrease in fluorescence response relative to that measured in the presence of human C5a alone. Agonist compounds induce an increase in fluorescence without the addition of C5a, which increase is at least partially blocked by known C5a receptor antagonists.

Example 22
Assays for Assessing the Agonist Activity of Small Molecule C5a Receptor Antagonists Preferred compounds provided herein are significant (eg, 5% A C5a receptor antagonist with no agonist activity. Specifically, this unwanted agonist activity can be assessed in the GTP binding assay of Example 20, for example, by small molecule mediated GTP binding in the absence of the natural agonist C5a. Similarly, in a calcium mobilization assay (eg, that of Example 21), small molecule compounds can be directly assayed for the ability of the compound to stimulate calcium levels in the absence of the natural agonist C5a. The preferred degree of C5a agonist activity exhibited by the compounds provided herein is less than 10%, more preferably less than 5%, and most preferably less than 2% of the response induced by the natural agonist C5a.

Claims (99)

A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

Where Ar ¹ is
i) at least one selectively substituted phenyl or a selectively substituted phenyl having a selectively substituted heterocyclic substituent attached thereto, or
ii) selectively substituted 9H-fluorenyl or substituted naphthyl;
iii) optionally substituted heteroaryl;
R ¹ is an optionally substituted cycloalkyl, an optionally substituted (cycloalkyl) alkyl, an optionally substituted (heteroaryl) alkyl, an optionally substituted (aryl) alkyl, optionally Substituted aryl, optionally substituted heteroaryl having about 5-7 ring atoms and 1 to 3 heteroatoms selected from N, O and S, or optionally substituted ( Aryl) alkyl, wherein the aryl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) fused to a 5-7 membered saturated or partially unsaturated ring, independently substituted with 0-2 substituents selected from halogen, alkyl and alkoxyl;
R ² is alkyl, cycloalkyl, (cycloalkyl) alkyl, heteroaryl, (heteroaryl) alkyl, aryl, (aryl) alkyl, indanyl or tetrahydronaphthyl, each of which is optionally substituted, or
R ² is an optionally substituted phenyl (C ₀ -C ₂ alkyl), wherein the phenyl moiety is (a) 0, 1 or 2 independently selected from N, O and S. Having ring atoms, the remaining ring atoms being carbon, and (b) independently substituted with 0 to 3 substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxyl, Fused to a ~ 7 membered saturated or partially unsaturated ring. ^2. The compound or salt of claim 1, wherein R2 is selected from indanyl, (aryl) alkyl, and cycloalkyl, each of which is optionally substituted. Ar ¹
i) phenyl having at least one phenyl substituent or a heterocyclic substituent attached thereto, wherein each phenyl, phenyl substituent, or heterocyclic substituent is independently halogen, amino, cyano, hydroxy, C _1- C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, and -NHC ( = O) phenyl substituted with 0 to 4 substituents selected from C ₁ -C ₂ alkyl;
ii) are independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono - and di -C ₁ - C ₄ alkylamino, C ₁ -C _{2 alkylthio, -NHC (= O) C 1} -C 2 alkyl, one to three selected from optionally substituted phenyl, and optionally substituted thienyl Naphthyl substituted with a substituent;
iii) Independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C _1- 9h-fluorenyl substituted with 0 to 3 substituents selected from C ₄ alkylamino, C ₁ -C ₂ alkylthio, —NHC (═O) C ₁ -C ₂ alkyl;
iv) Independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C _1- Heteroaryl substituted with 0 to 3 substituents selected from C ₄ alkylamino, C ₁ -C ₂ alkylthio, —NHC (═O) C ₁ -C ₂ alkyl;
Selected from
R ¹ is
i) halogen each is independently hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy , C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, mono- and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl (Heteroaryl) C ₀ -C ₄ alkyl or (aryl) C substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl ₀ -C ₄ alkyl; or
ii) 0 to 5 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Substituted (aryl) (C ₁ -C ₄ ) alkyl, wherein the aryl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S; The remaining ring atoms are carbon and (b) independently substituted with 0 to 2 substituents selected from halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, (Aryl) (C ₁ -C ₄ ) alkyl, fused to a 7-membered saturated or partially unsaturated ring;
And
R ² is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (heteroaryl) C ₁ -C ₄ alkyl, (aryl) C ₁ -C ₄ alkyl, indanyl, And / or selected from tetrahydronaphthyl, each of which is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and 0-5 of which is substituted with a substituent a compound or salt according to claim 1 wherein is selected from phenyl. R ² is
(i) are independently halogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ substituted with 0-2 substituents selected from alkoxy 2-indanyl; and
(ii) are independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl And phenyl (C ₁ -C ₂ alkyl) substituted with 0 to 3 substituents selected from C ₁ -C ₂ haloalkoxy;
4. The compound of claim 3, wherein the compound is selected from: A compound or salt according to claim 3 represented by formula II:

Where Ar ¹ is
i) Independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and -NHC (= O) Substituted with 0 to 4 substituents selected from C ₁ -C ₂ alkyl, each of which is independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl Phenyl substituted with 0-3 substituents selected from
ii) independently a) halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono - and di -C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, and _{-NHC (= O) C 1 -C} 2 alkyl, and (b) a halogen, each is independently, C ₁ -C ₂ alkyl, C ₁ - Substituted with 1 to 3 substituents selected from phenyl and thienyl substituted with 0 to 3 substituents selected from C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Naphthyl; or
iii) Independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C _1- 9H-fluorenyl substituted with 0 to 3 substituents selected from C ₄ alkylamino, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl;
iv) Independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C _1- Heteroaryl substituted with 0 to 3 substituents selected from C ₄ alkylamino, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl;
And
Ar ² is
i) phenyl,
ii) naphthyl,
iii) a heterocycle having 1 or 2 rings, 3 to 8 atoms in each ring, and 1 to 3 heteroatoms independently selected from N, O and S; and
iv) a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being carbon Condensed phenyl;
Selected from
i), ii), iii) and each independently halogen iv), _{hydroxy, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{2 haloalkyl,} C Substituted with 0 to 5 substituents selected from ₁ -C ₂ haloalkoxy _, C ₁ -C ₂ alkylthio, and -NHC (= O) C ₁ -C ₂ alkyl;
R ² is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (heteroaryl) C ₁ -C ₄ alkyl, (aryl) C ₁ -C ₄ alkyl, and indanyl Each of which is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ Substituted with 0 to 3 substituents selected from -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; and
