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Definitions

• CRTH2 is a G protein-coupled ⁇ emoattractant receptor expressed on Th2 cells (Nagata et al, J. Immunol, 1999, 162, 1278-1286), eosinophils, and basophils (Hirai et al, J. Exp. Med., 2001, 193, 255-261).
• Prostaglandin D2 (PGD2) is a natural ligand for CRTH2, and is the major inflammatory mediator produced from mast cells. It has been shown that activation of CRTH2 by PGD2 induces migration and activation of Th2 cells (Hirai et al, J. Exp. Med.
• compounds which are modulators, preferably inhibitors, of the interaction between CRT ⁇ 2 and PGD2 should be useful for the treatment of diseases and disorders that are mediated by CRTH2, PGD2, Th2 cells, eosinophils, and/or basophils.
• diseases include but are not limited to allergic disorders, asthmatic disorders, and inflammatory disorders such as allergic rhinitis, allergic asthma, bronchoconstriction, atopic dermatitis and systemic inflammatory disorders.
• Ring A is an optionally substituted monocyclic aromatic ring
• R is -Xi-R 1 , wherein: Xi is a bond, S(O), S(0) 2 , C(O) or C(0)NH, provided that when X, is a bond, SO or S0 2 , then R 1 is not H; and R 1 is H or an optionally substituted, cycloaliphatic group, aromatic group or non- aromatic heterocyclic group
• X is -C(O)- or -C(R 2 ) 2 -, wherein: each R 2 is independently -H, -X 4 -R 8 or an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or a n ⁇ n-aromatic heterocyclic group
• R x is -X 2 -R 4 , wherein: X 2 is a bond, S(O), S(0) 2 , C(O) or C(0)NH; and R 4 is -H
• the present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Ring A is an optionally substituted monocyclic aromatic ring;
• R is -X 2 -R , and R is an optionally substituted aromatic group; or -NR X R , taken together, is an optionally substituted non-aromatic nitrogen containing heterocyclic group;
• X is -C(0)- or -C(R 2 ) 2 -;
• Xi and X 2 are each independently a bond, S(O), S(0) 2 , C(O) or C(0)NH;
• R 1 is H or an optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group; provided that when Xi is a bond, SO or S0 2 , then R 1 is not H;
• each R 2 is independently H, -X4-R 8 or an optionally substituted, aliphatic group, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
• R 4 is H, -X ⁇ -R 10 or an optionally substituted, aliphatic group, cycloaliphatic group,
• compounds of formula I include compounds other than: 2-Methyl- N-phenyl-N- [1 ,2,3,4-tetrahydro-2-methyl- 1 -(2-methyl- 1 -oxobutyl)-4-quinolinyl]-butamide; N-(l - Acetyl-l,2,3,4-tetrahydro-2-methyl-4-quinolinyl)-N-phenyl-heptamide; N-phenyl-N-[l,2,3,4- tetrahydro-2-methyl-l-(l-oxo-3-phenylpropyl)-4-quinolinyl]- benzenepropanamide; N-phenyl-N- [l,2,3,4-tetrahydro-2-methyl-l-(3-nitrobenzoyl)-4-quinolinyl]- hexanamide; N-[l,l'-biphenyl]-3-yl- N-[l,2,2,3,4-tetra
• X is -CHR 2 -, R 2 is -H, methyl or ethyl; R 3 is a substituted or unsubstituted aromatic group; R 5 and R 6 are -H; and the remainder of the variables in Structural Formula (I) are as defined above. More preferably, the compound is represented by a structural formula selected from Structural Formulas (II)-(VIII):
• Phenyl Ring A is a substituted or unsubstituted phenyl group. Unless otherwise indicated suitable substituents for Phenyl Ring A are provided in the section below describing suitable aryl ring substituents.
• R ! in Structural Formulas (II)-(IV) and (VI)-(VIII) is -H, optionally substituted, cycloaliphatic group, aromatic group or non-aromatic heterocyclic group, provided that R 1 in Structural Formulas (IH) is not -H.
• R 2 in Structural Formulas (II)-(VIII) is -H, methyl or ethyl.
• R 3 in Structural Formulas (II)-(VIII) is an optionally substituted phenyl group.
• R 4 in Structural Formulas (II)-(VI) and (Vffl) is -H, -CH 2 C(0)R 14 , -CH 2 R 15 , -CH 2 OR 14 or an optionally substituted -C 3 alkyl group or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group, provided that R 4 in Structural Formula (VI) is not -H; and R 4 in Structural Formulas (VII) is -(CH 2 ) n -R 13a .
• R 13a is -H, -CH 2 C(0)R 14 , -CH 2 R 15 , -CH 2 OR 14 or an optionally substituted C C 3 alkyl group or an optionally substituted cycloalkyl group, aromatic group or non-aromatic heterocyclic group.
• Each R 14 is independently an -H or an optionally substituted alkyl group, aromatic group, cycloalkyl group or non-aromatic heterocyclic group.
• Each R 15 is independently an optionally aromatic group, cycloalkyl group or non-aromatic heterocyclic group.
• n 0, 1, 2 or 3.
• R 1 , R 4 and R 13a in Structural Formulas (II)-(VIII) are R 1 and
• R 13a are an optionally substituted, phenyl, pyridyl, furanyl, thiophenyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, benzofuranyl, tetrazolyl, thiazolyl, benzyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, benzomorpholinyl, benzopyrazolyl, indolyl, -CH 2 -(-V-pyridyl), -CH 2 -furanyl,
• R 4 is -C alkyl, -CH 2 OH, -CH 2 OCH 3 ,
• Ring A is optionally substituted at the five, six, seven and/or the eight position.
• the compounds in Structural Formulas (II)-(VIII) have one of the following features and preferably all of the following features: Phenyl Ring A is optionally substituted at the five, six, seven and/or eight position with R n , wherein R 11 is selected from substituents provided in the section below describing suitable aryl ring substituents unless otherwise indicated herein.
• R 1 is phenyl, thiophenyl, furanyl, pyridyl, oxazolyl, benzotriazole, pyrimidinyl, isoxazolyl or benzomorpholinyl, each group being optionally substituted with R n ;
• R 3 is [R ⁇ ]-phenyl; and
• R 4 is methyl, ethyl, propyl, ir ⁇ -propyl, w-butyl, sec-butyl, fert-butyl, -CH 2 OCH 3 or
• R 3 is phenyl substituted with one to four atoms or groups selected from the group consisting of Br, CI, -CH 3 , -N(R 16 ) 2 , -NHC(0)OR", -S(0) 2 CH 3 , -S(0) 2 N(R 16 ) 2 and -R 13 C(0)N(R 16 ) 2 , where R 16 is C C 6 alkyl.
• Ring A in Structural Formulas (I) is a monocyclic heteroaryl group such as thiophene, furan, pyridine, pyrazole, pyrrole, [2,3]pyrimidine, [3,4]pyrimidine, [4,5]pyrimidine, [5,6]pyrimidine, oxazole, isoxazole or 1,2,3-triazole, each group being optionally substituted with R n .
• the compound preferably has at least one and preferably all of the following features: X is -CHR 2 -, R 2 are -H, methyl or ethyl; R 5 and R 6 are -H; and R 3 is a substituted or unsubstituted phenyl group.
• R 1 and R 4 are independently -H, -CH 2 C(0)R 14 , -CH 2 R 15 or -CH 2 OR 14 or an optionally substituted alkyl group, cycloalkyl group, aromatic group or non-aromatic heterocyclic group; and R 14 and R 15 are as described above for Structural Formula (II).
• Ring A in Structural Formula (I) is a monocyclic heteroaryl, as described in the preceding paragraph, commonly selected values for Xi and X 2 are as follows: Xj and X 2 are both C(O); Xi is S(0) 2 and X 2 is C(O); Xi is C(0)NH and X 2 is C(O); Xj is a bond and X 2 is C(O); and X 2 is C(O); Xi is C(O) and X 2 is S(0) 2 ; Xi is C(O) and; Xi is C(O) and X 2 is a bond; or X, is C(O) and X 2 is C(0)NH.
• Phenyl Ring A in Structural Formulas (II)-(VIII) is replaced with one of the monocyclic aromatic groups described in the preceding paragraph and the remainder of the variables are as described above.
• a compound represented by Structural Formula (II) and methods of use thereof for inhibiting CRTH2 in a subject in need of treatment therefore and pharmaceutical compositions comprising the same wherein R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (II).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (II).
• R 3 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 4 are as described above for Structural Formula (II).
• R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (II).
• R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (III).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (III).
• R 3 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 4 are as described above for Structural Formula (IV).
• a compound represented by Structural Formula (TV) and methods of use thereof for inhibiting CRTH2 wherein R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (IV).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (IV).
• R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (V).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (V).
• R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (VI).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (VI).
• R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (VII).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (VII).
• R 4 has the value corresponding to any one of the compounds in Table 1 - 6 and R 1 and R 3 are as described above for Structural Formula (VIII).
• VTII Structural Formula
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (VIII).
• R 1 has the value corresponding to any one of the compounds in Table 1 - 6 and R 3 and R 4 are as described above for Structural Formula (VIII).
• Specific examples of compounds of general formula I are shown in the Exemplification Section herein.
• CRTH2 inhibitors contain one or more chiral centers.
• the presence of chiral centers in a molecule gives rise to stereoisomers.
• enantiomers exist for every chiral center in a molecule; and a pair of diastereomers exist for every chiral center in a compound having two or more chiral centers.
