EP2059502A2 - Proline urea ccr1 antagonists for the treatment of autoimmune diseases or inflammation - Google Patents

Proline urea ccr1 antagonists for the treatment of autoimmune diseases or inflammation

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Publication number
EP2059502A2
EP2059502A2 EP07799631A EP07799631A EP2059502A2 EP 2059502 A2 EP2059502 A2 EP 2059502A2 EP 07799631 A EP07799631 A EP 07799631A EP 07799631 A EP07799631 A EP 07799631A EP 2059502 A2 EP2059502 A2 EP 2059502A2
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EP
European Patent Office
Prior art keywords
alkyl
compound according
moiety
substituted
aromatic ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP07799631A
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German (de)
French (fr)
Inventor
James Robert Merritt
Ray A. James
Jinqi Liu
Ruiyan Liu
Jeffrey Lowrie
Michelle Morris
Andrew Roughten
Vidyadhar Paradkar
Chongwu Zhang
Rui Zhang
Michael Ohlmeyer
Koc Kan Ho
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ligand Pharmaceuticals Inc
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Ligand Pharmaceuticals Inc
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Publication of EP2059502A2 publication Critical patent/EP2059502A2/en
Withdrawn legal-status Critical Current

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to proline urea CCRl antagonists which are useful for the treatment and prevention of inflammatory and autoimmune diseases.
  • CCRl which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP- l ⁇ ).
  • CCRl is a therapeutic target for a variety of diseases.
  • CCRl-mediated leukocyte recruitment is important for interstitial inflammation in the kidney and that CCRl blockade late in renal disease can halt disease progression and improve renal function (J Am Soc Nephrol 15: 1504-1513, 2004).
  • an animal model of neutrophil recruitment in response to MIP- l ⁇ demonstrates the positive biological and pharmacodynamic activity of CCRl antagonists (US 2005/0288319 Al).
  • proline urea CCRl antagonists are provided. These compounds are useful for the treatment and prevention of inflammatory and autoimmune diseases.
  • compounds of the formula I wherein
  • B is halo-substituted phenyl or halo-substituted monocyclic heteroaryl;
  • R 1 is chosen from (Ci-C 3 )alkyl and hydro xy(C 2 -C 3 )alkyl , or R 1 is bonded to B so as to form a five- to seven- membered ring which is fused to B;
  • R 2a is H or lower alkyl;
  • R 8 is H or methyl; or Y, R 8 and the carbon atom to which R 8 is attached combine to form a three-membered carbocyclic ring;
  • X is chosen from O, S, CH-NO 2
  • a ⁇ is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5-7 membered non-aromatic ring, wherein in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C 1-6 alkyl, - 0-C 1 - ⁇ alkyl and perfluoroC ⁇ alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from Ci ⁇ alkyl, OH and -OCi ⁇ alkyl, the moiety being connected to
  • the compound of formula I is of the formula IA:
  • R 1 is selected from (C 1-3 )alkyl, hydro XyI(C 1 -3 )alkyl, and (C 1-3 )oxaalkyl; and R 2 is halogen.
  • the compound of formula I is of the formula IB:
  • A is a group A 1 . In some embodiments, when A is a group
  • a 1 , A 1 is substituted with from 1 to 3 electron- withdrawing substituents.
  • the electron-withdrawing substituents are selected from the group consisting of
  • C 1-6 alkyl aryl, heteroaryl, halogen, perfluoroCi ⁇ alkyl, -O-Ci ⁇ alkyl, -O-perfluoroCi.
  • A is 4-chloro-2,6-difluorophenyl. In some embodiments A is 4- trifiuoromethyl-2,6-dimethylphenyl.
  • A is a group A 11 In some embodiments, when A is a group
  • a 11 is substituted by at least one of the following substituents: C ⁇ alkyl and substituted phenyl.
  • a 11 is 5-(6-fluorophenyl)-isoxazol-4-yl, R 1 is methyl, R 2 is
  • A is a group A m
  • a 111 is l-[2-chlorophenyl]-ethyl
  • R 1 is methyl
  • R 2 is Cl
  • R 8 is H.
  • A is a group A IV .
  • ATM is a group AP / ⁇ .
  • ATM* is
  • a IVa is selected from the group
  • R 1 is methyl
  • R 2 is Cl
  • R 8 is H.
  • a . IVa has the following stereochemistry:
  • a Ivb is wherein one of W 1 and W 2 is CH 2 CH 2 ,
  • R and R" are each independently lower alkyl, and Z , Z and Z are each independently selected from H, halogen, C h alky!, Ci ⁇ alkoxy, and perfluoroCi-ealkyl.
  • ATM is 6-chlorochroman-3-yl
  • R 1 is methyl
  • R 2 is Cl
  • R 8 is H.
  • a ⁇ is a group A ⁇ 0 .
  • W 3 and W 4 wherein (a) one of W 3 and W 4 is N and the other of W 3 and W 4 is CH, or (b) one of W 3 and W 4 is NH, O or S and the other of W 3 and W 4 is a bond, and Z 1 , Z 2 and Z 3 are each independently selected from H, halogen, Ci-ealkyl, C ⁇ alkoxy, and perfluoroCi-ealkyl.
  • W 3 is CH and W 4 is N.
  • a ⁇ 0 has the structure:
  • ATM is selected from: and wherein one ofW 1 and W 2 is O, S or N(loweralkyl), and the other of W 1 and W 2 is CH 2 ; and wherein (a) one of W 3 and W 4 is N and the other of W 3 and W 4 is CH, or (b) one of W 3 and W 4 is NH, O or S and the other of W 3 and W 4 is a bond, and Z 1 , Z 2 and Z 3 are each independently selected from H, halogen, C ⁇ alkyl, Ci ⁇ alkoxy, and perfluoroCi ⁇ alkyl.
  • ATM is 3,4-dihydro-2H-pyrano [2,3-b]pyridine-4-yl.
  • A is a group A . In some embodiments, A is cycloalkyl. [0018] In some embodiments, Y is chosen from -CHOH- and -O-. In some embodiments Y is -CH 2 -.
  • X 2 is O.
  • A is chosen from (C 1 -Ce) linear alkyl, (C 1 -C O ) branched alkyl, (C 3 -C 1O )CyClOaIlCyI and substituted (C 3 -C 1O )CyClOaIlCyI.
  • A is chosen from benzene, naphthalene, indane, tetralin and their substituted counterparts.
  • A is chosen from isoxazole, thiophene, furan, pyrrole, pyridine, piperidine, oxazole, thiazole, pyrazole, and their substituted counterparts.
  • A is chosen from benzopyran, dihydrobenzopyran, indole, benzofuran, benzothiene, quinoline, isoquinoline, naphthyridine, benzimidazole, benzoxadiazole and benzothiadiazole and their substituted counterparts. In some embodiments A is chosen from
  • R 5 is chosen from (C 1 -C 6 )alkyl, phenyl, benzyl, -CH 2 OH, -
  • R 6 is chosen from hydrogen, (Ci-C 6 )alkyl, phenyl, benzyl, and when attached to carbon, - CH 2 OH;
  • X 5 is S or O;
  • X 6 is -CH- or -N-, and X 7 is -CH 2 - or -O-.
  • the compound of formula I is of the formula Id.
  • A is chosen from phenyl, benzyl, lndanyl, pyridinyl, cyclohexyl and their mono and di-substituted counterparts. In some embodiments, when the compound is of formula Id, A is chosen from phenyl and benzyl, each optionally substituted with one or two substituents chosen from halogen, CF 3 ,
  • R 1 is methyl
  • R 2 is chosen from Cl and F In some embodiments R 2 is 4-
  • compositions comprising one or more compounds of formulae I or II and a pharmaceutically acceptable carrier.
  • inflammatory or autoimmune diseases comprising administering a compound of formulae I or II.
  • the inflammatory disease or autoimmune disease is rheumatoid arthritis or multiple sclerosis.
  • the cancer is multiple myeloma.
  • a disease disease or condition selected from the group consisting of hepatocellular carcinoma, respiratory synctial virus (RSV), kidney disease, allergic asthma, Alport disease (which includes glumerulosclerosis and progressive renal fibrosis), prion diseases, sepsis, T-cell mediated liver diseases, severe respiratory viruses, chronic renal injury, and transplant and cardio allograft vascalopathy (chronic rejection) comprising administering a compound of formula I or II.
  • a disease disease or condition selected from the group consisting of hepatocellular carcinoma, respiratory synctial virus (RSV), kidney disease, allergic asthma, Alport disease (which includes glumerulosclerosis and progressive renal fibrosis), prion diseases, sepsis, T-cell mediated liver diseases, severe respiratory viruses, chronic renal injury, and transplant and cardio allograft vascalopathy (chronic rejection) comprising administering a compound of formula I or II.
  • the Alport disease is renal fibrosis.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms.
  • lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t- butyl and the like.
  • Preferred alkyl and alkylene groups are those of C 20 or below.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms.
  • Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • C 1 to C 2 o hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.
  • carbocycle refers to a cyclic structure, the ring or rings of which are composed only of carbon.
  • phenyl, naphthyl, cyclopentyl and cycloheptadienyl are carbocycle residues, pyrolidinyl is not.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy,
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylamino ethyl and methylthiopropyl.
  • Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t- butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents.
  • Heteroaryl contains 0-3 heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10- membered aromatic or heteroaromatic rings and tricyclic 13- or 14-membered aromatic or heteroaromatic rings.
  • Aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fiuorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, 4,5,6,7-tetrahydrobenzofuran, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • the terms "unsaturated aryl” or “unsaturated heteroaryl” refer to aryl and heteroaryl moieties, respectively, which are aromatic in all rings of the moiety.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Hetero arylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like. [0039] Heterocycle means a carbocycle in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • heterocycles that fall within the scope of embodiments of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, isobenzofuran, dihydrobenzofuran, tetrahydrobenzofiiran, benzothiophene, benzothiophene oxide, benzothiophene dioxide, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, benzooxadiazole, dihydrobenzooxadiazole, benzothiadiazole,
  • heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
  • heterocyclyl residues additionally include piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4- piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thia
  • Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to six H atoms in each residue are replaced with halogen, haloalkyl (which includes monohaloalkyl up to perhaloalkyl), hydroxy, loweralkoxy, haloloweralkoxy (which includes monohaloalkoxy up to perhaloalkoxy), carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, acyl, acyloxy (also referred to as alkylcarbonyloxy), -COOH, oxaalkyl, thiaalkyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, haloloweralkylthiol (which includes
  • the substituent group is aryl, cycloalkyl, heterocyclyl, aryloxy, cycloalkyloxy or heterocyclyloxy, e.g. when in a "substituted alkyl" moiety one of the hydrogen atoms is replaced by aryl, cycloalkyl, heterocyclyl, aryloxy, cycloalkyloxy or heterocyclyloxy, the substituent group itself many be further substituted with one to three groups selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, thiaalkyl, alkyl-SO 2 - and -S0 2 -heterocycle.
  • Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. also refer to perhalogenated alkyl, aryl, cycloalkyl, or heterocyclyl, i.e. where all the hydrogen atoms on the alkyl, aryl, cycloalkyl, or heterocyclyl moiety are replaced with halogen.
  • substituted aryl or substituted heteroaryl and said aryl or heteroaryl moiety contains a non- aromatic portion (e.g.
  • the substituent may be attached to either the aromatic or the non-aromatic portion of the aryl or heteroaryl moiety.
  • Substituted counterparts means the named substituent, but substituted. For instance, if A is chosen from benzene or naphthalene and their substituted counterparts, then the substituted counterpart for benzene is substituted benzene, and the substituted counterpart for naphthalene is substituted napthalene. In particular, for instance, where A is pyridinyl, a mono-substituted counterpart is and where Q is benzene (i.e. phenyl), a di-substituted counterpart is
  • halogen means fluorine, chlorine, bromine or iodine.
  • prodrug refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds in accordance with embodiments of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid- catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
  • R 1 is always chosen from (C 1 -C 3 )alkyl and hydroxy(C 2 -C 3 )alkyl although, in accordance with standard patent practice, in dependent claims it may be restricted to a subset of these values.
  • the compounds in accordance with embodiments of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include H, C, S, F, and Cl, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3 H, and carbon- 14, i.e., 14 C, radioisotopes are particularly known for their ease in preparation and detectability.
  • Radiolabeled compounds of Formulas I- II and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • the terms "methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders.
  • the term "preventing” as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition.
  • the term "mammal” is used in its dictionary sense.
  • the term “mammal” includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Car ⁇ sfamiliaris), cats, rabbits, guinea pigs, and primates, including humans.
  • the compounds described herein contain at least one asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomer ⁇ forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • R optically active
  • S secondary reagents
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • all tautomeric forms are also intended to be included, unless indicated otherwise.
  • the graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr I Chem. Ed. 62.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion, unless noted otherwise.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • solvate refers to a compound of Formulae I or II in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
  • suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19* Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfomc (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Me, Et, Ph, Tf, Ts, Ac, Boc and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl, acyl, butyloxycarbonyl and methanesulfonyl respectively.
  • HPLC, THF, DCM and DMSO represent high performance liquid chromatography, tetrahydrofuran, dichloromethane and dimethylsulfoxide, respectively.
  • a comprehensive list of abbreviations utilized by organic chemists i.e. persons of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations" is incorporated herein by reference.
  • the compounds of formulae I and II may be administered as the raw chemical, in other embodiments of the invention they may be presented as a pharmaceutical composition.
  • a pharmaceutical compositions comprising a compound of formulae I or II or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier, which constitutes one or more accessory ingredients.
  • Formulations in accordance with embodiments of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions in accordance with embodiments of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must, of course, be compatible with the active ingredient to insure the stability of the formulation.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formulae I or II, or a combination thereof, which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • Combination therapy can be achieved by administering two or more agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • combination therapy two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible.
  • Combination therapy can also include two or more administrations of one or more of the agents used in the combination. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
  • CCRl antagonists As such, they have utility in treating and preventing autoimmune disease and inflammatory diseases.
  • CCRl antagonists are therapeutic targets for the treatment and prevention of a variety of diseases, including autoimmune diseases (such as rheumatoid arthritis, Takayasu arthritis, psoriatic arthritis, ankylosing spondylitis, type 1 diabetes (recent onset), lupus, inflammatory bowel disease, Crohn's disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, thyroiditis and vasculitis); fibrosis (e.g. pulmonary fibrosis (i.e.
  • idiopathic pulmonary fibrosis interstitial pulmonary fibrosis
  • fibrosis associated with end-stage renal disease fibrosis caused by radiation, tubulo interstitial fibrosis, subepithelial fibrosis, scleroderma (progressive systemic sclerosis), hepatic fibrosis (including that caused by alcoholic or viral hepatitis), primary and secondary biliary cirrhosis); diabetic nephropathy; allergic conditions (such as asthma, contact dermatitis and atopic dermatitis); acute and chronic lung inflammation (such as chronic bronchitis, chronic obstructive pulmonary disease, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, immune complex alveolitis); atherosclerosis; vascular inflammation resulting from tissue transplant or during restenosis (including, but not limited to restenosis following angioplasty and/or stent insertion); other acute and chronic inflammatory conditions (such as synovial inflammation caused by arth
  • Compounds of formula I and II may also inhibit the production of metallo proteinases and cytokines at inflammatory sites (including but not limited to MMP9, TNF, IL-I, and IL-6) either directly or indirectly (as a consequence of decreasing cell infiltration) thus providing benefit for diseases or conditions linked to these cytokines (such as joint tissue damage, hyperplasia, pannus formation and bone resorption, hepatic failure, Kawasaki syndrome, myocardial infarction, acute liver failure, septic shock, congestive heart failure, pulmonary emphysema or dyspnea associated therewith).
  • cytokines such as joint tissue damage, hyperplasia, pannus formation and bone resorption, hepatic failure, Kawasaki syndrome, myocardial infarction, acute liver failure, septic shock, congestive heart failure, pulmonary emphysema or dyspnea associated therewith.
  • Compounds of formula I and II may also prevent tissue damage caused by inflammation induced by infectious agents (such as viral induced encephalomyelitis or demyelination, viral inflammation of the lung or liver (e.g. caused by influenza or hepatitis or respiratory syncytial virus), gastrointestinal inflammation (for example, resulting from H.
  • infectious agents such as viral induced encephalomyelitis or demyelination, viral inflammation of the lung or liver (e.g. caused by influenza or hepatitis or respiratory syncytial virus), gastrointestinal inflammation (for example, resulting from H.
  • pylori infection inflammation resulting from: bacterial meningitis, HIV- 1, HIV-2, HIV-3, cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex) fungal meningitis, lyme disease, malaria), arterial remodeling characterized by neointima formation and medial thickening for mediating inflammatory cell recruitment and endothelial dysfunction.
  • CMV cytomegalovirus
  • Herpes viruses Herpes zoster and Herpes simplex fungal meningitis, lyme disease, malaria
  • arterial remodeling characterized by neointima formation and medial thickening for mediating inflammatory cell recruitment and endothelial dysfunction.
  • R 1 is methyl. In some embodiments, R 1 is bonded to B to form a fused bicyclic ring such as:
  • X 2 is chosen from O, S and NCN. In some embodiments X 2 is O. In some embodiments Y is -CH 2 -.
  • A is a group A 1 , i.e. a mono- or bicyclic unsaturated aryl which is substituted with from 0 to 3 substituents.
  • the substituents are selected from the group consisting of C 1 ⁇ alkyl, aryl, heteroaryl, halogen, perfluoroCi.
  • A is a group A 11 , i.e. a mono- or bicyclic unsaturated heteroaryl which is substituted with from 0 to 3 substituents.
  • the substituents are selected from the group consisting Of C 1-6 alkyl, aryl, heteroaryl, halogen, perfluoroCi ⁇ alkyl, -O-C ⁇ alkyl, -O-perfluoroCi-ealkyl, -S-C ⁇ alkyl, -S-perfluoroC ⁇ alkyl, -
  • A is a group A
  • A is a group A IV .
  • ATM is a group
  • ATM is a group A ⁇ . In some embodiments, ATM is a group
  • a IVc is a group ATM .
  • the compound is of formula I, and A is a group A v , i.e. A is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted non-aromatic heterocyclyl.
  • the compound is of formula II, and A is a group A v , i.e. A is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted non-aromatic heterocyclyl.
  • A is chosen from the following structures : wherein
  • R 6 is chosen from hydrogen, (C 1 -C 6 )alkyl, phenyl, benzyl, and, when attached to carbon, - CH 2 OH;
  • X 5 is S or O;
  • X 6 is -CH- or -N-, and X 7 is -CH 2 - or -O-.
  • R 2 is chosen from Cl and F In some embodiments, R 2 is 4- Cl. In some embodiments, R 2 is chosen from Cl and F, and when Y is CH 2 , the carbon at position 2 of the pyrolidine ring is of the R configuration. In some embodiments A is substituted phenyl or benzyl.
  • compositions comprising one or more compounds of formula I or II and a pharmaceutically acceptable carrier, which can be administered to a patient in need of such treatment or prevention.
  • Pharmaceutical formulations comprising the aforementioned genera act to antagonize the CCRl receptor.
  • the pharmaceutical formulations may be administered alone or in combination with another agent, hormone, or drug, and may be administered by any number of acceptable routes.
  • Pharmaceutical formulations suitable for the use in accordance with embodiments of the invention include formulations wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
  • tert-Butyl-4-isocyanatopiperidine-l-carboxylate To a stirred solution of triphosgene (0.22 g, 0.74 mmol) in dichloromethane (5 ml) cooled to O 0 C was added dropwise a premixed solution of 4-aminopiperidine-l-carboxylic acid tert- butyl ester (0.40 g, 1.99 mmol) and N,N-diisopropylethylamine (0.76 ml, 4.36 mmol) dissolved in dichloromethane (8 ml) slowly via a syringe. The reaction mixture was stirred for an hour at room temperature. The isocyanate thereby generated was used directly in the next step without any further manipulation or purification.