R ³ and R ⁴ are independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, and C ₂ -C ₄ alkynyl. R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C Phenyl (C ₁ -C ₂ alkyl) substituted with 0 to 5 substituents selected from ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl;
Or
ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl _, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Substituted (phenyl) C ₁ -C ₄ alkyl, wherein the phenyl moiety (a) has 0, 1 or 2 ring atoms independently selected from N, O and S, and the remaining The ring atom is carbon and (b) 5-7 membered, substituted with 0-2 substituents independently selected from halogen, C ₁ -C ₂ alkyl, and C ₁ -C ₂ alkoxy _4. A compound or salt according to claim 3 which is (phenyl) C ₁ -C ₄ alkyl fused to a saturated or partially unsaturated ring. R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C Benzyl substituted with 0 to 5 substituents selected from ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl;
Or
ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy a phenyl substituted -CH _2, the phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms carbon And (b) fused to a 5-7 membered saturated or partially unsaturated ring, independently substituted with 0-2 substituents selected from chloro, fluoro, methyl, and methoxy. Phenyl-CH ₂
7. The compound or salt according to claim 6, wherein R ² is
i) 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl, and methoxy; or
ii) 0 to 3 of each independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 8. A compound or salt according to claim 7, which is benzyl, piperonyl, benzodioxanylmethyl, and benzofuranylmethyl substituted with a substituent. Chloro R ² is independently fluoro, methyl, and substituted with 0-2 substituents selected from methoxy and 2-indanyl, compound or salt of claim 8. R ² is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl , C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-3 substituents selected from phenyl, a compound or salt according to claim 7 wherein. A compound or salt according to claim 3 represented by formula III:

Wherein Ar ³ is independently halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di- (C ₁ -C ₄ alkyl) amino, C Phenyl substituted with 0 to 3 substituents selected from _1- C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl , Pyridyl, furanyl, thienyl, imidazolyl, pyrrolyl, virazolyl, oxazolyl, naphthyl, thiazolyl, or pyrimidinyl; and
R ⁶ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and -NHC ( = O) represents 0 to 4 substituents selected from C ₁ -C ₂ alkyl. R ² is
i) 0 to 2 each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with a substituent; or
ii) halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-3 substituents selected from phenyl, piperonyl, benzodioxanyl methyl, and benzofuranyl methyl, claim 11. The compound or salt according to 11. R ² is
i) 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy; or
ii) each is independently halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, 0-3 substituents selected from C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy 13. A compound or salt according to claim 12, which is benzyl, piperonyl, benzodioxanylmethyl or benzofuranylmethyl substituted with a group. R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-5 substituents selected from phenyl; or
ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy phenyl substituted -CH ₂ - a, wherein said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms carbon And (b) fused to a 5-7 membered saturated or partially unsaturated ring independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy. Phenyl-CH _2-
12. A compound or salt according to claim 11 wherein R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ Benzyl substituted with 0-5 substituents selected from -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or
ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy phenyl substituted -CH ₂ - a, wherein said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms carbon And (b) fused to a 5-7 membered saturated or partially unsaturated ring independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy. Phenyl-CH _2-
13. A compound or salt according to claim 12, which is R ¹ is
(i) independently a halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, -NC (= O) C ₁ -C ₂ alkyl, mono- and di (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-5 substituents selected from phenyl; or
(ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Phenyl-CH _2- substituted with a phenyl moiety having (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being Fused to a 5-7 membered saturated or partially unsaturated ring that is carbon and (b) independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy Phenyl-CH _2-
14. A compound or salt according to claim 13 which is Ar ³ is each independently halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ 2-thienyl or 3 substituted with 0 to 3 substituents selected from haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl 12. A compound or salt according to claim 11 which is -thienyl. Ar ³ is independently halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and C ₁ -C ₂ alkylthio, and -NHC (= O) phenyl substituted with 0-3 substituents selected from C ₁ -C ₂ alkyl, according to claim 11, wherein Compound or salt. R ² is
i) 0 to 2 each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, and C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with a substituent; or
ii) halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, 0-3-benzyl substituted with a substituent selected from thienyl and phenyl, piperonyl, benzodioxanyl methyl, and benzofuranyl methyl claim 17 The described compound. R ² , each independently of halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C is ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, benzyl substituted with 0-3 substituents selected from thienyl and phenyl, piperonyl, benzodioxanyl methyl or benzofuranyl methyl, wherein Item 20. A compound or salt according to Item 19. R ² is independently chloro, fluoro, 0-2 to 2-indanyl substituted with a substituent selected from methyl and methoxy, the compound or salt according to claim 19, wherein. R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-5 substituents selected from phenyl; or
ii) (phenyl) independently substituted with 0 to 3 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, haloalkyl, and C ₁ -C ₂ haloalkoxy C ₁ -C ₄ alkyl, wherein the phenyl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, with the remaining ring atoms being carbon. And (b) fused to a 5-7 membered saturated or partially unsaturated ring, independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy. it is there (phenyl) C ₁ -C ₄ alkyl, a compound or salt of any one of claims 19 to 21. R ¹ is
(i) independently a halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, Benzyl substituted with 0-5 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or
(ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Phenyl-CH _2- substituted with a phenyl moiety having (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being Fused to a 5-7 membered saturated or partially unsaturated ring that is carbon and (b) independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy Phenyl-CH _2-