• Structural Formulas (I)-(VIII) do not explicitly depict stereochemistry, it is to be understood that these formulas encompass enantiomers free from the corresponding optical isomer, racemic mixtures, mixtures enriched in one enantiomer relative to its corresponding optical isomer, a diastereomer free of other diastereomers, a pair of diastereomers free from other diasteromeric pairs, mixtures of diasteromers, mixtures of diasteromeric pairs, mixtures of diasteromers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diasteromeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).
• a preferred diastereomeric pair is when R 2 and NR X R 3 in Structural Formulas (I)-(VIII) are cis relative to one another.
• the cis diastereomeric pair for the compound represented by Structural Formula (II) is shown below in Structural Formulas (TX) and (X): (IX) (X).
• Structural Formula (X) represents a more preferred optical isomer for the compound represented by Structural Formulas (I) and (III)-(VIII) and in Tables 1- 6.
• a structure depicting one optical isomer or a reference to one optical isomer is meant to include enantiomeric mixtures which are enriched with the depicted or referenced enantiomer relative to its optical isomer, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.
• a structure depicting a diastereomeric pair or a reference to one diasteromeric pair is meant to include mixtures which are enriched with the depicted or referenced diastereomeric pair relative to other diastereomers or diastereomeric pair(s) for the compound, for example, a molar excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.
• the enantiomers of the present invention may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
• enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
• the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Specific procedures for chromatographically separating diastereomeric pairs of precursors used in the preparation of compounds disclosed herein are provided in Scheme 1 and 2.
• compounds of the present invention may be associated in isolated form with solvent or water, as in a "solvate” or "hydrate”.
• references to the disclosed compounds or structural formulas depicting the disclosed compounds are meant to include such solvates and hydrates.
• aliphatic as used herein means straight-chain or branched hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.
• An aliphatic group is typically C ⁇ - 8 , more typically Cj-s.
• suitable aliphatic groups include substituted or unsubstituted linear or branched alkyl, alkenyl, alkynyl groups and hybrids thereof.
• alkyl alkoxy
• hydroxyalkyl “alkoxyalkylene"
• alkoxycarbonyl used alone or as part of a larger moiety includes both straight and branched saturated chains containing one to eight carbon atoms.
• alkenyl and alkynyl used alone or as part of a larger moiety shall include both straight and branched chains containing two to eight carbon atoms and one or more double and/or triple bonds, respectively.
• cycloaliphatic used alone or as part of a larger moiety shall include cyclic C 3 -
• Cio hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic. Cycloaliphatic groups are typically C 3 . ⁇ 0 , more typically C 3 _ 7 .
• cycloalkyl is an cyclic aliphatic group that is completely saturated.
• Alkoxy means (alkyl)-O-;
• alkoxyalkylene means (alkyl)-O-(alkylene) such as methoxymethylene (CH 3 OCH 2 );
• hydroxyalkyl means hydroxy substituted alkyl group;
• alkoxy carbonyl means a carbonyl substituted with a carbonyl as in (alkyl)-O-C(O)-; and
• aralkyl mean alkyl substituted with an aromatic group.
• a "C ⁇ -C aralkyl group for example, has a C C alkyl group substituted with an aromatic group.
• heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
• nitrogen includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be
• N (as in 3,4-dihydro-2 -pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
• aromatic group used alone or as part of a larger moiety as in “aralkyl”,
• aralkoxy or “aryloxyalkyl” includes to carbocyclic aromatic ring groups and heteroaryl rings groups.
• aromatic group may be used interchangeably with the terms “aryl”, “aryl ring” or
• Carbocyclic aromatic ring groups have only carbon ring atoms and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include 1 -naphthyl, 2-naphthyl, 1- anthracyl and 2-anthracyl.
• Carbocyclic aromatic ring is a group in which an aromatic ring is fused to one or more non-aromatic rings (aliphatic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
• non-aromatic rings aliphatic or heterocyclic
• heteroaryl or “heteroaromatic”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ring groups having five to fourteen members, including monocyclic heteraromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other carbocyclic or heteroaromatic aromatic rings .
• heteroaryl rings examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrazolyl, 2- ⁇ yridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5- triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, be
• heteroaryl is a group in which a heteroaryl ring is fused to one or more cycloaliphatic or non-aromatic heterocyclic groups where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3, 4-d] pyrimidinyl.
• heteroaryl may be interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
• non-aromatic heterocyclic ring used alone or as part of a larger moiety as in “hetercyclylalkyl”, refers to non-aromatic ring systems typically having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S.
• non-aromatic heterocyclic rings examples include 3-1H- benzimidazol-2-one, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, [l,3]-dioxalanyl, [l,3]-dithiolanyl, [l,3]-dioxanyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3- thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrorolidinyl, 1-piperazinyl, 2- piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolony
• a “hydrocarbyl group” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer.
• n is an integer from 1 to 6, more preferably from 2 to 4 and more preferably from 2 to 3.
• a “substituted hydrocarbyl” is a hydrocarbyl group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents are as described below for a substituted aliphatic group.
• a hydrocarbyl group can be optionally interrupted by one or more functional groups.
• a hydrocarbyl is interrupted by a functional group when one of the internal methylenes is replaced with the functional group.
• suitable "interrupting functional groups” include -O-, -S-, -N(R )-, -S(O)-, -S0 2 -, -C(O)-, -OC(O)-, -N(R a )C(0)-, -C(0)N(R a )-, -S0 2 N(R a )-, and -N(R a )S0 2 -.
• R a is -H or a C 1 -C 3 alkyl group.
• An aromatic group (including Ring A, carbocyclic aromatic, heteroaryl, aralkyl, aralkoxy, aryloxyalkyl and heteroaralkyl and the like) group may contain one or more substituents.
• suitable substituents on an unsaturated carbon atom of an aromatic group include a halogen -R°, - OR°, -SR°, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O(Ph), substituted -O(Ph), -CH 2 (Ph), substituted -CH 2 (Ph), -CH 2 CH 2 (Ph), substituted -CH 2 CH 2 (Ph), -N0 2 , -CN, -N(R') 2 , -NR'C0 2 R°, -NR'C(0)R°, -NR'NR'C(0)R°, -N(R')C(0)
• R' is R°, -C0 2 R°, -S0 2 R° or -C(0)R° and preferably hydrogen, C M aliphatic, C0 2 R°, S0 2 R° or C(0)R°.
• R° is hydrogen or substituted or unsubstituted aliphatic, cycloaliphatic, arpmatic, aralkyl or non-aromatic heterocyclic group, and preferably hydrogen, _6 alkyl, phenyl (Ph), -CH 2 (Ph), aralkyl, non-aromatic heterocyclic group or heteroaryl; y is 0-6; and V is C C 6 alkylene group.
• substituents on the aliphatic group or the phenyl ring of R° include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, aminoalkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
• An aliphatic group or a non-aromatic heterocycle may contain one or more substituents.
• Each R* is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group.
• substituents on the aliphatic group represented by R * include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,. dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
• substituents on the aliphatic group or the phenyl ring represented by R + include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
• Another embodiment of the present invention is a compound represented by Structural
• Ring A is an optionally substituted monocyclic aromatic
• R x is -X 2 -R 4 ; X, and X 2 are each independently -S(0) 2 -, -C(0)-, or -C(0)NH-; R s: A) an aromatic group or heteroaromatic group having 5-6 ring atoms, fused to a monocyclic non-aromatic heterocyclic ring or monocyclic aromatic or heteroaromatic ring wherein the non-aromatic heterocyclic ring, the aromatic ring, or the heteroaromatic ring are optionally substituted; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted by: i) T'-V-T-R*; ii) T'-V-T-M-R ; or iii) V-R 9 , wherein R 9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and wherein the aromatic or heteroaromatic group having 5-6 ring atoms optionally is further substituted by 1-2 independently selected
• each R z is independently selected from halogen, haloalkyl, R°, -OR 0 , -O(haloalkyl), -SR°, -N0 2 , -CN, -N(R') 2 , -NR'C0 2 R°, -NR'C(0)R°, -NR'NR'C(0)R°, -N(R')C(0)N(R') 2 , -NR'NR'C(0)N(R') 2 , -NR'NR'C0 2 R°, -C(0)C(0)R°, -C(0)CH 2 C(0)R°, -C0 2 R°, -C(0)R°, -C(0)N(R°) 2 , -OC(0)R°, -OC(0)N(R°) 2 , -S(0) 2 R°, -S0 2 N(R')2, -S(0)R°, -NR'S0 2 N(R') 2 , -NR
• R + is -H, a C C 3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -N0 2 , amine, alkylamine or dialkylamine; or -N(R + ) 2 is a
• R 3 is an optionally substituted monocyclic or bicyclic group selected from aromatic, heteroaromatic, non-aromatic carbocyclic, or non-aromatic heterocyclic; and R 4 is optionally substituted - ⁇ alkyl, ⁇ hydroxyalkyl, or optionally substituted C 3 - 6 cycloalkyl.