  • (S)-8-fluoro-4-isocyanatochroman To a stirred solution of triphosgene (22 mg, 0.074 mmol) in DCM (0.5 ml) cooled to O 0 C was added dropwise a premixed solution of (S)-8-fluorochroman-4-amine (33 mg, 0.20 mmol) and DIEA (0.077 ml, 0.44 mmol) dissolved in DCM (0.8 ml) slowly via a syringe. The reaction mixture was stirred for an hour at room temperature. The isocyanate thereby generated was used directly in next step without any further manipulation or purification.
  • reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO 4 , 5% aquesous NaHCO 3 , and brine, dried over Na 2 SO 4 filtered and then concentrated in vacuo.
  • Preparative HPLC purification provided the desired compound as a white solid (65.4 mg, 72%).
  • Step B (y)-2-(4-(trifluoroinethyl)benzylideneaiiiino)-2-phenylethane-triiiiethylsilylether.
  • (S)-2- [(S)-l-(4-(trifluoromethyl)phenyl] propylamino-2-phenylethane- trimethylsilylether To a 100 mL round bottom flask (flame-dried at -5O 0 C) were added anhydrous THF (12.5 mL) and EtMgCl (2.0 M in Et 2 O, 14.4 mL). At -5O 0 C, half of the material from Step B in anhydrous THF (12.5 mL) was added dropwise.
  • Step D [00112] (i?)-l-(l-isocyanato-2-methylpropyl)-4-(trifluoromethyl)benzene.
  • Triphosgene (43.5 mg, 0.15 mmol) in dichloromethane (1 niL) was added dropwise to (S)- 2- methyl- 1- [4-(trifluoromethyl)phenyl]propan-l-amine (95.9 mg, 0.44 mmol) in dichloromethane (1 niL). The mixture was stirred at room temperature for 3 h; precipitate formed. This material was used directly to the next step.
  • Step B [00134] ⁇ -chloro-S ⁇ -dihydro-lH-chromen-S-amine. 6-chloro-3-nitro-2H-chromene (1.055 g) was dissolved in Et 2 O (100 mL). Lithium aluminum hydride (LA ⁇ ) (605 mg, 3.2 eq) was added in several portions. The reaction mixture was refluxed overnight under argon. It was then cooled down, and the reaction quenched by adding dropwise H 2 O (2 mL), 2 N NaOH (1.25 mL), and more H 2 O (6 mL). The mixture was filtered and the filtrate was collected. The aqueous phase was extracted with Et 2 O. The combined organic phase was dried over Na 2 SO 4 , and concentrated.
  • LA ⁇ Lithium aluminum hydride
  • a mixture including scintillation proximity assay (SPA) beads and cell membrane expressing human CCRl, was prepared in assay buffer (130 mM NaCl + 5 niM KCl + ImM MnCl + 50 niM Tris HCl at pH 7.4 + 0.1% bovine serum albumin (BSA)) at the ratio of 50 ⁇ g/ml membrane to 10 mg/ml SPA beads. 10 ⁇ l of the mixture was transferred to each well of a 384- well assay plate yielding a final concentration for the membrane and SPA beads of 0.5 ⁇ g/well and 100 ⁇ g/well, respectively
  • Human monocyte cell line THPl and a 5 mM chemotaxis plate from Chemicon were used. Cells were resuspended at 2 x 10 6 cells/ml in assay buffer (RPMI with 0.1% BSA). Compounds were initially diluted in DMSO and then with the assay buffer. Compounds were preincubated with the cells at 37 0 C for 15 minutes. A solution of 1 nM MIP- l ⁇ in the assay buffer was prepared. 150 ⁇ l of InM MIP- l ⁇ solution was then added to the bottom chamber ofthe assay plate, the insert re-placed into the assay plate and the plate allowed to equilibrate for 15 minutes at 37°C.

Abstract

Compounds of the formulae (I) and (II) are disclosed. The compounds are CCRl antagonists which are useful for the treatment and prevention of inflammatory and autoimmune diseases. Other embodiments are also disclosed.

Description

PROLINE UREA CCRl ANTAGONISTS FOR AUTOIMMUNE DISEASES &
INFLAMMATION
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Appl. Ser. No. 60/807,837, filed July 20, 2006, the contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to proline urea CCRl antagonists which are useful for the treatment and prevention of inflammatory and autoimmune diseases.
BACKGROUND
[0003] The selective accumulation and activation of leukocytes in inflamed tissues contributes to the pathogenesis of inflammatory and autoimmune diseases. Chemokines and their receptors, which belong to a family of seven transmembrane G- protein coupled receptors are involved in the selective accumulation and activation of leukocytes in inflamed tissues, and in the pathogenesis of inflammatory and autoimmune diseases. One such receptor is CCRl which is a receptor for CC chemokines, such as CCL5 (RANTES) and CCL3 (MIP- lα).
[0004] CCRl is a therapeutic target for a variety of diseases. In vivo studies on mice indicate that CCRl-mediated leukocyte recruitment is important for interstitial inflammation in the kidney and that CCRl blockade late in renal disease can halt disease progression and improve renal function (J Am Soc Nephrol 15: 1504-1513, 2004). Further, an animal model of neutrophil recruitment in response to MIP- lα demonstrates the positive biological and pharmacodynamic activity of CCRl antagonists (US 2005/0288319 Al).
SUMMARY OF THE INVENTION
[0005] In accordance with embodiments of the present invention there are provided proline urea CCRl antagonists. These compounds are useful for the treatment and prevention of inflammatory and autoimmune diseases. [0006] In an embodiment of the invention, there are provided compounds of the formula I wherein
B is halo-substituted phenyl or halo-substituted monocyclic heteroaryl; R1 is chosen from (Ci-C3)alkyl and hydro xy(C2-C3)alkyl , or R1 is bonded to B so as to form a five- to seven- membered ring which is fused to B; R2a is H or lower alkyl; Y is chosen from -CH2-, - CHOH-, -C(=O)-, -CH(C1-8alkyl)-, -CHOC(=O)-(C1-8)alkyl, -C(OH)(C1-8alkyl)- and -O-; R8 is H or methyl; or Y, R8 and the carbon atom to which R8 is attached combine to form a three-membered carbocyclic ring; X is chosen from O, S, CH-NO2 and N-C≡N; and A is selected from the group consisting of A1, A11, Am, AIV and Av, wherein: A1 is mono- or bicyclic unsaturated aryl which is substituted with from O to 3 substituents; A11 is mono- or bicyclic unsaturated heteroaryl which is substituted with from O to 3 substituents; A111 is -C^alkyl-aryl or -C^alkyl-heteroaryl, wherein said aryl and heteroaryl moieties are mono- or bicyclic and are substituted with from O to 3 substituents; and wherein in each case said C^alkyl moiety is optionally substituted with lower alkyl or phenyl; Av is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocyclyl; and A is selected from the group consisting of AIVa, A™ , A^0 and A™ , wherein AIVa is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 member non-aromatic ring, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, -0-C1^ alkyl and perfluoroCi.6 alkyl, the moiety being substituted in the non- aromatic ring portion thereof with from 0-3 substituents selected from Ci^alkyl, OH and -OCi-ealkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety; A^ is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5-7 membered non-aromatic ring, wherein in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, - 0-C1 -β alkyl and perfluoroC^ alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from Ci^alkyl, OH and -OCi^alkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety through a carbon atom which is not adjacent to the ring heteroatom, A c is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5-7 membered non- aromatic ring, wherein in the aromatic ring portion of the moiety 1-3 carbon atoms have been replaced with heteroatoms, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, -0-C1^ alkyl and perfluoroCi-6 alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from C^alkyl, OH and -OC^alkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety, A is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the aromatic ring portion of the moiety 1-3 carbon atoms have been replaced with heteroatoms and in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, -0-C1.6 alkyl and perfluoro C1 _6 alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from C^alkyl, OH and -OC^alkyl, the moiety being connected to the rest of the molecule via the non- aromatic ring portion of the moiety through a carbon atom which is not adjacent to the ring heteroatom.
[0007] In accordance with another embodiment of the invention, there are provided compounds of formula II.
wherein B, Y, R1, R2a and R8 are as defined above, and A is selected from the group consisting of A1, A11, A111, A™ and Av, wherein A1, A11, A111 and AIV are as defined above, and Av is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted non-aromatic heterocyclyl. [0008] In some embodiments, the compound of formula I is of the formula IA:
wherein R1 is selected from (C1-3 )alkyl, hydro XyI(C1 -3)alkyl, and (C1-3 )oxaalkyl; and R2 is halogen. [0009] In some embodiments, the compound of formula I is of the formula IB:
[0010] In some embodiments, A is a group A1. In some embodiments, when A is a group
A1, A1 is substituted with from 1 to 3 electron- withdrawing substituents. In some embodiments, the electron-withdrawing substituents are selected from the group consisting
Of C1-6 alkyl, aryl, heteroaryl, halogen, perfluoroCi^alkyl, -O-Ci^alkyl, -O-perfluoroCi.
6alkyl, -S-C1-6alkyl, -S-perfluoroC1-6alkyl, -SONH2, -SON(C1-6alkyl)2, -CN and -NO2. In some embodiments A is 4-chloro-2,6-difluorophenyl. In some embodiments A is 4- trifiuoromethyl-2,6-dimethylphenyl.
[0011] In some embodiments, A is a group A11 In some embodiments, when A is a group
A11, A11 is substituted by at least one of the following substituents: C^alkyl and substituted phenyl. In some embodiments, A11 is 5-(6-fluorophenyl)-isoxazol-4-yl, R1 is methyl, R2 is
Cl and R8 is H.