23. A compound or salt according to claim 22 which is R ¹ is optionally independently halogen, hydroxy, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C Substituted with 0 to 3 substituents selected from _1- C ₂ alkyl, mono- or di (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and phenyl 24. A compound or salt according to claim 23, wherein R ¹ is chloro independently are each fluoro, methyl and 0-3 piperonyl or benzofuranyl methyl substituted with a substituent selected from methoxy, compound or salt of claim 23. R ² is
i) 0 to 2 each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, and C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with a substituent; or
ii) halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, 0-3-benzyl substituted with a substituent selected from thienyl and phenyl, piperonyl, benzodioxanyl methyl, and benzofuranyl methyl claim 18 The described compound. R ² , each independently of halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C is ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-3 substituents selected from phenyl, piperonyl, benzodioxanyl methyl or benzofuranyl methyl, 27. A compound or salt according to claim 26. R ² is independently chloro, fluoro, it is 2-indanyl substituted with 0-2 substituents selected from methyl and methoxy, the compound or salt according to claim 26, wherein. R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-5 substituents selected from phenyl; or
ii) (phenyl) independently substituted with 0 to 3 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, haloalkyl, and C ₁ -C ₂ haloalkoxy C ₁ -C ₄ alkyl, wherein the phenyl moiety has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, with the remaining ring atoms being carbon. And (b) fused to a 5-7 membered saturated or partially unsaturated ring, independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy. it is there (phenyl) C ₁ -C ₄ alkyl, a compound or salt of any one of claims 26 to 28. R ¹ is
(i) independently a halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, Benzyl substituted with 0-5 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or
(ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Phenyl-CH _2- substituted with a phenyl moiety having (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being Fused to a 5-7 membered saturated or partially unsaturated ring that is carbon and (b) independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy Phenyl-CH _2-
30. The compound or salt of claim 29, wherein R ¹ is optionally independently halogen, hydroxy, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C Substituted with 0 to 3 substituents selected from _1- C ₂ alkyl, mono- or di (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and phenyl 31. A compound or salt according to claim 30 which is benzylated. R ¹ is chloro each is independently fluoro, 0-3 piperonyl or benzofuranyl methyl substituted with a substituent selected from methyl and methoxy, the compound or salt according to claim 30, wherein. A compound or salt according to claim 3 represented by formula IV:

Where Z ¹ is carbon or nitrogen;
Z ² , Z ³ , and each occurrence of Z ⁴ are independently CR ⁷ , NR ⁸ , S and so that each S or O ring atom, if any, is located between two CR ⁷ groups. Selected independently from O,
p is an integer ranging from 1 to 2;
R ⁶ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and -NHC ( = O) represents 0 to 4 substituents selected from C ₁ -C ₂ alkyl;
R ⁷ is independently at each occurrence hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C Selected from _2- C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, mono- and di- (C ₁ -C ₆ alkyl) amino, cyano, nitro, and C ₁ -C ₆ alkanoyl ;And
R ⁸ is independently at each occurrence hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, And C ₁ -C ₆ alkanoyl.

There comprises 1-4 nitrogen ring atoms independently hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ halo 34. Substituted with 0 to 3 substituents selected from alkoxy, mono- and di-C ₁ -C ₆ alkylamino, and C ₁ -C ₆ alkanoyl; and p is 1 or 2 Or a salt of 34. A compound or salt according to claim 33 represented by formula V:

Wherein one of Z ² or Z ³ is sulfur or oxygen; and
R ⁹ is independently selected from hydrogen, fluoro, chloro, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₆ haloalkoxy 0-3 Represents one substituent. 34. A compound or salt according to claim 33 represented by formula VI:

Wherein Z ³ is nitrogen or CR ⁹ ; and
R ⁹ is independently selected from hydrogen, fluoro, chloro, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₆ haloalkoxy 0-3 Represents one substituent. R ² is
i) 0 to 2 each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 2-indanyl, C ₃ -C ₇ cycloalkyl, and C ₃ -C ₇ cycloalkyl (C ₁ -C ₄ alkyl) substituted with a substituent; and
ii) halogen each is independently hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, benzyl substituted with 0-3 substituents selected from thienyl and phenyl, piperonyl, benzodioxanyl methyl, and benzofuranyl methyl;
37. A compound or salt according to any one of claims 33 to 36, selected from: R ² , each independently of halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C is ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and benzyl substituted with 0-3 substituents selected from phenyl, piperonyl, benzodioxanyl methyl or benzofuranyl methyl, 38. A compound or salt according to claim 37. R ² is independently chloro, fluoro, substituted with 0-2 substituents selected from methyl and methoxy 2-indanyl, compound or salt according to claim 37, wherein. R ¹ :
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₂ alkyl) amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, C (Phenyl) C ₁ -C ₂ alkyl substituted with 0 to 5 substituents selected from ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or
ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Substituted (phenyl) C ₁ -C ₄ alkyl, wherein the phenyl moiety (a) has 0, 1 or 2 ring atoms independently selected from N, O and S, and the remaining 5-7 membered saturated or partially unsaturated where the ring atom is carbon and (b) independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy is a fused to a ring (phenyl) C ₁ -C ₄ alkyl, a compound or salt of any one of claims 33 to 39. R ¹ is
i) are independently halogen, hydroxy, nitro, _{cyano, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C _{4 alkylthio, -NC (= O) C 1} -C 2 alkyl, mono- - and di - (C ₁ -C ₄ alkyl), amino, C ₂ -C ₃ alkanoyloxy, C ₁ -C ₃ alkoxycarbonyl, Benzyl substituted with 0-5 substituents selected from C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, thienyl, and phenyl; or
ii) 0 to 3 substituents independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy phenyl substituted -CH ₂ - a, wherein said phenyl moiety has 0, 1 or 2 ring atoms selected from N, O and S are independently (a), the remaining ring atoms carbon And (b) fused to a 5-7 membered saturated or partially unsaturated ring independently substituted with 0-2 substituents selected from chloro, fluoro, methyl and methoxy. Phenyl-CH _2-