• Ring A is an optionally substituted monocyclic aromatic
• R x is -X 2 -R 4
• Xi and X 2 are each independently -S(0) 2 -, -C(O)-, or -C(0)NH-
• R 1 is: A) an aromatic group or heteroaromatic group having 5-6 ring atoms, substituted by: i) T'-V-T-R ⁇ ; ii) T T-M-R ; or iii) V-R 9 wherein R 9 is an optionally substituted non-aromatic carbocyclic or heterocyclic group; and wherein the aromatic or heteroaromatic group represented by R 1 optionally is further substituted by 1-2 independently selected groups represented by R z ; or B) an aromatic group or heteroaromatic group having 5-6 ring atoms, fused to a monocyclic non-aromatic heterocyclic ring or
• T 1 is a covalent bond, or a C 14 o straight chain alkylene, wherein T and T 1 together contain no more than 10 carbon atoms, and wherein T and T 1 are optionally and independently substituted at any one or more substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy, spiro cycloalkyl, optionally N-substituted nitrogen containing spiro non-aromatic heterocyclic group, amine, alkylamine, dialkylamine, or hydroxyl; each R 5 is independently -H, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, -C(0)OCH 2 C 6 H 5 , S(0) 2 CH 3 ,
• compounds of the invention are compounds other than one of the following compounds:
• R 1 is phenyl para substituted with V-T-R ⁇
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• Xi is -C(O) and V is -O-
• T-R ⁇ is -CH 2 -CH 2 -C(CH 3 ) 2 -CONH 2 , -CH 2 -CH 2 -C(CH 3 ) 2 - OH, -CH 2 -CH 2 -CH 2 -C(CH 3 ) 2 -OH, -CH 2 -CH 2 -C(CH 3 ) 2 -COOH, -CH 2 -C (spiro cyclopropyl)-CH 2 - COOH, or -CH 2 -C(CH 3 ) 2 -COOH.
• R 1 is phenyl para substituted with V-T-R ⁇
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• Xi is -C(O)
• V is a covalent bond
• T-R ⁇ is -CH 2 -CH 2 -COOH.
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• X is C(O)
• R 1 is phenyl para substituted with V-R 9 wherein R 9 is an optionally substituted non-aromatic heterocyclic group, V is a covalent bond
• R 1 is iV-morpholinyl, -V-ethoxycarbonyl-4-pi ⁇ erdinyl, -V-acetyl-4-piperdinyl, N- ethoxycarbonyl-4-piperid-3-enyl, -V-pyrrolidinyl, JV-ethyl-iV'-piperazinyl, -V-acetyl-iV'-piperazinyl, N- (2'-hydroxyacetyl)-iV'-piperazinyl, / -(CH 2 C(0)OH-yV'-piperazinyl, or -V-(CH 2 C(0)NH 2 )-
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• Xi is C(O)
• R 1 is phenyl para substituted with V-R 9 wherein R 9 is an optionally substituted non-aromatic heterocyclic group, V is -0-, R 1 is -V-ethoxycarbonyl-4-piperdinyl or -V-acetyl-4-piperdinyl.
• R 2 is methyl
• R 3 is phenyl
• R x is C(0)CH 2 CH 3
• Xj is C(O)
• R 1 is phenyl para substituted with a non-aromatic heterocyclic group
• R 1 is -V-acetyl-4-piperdinyl, or -V-morpholinyl.
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• X x is C(0) and R 1 is phenyl fused to an optionally substituted non-aromatic heterocyclic group
• R 1 tetrahydrofuranyl or N'- methyl morpholinyl.
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• X is C(O)
• R 1 is pyridinyl para substituted with a non aromatic heterocyclic group
• R 1 is tV-morpholinyl.
• R 1 is C(O) and R 1 is phenyl fused to an optionally substituted aromatic group, R 1 is ⁇ sopropyl triazolyl, -V-methyl triazolyl, IV- isopropyl imidazolyl, 2, methyl N hydroxyethyl imidazolyl, 2, methyl N carboxymethyl imidazolyl, N carboxyethyl triazolyl JV-isopropyl pyrazolyl.
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• X is C(O)
• R 1 is imidazolyl fused to an optionally substituted aromatic group
• R 1 is phenyl
• R 2 is methyl
• R 3 is para chlorophenyl
• R x is C(0)CH 3
• X t is C(O)
• R 1 is thiazolyl fused to an optionally substituted aromatic group
• R 1 is phenyl.
• compounds of the invention are compounds other than compounds disclosed in our U.S. Patent Application 10/678,872 filed October 4, 2003 (the entire contents of which are inco ⁇ orated herein by reference).
• compounds of the invention are compounds other than: ( ⁇ )-Cw-N-[l-(lH-indole-2-carbonyl)-2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl- propionamide; ( ⁇ )-Ct5-N-[l-(benzofuran-2-carbonyl)-2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl]-N- phenyl-propionamide; ( ⁇ )-C ⁇ - ⁇ 4-[2-methyl-4-(phenyl-propionyl-amino)-3,4-dihydro-2H-quinoline- l-carbonyl]-phenoxy ⁇ -acetic acid ethyl ester; ( ⁇ )-Cw ⁇ 4-[2-Methyl-4-(phenyl-propionyl-amino)-3,4- dihydro-2H-quinoline-l-carbonyl
• the present invention is a compound represented by Structural Formulas (II-A), (III-A) or (IV-A).
• Ar in Structural Formula (HI-A) is a monocyclic aromatic ring.
• Cy in Structural Formula (IV) is a monocyclic non-aromatic carbocyclic or heterocyclic group. All other variables in Structural Formulas (II-A)-(IV-A) are as described for Structural Formula (I-A).
• V in Structural Formulas (II-A)-(IV-A) is a covalent bond, -0-, or -N(R , and T in Structural Formulas (II-A)-(IV- A) is a C ⁇ - 6 straight chain alkylene optionally substituted at any one or more substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N- substituted nitrogen containing spiro non-aromatic heterocyclic group, amine, alkylamine, dialkylamine, or hydroxyl.
• V is a covalent bond, -NR'- or -0-; and T is a C ⁇ - 10 straight chain alkylene (preferably C ⁇ - 5 , more preferably C 1 - 3 ) optionally mono- substituted at any substitutable carbon atom with halide, alkyl, haloalkyl, amine, dialkylamine, or hydroxyl.
• R ⁇ in Structural Formula (I-A) and (II-A) is -C(0)OR 5 , -C(0)N(R 5 ) 2 , -NR 5 C(0)R 5 , -NR 5 C(0)0R 5 , -S(0) 2 N(R 5 ) 2 , -NR 5 S(0) 2 R 5 , -OR 5 , -CN, -NR 5 C(0)N(R 5 ) 2 , -N(R 5 ) 2 , an optionally substituted non-aromatic heterocyclic group represented by R 7 , or an optionally substituted heteroaryl group represented by R 8 .
• R 7 is an optionally substituted piperidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahyrothiophene, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, or piperidinyl.
• R 8 is an optionally substituted furanyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, thienyl, or imidazolyl, and all the remainder of the variables are as described in the previous paragraph.
• R ⁇ in Structural Formula (I-A) and (II-A) is -C(0)OR 5 , -C(0)N(R 5 ) 2 , - NR 5 C(0)R 5 , -NR s C(0)OR 5 , -S(0) 2 N(R 5 ) 2 , -NR 5 S(0) 2 R 5 , -NR 5 C(0)N(R 5 ) 2 , -OH, an optionally substituted non-aromatic heterocyclic group represented by R 7 or an optionally substituted heteroaryl group represented by R 8 .
• R 7 is piperidinonyl, mo ⁇ holinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, or piperidinyl.
• R 8 is tetrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, or imidazolyl.
• R 5 is independently H or alkyl, or N(R 5 ) 2 is a nitrogen-containing non- aromatic heterocyclic group.
• V is a covalent bond, or -0-; and T is a C 1 - 5 straight chain alkylene optionally substituted at the carbon atom adjacent to R ⁇ with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N-substituted nitrogen containing spiro non-aromatic heterocyclic group, amine, dialkylamine, or hydroxyl.
• R 1 in Structural Formula (I-A)-(III-A) is a phenyl ring optionally substituted by at the meta and para positions (more preferably para) by V-T-R ⁇ or V-T-M-R ⁇ .
• R ⁇ is -C(0)OR 5 , -C(0)N(R 5 ) 2 , -OH, N-mo ⁇ holinyl, 2-mo ⁇ holinyl, 3-mo ⁇ holinyl, N-substituted 2-mo ⁇ holinyl, N-substituted 3-mo ⁇ holinyl, N-imidazolidinyl, 2-imidazolidinyl, 4- imidazolidinyl, 5-imidazolidinyl, -V-substituted 2-imidazolidinyl, N '-substituted N-irnidazolidinyl, N- substituted 4-imidazolidinyl, -V-substituted 5-imidazolidinyl, N-imidazolidinonyl, 4-imidazolidinonyl, 5-imidazolidinonyl, iV-substituted 4-imidazolidinonyl, N-substi
• V is -0-
• T is a C ⁇ - 3 straight chain alkylene substituted at the carbon adjacent to R ⁇ with fluoro, methyl, gem dimethyl, gem difluoro fluoromethyl, spiro cyclopropyl, spiro cyclobutyl, optionally N- substituted spiro azetidinyl, optionally N-substituted spiro aziridinyl, optionally N-substituted sprio pyrrolidinyl, optionally N-substituted spiro piperidinyl, amine, methylamine, dimethylamine, or hydroxyl.
• R ⁇ is -C(0)OR 5 , -C(0)N(R 5 ) 2 , -OH, N-tetrazolyl, 5-tetrazolyl, iV- substituted 5-tetrazolyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; N-substituted 2- imidazolyl, N-substituted 4-imidazolyl, or N-substituted 5-imidazolyl.
• R 5 is -H, methyl, or ethyl.
• R 1 in Structural Formula (I-A)-(HI-A) is a phenyl ring optionally substituted by at the para position by V-T-R Y or V-T-M-R Y .
• the present invention is a compound represented by Structural Formula (V-A):
• R 9 in Structural Formula (V-A) is an optionally substituted cyclohexanyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothienyl, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, isothiazolidinyl S,S, dioxide, piperidinyl, or 1,2,5- thiadiazolidine S, S-dioxide.
• R 9 in Structural Formula (V-A) is an optionally substituted cyclohexanyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahydrothienyl, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, isothiazolidinyl S,S, dioxide, or piperidinyl.