[0012] In some embodiments, A is a group Am In some embodiments, when A is a group Am, A111 is l-[2-chlorophenyl]-ethyl, R1 is methyl, R2 is Cl and R8 is H.
[0013] In some embodiments, A is a group AIV. In some embodiments, when A is a group A™, A™ is a group AP/Λ. In some embodiments. In some embodiments, A™* is
selected from: wherein Z1, Z2 and Z3 are each independently selected from H, halogen, Chalky!, C^alkoxy, and perfluoroCi^alkyl, and m = 0, 1 or 2. In some embodiments A IVa is selected from the group
is
1,2,3,4-tetrahydronapthalen-l-yl, R1 is methyl, R2 is Cl and R8 is H. In some embodiments
A . IVa has the following stereochemistry:
[0014] In some embodiments, when A is a group A 5 A is a group A t IVb . In some
embodiments, AIvb is wherein one of W1 and W2 is CH2CH2,
CH2(CRR"), (CRR")CH2, CH2, CRR" or a bond and the other of W1 and W2 is O, S, or
1 0 1X
N(loweralkyl), wherein R and R" are each independently lower alkyl, and Z , Z and Z are each independently selected from H, halogen, Chalky!, Ci^alkoxy, and perfluoroCi-ealkyl.
In some embodiments,
embodiments, A™ is 6-chlorochroman-3-yl, R1 is methyl, R2 is Cl and R8 is H. [0015] In some embodiments, when A is a group A^, AΛ is a group A^0. In some
embodiments, wherein (a) one of W3 and W4 is N and the other of W3 and W4 is CH, or (b) one of W3 and W4 is NH, O or S and the other of W3 and W4 is a bond, and Z1, Z2 and Z3 are each independently selected from H, halogen, Ci-ealkyl, C^alkoxy, and perfluoroCi-ealkyl. In some embodiments W3 is CH and W4 is N. In some embodiments A^0 has the structure:
[0016] In some embodiments, when A is a group A L IV5 A * IV is a group A , IVd . In some
embodiments, A™ is selected from: and wherein one ofW1 and W2 is O, S or N(loweralkyl), and the other of W1 and W2 is CH2; and wherein (a) one of W3 and W4 is N and the other of W3 and W4 is CH, or (b) one of W3 and W4 is NH, O or S and the other of W3 and W4 is a bond, and Z1, Z2 and Z3 are each independently selected from H, halogen, C^alkyl, Ci^alkoxy, and perfluoroCi^alkyl. In some embodiments A™ is 3,4-dihydro-2H-pyrano [2,3-b]pyridine-4-yl.
[0017] In some embodiments, A is a group A . In some embodiments, A is cycloalkyl. [0018] In some embodiments, Y is chosen from -CHOH- and -O-. In some embodiments Y is -CH2-.
[0019] In some embodiments, X2 is O.
[0020] In some embodiments, A is chosen from (C1-Ce) linear alkyl, (C1-CO) branched alkyl, (C3-C1O)CyClOaIlCyI and substituted (C3-C1O)CyClOaIlCyI. In some embodiments A is chosen from benzene, naphthalene, indane, tetralin and their substituted counterparts. In some embodiments A is chosen from isoxazole, thiophene, furan, pyrrole, pyridine, piperidine, oxazole, thiazole, pyrazole, and their substituted counterparts. In some embodiments A is chosen from benzopyran, dihydrobenzopyran, indole, benzofuran, benzothiene, quinoline, isoquinoline, naphthyridine, benzimidazole, benzoxadiazole and benzothiadiazole and their substituted counterparts. In some embodiments A is chosen from
wherein R5 is chosen from (C1-C6)alkyl, phenyl, benzyl, -CH2OH, -
CF3, -OCF3, Br, Cl, F, CN, NO2, (C1-C6)alkoxy, phenoxy, -SO2NHR6, -SO2N(R6)2, -
C(=O)R6, -COOR6, " ; R6 is chosen from hydrogen, (Ci-C6)alkyl, phenyl, benzyl, and when attached to carbon, - CH2OH; R7 is chosen from hydrogen, (C1-C6)alkyl, phenyl, benzyl, -C(=O)R6, -COOR6 and SO2R6; X5 is S or O; X6 is -CH- or -N-, and X7 is -CH2- or -O-. [0021] In some embodiments, the compound of formula I is of the formula Id.
In some embodiments when the compound is of formula Id, A is chosen from phenyl, benzyl, lndanyl, pyridinyl, cyclohexyl and their mono and di-substituted counterparts. In some embodiments, when the compound is of formula Id, A is chosen from phenyl and benzyl, each optionally substituted with one or two substituents chosen from halogen, CF3,
(C1-C6)alkyl, phenoxy, methylenedioxy, -COOH, -C(=O)OCH3 and (C1-C6)alkoxy.
[0022] In some embodiments, R1 is methyl.
[0023] In some embodiments, R2 is chosen from Cl and F In some embodiments R2 is 4-
Cl.
[0024] There are also provided, in accordance with embodiments of the invention, pharmaceutical formulations comprising one or more compounds of formulae I or II and a pharmaceutically acceptable carrier.
[0025] There are also provided, in accordance with embodiments of the invention, methods of treating or preventing inflammatory or autoimmune diseases comprising administering a compound of formulae I or II. In some embodiments the inflammatory disease or autoimmune disease is rheumatoid arthritis or multiple sclerosis.
[0026] There are also provided, in accordance with embodiments of the invention, methods of treating or preventing endometriosis comprising administering a compound of formulae I or II.
[0027] There are also provided, in accordance with embodiments of the invention, methods of treating or preventing cancer comprising administering a compound of formulae
I or II. In some embodiments, the cancer is multiple myeloma.
[0028] There are also provided, in accordance with embodiments of the invention, methods of treating or preventing a disease disease or condition selected from the group consisting of hepatocellular carcinoma, respiratory synctial virus (RSV), kidney disease, allergic asthma, Alport disease (which includes glumerulosclerosis and progressive renal fibrosis), prion diseases, sepsis, T-cell mediated liver diseases, severe respiratory viruses, chronic renal injury, and transplant and cardio allograft vascalopathy (chronic rejection) comprising administering a compound of formula I or II. In some embodiments the Alport disease is renal fibrosis.
DETAILED DESCRIPTION OF THE INVENTION
[0029] Throughout this application, references are cited. The disclosure of these publications in their entireties are hereby incorporated by reference as if written herein.
Definitions [0030] In this specification the terms and substituents are defined when introduced and retain their definitions throughout.
[0031] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms.
Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t- butyl and the like. Preferred alkyl and alkylene groups are those of C20 or below.
Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
[0032] C1 to C2o hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.
[0033] The term carbocycle refers to a cyclic structure, the ring or rings of which are composed only of carbon. For example, phenyl, naphthyl, cyclopentyl and cycloheptadienyl are carbocycle residues, pyrolidinyl is not.
[0034] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
[0035] Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy,
3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art
[see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1(196, but without the restriction of ^|127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds). Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylamino ethyl and methylthiopropyl.
[0036] Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t- butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons.
[0037] Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents. Heteroaryl contains 0-3 heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10- membered aromatic or heteroaromatic rings and tricyclic 13- or 14-membered aromatic or heteroaromatic rings. Aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fiuorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, 4,5,6,7-tetrahydrobenzofuran, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole. The terms "unsaturated aryl" or "unsaturated heteroaryl" refer to aryl and heteroaryl moieties, respectively, which are aromatic in all rings of the moiety.
[0038] Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Hetero arylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like. [0039] Heterocycle means a carbocycle in which from one to four carbons is replaced by a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples of heterocycles that fall within the scope of embodiments of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, isobenzofuran, dihydrobenzofuran, tetrahydrobenzofiiran, benzothiophene, benzothiophene oxide, benzothiophene dioxide, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran, benzooxadiazole, dihydrobenzooxadiazole, benzothiadiazole, dihydrobenzothiadiazole, benzooxazole, benzoisoxazole, benzothiazole, benzoisothiazole, tetrahydrobenzooxazole, tetrahydrobenzoisoxazole, tetrahydrobenzothiazole, tetrahydrobenzoisothiazole and the like. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Examples of heterocyclyl residues additionally include piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4- piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl and tetrahydroquinolinyl.
[0040] Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to six H atoms in each residue are replaced with halogen, haloalkyl (which includes monohaloalkyl up to perhaloalkyl), hydroxy, loweralkoxy, haloloweralkoxy (which includes monohaloalkoxy up to perhaloalkoxy), carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, acyl, acyloxy (also referred to as alkylcarbonyloxy), -COOH, oxaalkyl, thiaalkyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, haloloweralkylthiol (which includes monohalothiol up to perhalothiol), sulfoxide, sulfonamide, dialkylsulfonamide, aryl-SO2-, substituted aryl-SO2-, alkyl-SO2-, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, aryloxy, or heteroaryloxy. When the substituent group is aryl, cycloalkyl, heterocyclyl, aryloxy, cycloalkyloxy or heterocyclyloxy, e.g. when in a "substituted alkyl" moiety one of the hydrogen atoms is replaced by aryl, cycloalkyl, heterocyclyl, aryloxy, cycloalkyloxy or heterocyclyloxy, the substituent group itself many be further substituted with one to three groups selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, thiaalkyl, alkyl-SO2- and -S02-heterocycle. Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. also refer to perhalogenated alkyl, aryl, cycloalkyl, or heterocyclyl, i.e. where all the hydrogen atoms on the alkyl, aryl, cycloalkyl, or heterocyclyl moiety are replaced with halogen. Furthermore, when reference is made to substituted aryl or substituted heteroaryl, and said aryl or heteroaryl moiety contains a non- aromatic portion (e.g. tetralin or 4,5,6,7-tetrahydrobenzo[c][l,2,5]oxadiazole), the substituent may be attached to either the aromatic or the non-aromatic portion of the aryl or heteroaryl moiety.