41. The compound or salt of claim 40, wherein R ¹ is independently halogen, hydroxy, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, —NC (═O) C ₁ -C ₂ alkyl With benzyl substituted with 0 to 3 substituents selected from mono- and di- (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and phenyl 42. The compound or salt of claim 41, wherein R ¹ is chloro independently are each fluoro, methyl and piperonyl or benzofuranyl methyl substituted with 0-2 substituents selected from methoxy, the compound or salt according to claim 40, wherein. 6. A compound or salt according to claim 5 represented by formula VII:

Where Z ¹ is carbon or nitrogen;
Z ² , Z ³ , and each occurrence of Z ⁴ are CR ⁷ , NR ⁸ , S and O, so that each S or O ring atom, if present, is located between two CR ⁷ groups. Selected independently from
p is an integer ranging from 1 to 2;
R ⁶ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, and -NHC ( = O) represents 0 to 4 substituents selected from C ₁ -C ₂ alkyl;
R ⁷ is independently at each occurrence hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C Selected from _2- C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, mono- and di- (C ₁ -C ₆ alkyl) amino, cyano, nitro, and C ₁ -C ₆ alkanoyl ;And
R ⁸ is independently at each occurrence hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, And C ₁ -C ₆ alkanoyl. Ar ²
i) phenyl; or
ii) a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being carbon Condensed phenyl,
Each of i) and ii) are independently halogen, _{hydroxy, -COOH, -CONH 2, C 1} -C 2 alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ halo Substituted with 0 to 2 substituents selected from alkoxy;
R ² is
i) 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy; or
ii) 0 to 3 of each independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Benzyl, piperonyl, benzodioxanylmethyl, or benzofuranylmethyl substituted with a substituent,
R ³ and R ⁴ are hydrogen;
The group:

0 to 3 each of which is independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Phenyl or thienyl substituted with a substituent; and
R ⁶ is independently 0 to 2 substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy Represent,
45. A compound or salt according to claim 44. The compound of claim 1 represented by formula VIII or a pharmaceutically acceptable salt thereof:

[Where:
R is
(i) halogen, hydroxy, C ₁ -C ₃ haloalkyl, or C ₁ -C ₃ haloalkoxy, or
(ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ substituted with 0 to 4 substituents selected from-and di (C ₁ -C ₄ ) alkylamino -C ₆ alkoxy, mono- - or di - (C ₁ -C ₆ alkyl) amino, or C ₃ -C ₇ cycloalkyl (C ₀ -C ₄ alkyl),
(iii) phenyl, or
(iv) a heterocycle having 4 to 8 ring atoms and 1 to 3 heteroatoms independently selected from N, O and S;
(iii) and each independently hydroxy (iv), halogen, amino, cyano, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- - and di -C ₁ -C ₆ alkylamino, Mono- and di-C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ It is substituted with 0-3 substituents selected from -C ₂ alkyl;
R ² is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, (heteroaryl) C ₀ -C ₂ alkyl, (aryl) C ₀ -C ₂ alkyl, or indanyl Each of which is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, COOH, —NC (═O) C ₁ -C ₂ alkyl, C Substituted with 0 to 3 groups selected from ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy; or
R ² is (phenyl) C ₀ -C ₂ alkyl, wherein the phenyl moiety (a) has 0, 1 or 2 ring atoms independently selected from N, O and S, and the remaining ring atoms are carbon, and (b) are independently halogen, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ halo Fused to a 5-7 membered saturated or partially unsaturated ring substituted with 0-3 substituents selected from alkoxy;
R ³ and R ⁴ are independently hydrogen, methyl or ethyl;
R ⁵ and R ⁶ are each independently halogen, hydroxy, cyano, nitro, amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, Mono- and di- (C ₁ -C ₆ ) alkylamino, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C ₁ -C ₂ alkyl Represents zero or more substituents selected from:
Ar ² is
i) phenyl,
ii) naphthyl,
iii) a heterocycle having 1 or 2 rings, 3 to 8 atoms in each ring, and 1 to 3 heteroatoms independently selected from N, O and S; or
iv) a 5- to 7-membered saturated or partially unsaturated ring having 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being carbon Represents condensed phenyl,
each of i), ii), iii), and iv) is independently
a) halogen, hydroxy, cyano, amino, -COOH, -CONH _2, C ₁ -C ₃ haloalkyl, and C ₁ -C ₃ haloalkoxy,
b) halogen each is independently hydroxy, amino, oxo, cyano, -COOH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- - and di (C ₁ -C ₄₎ alkylamino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ alkylcarboxamide, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkyl sulfonate, C _2- C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₄ substituted with 0 to 5 substituents selected from C ₄ alkyl esters, and C ₁ -C ₄ alkoxycarbonyl ₁ -C ₆ alkoxy, mono- and di- (C ₁ -C ₆ alkyl) amino, and (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl,
c) C ₁ -C ₄ alkyl carboxamide, C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkyl sulfonates, C ₂ -C ₄ alkyl esters, C ₁ -C ₄ alkoxycarbonyl, and heterocycloalkyl (C ₀ -C ₄ alkyl), and
d) having 1 or 2 rings, 3 to 8 atoms in each ring, and 1 to 3 heteroatoms independently selected from N, O and S, independently halogen, hydroxy 0 selected from nitro, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and a 5-7 membered heterocycloalkyl substituent Substituted with ₀ to 5 substituents selected from (heterocyclic) C ₀ -C ₄ alkyl substituted with ~ 3 groups. R is
(i) halogen, hydroxy, C ₁ -C ₃ haloalkyl, and C ₁ -C ₃ haloalkoxy,
(ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C, substituted with 0 to 4 substituents selected from-and di- (C ₁ -C ₄ alkyl) amino ₁ -C ₆ alkyl ₁ -O-, C ₁ -C ₆ alkoxy, mono- or di- (C ₁ -C ₆ alkyl) amino, or C ₃ -C ₇ cycloalkyl (C ₀ -C ₄ alkyl),
(iii) phenyl, and
(iv) selected from pyridinyl, pyrimidinyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, thiazolyl, isoxazolyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl;
(iii) and each independently hydroxy (iv), halogen, amino, cyano, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono- - and di -C ₁ -C ₆ alkylamino, Mono- and di-C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₂ alkylthio, and —NHC (═O) C Substituted with 0 to 3 substituents selected from ₁ -C ₂ alkyl;
R ² is C ₃ -C ₇ cycloalkyl, (C ₃ -C ₇ cycloalkyl) C ₁ -C ₄ alkyl, pyridylmethyl, pyrimidinylmethyl, pyrazinylmethyl, thienylmethyl, quinazolinylmethyl, benzothiazolylmethyl, in Drillylmethyl, benzimidazolylmethyl, phenyl, benzyl, phenethyl or indanyl; each of which is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio,- Substituted with 0 to 3 groups selected from COOH, —NC (═O) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy; or
R ² (a) has 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy 5 substituted with 0 to 3 substituents selected from: cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy Benzyl fused to a ~ 7 membered saturated or partially unsaturated ring;
Ar ² is
i) phenyl,
ii) naphthyl,
iii) pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl, or benzimidazolyl, or
iv) (a) 5-7 membered saturated or partially unsaturated, having 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms being carbon Represents phenyl fused to the ring of
each of i), ii), iii) and iv) is independently
a) halogen, hydroxy, cyano, amino, -COOH, -CONH _2, C ₁ -C ₃ haloalkyl, and C ₁ -C ₃ haloalkoxy,