• R 9 is preferably meta o ⁇ para to the carbon atom bonded to the carbonyl, more preferably para.
• V is preferably a covalent bond or -0-, more preferably a covalent bond.
• R 9 in Structural Formula (V-A) is oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, mo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, or piperidinyl, each optionally substituted by alkyl, halide, haloalkyl, hydroxyalkyl, - C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 , -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , - S(0) 2 R 12
• the group is N-substituted with T 2 -R ⁇ ⁇ which is defined below, and optionally substituted at one or more substitutable ring carbon atoms with one or more groups listed above in this paragraph.
• R 9 in Structural Formula (V-A) is N-mo ⁇ holinyl, 2-mo ⁇ holinyl, 3- mo ⁇ holinyl, N-substituted 2-mo ⁇ holinyl, N-substituted 3-mo ⁇ holinyl, N-pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, N-substituted 2-pyrrolidinyl, N-substituted 3-pyrrolidinyl, N-piperazinyl, 2-piperazinyl, N'-substituted N-piperazinyl, N-substituted 2-piperazinyl, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, N-substituted 2-piperidinyl, N-substituted 3-piperidinyl, N-substituted 4- piperidinyl, each optional
• R 9 in Structural Formula (V-A) is N-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, N-substituted 2-piperidinyl, N-substituted 3-piperidinyl, N-substituted 4- piperidinyl, N-piperazinyl, 2-piperazinyl, N'-substituted N-piperazinyl, or N-substituted 2-piperazinyl, and is optionally substituted by at any substitutable carbon atom by chloride, fluoride, bromide, methyl, ethyl, -C(0)OR 12 , -OC(0)R 12 , -C(0)R 12 or C(0)NH 2 , and wherein the N-substitu
• the present invention is a compound represented by Structural Formula (VI-A):
• B is an optionally substituted monocyclic non-aromatic heterocyclic ring represented by R 10 , or a monocyclic aromatic ring (preferably heteroaromatic) represented by R 13 ; all other variables in Structural Formula (VI-A) are as described for Structural Formula (I-A).
• R 10 in Structural Formula (VI-A) is oxazolidinyl, oxazolidinonyl, dioxolanyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dithiolanyl, pyrrolidinyl, piperazinyl, piperidinyl, piperidinyl, tetrahydrothienyl S,S dioxide, thiomo ⁇ holinyl S,S dioxide, tetrahydrothiopyranyl S,S dioxide, each of which are optionally substituted.
• R 13 is pyrazolyl, triazolyl, imidazolyl, furanyl, pyrrolyl, thienyl, cyclopentadienyl, and thienyl S,S dioxide, each of which are optionally substituted. All other variables in Structural Formula (VI-A) are as described in the previous paragraph.
• R 10 examples include tetrahydrofuranyl, tetrahydropyranyl, mo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl, or piperidinyl each of which is optionally substituted at any substitutable carbon ring atom with alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 -, -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , -S(0) 2 N(R 12 ) 2 , -S(0) 2 OR 12 , -S(0)OR 12 , -OR 12 , -SR 12 , -CN, -NR 12 C
• R 10 include tetrahydrofuranyl, tetrahydropyranyl, mo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl, or piperidinyl each of which is optionally substituted at any substitutable carbon ring atom with alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 -, -C(0)N(R 12 ) 2 , - NR 12 C(0)R 12 , -NR 12 C(0)0R 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , -S(0) 2 N(R 12 ) 2 , -S(0) 2 OR 12 , -S(0)OR 12 , - OR 12 , -SR 12 , -CN, -SR 12 , -CN, -
• R 12 is independently H, alkyl, haloalkyl, or hydroxyalkyl.
• R 10 is dioxolanyl, tetrahydrofuranyl, mo ⁇ holinyl, each optionally substituted at any substitutable carbon atom by alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , or -C(0)N(R 12 ) 2 , or each optionally substituted at any substitutable nitrogen atom by alkyl, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , or - C(0)N(R 12 ) 2 .
• R 13 is triazolyl, imidazolyl, or pyrrolyl each optionally substituted at any substitutable carbon atom by alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , or -C(0)N(R 12 ) 2 , and each optionally substituted at any substitutable nitrogen atom by alkyl, haloalkyl, hydroxyalkyl, C(0)OR 12 , -C(0)R 12 , -R 12 C(0)OR 12 , -S(0) 2 R 12 , S(0) 2 N(R 12 ) 2 , -C(0)N(R 12 ) 2 .
• R 10 is mo ⁇ holinyl and is optionally N-substituted by methyl, ethyl, -C(0)OR 12 , C(0)NH 2 or -C(0)R 12
• R 13 is triazolyl and is optionally N- substituted by methyl, ethyl, -C(0)OR 12 , C(0)NH 2 or -C(0)R 12
• each R 12 is independently -H, methyl, or ethyl.
• Ring B a monocyclic non-aromatic heterocycle or a monocyclic heteroaryl group comprising a ring nitrogen atom that is substituted with T 2 -R Y1 .
• These monocyclic non-aromatic and heteroaryl groups are optionally further substituted.
• the monocyclic non-aromatic heterocyclic ring is represented by R 10
• the monocyclic heteroaromatic ring is represented by R 13 .
• R 10 examples include oxazolidinyl, oxazolidinonyl, thiazolidinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl, or piperidinyl, each of which is N-substituted with T 2 -R Y1 and optionally further substituted at any one or more ring carbon atoms by alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 -, -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)0R 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , -S(0) 2 N(R 12 ) 2 , -S
• R 10 examples include oxazolidinyl, oxazolidinonyl, thiazolidinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl, or piperidinyl, each of which is N-substituted with T 2 -R Y1 and optionally further substituted at any one or more ring carbon atoms by alkyl, halide, haloalkyl, hydroxyalkyl, - C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 -, -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , - S(0) 2 R 12 , -S(0) 2 COR 12 , -S(0) 2 N(R 12 ) 2
• R 13 examples include pyrazolyl, triazolyl, imidazolyl, or pyrrolyl, each of which is N-substituted with T 2 -R Y1 and optionally further substituted at any one or more ring carbon atoms with alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , - R 12 C(0)OR 12 -, -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , - S(0) 2 N(R 12 ) 2 , -S(0) 2 OR 12 , -S(0)OR 12 , -OR 12 , -SR 12 , -CN, -NR 12 C(0)N(R 12 ) 2 , -OC(0)N(R 12 ) 2
• R 13 Other examples of suitable values for R 13 include pyrazolyl, triazolyl, imidazolyl, or pyrrolyl, each of which is N-substituted with T 2 -R Y1 and optionally further substituted at any one or more ring carbon atoms with alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , - OC(0)R 12 , -R 12 C(0)0R 12 -, -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , - S(0) 2 N(R 12 ) 2 , -S(0) 2 OR 12 , -S(0)OR 12 , -OR 12 , -SR 12 , -CN, -NR 12 C(0)N(R 12 ) 2 , -OC(0)N(R 12
• T 2 in Structural Formula (VI-A) is - ⁇ is a straight chain alkylene optionally substituted at any one or more substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N-substituted nitrogen containing spiro non-aromatic heterocyclic group, amine, alkylamine, dialkylamine, or hydroxyl.
• R Y1 is -C(0)OR 5 , -C(0)N(R 5 ) 2 , -NR 5 C(0)R 5 , -NR 5 C(0)OR 5 , -S(0) 2 N(R 5 ) 2 , -NR 5 S(0) 2 R 5 , -OR 5 , -CN, -NR 5 C(0)N(R 5 ) 2 , -N(R 5 ) 2 , an optionally substituted non-aromatic heterocyclic group represented by R 7 , or an optionally substituted heteroaryl group represented by R 8 .
• R 7 is an optionally substituted piperidinonyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, tetrahyrothiophene, mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, dioxanyl, dioxolanyl, dithiolanyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, or piperidinyl.
• R 8 is an optionally substituted furanyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, thiazolyl, thienyl, or imidazolyl.
• R 10 examples include mo ⁇ holinyl, thiomo ⁇ holinyl, imidazolidinyl, imidazolidinonyl, pyrrolidinyl, piperazinyl, or piperidinyl each of which is N- substituted with T 2 -R Y1 and further optionally substituted at any substitutable carbon ring atom with alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 -, - C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , -S(0) 2 N(R 12 ) 2 , -S(0) 2 OR 12 , -S(0)OR 12 , -OR 12 , -SR 12 , -CN
• R 13 examples include triazolyl, imidazolyl, or pyrrolyl, each of which is N-substituted with T 2 -R Y1 and further optionally substituted at any substitutable ring carbon atom with alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , -R 12 C(0)OR 12 -, -C(0)N(R 12 ) 2 , -NR 12 C(0)R 12 , -NR 12 C(0)OR 12 , -S(0) 2 R 12 , -S(0) 2 COR 12 , -S(0) 2 N(R 12 ) 2 , -S(0) 2 OR 12 , -S(0)OR 12 , - OR 12 , -SR 12 , -CN, -NR 12 C(0)N(R 12 ) 2 , -OC(0)N(R 12 ) 2 , or -N(R 12 )
• R Y1 is -C(0)OR 5 , -C(0)N(R 5 ) 2 , - NR 5 C(0)R 5 , -NR 5 C(0)OR 5 , -S(0) 2 N(R 5 ) 2 , -NR 5 S(0) 2 R 5 , -NR 5 C(0)N(R 5 ) 2 , -OH, an optionally substituted non-aromatic heterocyclic group represented by R 7 or an optionally substituted heteroaryl group represented by R 8 .