[0041] Substituted counterparts means the named substituent, but substituted. For instance, if A is chosen from benzene or naphthalene and their substituted counterparts, then the substituted counterpart for benzene is substituted benzene, and the substituted counterpart for naphthalene is substituted napthalene. In particular, for instance, where A is pyridinyl, a mono-substituted counterpart is and where Q is benzene (i.e. phenyl), a di-substituted counterpart is
[0042] The term "halogen" means fluorine, chlorine, bromine or iodine. [0043] The term "prodrug" refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds in accordance with embodiments of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid- catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
[0044] The variables are defined when introduced and retain that definition throughout. Thus, for example, R1 is always chosen from (C1-C3 )alkyl and hydroxy(C2-C3)alkyl although, in accordance with standard patent practice, in dependent claims it may be restricted to a subset of these values.
[0045] It will be recognized that the compounds in accordance with embodiments of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include H, C, S, F, and Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. 3H, and carbon- 14, i.e., 14C, radioisotopes are particularly known for their ease in preparation and detectability. Radiolabeled compounds of Formulas I- II and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent. [0046] The terms "methods of treating or preventing" mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders. The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.
[0047] Throughout this application, various publications are referred to. The disclosures of these publications in their entireties are hereby incorporated by reference as if written herein.
[0048] The term "mammal" is used in its dictionary sense. The term "mammal" includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Carύsfamiliaris), cats, rabbits, guinea pigs, and primates, including humans. [0049] The compounds described herein contain at least one asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomer^ forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless indicated otherwise, embodiments of the present invention are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included, unless indicated otherwise. [0050] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr I Chem. Ed. 62. 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines and single thin lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, the formula Ia is intended to encompass both of the pure enantiomers and mixtures of the two in any proportion, e.g. racemates; the formula Ib is intended to encompass a single pure enantiomer of undetermined absolute configuration; and Ic designates a single pure enantiomer of (R) absolute configuration:
1c
[0051] The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion, unless noted otherwise.
[0052] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups" Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference. Particular attention is drawn to the chapters entitled "Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols" (pages 10-86).
[0053] As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound.
[0054] The term "solvate" refers to a compound of Formulae I or II in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19* Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
[0055] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfomc (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. [0056] The following abbreviations and terms have the indicated meanings throughout: Ac = acetyl; Bu = butyl; c- = cyclo; DIEA = N,N-diisopropylethyl amine; HOAc = acetic acid; mesyl = methanesulfonyl; rt = room temperature; sat'd = saturated; s- = secondary; t- = tertiary; TMS = trimethylsilyl; tosyl = p-toluenesulfonyl. The abbreviations Me, Et, Ph, Tf, Ts, Ac, Boc and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl, acyl, butyloxycarbonyl and methanesulfonyl respectively. The abbreviations HPLC, THF, DCM and DMSO represent high performance liquid chromatography, tetrahydrofuran, dichloromethane and dimethylsulfoxide, respectively. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations" is incorporated herein by reference.
[0057] While in some embodiments of the invention the compounds of formulae I and II may be administered as the raw chemical, in other embodiments of the invention they may be presented as a pharmaceutical composition. In accordance with embodiments of the present invention, there are provided a pharmaceutical compositions comprising a compound of formulae I or II or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0058] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [0059] Formulations in accordance with embodiments of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
[0060] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
[0061 ] The pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier" also encompasses controlled release means. [0062] Compositions in accordance with embodiments of the present invention may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must, of course, be compatible with the active ingredient to insure the stability of the formulation.
[0063] The dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formulae I or II, or a combination thereof, which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. [0064] Combination therapy can be achieved by administering two or more agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation. Other combinations are also encompassed by combination therapy. For example, two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so. Combination therapy can also include two or more administrations of one or more of the agents used in the combination. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
[0065] Compounds of the genera are CCRl antagonists. As such, they have utility in treating and preventing autoimmune disease and inflammatory diseases. In particular, CCRl antagonists are therapeutic targets for the treatment and prevention of a variety of diseases, including autoimmune diseases (such as rheumatoid arthritis, Takayasu arthritis, psoriatic arthritis, ankylosing spondylitis, type 1 diabetes (recent onset), lupus, inflammatory bowel disease, Crohn's disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, thyroiditis and vasculitis); fibrosis (e.g. pulmonary fibrosis (i.e. idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis), fibrosis associated with end-stage renal disease, fibrosis caused by radiation, tubulo interstitial fibrosis, subepithelial fibrosis, scleroderma (progressive systemic sclerosis), hepatic fibrosis (including that caused by alcoholic or viral hepatitis), primary and secondary biliary cirrhosis); diabetic nephropathy; allergic conditions (such as asthma, contact dermatitis and atopic dermatitis); acute and chronic lung inflammation (such as chronic bronchitis, chronic obstructive pulmonary disease, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, immune complex alveolitis); atherosclerosis; vascular inflammation resulting from tissue transplant or during restenosis (including, but not limited to restenosis following angioplasty and/or stent insertion); other acute and chronic inflammatory conditions (such as synovial inflammation caused by arthroscopy, hyperuremia, or trauma, osteoarthritis, ischemia reperfusion injury, glomerulonephritis, nasal polyosis, enteritis, Behcet's disease, preeclampsia, oral lichen planus, Guillian-Barre syndrome); acute and/or chronic transplant rejection (including xenotransplantation); HIV lnfectivity (co-receptor usage); granulomatous diseases (including sarcoidosis, leprosy and tuberculosis); conditions associated with leptin production (such as obesity, cachexia, anorexia, type II diabetes, hyperlipidemia and hypergonadism); Alzheimer's disease and other neurodegenerative diseases; osteolytic lesion and sequelae associated with certain cancers such as multiple myeloma; diagnosis and treatment of endometriosis; analgesia. Compounds of formula I and II may also inhibit the production of metallo proteinases and cytokines at inflammatory sites (including but not limited to MMP9, TNF, IL-I, and IL-6) either directly or indirectly (as a consequence of decreasing cell infiltration) thus providing benefit for diseases or conditions linked to these cytokines (such as joint tissue damage, hyperplasia, pannus formation and bone resorption, hepatic failure, Kawasaki syndrome, myocardial infarction, acute liver failure, septic shock, congestive heart failure, pulmonary emphysema or dyspnea associated therewith). Compounds of formula I and II may also prevent tissue damage caused by inflammation induced by infectious agents (such as viral induced encephalomyelitis or demyelination, viral inflammation of the lung or liver (e.g. caused by influenza or hepatitis or respiratory syncytial virus), gastrointestinal inflammation (for example, resulting from H. pylori infection), inflammation resulting from: bacterial meningitis, HIV- 1, HIV-2, HIV-3, cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex) fungal meningitis, lyme disease, malaria), arterial remodeling characterized by neointima formation and medial thickening for mediating inflammatory cell recruitment and endothelial dysfunction.
[0066] In some embodiments, R1 is methyl. In some embodiments, R1 is bonded to B to form a fused bicyclic ring such as:
[0067] In some embodiments X2 is chosen from O, S and NCN. In some embodiments X2 is O. In some embodiments Y is -CH2-.
[0068] In some embodiments, A is a group A1, i.e. a mono- or bicyclic unsaturated aryl which is substituted with from 0 to 3 substituents. In some embodiments, the substituents are selected from the group consisting of C1^ alkyl, aryl, heteroaryl, halogen, perfluoroCi.
6alkyl, -O-C1-6alkyl, -O-perfluoroQ ^alkyl, -S-C1-6alkyl, -S-perfluoroC1-6alkyl, -SONH2, -
SON(C1-6alkyl)2 and -NO2.
[0069] In some embodiments, A is a group A11, i.e. a mono- or bicyclic unsaturated heteroaryl which is substituted with from 0 to 3 substituents. In some embodiments, the substituents are selected from the group consisting Of C1-6 alkyl, aryl, heteroaryl, halogen, perfluoroCi^alkyl, -O-C^alkyl, -O-perfluoroCi-ealkyl, -S-C^alkyl, -S-perfluoroC^alkyl, -
SONH2, -SON(Ci-6alkyl)2 and -NO2.
[0070] In some embodiments, A is a group A
[0071] In some embodiments, A is a group AIV. In some embodiments, A™ is a group
AIVa. In some embodiments, A™ is a group A^. In some embodiments, A™ is a group
AIVc. In some embodiments, AIV is a group A™ .
[0072] In some embodiments, the compound is of formula I, and A is a group Av, i.e. A is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted non-aromatic heterocyclyl. In some embodiments, the compound is of formula II, and A is a group Av, i.e. A is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted non-aromatic heterocyclyl.
[0073] In some embodiments A is chosen from the following structures : wherein
R3 is chosen from (C1-C6)alkyl, phenyl, benzyl, -CH2OH, -CF3, -OCF3, Br, Cl, F, CN, NO2, (Ci-C6)alkoxy, phenoxy, -SO2NHR6, -SO2N(R6)2, -C(=O)R6, -COOR6,
and R6 is chosen from hydrogen, (C1-C6)alkyl, phenyl, benzyl, and, when attached to carbon, - CH2OH; R7 is chosen from hydrogen, (C1-C6)alkyl, phenyl, benzyl, -C(=O)R6, -COOR6 and SO2R6; X5 is S or O; X6 is -CH- or -N-, and X7 is -CH2- or -O-.
[0074] In some embodiments, R2 is chosen from Cl and F In some embodiments, R2 is 4- Cl. In some embodiments, R2 is chosen from Cl and F, and when Y is CH2, the carbon at position 2 of the pyrolidine ring is of the R configuration. In some embodiments A is substituted phenyl or benzyl.
[0075] There are also provided, in accordance with embodiments of the invention, methods of preventing or treating inflammatory diseases and autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. There are also provided, in accordance with embodiments of the invention, pharmaceutical formulations comprising one or more compounds of formula I or II and a pharmaceutically acceptable carrier, which can be administered to a patient in need of such treatment or prevention. Pharmaceutical formulations comprising the aforementioned genera act to antagonize the CCRl receptor. The pharmaceutical formulations may be administered alone or in combination with another agent, hormone, or drug, and may be administered by any number of acceptable routes. Pharmaceutical formulations suitable for the use in accordance with embodiments of the invention include formulations wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
[0076] Processes for obtaining compounds in accordance with embodiments of the invention are presented below.