b) halogen each is independently hydroxy, amino, oxo, cyano, -COOH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, mono- - and di (C ₁ -C ₄₎ alkylamino, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy C ₁ -C ₄ alkylcarboxamide, C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkyl sulfonate, C ₂ -C C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ substituted with 0-5 substituents selected from ₄ alkyl esters, and C ₁ -C ₄ alkoxycarbonyl -C ₆ alkoxy, mono- - and di - (C ₁ -C ₆ alkyl) amino, and (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl,
c) C ₁ -C ₄ alkyl carboxamide, C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl sulfinyl, C ₁ -C ₄ alkyl sulfonyl, C ₁ -C ₄ alkyl sulfonate, C ₂ -C ₄ alkyl ester, C ₁ -C ₄ alkoxycarbonyl, and
d) halogen each is independently hydroxy, nitro, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, pyrrolidinyl, morpholinyl, thiomorpholinyl (Pyrrolidinyl) C ₀ -C ₄ alkyl, (morpholinyl) C ₀ -C ₄ alkyl, (thiomorpholinyl) C ₀ -C ₄ alkyl, (piperazinyl) substituted with 0 to 3 groups selected from piperazinyl and piperidinyl ) C ₀ -C ₄ alkyl, and (piperidinyl) C ₀ -C ₄ alkyl, and (thiazolyl) C ₀ -C ₄ alkyl, (piperidyl) C ₀ -C ₄ alkyl, (morpholinyl) C ₀ -C ₄ alkyl, 47. Substituted with 0 to 5 groups selected from (pyrrolidinyl) C ₀ -C ₄ alkyl, (piperidinyl) C ₀ -C ₄ alkyl, and (piperazinyl) C ₀ -C ₄ alkyl. Or a salt of 47. A compound or salt according to claim 46 of formula IX:

Wherein R ⁷ is independently halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- and di- (C _{1 to} C ₂ alkyl) represents 0 to 3 substituents selected from amino. R ⁵ and R ⁶ are independently halogen, cyano, nitro, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono- and di - (C ₁ -C ₂ alkyl) is selected from an amino compound or salt according to claim 48, wherein. R is (i) halogen and hydroxy, and (ii) a halogen, each is independently hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and C ₁ -C ₆ alkyl and C ₁ -C ₆ substituted with 0 to 4 substituents selected from mono- and di- (C ₁ -C ₄ alkyl) amino 50. A compound or salt according to claim 49, selected from alkoxy. R is C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy, compound or salt of claim 49. R is hydroxy and each is independently halogen, amino, cyano, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkylamino, (C ₁ -C ₂ alkylamino) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C phenyl substituted with ₂ 0-3 substituents selected from haloalkoxy, thienyl, or pyridyl, as claimed in claim 49 Compound or salt. Halogen Ar ² is independently hydroxy, cyano, _{amino, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, and 5-, containing 1, 2, or 3 heteroatoms independently selected from N, O and S 53. A compound or salt according to any one of claims 50 to 52, which is phenyl substituted with 0 to 5 groups selected from 7-membered heterocycloalkyl groups. Ar ² , each independently of halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C Substituted with 0-5 groups selected from ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl and piperidinyl 53. A compound or salt according to any one of claims 50 to 52, which is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl, or benzimidazolyl. Ar ² has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy Substituted with 0 to 3 substituents selected from cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, 53. A compound or salt according to any one of claims 50 to 52, which is phenyl fused to a 5-7 membered saturated or partially unsaturated ring. R ² is independently halogen, hydroxy, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₂ haloalkyl, and C ₁ -C a benzyl or phenethyl substituted _with 0-3 groups selected from haloalkoxy, compound or salt of claim 46. R ₅ and R ₆ are independently halogen, cyano, nitro, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, mono- and di- (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, and are selected from C ₁ -C ₂ haloalkoxy, compound or salt according to claim 56, wherein. R is
(i) halogen and hydroxy, and
(ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono - and di - (C ₁ -C ₄ alkyl) of claim 57 selected from 0-4 C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy substituted with a substituent selected from amino Compound or salt. A compound or salt according to claim 57, wherein R is C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy. R is hydroxy and each is independently halogen, amino, cyano, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkylamino, (C ₁ -C ₂ alkylamino) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C phenyl substituted with ₂ 0-3 substituents selected from haloalkoxy, thienyl, or pyridyl, as claimed in claim 57 Compound or salt. Ar ² , each independently of halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C Substituted with 0 to 5 groups selected from ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and piperidinyl 61. A compound or salt according to any one of claims 58 to 60 which is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl or benzimidazolyl. Ar ² has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy Substituted with 0 to 3 substituents selected from cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, 61. A compound or salt according to any one of claims 58 to 60 which is phenyl fused to a 5 to 7 membered saturated or partially unsaturated ring. R ² has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy Substituted with 0 to 3 substituents selected from cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, 47. The compound or salt of claim 46, which is benzyl fused to a 5-7 membered saturated or partially unsaturated ring. R ₅ and R ₆ are independently halogen, cyano, nitro, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, mono- and di- (C ₁ -C ₂ alkyl) amino, C ₁ -C ₂ haloalkyl, and are selected from C ₁ -C ₂ haloalkoxy, compound or salt according to claim 63, wherein. R is
(i) halogen and hydroxy, and
(ii) each independently halogen, hydroxy, amino, oxo, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, and mono - and di - (C ₁ -C ₄ alkyl) is selected from 0-4 C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy substituted with a substituent selected from amino, claim 64, wherein Or a salt of A compound or salt according to claim 64, wherein R is C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy. R is hydroxy and each is independently halogen, amino, cyano, nitro, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ alkylamino, (C ₁ -C ₂ alkylamino) C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ phenyl substituted with 0-3 substituents selected from haloalkoxy, thienyl, or pyridyl, according to claim 64, wherein Compound or salt. Ar ² , each of which is halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy Phenyl substituted with 0 to 5 groups selected from C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and piperidinyl, 68. A compound or salt according to any one of claims 65 to 67 which is pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl or benzimidazolyl. Ar ² has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy Substituted with 0 to 3 substituents selected from cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, 68. A