• Each R 5 is independently H or alkyl, or N(R 5 ) 2 is a nitrogen-containing non- aromatic heterocyclic group.
• R 7 is piperidinonyl, mo ⁇ holinyl, imidazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, or piperidinyl.
• R 8 is tetrazolyl, oxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyridinyl, or imidazolyl.
• T 2 is a C 1 - 5 straight chain alkylene optionally substituted at the carbon atom adjacent to R ⁇ with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, spiro cycloalkyl, optionally N- substituted nitrogen containing spiro non-aromatic heterocyclic group, amine, dialkylamine, or hydroxyl.
• R 10 examples include mo ⁇ holinyl, pyrrolidinyl, piperazinyl, or piperidinyl each of which is N-substituted with T 2 -R ⁇ l and further optionally substituted at any substitutable carbon atom by alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , - C(0)R 12 , -OC(0)R 12 .
• R 13 examples include imidazolyl, or pyrrolyl each of which is N-substituted with T 2 -R ⁇ l and further optionally substituted at any substitutable carbon atom by alkyl, halide, haloalkyl, hydroxyalkyl, -C(0)OR 12 , -C(0)R 12 , -OC(0)R 12 , or -C(0)N(R 12 ) 2 , and each optionally substituted at any substitutable nitrogen atom by alkyl, haloalkyl, hydroxyalkyl, C(0)OR 12 , -C(0)R 12 , -R 12 C(0)OR 12 , -S(0) 2 R 12 , S(0) 2 N(R 12 ) 2 , -C(0)N(R 12 ) 2 .
• R Y1 is -C(0)OR 5 , - C(0)N(R 5 ) 2 , -OH, N-mo ⁇ holinyl, 2-mo ⁇ holinyl, 3-mo ⁇ holinyl, N-substituted 2-mo ⁇ holinyl, N- substituted 3-mo ⁇ holinyl, N-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, N- substituted 2-imidazolidinyl, N'-substituted N-imidazolidinyl, N-substituted 4-imidazolidinyl, N- substituted 5-imidazolidinyl, N-imidazolidinonyl, 4-imidazolidinonyl, 5-imidazolidinonyl, N- substituted 4-imidazolidinonyl, N-substituted 5-imidazolidinonyl, N-pyrrolidinyl
• T 2 is a C1-3 straight chain alkylene substituted with fluoro, methyl, gem dimethyl, gem difluoro fluoromethyl, spiro cyclopropyl, spiro cyclobutyl, optionally N-substituted spiro azetidinyl, optionally N-substituted spiro aziridinyl, optionally N- substituted spiro pyrrolidinyl, optionally N-substituted spiro piperidinyl, amine, methylamine, dimethylamine, or hydroxyl.
• R 10 include mo ⁇ holinyl, N- substituted with T 2 -R Y1 and further optionally substituted at the carbon alpha to the nitrogen atom with methyl or gem dimethyl.
• suitable values for R 13 include imidazolyl N- substituted with T 2 -R Y1 and further optionally substituted at the carbon alpha to the nitrogen atom with methyl or gem dimethyl.
• R ⁇ l is -C(0)OR 5 , -C(0)N(R 5 ) 2 , -OH, N-tetrazolyl, 5-tetrazolyl, N- substituted 5-tetrazolyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; N-substituted 2- imidazolyl, N-substituted 4-imidazolyl, or N-substituted 5-imidazolyl.
• R 1 is an optionally substituted phenyl ring fused to the group represented by R 10 as represented by the following Structural Formulas: O f O O
• R 1 is an optixonally substituted phenyl ring fused to the group represented by R 13 as represented by the following Structural Formulas:
• the Structural Formulas shown above for the fused bicyclic rings can be further optionally substituted at one or more substitutable carbon atoms or nitrogen atoms. Examples of suitable substituents as described above for the groups represented by R 10 and R 13 . In a more specific embodiment, any one of the fused bicyclic ring systems shown above that have substitutable nitrogen atoms are N-substituted with T 2 -R Y1 . T 2 -R ⁇ l is as described above.
• Ring A (preferably phenyl ring A) in Structural Formulas (I-A)-(VI-A) is optionally substituted (preferably at the six and seven positions) with one or more groups represented by R 14 ;
• Structural Formulas (I-A)-(V-A) R 1 is an aromatic group (preferably a phenyl ring) optionally substituted by 1-2 independently selected groups represented by R z ;
• Structural Formulas (I-A)-(VI-A) R 3 is an aromatic group (preferably e.g., a phenyl ring) optionally substituted with one or more groups represented by R 11 .
• Suitable values for R 14 , R z , and R 11 are ones that do not substantially decrease the ability of the compound of the invention to inhibit CRTH2.
• suitable substituents are halogen, haloalkyl, R°, -OR°, -O(haloalkyl), -SR°, -N0 2, -CN, -N(R') 2 , - NR'C0 2 R°, -NR'C(0)R°, -NR'NR'C(0)R°, -N(R')C(0)N(R') 2 , -NR'NR'C(0)N(R') 2 , -NR'NR'C0 2 R°, -C(0)C(0)R°, -C(0)CH 2 C(0)R°, -C0 2 R°, -C(0)R°, -C(O)N(R 0 ) 2 , -OC(0)R°, -OC(0)N(R°) 2 , -S(0) 2 R°, -S
• R 11 examples include 3,4-methylene-dioxy and 3,4-ethylene-dioxy.
• suitable substituents for R 11 also include halogen, haloalkyl, R°, -OR 0 , -O(haloalkyl), -SR°, 3,4-methylene- dioxy, 3,4-ethylene-dioxy, -N0 2 , -CN, -N(R') 2 , -NR'C0 2 R°, -NR'C(0)R°, -NR'NR'C(0)R°, -N(R')C(0)N(R') 2 , -NR'NR'C(0)N(R') 2 , -NR'NR'C0 2 R°, -C(0)C(0)R°, -C(0)CH 2 C(0)R°, -C0 2 R°, -C(0)R°, -C(0)N(R°) 2 , -OC(0)R°, -OC(0)N(R°) 2 ,
• Each R ' is independently hydrogen, alkyl, -C(O)0R°, S(0) 2 R°, or -C(0)R°.
• Each R° is independently hydrogen or an alkyl group, non-aromatic heterocyclic group or aromatic group and the alkyl, non-aromatic heterocyclic group and aromatic group represented by R° is optionally substituted with one or more independently selected groups represented by R # .
• R + is -H, a C C 3 alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -N0 2 , amine, alkylamine or dialkylamine; or -N(R + ) 2 is a non-aromatic heterocyclic group, provided that non-aromatic heterocyclic groups represented by R + and -N(R + ) 2 that comprise a secondary ring amine are optionally acylated or alkylated.
• R z and R 11 are halogen, haloalkyl, -R°, -OR 0 , -O(haloalkyl), -C0 2 R°, -C(0)R°, -NR'S0 2 R°, -C(0)N(R°) 2 , -OC(0)R°, and -OC(O)N(R 0 ) 2 .
• 3,4-methylene-dioxy and 3,4- ethylene-dioxy, and -N(R') 2 are also preferred values for R ⁇ .
• Each R° is independently hydrogen, haloalkyl or an alkyl group, each R' is independently H or alkyl.
• R 3 is a phenyl ring optionally substituted at the meta or para positions with one or more groups represented by R ⁇ . More preferred values for R 11 andR z are halogen, haloalkyl, - R°, -OR 0 , and -O(haloalkyl). -NR'SO 2 R 0 and -N(R') 2 are also preferred values for R n . [00121] More preferably, R 3 is a phenyl ring optionally substituted at the, para position with R 11 . R 1 is a phenyl ring optionally substituted at the meta position by R z .
• R z and R 11 are chloride, fluoride, bromide, -OR 0 , or R°.
• -NR'S0 2 R° and -N(R') 2 are also preferred values for R 11 .
• Each R° is independently hydrogen, haloalkyl or a C ⁇ - 3 alkyl group.
• Each R' is independently hydrogen or a C ⁇ - 3 alkyl group.
• R 14 is an optional substituent, preferably at the six an seven positions on phenyl ring A; preferred values are halogen R°, -OR 0 , -C0 2 R°, -C(0)R°, -C(0)N(R°) 2 , -CN, -OC(0)R°, (CH 2 ) n C0 2 R 0 > 0(CH 2 ) n C0 2 R°, NHS0 2 R°, NHC(0)N(R°) 2 , (CH 2 ) accentOH, 0(CH 2 ) n OH, (CH 2 ) n C(0)N(R°) 2 , or 0(CH 2 ) n C(0)N(R°) 2 .
• R° is hydrogen, haloalkyl or a . 3 alkyl group.
• Another embodiment of the present invention is a compound represented by Structural Formula (X-A): (X-A) V is a covalent bond or -0-. T is an unsubstituted straight chained C M0 alkylene.
• R ⁇ is -C(0)OR 5 , -C(0)R 5 , -OC(0)R 5 , -C(0)N(R 5 ) 2 , -NR 5 C(0)R 5 , -NR 5 C(0)OR 5 , -S(0) 2 R 5 , - S(0) 2 COR 5 , -S(0) 2 N(R 5 ) 2 , -NR 5 S(0) 2 , -NR 5 S(0) 2 R 5 , S(0) 2 OR 5 , -S(0)OR 5 , -SR 5 , -C(0)NR 5 S(0) 2 R 5 , - CN, -NR 5 C(0)N(R 5 ) 2 , -OC(0)N(R 5 ) 2 , -N(R 5 ) 2 , -OR 5 , an optionally substituted non-aromatic heterocyclic group or an optionally substituted heteroaryl group.