EXAMPLES
Example 1
Step A
[0077] (R)-tert-butyl 2- [(4-chlorobenzyl)(methyl)carbamoyl] pyrrolidine-1 - carboxylate. (R)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.15 g, lO mmol) was dissolved in dichloromethane (10ml). N-(4-chlorobenzyl)-N-methylamine (1.56 g, 10 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.92 g) were added with stirring. The reaction mixture was stirred for 12 h then washed with water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to afford a white amorphous solid (2.3 g, 65%). MS" calculated: 352.16, found (MH+): 352.7.
Step B
[0078] (R)-N-(4-chlorobeiizyl)-N-inethylpyrroIidine-2-carboxaiiiide hydrochloride.
(R)-tert-butyl 2-[(4-chlorobenzyl)(methyl)carbamoyl]pyrrolidine-l-carboxylate from Step A (2.3 g, 6.5 mmol) was dissolved in 4M HCl in dioxane (10 ml) and stirred for 2hr. Evaporation of solvent afforded a white amorphous solid (1.8 g, 99%). 1H NMR (300 MHz, d-CHCl3) δ 1.91 (m, IH), 2.05 (m, IH), 2.18 (m, IH), 2.52 (m, IH), 2.95 (s, 3H), 3.48 (m, IH), 3.58 (m, IH), 4.54 (m, 2H), 4.79 (m, IH), 7.14 (d, 2H), 7.32 (m, 2H), 7.72 (m, IH).
Step C
[0079] (R)-N2-(4-chlorobenzyl)-N2-methyl-N1-[4-(trinuoromethyl)phenyl] pyrrolidine- 1,2-dicarboxamide. (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2- carboxamide hydrochloride from Step B (50 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml). 4-(trifluoromethyl)phenyl isocyanate (0.030 ml, 0.2 mmol) and N,N-diisopropylethylamine (0.050 ml) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Purification by silica gel column chromatography (ethyl acetate/hexane) afforded the desired product as a white amorphous solid (40.9 mg, 47%). 1H NMR (300 MHz, d-DMSO) δ 1.66 (m, IH), 1.84 (m, 2H), 2.12 (m, IH), 2.91 (s, 3H), 3.50 (m, 2H), 4.30 (m, IH), 4.47 (m, IH), 4.71 (m, IH), 7.24 (m, 4H), 7.49 (d, 2H), 7.63 (m, 2H), 8.58 (s, IH). MS: calculated: 439.13, found (MH+): 439.8.
Example 2
[0080] (R)-4-chlorophenyl 2-[(4-chlorobenzyl)(methyl)carbamoyl] pyrrolidine- 1- carboxylate. (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride from Example 1 (50 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml). 4- chlorophenyl chloroformate (0.030 ml, 0.2 mmol) and N,N-diisopropylethylamine (0.050 ml) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Purification by silica gel column chromatography (EtOAC/hexane) afforded the desired product as a white amorphous solid (47 mg, 58%). 1H NMR (300 MHz, d-DMSO) δ 1.83 (m, 3H), 2.22 (m, IH), 2.87 (s, 3H), 3.56 (m, IH), 4.36 (m, IH), 4.76 (m, 2H), 6.90 (m, IH), 7.07 (m, 4H), 7.30 (m, 3H). MS: calculated. 406.09, found (MH+): 406.8.
Example 3
Step A
[0081] (R)-(l-isocyanatoethyl)cyclohexane. Triphosgene (43.5 mg, 0.15 mmol) in DCM (1 niL) was added dropwise to a solution of (R)-I -eye lohexylethanamine (56 mg, 0.44 mmol) in DCM (1 mL). The resulting solution was stirred at room temperature for 3 h. The material was directly used in the next step without further purification.
Step B
[0082] (R)-N2-(4-chlorobenzyl)-N1 - [(R)- 1 -cyclohexylethyl] -N2-methylpyrrolidine- 1,2- dicarboxamide. The above reaction mixture was added dropwise to a solution of (R)-N-(4- chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride (116 mg, 0.4 mmol) and N,N-diisopropylethyl amine (DIEA) (175 DL) in DCM (2 mL). The mixture was stirred at room temperature for 10 min, and purified by preparative HPLC to afford the desired product (78.7 mg, 49%). 1H NMR (300 MHz, d-CHC13) δ 0.95-1.36 (m, 9H), 1.65-1.77 (m, 5H), 1.91 (m, IH), 2.01-2.06 (m. IH), 2.24 (m, 2H), 2.97 (s, IH), 3.02 (s, 2H), 3.37 (m, IH), 3.53 (m, IH), 3.70 (m, IH), 4.48-4.74 (m, 2H), 4.86-4.93 (m, IH), 7.17 (m, 2H), 7.28 (m, 2H). MS: calculated: 405.22, found (MH+): 406.0.
Example 4
Step A
[0083] tert-Butyl-4-isocyanatopiperidine-l-carboxylate. To a stirred solution of triphosgene (0.22 g, 0.74 mmol) in dichloromethane (5 ml) cooled to O0C was added dropwise a premixed solution of 4-aminopiperidine-l-carboxylic acid tert- butyl ester (0.40 g, 1.99 mmol) and N,N-diisopropylethylamine (0.76 ml, 4.36 mmol) dissolved in dichloromethane (8 ml) slowly via a syringe. The reaction mixture was stirred for an hour at room temperature. The isocyanate thereby generated was used directly in the next step without any further manipulation or purification.
Step B
[0084] (R)-tert-Butyl 4-(2-(carbamoyl)pyrrolidine-l-carboxamido)piperidine-l- carboxylate. To the crude reaction mixture from Step A containing tert-butyl-4- isocyanatopiperidine-1-carboxylate (0.45 g, 2.0 mmol) stirred in dichloromethane (13 ml) was added a solution of (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride (0.5 g, 2.0 mmol) and N,N-diisopropylethylamine (0.76 ml, 4.36 mmol) in dichloromethane (5 ml) in one portion. The resulting mixture was then allowed to stir at room temperature 12 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO4, 5% aquesous NaHCO3, and brine, dried over Na2SO4, filtered and then concentrated in vacuo. Flash chromatography purification (hexane/EtOAc) provided the desired product as a white powder (0.73g, 78%). 1H NMR (300 MHz, d-CHCl3) δ 1.43 (s, 9H), 1 89 (m, 5H), 2.11 (m, IH), 2.22 (m, 2H), 2.87 (m, 2H), 3.01 (s, 3H), 3.28 (m, IH), 3.49 (m, IH), 3.72 (m, IH), 4.0 (m, 2H), 4.67 (m, 2H), 4.84 (m, IH), 7.30 (m, 4H). MS: calculated: 478.23, found (MH+): 478.8.
Step C
[0085] (R)-N2-(4-chlorobenzyl)-N2-methyl-N1-(piperdin-4-yl)pyrroUdine-l,2- dicarboxamide hydrochloride. (R)-tert-Butyl 4-(2-(carbamoyl)pyrrolidine-l- carboxamido)piperidine-l-carboxylate from Step B (0.73 g, 1.53 mmol) was treated with a chilled solution of ethanol (15 ml) containing hydrochloric acid (15 wt.%). The reaction mixture was stirred for 2 h at room temperature and then evaporated to dryness. The residue was azeotroped with anhydrous dichloromethane (25 ml, 3x). A white foamy product (0.58 g, 100%) was obtained. This was used in the next step directly without further purification. 1H NMR (300 MHz, d-CH3OH) δ 1.90 (m, 3H), 2.01 (m, 5H), 2.22 (m, IH), 3.00 (s, 3H), 3.07 (m, 2H), 3.49 (m, 4H), 3.77 (m, IH), 4.50 (m, 2H), 4.80 (m, IH), 7.30 (m, 4H). MS. calculated: 378.18, found (MH+): 379.0.
Step D
[0086] (R)-N2-(4-chlorobenzyl)-N2-methyl-N1-(l-methyIsuIfonyl)piperdύi-4- yl)pyrrolidine-l,2-dicarboxamide. To a stirred solution of (R)-N2-(4-chlorobenzyl)-N2- methyl-N1-(piperdin-4-yl)pyrrolidine-l,2-dicarboxamide hydrochloride from Step C (50 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.045 ml, 0.26 mmol) in dichloromethane (2 ml) was added methanesulfonyl chloride (0.010 ml, 0.13 mmol). The reaction mixture was stirred for 12 h at room temperature and then evaporated to dryness. Preparative HPLC purification provided the desired compound as a white solid (34.7 mg, 58%). 1H NMR (300 MHz, d-CHCl3) δ 1.50 (m, 2H), 1.87 (m, 2H), 2.02 (m, 2H), 2.17 (m, 2H), 2.76 (s, 3H), 2.98 (s, 3H), 3.32 (m, IH), 3.55 (m, 3H), 3.75 (m, 2H), 4.34 (m, IH), 4.58 (m, 2H), 4.82 (m, IH), 7.22 (m, 4H). MS: calculated: 456.16, found (MH+): 456.9. [0087] (R)-N2-(4-chlorobenzyl)-N2-methyl-N1-(l-tosylpiperdin-4-yl)pyrroUdine-l,2- dicarboxamide. To a stirred solution of (R)-N -(4-chlorobenzyl)-N -methyl-N -(piperdin- 4-yl)pyrrolidine-l,2-dicarboxamide hydrochloride from Step C (50 mg, 0.13 mmol) and DIEA (0.045 ml, 0.26 mmol) in DCM (2 ml) was added p-tolylsulfonyl chloride (24 mg, 0.13 mmol). The reaction mixture was stirred for 12 h at room temperature and then evaporated to dryness. Preparative HPLC purification provided the desired compound as a white solid (54.6 mg, 78%). 1H NMR (300 MHz, d-CHCl3) δ 1.48 (m, 2H), 2.21 (m, IH), 1.98 (m, 3H), 2.35 (m, 2H), 2.42 (s, 3H), 2.97 (s, 3H), 3.28 (m, IH), 3.48 (m, 3H), 3.72 (m, 2H), 4.18 (m, IH), 4.51 (m, 2H), 4.79 (m, IH), 7.14 (m, 2H), 7.22 (m, 2H), 7.31 (m, 2H), 7.59 (m, 2H). MS" calculated: 532.19, found (MH+)- 532.8.