compound or salt according to any one of claims 65 to 67 which is phenyl fused to a 5 to 7 membered saturated or partially unsaturated ring. Ar ¹ is independently halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di-C ₁ -C ₄ alkylamino, C ₁ -C ₂ alkylthio, -NHC (= O) is a C ₁ -C heteroaryl substituted with ₂ 0-3 substituents selected from alkyl, according to claim 5, wherein Compound or salt. Ar ¹ , each independently of halogen, amino, cyano, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- and di -C ₁ -C ₄ indolyl or indazolyl substituted with 0-3 substituents selected from alkylamino, a compound or salt according to claim 70, wherein. Hydrogen R ³ and R ⁴ are independently selected from methyl and ethyl 6. The compound of claim 5, wherein. Halogen Ar ² is independently hydroxy, cyano, _{amino, -COOH, -CONH 2, C 1} -C 4 alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, 5-7 containing C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, and 1, 2 or 3 heteroatoms independently selected from N, O and S 73. A compound or salt according to claim 72, which is phenyl substituted with 0 to 5 groups selected from membered heterocycloalkyl groups. Ar ² , each independently of halogen, hydroxy, cyano, amino, —COOH, —CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C Substituted with 0-5 groups selected from ₂ haloalkoxy, C ₁ -C ₂ alkylthio, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl and piperidinyl 73. A compound or salt according to claim 72, which is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl or benzimidazolyl. Ar ² has (a) 0, 1 or 2 ring atoms independently selected from N, O and S, the remaining ring atoms are carbon, and (b) independently halogen, hydroxy Substituted with 0 to 3 substituents selected from cyano, amino, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy, 73. The compound or salt of claim 72, which is phenyl fused to a 5-7 membered saturated or partially unsaturated ring. R ² is
i) 2-indanyl substituted with 0 to 2 substituents independently selected from chloro, fluoro, methyl and methoxy; or
ii) 0 to 3 of each independently selected from halogen, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl, and C ₁ -C ₂ haloalkoxy 76. A compound or salt according to any one of claims 72 to 75, selected from benzyl, piperonyl, benzodioxanylmethyl and benzofuranylmethyl substituted with a substituent. R ² is independently chloro, fluoro, 0-2 is 2-indanyl substituted with a substituent, the compound or salt of any one of claims 72-75 which is selected from methyl and methoxy. 4'-trifluoromethyl-biphenyl-2-carboxylic acid benzo [1,3] dioxol-5-ylmethyl-benzyl-amide;
3-methyl-biphenyl-2-carboxylic acid benzyl-indan-2-yl-amide;
N, N-dibenzyl-4′-fluoro-1,1′-biphenyl-2-carboxamide;
3 '-(acetylamino) -N, N-dibenzyl-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-4 ′-(trifluoromethoxy) -1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2 '-(methylthio) -1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-4 ′-(ethylthio) -1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-3′-fluoro-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-3 ′, 4′-dimethyl-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2-thien-3-ylbenzamide;
N, N-dibenzyl-4 ′-(trifluoromethyl) -1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2'-methoxy-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-4′-methoxy-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2 ′, 4′-dimethoxy-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-3 ′, 4′-dimethoxy-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2'-chloro-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-3'-chloro-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-4'-chloro-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-2 ′, 3′-dichloro-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2 ′, 4′-dichloro-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-2'-methyl-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-3′-methyl-1,1′-biphenyl-2-carboxamide;
N, N-dibenzyl-4'-methyl-1,1'-biphenyl-2-carboxamide;
N, N-dibenzyl-3 ′, 5′-dichloro-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- [2- (4-methoxyphenyl) -1-methylethyl] -4′-methyl-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -4′-methyl-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -2- (4-methylthien-2-yl) benzamide;
N-benzyl-N- (indan-2-yl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-1-yl) -2'-fluoro-1,1'-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -3′-methoxy-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -2-thien-2-ylbenzamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (indan-2-yl) -3′-methoxy-1,1′-biphenyl-2-carboxamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (indan-2-yl) -9H-fluorene-4-carboxamide;
N-benzyl-N- (indan-2-yl) -4-methoxy-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -3-methoxy-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -4-hydroxy-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -3-hydroxy-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -5-methoxy-2- (5-methylthien-2-yl) -benzamide;
N-benzyl-N- (5-methoxy-indan-2-yl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (5-methyl-indan-2-yl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (2-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (3-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-fluorobenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (3-fluorobenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (2-fluorobenzyl) -1,1′-biphenyl-2-carboxamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (indan-2-yl) -1,1′-biphenyl-2-carboxamide;
N- (3,4-difluorobenzyl) -N- (indan-2-yl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (2-methoxybenzyl) -2-thien-3-ylbenzamide;
N- (indan-2-yl) -2'-fluoro-N- (2-methoxybenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-methoxybenzyl) -2-thien-3-ylbenzamide;
N- (indan-2-yl) -N- (3,5-dimethoxybenzyl) -2-thien-3-ylbenzamide;
N- (indan-2-yl) -2-thien-3-yl-N- (3-thien-3-ylbenzyl) -benzamide;
N- (indan-2-yl) -N- (2-naphthylmethyl) -2-thien-3-ylbenzamide;
N, N-dibenzyl-2'-fluoro-1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -4'-methyl-N- (4-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -3'-methoxy-N- (4-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -2'-fluoro-N- (4-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-fluorobenzyl) -4'-methyl-1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-fluorobenzyl) -3′-methoxy-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -2'-fluoro-N- (4-fluorobenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (2-fluorobenzyl) -4′-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (3-fluorobenzyl) -4′-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -2'-fluoro-N- (3-fluorobenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -4'-methyl-N- (3-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -3'-methoxy-N- (3-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -2'-fluoro-N- (3-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -4'-methyl-N- (2-methylbenzyl) -1,1'-biphenyl-2-carboxamide;
N- (indan-2-yl) -3-methoxy-N- (3-methoxybenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -5-methoxy-N- (3-methoxybenzyl) -2- (5-methylthien-2-yl) -benzamide;