• the compound of Structural Formula (X-A) excludes compounds where T-R ⁇ is-CH 2 R 20 , -CH 2 CH 2 R 21 , or -(CH 2 ) 3 R 22 .
• R 20 is -COOH, -C(0)NH 2 , -C(0)NHCH 3 , C(0)N(CH 3 ) 2 , 5-tetrazolyl, 4-pyridinyl, N-ethyl-4-piperidinyl, or C(0)N-mo ⁇ holinyl.
• R 21 is -COOH, N-mo ⁇ holinyl, C(0)NH 2 , N-pyrrolidin-2-onyl, N-imidazolyl, or N-pyrrolidinyl.
• R 22 is -COOH, C(0)N(CH 2 CH 3 ) 2 , C(0)NH(CH 2 CH 3 ), C(0)NH 2 , C(0)NHS(0) 2 CH 3 , C(0)NHOH, C(0)OCH 2 CH 3 , NH 2 , C(0)CH 3 , CN, NHS(0) 2 CF 3 , C(0)N-pyrrolidinyl, N-pyrrolidinyl, 5-tetrazolyl, 5- (l,2,4)oxadiazolyl, N-morpholinyl, or N-imidazolyl.
• N is a covalent bond or -0-;
• T is an straight chained -io alkylene substituted with alkyl, gem dialkyl, haloalkyl, spiro cycloalkyl, or an optionally ⁇ -substituted nitrogen containing spiro non-aromatic heterocyclic group;
• R ⁇ is R ⁇ is -C(0)OR 5 , -C(0)R 5 , -OC(0)R 5 , -C(0) ⁇ (R 5 ) 2 , -NR 5 C(0)R 5 , -NR 5 C(0)OR 5 , - S(0) 2 R 5 , -S(0) 2 COR 5 , -S(0) 2 N(R 5 ) 2 , -NR s S(0) 2 , -NR 5 S(0) 2 R 5 , S(0) 2 OR 5 , -S(0)OR 5 , -SR 5 , -C(0)NR 5 S(0) 2 R 5 ,
• V is-O-;
• T is an straight chained C ⁇ . 10 alkylene optionally substituted at any one or more substitutable carbon atoms with halide, alkyl, gem dialkyl, gem dihalo, haloalkyl, alkoxy, haloalkoxy, spiro cycloalkyl, optionally N-substituted nitrogen containing spiro non-aromatic heterocyclic group, amine, alkylamine, dialkylamine, or hydroxyl;
• R ⁇ is R ⁇ is -C(0)OR 5 , -C(0)R 5 , -OC(0)R 5 , -C(0)N(R 5 ) 2 , -NR 5 C(0)R 5 , -NR 5 C(0)OR 5 , - S(0) 2 R 5 , -S(0) 2 COR 5 , -S(0) 2 N(R 5 ) 2) -NR 5 S(0) 2 , -NR 5 S(0) 2 R 5 , S(0) 2 OR 5 ,
• alkylene as used herein means a straight chained hydrocarbon which is completely saturated.
• An alkylene group is typically C ⁇ _ ⁇ 0 , more typically C ⁇ _ 6 . more preferably from Ci- 5 and more preferably from C ⁇ - 3 .
• a "substituted alkylene” is an alkylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents are as described below for a substituted alkyl group.
• Preferred substituents for the alkylene group represented by T are fluoro, methyl, gem dimethyl, gem difiuoro fluoromethyl, spiro cyclopropyl, spiro cyclobutyl, optionally N-substituted spiro azetidinyl, optionally N-substituted spiro aziridinyl, optionally N-substituted spiro pyrrolidinyl, optionally N-substituted spiro piperidinyl, amine, methylamine, dimethylamine, or hydroxyl.
• a "substitutable alkylene carbon atom” is an alkylene carbon atom that is bonded to one or more hydrogen atoms. The hydrogen atoms can therefore optionally be replaced with the substituent.
• alkyl used alone or as part of a larger moiety include both straight and branched saturated chains containing one to ten carbon atoms, preferably one to six, more preferably one to five, and even more preferably one to three.
• a "substitutable allyl carbon atom” is an allyl carbon atom that is bonded to one or more hydrogen atoms. The hydrogen atom can therefore optionally be replaced with the substituent. Suitable substituents are as described for alkyl group.
• the terms "gem dialkyl”, and “gem dihalo” includes compounds where two alkyl substituents or two halo substituents, respectively, are attached to the same carbon atom, e.g., - C(CH 3 ) 2 - or C(F) 2 -.
• a "spiro cycloalkyl” or “spiro non-aromatic heterocyclic” group is a cycloalkyl or non- aromatic heterocyclic group which shares one ring carbon atom with a carbon atom in an alkylene group or alkyl group.
• non-aromatic carbocyclic or "cycloaliphatic” shall include cyclic C 3 . ⁇ 0 hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic. Cycloaliphatic groups are typically C 3 . ⁇ 0 , more typically C 3 . 7 .
• Alkoxy means (alkyl)-O-; "haloalkoxy”, means (halide)-0-; "alkoxyalkylene” means (alkyl)-O-(alkylene) such as methoxymethylene (CH 3 OCH 2 ); "hydroxyalkyl” means hydroxy substituted alkyl group, acylated means "-C(0)-(alkyl)”.
• heteroatom means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
• nitrogen includes a substitutable nitrogen of a heterocyclic ring.
• the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
• aromatic group includes carbocyclic aromatic ring groups and heteroaryl ring groups.
• aromatic group may be used interchangeably with the terms “aryl", “aryl ring” or "aromatic ring”.
• Carbocyclic aromatic ring groups have only carbon ring atoms and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include 1 -naphthyl, 2-naphthyl, 1- anthracyl and 2-anthracyl.
• Carbocyclic aromatic ring is a group in which an aromatic ring is fused to one or more non-aromatic rings (aliphatic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
• non-aromatic rings aliphatic or heterocyclic
• heteroaryl or “heteroaromatic”, refers to heteroaromatic ring groups having five to fourteen members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other carbocyclic or heteroaromatic aromatic rings .
• heteroaryl rings examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, oxadiazolyl, 2- oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl benzimidazolyl, be
• heteroaryl is a group in which a heteroaryl ring is fused to one or more cycloaliphatic or non-aromatic heterocyclic groups where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [3, 4-d] pyrimidinyl.
• heteroaryl may be interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
• non-aromatic heterocyclic group refers to non-aromatic ring systems typically having three to fourteen members, preferably three to six, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S.
• non-aromatic heterocyclic rings examples include 3-tetrahydrofuranyl, 2- tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [l,3]-dioxalanyl, [l,3]-dithiolanyl, [1,3]- dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-mo ⁇ holinyl, 3-mo ⁇ holinyl, N- mo ⁇ holinyl, 2-thiomo ⁇ holinyl, 3-thiomo ⁇ holinyl, 4-thiomo ⁇ holinyl, N-pyrrolidinyl, 2- pyrrolidinyl, 3-pyrorolidinyl, N-piperazinyl, 2-piperazinyl, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperidinonyl, 4-thi
• a "substituted aromatic group” is an aromatic group with a substituent at one or more substitutable ring carbon atoms or ring nitrogen atoms. Each substituent is independently selected. Examples of suitable substituents on an unsaturated carbon atom or substitutable carbon atom of an aromatic group are as described above for R z , R 11 , and R 14 .
• a "substitutable ring carbon atom" in an aromatic ring is a ring carbon atom that is bonded to a hydrogen atom.
• the hydrogen atom can therefore optionally be replaced with the substituent.
• the term "substitutable ring carbon atom” in an aromatic ring therefore excludes ring carbon atoms that are fused with other rings or that are depicted as already being bonded to a substituent.
• An alkyl group or a non-aromatic carbocycle or heterocycle may contain one or more substituents on any substitutable carbon atom.
• a “substitutable alkyl carbon atom” is an alkyl carbon atom that is bonded to one or more hydrogen atoms.
• the hydrogen atoms can therefore optionally be replaced with the substituent.
• Each R* is independently selected from hydrogen, an unsubstituted alkyl group or a substituted alkyl group.
• substituents on the alkyl group represented by R* include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
• substituents on the alkyl group or the phenyl ring represented by R 12 include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
• a "substitutable ring nitrogen atom" in a heteroaryl or nitrogen-containing non-aromatic heterocyclic group is a ring nitrogen atom that is bonded to a hydrogen atom. The hydrogen atom can therefore optionally be replaced with the substituent.
• substituted ring nitrogen atom therefore excludes ring nitrogen atoms that are depicted as already being bonded to a substituent, and ring nitrogen atoms that are ring atoms in two fused rings (as in, e.g., indolizine) and ring nitrogen atoms that have three covalent bonds to other ring atoms (as e.g., pyridine).
• compounds of the present invention may associated in isolated form with solvent or water, as in a "solvate” or "hydrate".
• references to the disclosed compounds or structural formulas depicting the disclosed compounds are meant to include such solvates and hydrates.
• the present invention provides compounds that are useful as inhibitors of CRTH2, and thus the present compounds are useful for treating (therapeutically or prophylactically) disorders with an inflammatory component and allergic conditions. They can also be used to inhibit inflammatory disorders and allergic conditions mediated by Th2 cells, eosinophils and basophils.
• compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
• these compositions optionally further comprise one or more additional therapeutic agents.
• a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
• pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
• pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C ⁇ _ alkyl) 4 salts.
• This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
• any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
• materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
• a method for the treatment of an inflammatory disease or a disease with an inflammatory component comprising administering an effective amount of a compound, or a pharmaceutical composition thereof to a subject in need thereof.
• Compounds and compositions of the invention are inhibitors of CRTH2, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation of one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils, and/or basophils is implicated in the disease, condition, or disorder.