[0088] (R)-N2-(4-chlorobenzyl)-N1-(l-benzoylpiperidin-4-yl)-N2-methylpyrroIidine- 1,2-dicarboxamide. To a stirred solution of (R)-N2-(4-chlorobenzyl)-N2-methyl-N1- (piperdin-4-yl)pyrrolidine-l,2-dicarboxamide hydrochloride from Step C (50 mg, 0.13 mmol) and DIEA (0.045 ml, 0.26 mmol) in DCM (2 ml) was added benzoyl chloride (0.015 ml, 0.13 mmol). The reaction mixture was stirred for 12 h at room temperature and then evaporated to dryness. Preparative HPLC purification provided the desired compound as a white solid (33.3 mg, 53%). 1H NMR (300 MHz, d-CHCl3) δ 1.32 (m, 2H), 1.87 (m, 2H), 1.98 (m, 2H), 2.19 (m, 2H), 2.99 (s, 3H), 3.15 (m, 2H), 3.32 (m, IH), 3.46 (m, IH), 3.73 (m, IH), 3.90 (m, IH), 4.57 (m, 3H), 4.82 (m, IH), 5.17 (br s, IH), 7.12 (m, IH), 7.31 (m, 3H), 7.38 (m, 5H). MS. calculated: 482.21, found (MH+). 482.9.
[0089] (R)-ethyl-4-(2-(carbamoyl)pyrrolidine-l -carboxamido)piperidine-l - carboxylate. To a stirred solution of (R)-N2-(4-chlorobenzyl)-N2-methyl-N1-(piperdin-4- yl)pyrrolidine-l,2-dicarboxamide hydrochloride from Step C (50 mg, 0.13 mmol) and DIEA (0.045 ml, 0.26 mmol) in DCM (2 ml) was added ethylchloroformate (0.012 ml, 0.13 mmol). The reaction mixture was stirred for 12 h at room temperature and then evaporated to dryness. Preparative HPLC purification provided the desired compound as a white solid (45.6 mg, 76%). 1H NMR (300 MHz, d-CHCl3) δ 1.23 (m, 3H), 1.35 (m, IH), 1.97 (m, 3H), 2.17 (m, 2H), 2.86 (m, 2H), 2.99 (s, 3H), 3.29 (m, IH), 3.49 (m, IH), 3.79 (m, IH), 4.08 (m, 2H), 4.14 (m, 4H), 4.49 (m, 2H), 4.85 (m, IH), 7.16 (m, IH), 7.28 (m, 2H), 7.32 (m, IH). MS: calculated: 450.2, found (MH+): 450.9. [0090] (R)-N2-(4-chlorobenzyl)-N1-(l-benzylpiperidin-4-yl)-N2-methylpyiτoπdine- 1,2-dicarboxamide. To a stirred solution of (R)-N -(4-chlorobenzyl)-N -methyl-N - (piperdin-4-yl)pyrrolidine-l,2-dicarboxamide hydrochloride from Step C (50 mg, 0.13 mmol) in 1,2-dichloroethane with 3% AcOH (2 ml) was added benzaldehyde (0.013 ml, 0.13 mmol). The reaction mixture was stirred for 2 h at room temperature before the addition of sodium triacetoxyboro hydride (28 mg, 0.13 mmol). The resulting mixture was then stirred at room temperature for 12 h. The mixture was concentrated and the residue diluted with dichloromethane (10 ml) and washed with NaHCO3 and brine, dried over Na2SO4, filtered and then evaporated to dryness. Preparative HPLC purification provided the desired compound as a white solid (29.6 mg, 48%). 1H NMR (300 MHz, d-CHCl3) δ 1.85 (m, 2H), 2.04 (m, 4H), 2.13 (m, 2H), 2.71 (m, 2H), 2.97 (s, 3H), 3.35 (m, IH), 3.51 (m, 3H), 3.86 (m, IH), 4.14 (m, 2H), 4.19 (br s, IH), 4.46 (m, 2H), 4.78 (m, IH), 7.13 (m, IH), 7.26 (m, 2H), 7.38 (m, IH), 7.44 (m, 5H). MS: calculated: 468.23, found (MH+): 469.0.
Example 5 - (RVN-fΦchlorobenzylVl-fcarbamimidoylVN-inethylpyn-olidine-l- carboxamide
Step A
[0091] Diphenyl cyanocarbonimidate (238 mg, 1.0 mmol) was dissolved in acetonitrile (2 ml). 4-(trifluoromethyl)aniline (0.116 ml, 1.0 mmol) was added and the mixture stirred at 85°C for 3 h. The reaction mixture was evaporated and the residue purified by silica gel column chromatography (EtOAc/hexane) to afford the desired product as a white amorphous solid (16 mg, 5%). (Poor yield was due to inferior quality of diphenyl cyanocarbonimidate reagent. )
Step B
[0092] The purified product from Step A (16 mg, 0.05 mmol) and (R)-N-(4- chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride from Example 1 (14 mg, 0.05 mmol) were dissolved in acetonitrile (1 ml) with N,N-diisopropylethylamine (0.050 ml). The mixture was stirred at 850C for 16 h. The reaction mixture was evaporated and the residue purified by silica gel column chromatography (EtOAc/ hexane) to afford the desired product as a white amorphous solid (15 mg, 64%). 1H NMR (300 MHz, d-DMSO) δ 1.78 (m, 4H), 2.89 (s, 3H), 3.37 (m, 2H), 4.29 (m, IH), 4.74 (d, IH), 5.00 (m, IH), 7.25 (m, 6H), 7.58 (m, 2H), 9.59 (s, IH). MS: calculated: 463.14, found (MH+): 464.0.
Example 6
[0093] (R)-N-(4-chlorobenzyl)-l-(carbamothioyl)-N-methylpyrrolidine-2- carboxamide. (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride (250 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (1 ml). 4- (trifluoromethyl)phenyl isothiocyanate (230 mg, 1.0 mmol) and N,N-diisopropylethylamine (0.250 ml) were added while stirring. The reaction mixture was stirred for 3 h then evaporated to dryness. Purification by silica gel column chromatography (EtO Ac/he xane) afforded the desired product as a white amorphous solid (316 mg, 70%). 1H NMR (300 MHz, d-DMSO) δ 1.99 (m, IH), 2.20 (m, 2H), 2.44 (m, IH), 3.14 (s, 3H), 3.88 (m, 2H), 4.42 (m, IH), 4.84 (m, IH), 5.49 (m, IH), 7.45 (m, 3H), 7.55 (m, IH), 7.80 (s, 4H), 9.47 (s,lH). MS: calculated: 455.10, found (MH+): 455.6.
Example 7
Step A
[0094] 2-(4-chlorobenzylamino)ethanol. 4-chlorobenzadehyde (2 g, 14.2 mmol), 2- aminoethanol (1.03 ml, 17.1 mmol) and sodium bicarbonate (2.4 g) were mixed in methyl alcohol (30 ml). The reaction mixture was refluxed for 4 h. The mixture was cooled to 5°C and sodium boro hydride (0.65 g) was added in 4 portions over 2 h. The reaction mixture was warmed to room temperature and stirred for 12 h. The reaction was quenched with a few drops of water and filtered. The solvent was evaporated and the residue was suspended in dichloromethane and washed with brine. The organic phase was filtered and dried over sodium sulfate. Evaporation of the solvent afforded a yellow liquid (1.9 g, 73%). MS: calculated: 185.06, found (MH+): 185.9,
Step B
[0095] (R)-tert-butyl 2-((4-chlorobenzyl)(2-hydroxyethyl)carbamoyl) pyrrolidine-1- carboxylate. (R)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.09 g, 9.7 mmol) was dissolved in dichloromethane (20 ml). 2-(4-chlorobenzylamino)ethanol (1.8 g, 9.7 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.92 g) were added with stirring. The reaction mixture was stirred for 12 h then washed with water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to afford a white amorphous solid (1.5 g, 40%). MS: calculated: 382.17, found (MH+): 382.8.
Step C
[0096] (R)-N-(4-chlorobenzyl)-N-(2-hydroxyethyl)pyrrolidine- 2-carboxamide hydrochloride. (R)-tert-butyl 2-((4-chlorobenzyl)(2-hydroxyethyl)carbamoyl) pyrrolidine-
1-carboxylate (1.5 g, 3.9 mmol) was dissolved in 4M HCl in dioxane (10 ml) and stirred for
2 h. Evaporation of solvent afforded a white amorphous solid (1.23 g, 99%).
MS: calculated: 282.11, found (MH+): 283.0.
Step D
[0097] (^-^ ^-chlorobenzy^-^ ^-hydroxyethy^-N^CS-methyl-S-phenyπsoxazol- 4-yl)pyrrolidine-l,2-dicarboxamide. (R)-N-(4-chlorobenzyl)-N-(2- hydroxyethyl)pyrrolidine-2-carboxamide hydrochloride (56 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml). 4-isocyanato-3-methyl-5-phenylisoxazole (40 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.050 ml) were added while stirring. The reaction mixture was stirred for 12 h then evaporated to dryness. Purification by silica gel column chromatography (ethyl acetate/hexane) afforded the desired product as a white amorphous solid (46.2 mg, 48%). 1H NMR (300 MHz, d-DMSO) δ 2.12 (m, 3H), 2.24 (s, 3H), 2.40 (m, IH), 3.65 (m, 6H), 4.73 (m, IH), 4.87 (m, IH), 4.93 (m, IH), 7.36 (s, 3H), 7.51 (s, IH), 7.59 (m, 3H), 7.96 (m, 2H). MS" calculated: 482.17, found (MH+): 483.0.