N- (indan-2-yl) -4-methoxy-N- (3-methoxybenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -5-methoxy-N- (3-methoxybenzyl) -2-thien-3-ylbenzamide;
N- (indan-2-yl) -4-methoxy-N- (2-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -4-methoxy-N- (3-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -4-methoxy-N- (4-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (2-fluorobenzyl) -4-methoxy-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (3-fluorobenzyl) -4-methoxy-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-fluorobenzyl) -4-methoxy-1,1′-biphenyl-2-carboxamide;
N- (3,4-difluorobenzyl) -N- (indan-2-yl) -4-methoxy-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -3-fluoro-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -2-fluoro-6- (5-methylthien-2-yl) -benzamide;
N-benzyl-N- (indan-2-yl) -2-methyl-6- (5-methylthien-2-yl) benzamide;
N-benzyl-N- (indan-2-yl) -4-methyl-1,1′-biphenyl-2-carboxamide;
N-benzyl-4-chloro-N- (indan-2-yl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (indan-2-yl) -5-methyl-2-thien-3-ylbenzamide;
N-benzyl-5-chloro-N- (indan-2-yl) -2-thien-3-ylbenzamide;
N- (indan-2-yl) -3-methyl-N- (2-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -3-methyl-N- (3-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -3-methyl-N- (4-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (2-fluorobenzyl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (3-fluorobenzyl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-fluorobenzyl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (3,4-difluorobenzyl) -N- (indan-2-yl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (3-methoxybenzyl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -N- (4-methoxybenzyl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (indan-2-yl) -3-methyl-1,1′-biphenyl-2-carboxamide;
N- (indan-2-yl) -3-methyl-N- (2-phenylethyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (2-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (3-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (4-methylbenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (2-fluorobenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (3-fluorobenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (4-fluorobenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (3,4-difluorobenzyl) -N- (indan-2-yl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (4-methoxybenzyl) -1,1′-biphenyl-2-carboxamide;
N- (1,3-benzodioxol-5-ylmethyl) -4-chloro-N- (indan-2-yl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (3-methoxybenzyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (indan-2-yl) -N- (2-phenylethyl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-4-chloro-N- (4-hydroxy-3,5-dimethylbenzyl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-N-{(1S, 2S) -2- [4- (2-methoxyphenyl) piperazin-1-yl] cyclohexyl} -1,1'-biphenyl-2-carboxamide;
N-benzyl-4-chloro-N- (2,3-dihydro-1-benzofuran-6-ylmethyl) -1,1′-biphenyl-2-carboxamide;
4-chloro-N- (3-methoxybenzyl) -N- (2-phenylethyl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-4-chloro-N- (1-naphthylmethyl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-N- (4-hydroxy-3,5-dimethylbenzyl) -2- (5-methylthien-2-yl) benzamide;
N-benzyl-N- [4- (difluoromethoxy) benzyl] -2- (5-methylthien-2-yl) benzamide;
N-benzyl-N- (2-chloro-4-hydroxybenzyl) -2- (5-methylthien-2-yl) benzamide;
N-benzyl-N- (4-hydroxy-3,5-dimethylbenzyl) -1,1′-biphenyl-2-carboxamide;
N-benzyl-N- [4- (difluoromethoxy) benzyl] -1,1′-biphenyl-2-carboxamide;
N-benzyl-2- (5-methylthien-2-yl) -N- [3- (trifluoromethyl) benzyl] benzamide;
2. The compound or salt according to claim 1, which is or a pharmaceutically acceptable salt thereof. N-benzyl-N- (2-methyl-benzyl) -2-pyrrol-1-yl-benzamide;
N-indan-2-yl-N- (3-methyl-benzyl) -2-pyrrol-1-yl-benzamide;
N-benzyl-N- (2-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-methoxybenzyl) -N- (2-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,2-diphenylethyl) -N- (2-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-difluorobenzyl) -N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-difluorobenzyl) -N- (2,2-diphenylethyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,6-dichlorobenzyl) -N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N-benzyl-N- (1,1′-biphenyl-2-ylmethyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,1′-biphenyl-2-ylmethyl) -N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,1′-biphenyl-2-ylmethyl) -N- (2-phenylbutyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,1′-biphenyl-2-ylmethyl) -N- (2,2-diphenylethyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,1′-biphenyl-2-ylmethyl) -N- (cyclohexylmethyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-dimethoxybenzyl) -N- (4-fluorobenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-methoxybenzyl) -N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (3-methoxybenzyl) -N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-methoxybenzyl) -N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethoxy) benzyl] benzamide;
N- (2,4-dimethoxybenzyl) -N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (3,5-dimethoxybenzyl) -N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-chlorobenzyl) -N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-chlorobenzyl) -N- (3-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-chlorobenzyl) -N- (4-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (4-chlorobenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-chlorobenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethoxy) benzyl] benzamide;
N- (4-chlorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethyl) benzyl] benzamide;
N- (4-methoxybenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethyl) benzyl] benzamide;
N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethyl) benzyl] benzamide;
N- (3,5-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethyl) benzyl] benzamide;
N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) -N- [2,4- (difluoro) benzyl] benzamide;
N- (2,4-difluorobenzyl) -N- (4-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-difluorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-dichlorobenzyl) -N- (2-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-dichlorobenzyl) -N- (3-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-dichlorobenzyl) -N- (4-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (2,4-dichlorobenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-dichlorobenzyl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethoxy) benzyl] benzamide;
N- (2,4-dichlorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,4-dichlorobenzyl) -N- (3,5-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-chloro-4-fluorobenzyl) -N- (3-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-chloro-4-fluorobenzyl) -N- (4-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (1,3-benzodioxol-5-ylmethyl) -N- (2-chloro-4-fluorobenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-chloro-4-fluorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2-chloro-4-fluorobenzyl) -N- (3,5-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,3-difluorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (3-chloro-2-fluorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (3-chloro-2-fluorobenzyl) -N- (3,5-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N-[(5-chlorothien-2-yl) methyl] -N- (4-methoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N-[(5-chlorothien-2-yl) methyl] -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N-[(5-chlorothien-2-yl) methyl] -N- (3,5-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,5-difluorobenzyl) -N- (2,4-dimethoxybenzyl) -2- (1H-pyrrol) -1-yl) benzamide;