• the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation of one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils, and/or basophils is implicated in the disease state.
• an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating an inflammatory disease or disease with an inflammatory component.
• an "effective amount” of a compound is an amount which inhibits binding of PGD2 to its receptor CRTH2 and thereby inhibits one or more processes mediated by the binding in a subject, for example, the release of proinflammatory mediators.
• An "effective amount” of a compound can achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with an inflammatory disease or a disease mediated by one or more of CRTH2, PGD2 (including DP activity), Th2 cells, eosinophils, and basophils.
• the inflammatory disease is an allergic condition.
• allergic conditions for which the disclosed compounds, pharmaceutical compositions and methods are believed to be particularly effective include atopic dermatitis, allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disorder, or allergic asthma.
• Other allergic conditions include systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies and dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis and urticaria.
• osteoarthritis examples include osteoarthritis, inflammatory bowel disease [e.g., such as ulcerative colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteritis, enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy, and ileoanal anastomosis] and disorders of the skin [e.g., psoriasis, erythema, pruritis, and acne].
• inflammatory bowel disease e.g., such as ulcerative colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue
• enteritis enteropathy associated with seronegative arthropathies
• microscopic or collagenous colitis eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy, and ileoanal anastomos
• autoimmune diseases also have an inflammatory component.
• examples include multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis and other nephritides, autoimmune thyroiditis, Behcet's disease and graft rejection (including allograft rejection or graft-versus-host disease).
• the inflammatory component of these disorders is believed to be mediated, at least in part, by CRTH2.
• Diseases characterized by repurfusion have an inflammatory component that is believed to be mediated, at least in part by, by CRTH2. Examples include stroke, cardiac ischemia, and the like. The disclosed compounds and compositions also can be used to treat these disorders.
• CRT ⁇ 2 diseases and conditions with an inflammatory component believed to be mediated by CRT ⁇ 2 include mastitis (mammary gland), vaginitis, cholecystitis, cholangitis or pericholangitis (bile duct and surrounding tissue of the liver), chronic bronchitis, chronic sinusitis, chronic inflammatory diseases of the lung which result in interstitial fibrosis, such as interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), hypersensitivity pneumonitis, collagen diseases and sarcoidosis.
• ILD interstitial lung diseases
• vasculitis e.g., necrotizing, cutaneous, and hypersensitivity vasculitis
• spondyloarthropathies e.g., spondyloarthropathies
• scleroderma e.g., atherosclerosis
• restenosis e.g., restenosis
• myositis including polymyositis, dermatomyositis
• pancreatitis e.g., pancreatitis and insulin-dependent diabetes mellitus.
• the invention provides a method of treating asthma comprising administering an effective amount of a compound of general formula I (and subsets thereof as described herein) to a subject in need thereof.
• the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating an inflammatory disease or allergic condition.
• the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
• the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
• patient means an animal, preferably a mammal, and most preferably a human.
• compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
• the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• the oral compositions can also include adj
• Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this pu ⁇ ose any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the abso ⁇ tion of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material with poor water solubility. The rate of abso ⁇ tion of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed abso ⁇ tion of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.
• the rate of compound release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) abso ⁇ tion accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetylene glycol, g
• Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
• the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• buffering agents include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
• the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
• the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
• the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects
• additional therapeutic agents which are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated".
• compounds of the invention can also be administered in combination with one or more additional therapeutic agents, such as, theophylline, ⁇ -adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents (e.g., cyclosporin A,
• hormones e.g., adrenocorticotropic hormone (ACTH)
• cytokines e.g., interferons (e.g., IFN ⁇ -la, IFN ⁇ -lb)) and the like.
• the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
• the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
• the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
• the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
• Another aspect of the invention relates to inhibiting CRTH2 activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound.
• biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
• pu ⁇ oses that are known to one of skill in the art.
• pu ⁇ oses include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
• Aother embodiment of the present invention is a method of preparing an amino acid compound represented by Structural Formula (XI-A):
• the method comprises the step of reacting Ar-NH 2 with a lactone represented by Structural Formula (XXII-A):
• Ar is an optionally substituted monocyclic aromatic group and R 2 is C C 3 alkyl.
• Ar is an optionally substituted phenyl group and R 2 is methyl or ethyl.
• Suitable substituents for Ar are as described above for Ring A or Phenyl Ring A, provided, however, that functional groups which can interfere with the reaction are protected. Functional groups which require protection will be readily apparent to the skilled artisan and include amines, alcohols, carboxylic acids, and the like.
• substituents include halo, cyano, R°, -OR 30 , -C0 2 R 31 , - C(0)R°, -C(0)N(R x ) 2> -OC(0)R°, (CH 2 ) administratC0 2 R 31 , 0(CH 2 ) n C0 2 R 31 , NHS0 2 R°, NHC(0)NR x 2 , (CH 2 ) n OR 30 , 0(CH 2 ) complicatOR 3 °, (CH 2 ) administratC(0)N(R x ) 2 , 0(CH 2 ) curatC(0)N(R x ) 2 ; n is an integer from 1-4; R° is independently hydrogen, C ⁇ - 3 haloalkyl or a C ⁇ - 3 alkyl group; one R x is -H or C C 3 alkyl and the other is an amine protecting group; R 30 is an alcohol protecting group; and R 31 is a carboxylic acid protecting group.
• Suitable protecting groups are well know in the art and are disclosed in, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (1991). The entire teachings of Greene and Wits are inco ⁇ orated herein by reference. More commonly, Ar is a phenyl group.
• the reaction of the aryl amine and cyclic lactone above can be carried out in solvents in which both reagents are soluble.
• solvents include protic solvents (e.g., water and methanol) and polar aprotic solvents (dimethylformamide, dimethyl sulfoxide,, hexamethylphosphoramide and the like).
• An excess of one reagent relative to the other can be used (e.g., up to a ten fold excess), however equimolar amounts are more typical.
• the reaction is typically carried out at the boiling point of the solvent being used, but can also commonly carried out at temperatures ranging from ambient temperature to temperatures as high as 200° C. Temperatures from 70° C to 90° C are most commonly used.
• Another embodiment is a method of preparing an intermediate compound represented by
• the method comprises the step of amidating the carboxylic acid group of the amino acid compound with NH 2 C(0)OR z .
• the group -C(0)OR z is an amine protecting group that taken together with -NH 2 forms a carbamate.
• R z is a substituted or unsubstituted alkyl, allyl or aryl group.
• Substituents that can be present on the alkyl, allyl or aryl group represented by R z are those which do not interfere in the reactions being carried and are readily recognizable to the skilled artisan. Examples include alkyl, halogen and alkoxy.
• R z suitable values for R z are well known to the skilled artisan and are described, for example, in Green and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons (1991). Specific examples include, but are not limited to, benzyl, methyl, ethyl, allyl, 2,2,2,-trichloromethyl, 2,2,2-trichloro-t-:rt-butyl, tert-butyl or fluorenylmethyl.
• the term "amidating a carboxylic acid with NH 2 C(0)OR z refers to converting a carboxylic acid (-COOH) to the amide -C(0)NHC(0)OR z in one or more reaction steps.
• carboxylic acid is first converted into a group that is more readily displaced by an amine or amide than -OH.
• -OH is converted into a better leaving group.
• a "leaving group” is a group which can readily be displaced by a nucleophile.
• the amino acid compound can be converted directly to the intermediate compound by activating the carboxylic acid of the amino acid compound and then reacting with NH 2 C(0)OR z .
• the carboxylic can be first be converted to carboxamide (-C(0)NH 2 ) by activating the carboxylic acid group of the amino acid compound and then reacting with NH 3 or a functional equivalent thereof (e.g., NIJ CI) and then protecting the resulting carboxamide.
• NH 2 C(0)OR z is used as a nucleophile
• the amidation is preferably carried out in the presence of at least one equivalent of a non-nucleophilic base such as an alkoxide (lithium ter-butoxide, potassium tert-butoxide, ilithium isopropoxide and potassium isopropoxide) or amide base (e.g., lithium or potassium isopropylamide or hexamethylpiperidide).
• -OH of the carboxylic acid is converted into a better leaving group by replacing it with a halogen, typically with chloride.
• the carboxylic acid is thereby converted into an acid halide, e.g., an acid chloride.
• Reagents suitable for preparing acid chlorides from carboxylic acids are well known in the art and include thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride.
• each carboxylic acid group is reacted with about one equivalent or a slight excess of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride in an inert solvent such as an ethereal solvent (e.g., diethyl ether, tetrahydrofuran or 1,4- dioxane), a halogenated solvent (e.g., methylene chloride or 1,2-dichloroethane) or aromatic solvent (e.g., benzene or toluene).
• an ethereal solvent e.g., diethyl ether, tetrahydrofuran or 1,4- dioxane
• a halogenated solvent e.g., methylene chloride or 1,2-dichloroethane
• aromatic solvent e.g., benzene or toluene
• the carboxylic acid is first converted into an "activated ester".
• An ester - COOR is said to be “activated” when -OR is readily displaced by an amine or amide than -OH. -OR is more easily displaced as R becomes more electron withdrawing.
• Some activated esters are sufficiently stable that they can be isolated, e.g., esters wherein R is phenyl or substituted phenyl.
• diphenylmalonate can be prepared from malonyl chloride and phenol, both commercially available from Aldrich Chemical Co., Milwaukee, WI., by procedures described above
• Other activated esters are more reactive and are generally prepared and used in situ.
• a "coupling agent” also referred to as a “carboxylic acid activating agent” which is a reagent that replaces the hydroxyl group of a carboxyl acid with a group which is susceptible to nucleophilic displacement.
• Examples of coupling agents include lj'-carbonyldiimidazole (GDI), isobutyl chloroformate, dimethylaminopropylethyl- carbodiimide (EDC), dicyclohexyl carbodiimide (DCC).
• GDI lj'-carbonyldiimidazole
• EDC dimethylaminopropylethyl- carbodiimide
• DCC dicyclohexyl carbodiimide
• the reaction is generally carried out in inert, aprotic solvents, for example, halogenated solvents such as methylene chloride, dichloroethane and chloroform, ethereal solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether and dimethylformamide.
• aprotic solvents for example, halogenated solvents such as methylene chloride, dichloroethane and chloroform, ethereal solvents such as tetrahydrofuran, 1,4-dioxane and diethyl ether and dimethylformamide.
• Suitable reaction temperature generally range from between about 0° to about 100°, but the reaction is preferably carried out at ambient temperature.
• Yet another embodiment of the present invention is a method of preparing a product compound represented by Structural Formula (XIV-A):
• the method comprises the step of reducing the amide carbonyl of the intermediate compound to form a second intermediate and then cyclizing the second intermediate to form the product compound.
• the variables in Structural Formula (XIV-A) are as described above for Structural Formulas (XI-A)-(XH ⁇ -A).
• the "amide carbonyl” is understood to be the carbonyl between the methylene carbon and nitrogen atom and not the carbonyl that is bonded to both a nitrogen and oxygen atom.
• a reducing agent which can reduces the amide carbonyl but not the carbamate group.
• Sodium borohydride together with a Lewis Acid such as magnesium chloride or calcium chloride is one common example.
• the reduction step is typically carried out in an alcoholic solvent such as methanol or ethanol.
• An excess of sodium borohydride and Lewis Acid of up to 50% can be used, but typically from 0.5 to 1.0 equivalents of sodium borohydride and 0.5 to 2.0 equivalents of Lewis Acid are used.
• the cyclization step is carried out in dilute aqueous or alcoholic acid, using, for example, 0.1 N to 10 N HCl, H 2 S0 4 , H 3 P0 or a sulfonic acid such as methane sulfonic acid, toluene sulfonic acid or phenyl sulfonic acid. More typically, between 0.8 N and 1.2 N acid is used. Commonly, an organic acid such acetic acid, benzoic acid, citric acid, and the like is also be present, for example between 0.5 equivalents to 10 equivalents. Typically, a co-solvent immiscible in water or alcohol is used.
• Another embodiment of the present invention is a method of preparing the product compound represented by Structural Formula (XIV-A) from the cyclic lactone represented by
• Structural Formula (XII-A) The method comprises combining the three reaction steps described above. Alternatively, the enantiomer of the compound represented by Structural Formula (XIV-A) is prepared using the same three reaction steps, provided, however, that the enantiomer of the starting lactone represented by Structural Formula (XII-A) is used.
• Yet another embodiment of the present invention is a compound represented by any one of Structural Formulas (XI-A)-(XIV-A).
• Formic acid-Standard conditions % C (Water) 95.0 HPllOO LC Pump Gradient Timetable % D (Acetonitrile) 5.0 % Formic Acid 0.1
• the gradient Timetable contains 5 entries which are : Flow (ml/rnin) 3.500 Stop Time (mins) 4.4 Time A% B% C% D% Flow Pressure Min Pressure (bar) 0 0.00 0.0 0.0 95.0 5.0 3.500 400 Max Pressure (bar) 400 3.50 0.0 0.0 0.0 100.0 3.500 400 Oven Temperature Left(°C) 25.0 4.30 0.0 0.0 100.0 3.500 400 Oven Temperature Right(°C) 25.0 4.40 0.0 0.0 95.0 5.0 4.000 400 5.00 0.0 0.0 95.0 5.0 4.000 400
• the tr ⁇ ras-isomer could be obtained by concentration of the filtrate.
• the residue was purified by Biotage flash system (95% hexane/5% diethyl ether) to yield the cis and trans isomers as a mixture.
• the resulting oily residue was then trituated with hexane to separate the cis isomer as a white solid and the filtrate was concentrated to give the trans isomer.
• the reaction mixture was evaporated in vacuo.
• the residue was purified by Biotage flash system (70% hexane/30% ethyl acetate to 60% hexane/40% ethyl acetate to 50% hexane/50% ethyl acetate) to yield the 2-acetyl trans isomers 35 % yield.
• N-phenyl-benzamide was made following general procedure A, substituting 3-methoxybenzoyl chloride for 2-furoyl chloride and 4-chlorobenzoyl chloride for acetyl chloride.
• (+)-Cis-N-[l-(3-chloro-benzoyl)-2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl- propionamide was following general procedure A made substituting 3-chlorobenzoyl chloride for 2- furoyl chloride and propionyl chloride for acetyl chloride.
• (+)-Cis- ⁇ -4-[2-Methyl-4- (phenyl-propionyl-amino)-3,4-dihydro-2H-quinoline-l-carbonyl]-phenoxy ⁇ -acetic acid (0.146 g) was dissolved in THF (2 mL) at room temperature.
• HOBt 0.063 g
• EDCI 0.071 g
• dimethylamine 2.0M solution in THF, 0.162 mL
• the reaction was diluted with ethyl acetate, washed with IN NaOH, IN HCl and brine. The organics were dried over MgS0 4 , filtered and concentrated down.
• (+)-Cw-N-[l-(3-dimethylamino-benzoyl)-2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl]-N- phenyl-propionamide was made following general procedure A, substituting 3-dimethylaminobenzoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• N-phenyl-acetamide was made following general procedure A substituting benzo[b]thiophene-3- carbonyl chloride for 2-furoyl chloride.
• N-phenyl-acetamide was made following general procedure A substituting 4-fluorobenzoyl chloride for 2-furoyl chloride and l-chloro-3- ⁇ henoxy-propan-2-one for acetyl chloride.
• -NMR (CDC1 3 ) ⁇ : 1.1 (3 H, d), 1.1 (1 H, m), 2.3 (1 H, m), 4.5 (2 H, s), 4.7 (1 H, m), 5.7 (1 H, m),
• N-phenyl-propionamide was made following general procedure A substituting benzo[b]thiophene-2- carbonyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• N-phenyl-propionamide was made following general procedure A substituting 3-fluoro-4- methoxybenzoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• N-phenyl-propionamide was made following general procedure A substituting 3-methyl-4- methoxybenzoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• N-phenyl-propionamide was made following general procedure A substituting 4-fluoro-3-methoxy benzoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• ⁇ -NMR (CDC1 3 ) ⁇ : 1.0-1.2 (7 H, m), 2.2-2.4 (3 H, m), 3.6 (3 H, s), 4.7 (1 H, m), 5.6 (1 H, m), 6.4 (1 H, d), 6.7-6.9 (4
• (+)-Cw-N- ⁇ l-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-l ,2,3,4-tetrahydro-quinolin-4- yl ⁇ -N-phenyl-propionamide was prepared from ( ⁇ )-cts-N-[l-(4-amino-benzoyl)-2-methyl-l,2,3,4- tetrahydro-quinolin-4-yl]-N-phenyl-propionamide.
• ( ⁇ )-Cz ' j-N-[2-methyl-l-(4-propylamino-benzoyl)-l,2,3,4-tetrahydro-quinolin-4-yl]-N- phenyl-propionamide was prepared from ( ⁇ )-czj-N-[l-(4-amino-benzoyl)-2-methyl-l, 2,3,4- tetrahydro-quinolin-4-yl]-N-phenyl-propionamide utilizing the reductive amination conditions described for the synthesis of ( ⁇ )-cw-N- ⁇ l-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-l, 2,3,4- tetrahydro-quinolin-4-yl ⁇ -N-phenyl-propionamide.
• (+)-Cz'_;-N-[l-(3-methoxy-benzoyl)-2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl- acetamide was made following general procedure A, substituting 3-methoxybenzoyl chloride for 2- furoyl chloride.
• N-(4-chloro-phenyl)-acetamide was made following general procedure A, substituting 3- methoxybenzoyl chloride for 2-furoyl chloride, and ( ⁇ )-czs-(6-chloro-2-methyl-l,2,3,4-tetrahydro- quinolin-4-yl)-(4-chloro-phenyl)-amine for ( ⁇ )-ct5-(2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl)- phenyl-amine.
• N-phenyl-propionamide was made following general procedure A, substituting 2-methyl-isonicotinoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• N-phenyl-propionamide was made following general procedure A, substituting 6-methyl-nicotinoyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• 4-yl-N-phenyl-acetamide was made following general procedure A, substituting 4-fluorobenzoyl chloride for 2-furoyl chloride and mo ⁇ holinoacetyl chloride for acetyl chloride.
• N-phenyl-propionamide was made following general procedure A, substituting benzo[c]isoxazole-3- carbonyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• (+)-Cz N- ⁇ l-[3-(4-fluoro-phenyl)-[l,2,4]oxadiazole-5-carbonyl]-2-methyl-l,2,3,4- tetrahydro-quinolin-4-yl ⁇ -N-phenyl-propionamide was made following general procedure A, substituting 3-(4-fluoro-phenyl)-[l,2,4]oxadiazole-5-carbonyl chloride for 2-furoyl chloride and propionyl chloride for acetyl chloride.
• (+)-Cz ' s-N-[l-(isoxazole-5-carbonyl)-2-methyl-l,2,3,4-tetrahydro-quinolin-4-yl]-N- phenyl-acetamide was made following general procedure A, substituting isoxazole-5-carbonyl chloride for 2-furoyl chloride.

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