N- (2,4-difluorobenzyl) -N- [2- (2-fluorophenyl) ethyl] -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-2-yl) -N- (3-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-2-yl) -N- (4-methylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-1-yl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethyl) benzyl] benzamide;
N- (2,3-dihydro-1H-inden-1-yl) -N- (4-methylbenzyl) -2- (1H-pyrrol) -1-yl) benzamide;
N-indan-2-yl-N- (4-methyl-benzyl) -2-pyrrol-1-yl-benzamide;
N- (4-chlorobenzyl) -N- (2,3-dihydro-1H-inden-1-yl) -2- (1H-pyrrol-1-yl) benzamide;
N- (4-chlorobenzyl) -N- (indan-2-yl) -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-2-yl) -2- (1H-pyrrol-1-yl) -N- [4- (trifluoromethyl) benzyl] benzamide;
N- (2,3-dihydro-1H-inden-1-yl) -N- (3,5-dimethylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-2-yl) -N- (3,5-dimethylbenzyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-2-yl) -N- (1-naphthylmethyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (2,3-dihydro-1H-inden-1-yl) -N- (2-naphthylmethyl) -2- (1H-pyrrol-1-yl) benzamide;
N- (indan-2-yl) -N- (2-naphthylmethyl) -2- (1H-pyrrol-1-yl) benzamide;
2. The compound or salt according to claim 1, which is or a pharmaceutically acceptable salt thereof. 2-methoxy-naphthalene-1-carboxylic acid benzyl-indan-2-yl-amide;
N-benzyl-N- (4-hydroxy-3,5-dimethylbenzyl) -2-methoxy-1-naphthamide;
2-methoxy-naphthalene-1-carboxylic acid (2-fluoro-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (3,4-difluoro-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid indan-2-yl-phenethyl-amide;
2-methoxy-naphthalene-1-carboxylic acid (3-methoxy-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (4-methoxy-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (4-methyl-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (2-methyl-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (4-fluoro-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (3-fluoro-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (3-methoxy-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid benzo [1,3] dioxol-5-ylmethyl-indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid (2-methyl-benzyl) -indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid (3-methyl-benzyl) -indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid (4-methyl-benzyl) -indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid (2-fluoro-benzyl) -indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid (3-fluoro-benzyl) -indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid (4-fluoro-benzyl) -indan-2-yl-amide;
2-methyl-naphthalene-1-carboxylic acid indan-2-yl-phenethyl-amide;
Naphthalene-1-carboxylic acid benzyl- (2-chloro-4-hydroxy-benzyl) -amide;
2-hydroxy-naphthalene-1-carboxylic acid (2-fluoro-benzyl) -indan-2-yl-amide;
2-hydroxy-naphthalene-1-carboxylic acid (4-methyl-benzyl) -indan-2-yl-amide;
2-phenyl-naphthalene-1-carboxylic acid (2-fluoro-benzyl) -indan-2-yl-amide;
2-phenyl-naphthalene-1-carboxylic acid (4-methyl-benzyl) -indan-2-yl-amide;
2- (5-methyl-thiophen-2-yl) -naphthalene-1-carboxylic acid (2-fluoro-benzyl) -indan-2-yl-amide;
2-methoxy-naphthalene-1-carboxylic acid (4-carbamoyl-3-hydroxy-benzyl) -indan-2-yl-amide;
4-{[Indan-2-yl- (2-methoxy-naphthalene-1-carbonyl) -amino] methyl} -benzoic acid;
48. The compound of claim 46, which is or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising at least one compound or salt according to claim 1 or a prodrug or hydrate thereof in combination with a physiologically acceptable carrier or excipient. Compounds standard in vitro C5a receptor - exhibits the following IC ₅₀ 500 nM in mediating chemotaxis or calcium mobilization assay, a compound or salt according to claim 1, wherein. Compounds standard in vitro C5a receptor - in mediating chemotaxis or calcium mobilization assay exhibits the following IC ₅₀ 100 nM, the compound or salt according to claim 1, wherein. Compounds standard in vitro C5a receptor - exhibits the following IC ₅₀ 25 nM in mediating chemotaxis or calcium mobilization assay, a compound or salt according to claim 1, wherein. Compounds standard in vitro C5a receptor - exhibits 10nM IC ₅₀ of less than or equal in mediating chemotaxis or calcium mobilization assay, a compound or salt according to claim 1, wherein. Compounds standard in vitro C5a receptor - in mediating chemotaxis or calcium mobilization assay exhibits the following IC ₅₀ 5 nM, the compound or salt according to claim 1, wherein.   2. The compound or salt of claim 1, wherein the compound exhibits less than 5% agonist activity in a GTP binding assay.   Inhibiting signal-transduction activity of cellular C5a receptor comprising contacting a cell expressing C5a receptor with at least one compound or salt of claim 1 thereby reducing signal transduction by C5a receptor how to.   90. The method of claim 88, wherein the cell is contacted in vivo in the animal.   90. The method of claim 89, wherein the animal is a human.   Contacting the C5a receptor with at least one compound or salt of claim 1 under conditions that detectably inhibit C5a binding to the C5a receptor and in an amount sufficient to inhibit such. A method of inhibiting binding of C5a to a C5a receptor in vitro.   The C5a receptor-expressing cell is contacted with at least one compound or salt of claim 1 in an amount sufficient to detectably inhibit C5a binding to a cell expressing the cloned C5a receptor in vitro. And thereby inhibiting the binding of C5a to the C5a receptor in a patient, comprising inhibiting the binding of C5a to the C5a receptor in a human patient.   A method of treating a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma, comprising administering to the patient a C5a receptor modulating amount of the compound of claim 1.   A patient suffering from stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury comprising administering to the patient a C5a receptor modulating amount of the compound of claim 1 How to treat.   A method of inhibiting C5a receptor-mediated cytochemistry, comprising contacting mammalian white blood cells with a C5a receptor modulating amount of a compound or salt according to claim 1. Contacting the tissue sample containing the C5a receptor with a detectably labeled compound under conditions that allow the compound to bind to the C5a receptor;
A method of localizing a C5a receptor in a tissue sample, comprising detecting bound compounds. (a) the pharmaceutical composition of claim 81 in a container; and
(b) A packaged pharmaceutical formulation comprising instructions for using the composition to treat a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma. (a) the pharmaceutical composition of claim 81 in a container; and
(b) A packaged pharmaceutical formulation comprising instructions using the composition to treat stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury.   82. The pharmaceutical composition of claim 81, wherein the pharmaceutical composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup, or transdermal patch.