Example 8
X = O, Y = CH2 x = cm, γ = o
Step A
[0098] (S)-6,8-difluoro-4-isocyanatochroman. To a stirred solution of triphosgene (22 mg, 0.074 mmol) in dichloromethane (0.5 ml) cooled to 00C was added dropwise a premixed solution of (S)-6,8-difluorochroman-4-amine (35 mg, 0.19 mmol) and DIEA (0.077 ml, 0.44 mmol) dissolved in DCM (0.8 ml) slowly via a syringe. The reaction mixture was stirred for an hour at room temperature. The isocyanate thereby generated was used directly in next step without any further manipulation or purification.
[0099] (S)-8-fluoro-4-isocyanatochroman. To a stirred solution of triphosgene (22 mg, 0.074 mmol) in DCM (0.5 ml) cooled to O0C was added dropwise a premixed solution of (S)-8-fluorochroman-4-amine (33 mg, 0.20 mmol) and DIEA (0.077 ml, 0.44 mmol) dissolved in DCM (0.8 ml) slowly via a syringe. The reaction mixture was stirred for an hour at room temperature. The isocyanate thereby generated was used directly in next step without any further manipulation or purification.
[00100] 8-fluoro-4-isocyanatoisochroman. To a stirred solution of triphosgene (22 mg, 0.074 mmol) in DCM (0.5 ml) cooled to 00C was added dropwise a premixed solution of 8- fluoroisochroman-4-amine (34 mg, 0.20 mmol) and DIEA (0.077 ml, 0.44 mmol) dissolved in dichloromethane (0.8 ml) slowly via a syringe. The reaction mixture was stirred for an hour at room temperature. The isocyanate thereby generated was used directly in next step without any further manipulation or purification.
Step B
[00101] (R)-Λr2-(4-chlorobenzyl)-7V1-((S)-6,8-difluorochroman-4-yl)-N2- methylpyrrolidine-l,2-dicarboxamide. To the crude reaction mixture from Step A containing (S)-6,8-difluoro-4-isocyanatochroman (40 mg, 0.20 mmol) stirred in DCM (1.3 ml) was added a solution of (R)-7V-(4-chlorobenzyl)-7V-methylpyrrolidine-2-carboxamide hydrochloride (50 mg, 0.20 mmol) and DIEA (0.077 ml, 0.44 mmol) in DCM (0.5 ml) in one portion. The resulting mixture was then allowed to stir at room temperature 12 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO4, 5% aquesous NaHCO3, and brine, dried over Na2SO4 filtered and then concentrated in vacuo. Preparative HPLC purification provided the desired compound as a white solid (65.4 mg, 72%). 1H NMR (300 MHz, d-CHCl3) δ 1.55 (m, IH), 1.87 (m, IH), 2.02 (m, 2H), 2.18 (m, 2H), 3.03 (s, 3H), 3.31 (m, IH), 3.51 (m, IH), 4.25 (m, 2H), 4.49 (m, 2H), 4.68 (m, IH), 5.03 (m, IH), 6.75 (m, IH), 6.91 (m, IH), 7.15 (m, IH), 7.27 (m, 3H). MS: calculated: 463.15, found (MH+): 463.8. 1,2-dicarboxamide (20). To the crude reaction mixture from Step A containing (S)-8- fluoro-4-isocyanatochroman (38 mg, 0.20 mmol) stirring in DCM (1.3 ml) was added a solution of (R)-iV-(4-chlorobenzyl)-iV-methylpyrrolidine-2-carboxamide hydrochloride (50 mg, 0.20 mmol) and DIEA (0.077 ml, 0.44 mmol) in DCM (0.5 ml) in one portion. The resulting mixture was then allowed to stir at room temperature 12 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO4, 5% aquesous NaHCO3, and brine, dried over Na2SO4 filtered and then concentrated in vacuo. Preparative HPLC purification provided the desired compound as a white solid (33 mg, 38%). 1H NMR (300 MHz, d-CHCl3) δ 1.98 (m, 2H), 2.20 (m, 4H), 3.03 (s, 3H), 3.29 (m, IH), 3.49 (m, IH), 4.32 (m, 2H), 4.52 (m, IH), 4.70 (m, 2H), 5.04 (m, IH), 6.80 (m, IH), 6.94 (m, IH), 7.05 (m, IH), 7.13 (m, IH), 7.28 (m, 3H). MS: calculated: 445.16, found (MH+): 445.9.
[00103] (2R)-N2-(4-chlorobeiizyl)-jV1-(8-fluoroisochroman-4-yl)-Λr2-methylpyrroIidine- 1,2-dicarboxamide. To the crude reaction mixture from Step A containing 8-fluoro-4- isocyanatoisochroman (39 mg, 0.20 mmol) stirred in DCM (1.3 ml) was added a solution of (R)-jV-(4-chlorobenzyl)-7V-methylpyrrolidine-2-carboxamide hydrochloride (50 mg, 0.20 mmol) and DIEA (0.077 ml, 0.44 mmol) in DCM (0.5 ml) in one portion. The resulting mixture was then allowed to stir at room temperature 12 h. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with 10% aqueous KHSO4, 5% aqueous NaHCO3, and brine, dried over Na2SO4 filtered and then concentrated in vacuo. Preparative HPLC purification provided the desired compound as a white solid (40. lmg, 46%). 1H NMR (300 MHz, d-CH3OH) δ 1.90 (m, IH), 2.05 (m, 2H), 2.32 (m, IH), 3.10 (s, 3H), 3.46 (m, IH), 3.53 (m, IH), 3.81 (m, IH), 3.98 (m, IH), 4.57 (m, 2H), 4.89 (m, 3H), 5.02 (m, IH), 6.98 (m, IH), 7.32 (m, 6H). MS: calculated: 445.16, found (MH+): 445.9,
Example 9
Step A
[00104] (5)-2-(4-(trifluoromethyl)beiizyUdeneamino)-2-phenylethanol. In a 250 niL round bottom flask, equipped with Dean- Stark trap and a reflux condenser, 4- (trifluoromethyl)benzaldehyde (4.0 g, 23.0 mmol), (S)-2 (+)-phenylglycinol (3.31 g, 24.15 mmol) and anhydrous THF (126 niL) were mixed and heated at reflux under argon for 2 h with removal of solvent. The residue was used directly in the next step without further purification.
Step B (y)-2-(4-(trifluoroinethyl)benzylideneaiiiino)-2-phenylethane-triiiiethylsilylether.
1,1,1,3,3,3-hexamethyldisilazane (0.73 eq, 3.6 mL), (NH4)2SO4 (0.1 eq, 304 mg) and anhydrous THF (90 mL) were added to the residue from Step A. The reaction mixture was heated at 7O0C for 3 h, under argon. The solvent was removed in vacuo to afford the title compound (8.21 g, 94% for 2 steps). 1H NMR (300 MHz, d-CHCl3) δ 0.10 (s, 9H), 3.85 (m, 2H), 4.43 (q, IH), 7.26-7.37 (m, 3H), 7.48 (d, 2H), 7.66 (d, 2H), 7.91 (d, 2H), 8.37 (s, IH).
Step C
[00105] (S)-2- [(S)-l-(4-(trifluoromethyl)phenyl] propylamino-2-phenylethane- trimethylsilylether. To a 100 mL round bottom flask (flame-dried at -5O0C) were added anhydrous THF (12.5 mL) and EtMgCl (2.0 M in Et2O, 14.4 mL). At -5O0C, half of the material from Step B in anhydrous THF (12.5 mL) was added dropwise. The reaction mixture was stirred at -4O0C for 1 h and then at room temperature for 1 h, then added dropwise to cold, saturated NH4Cl (42 mL) with stirring at O0C. Ethyl ether (63 mL) was added and layers were separated. The organic layer was concentrated to about 12 mL. A small amount of the mixture was dried down to take an NMR. H NMR (300 MHz, d- CHCl3) δ 0.10 (s, 9H), 0.81 (t, 3H), 1.72-1.82 (m, 2H), 3.62 (m, 3H), 3.80 (q, IH), 7.17 (s, 4H), 7.28 (d, 2H), 7.43 (d, 2H).
Step D
[00106] (S)-2-(5)-l-[4-(trinuoromethyl)phenyl]propylamino-2-phenylethanol. THF (21 niL) was added to the above organic solution from Step C. The solution was cooled to O0C and H2SO4 (2.5 M, 12.6 mL) was added dropwise with stirring. After 2 h of stirring the mixture was carefully basified with 2N NaOH at O0C and extracted with Et2O (3 X 50 mL). Combined organic layers were dried over Na2SO4 and concentrated. The residue was purified with flash column chromatography and eluted with 30% EtOAc/hexane to afford 1.43 g of the title compound (41%). 1H NMR (300 MHz, d-CHCl3) δ 0.79 (t, 3H), 1.72 (m, IH), 1.87 (m, IH), 3.55-3.64 (m, 2H), 3.73-3.81 (m, 2H), 7.15 (dd, 2H), 7.24-7.30 (m, 5H), 7.50 (d, 2H). MS calculated: 323.15, found (MH+): 324.5.
Step E
(S)-l-[4-(trlfluoromethyl)phenyl]propylamine. 40% MeNH2 in water (11.3 mL, 30 eq) was added to a solution of (S)-2-(S)-l-[4-(trifiuoromethyl)phenyl]propylamino-2- phenylethanol (1.43 g, 4.42 mmol) in MeOH (17 mL). The solution was cooled to O0C and a solution OfH5IOe (6.0 g, 6 eq) in water (17 mL) was added dropwise. A white precipitate formed. The resulting reaction mixture was stirred at room temperature overnight. Et2O (85 mL) and water (57 mL) were added. The organic layer was separated, and the aqueous layer was extracted with Et2O (85 mL). The combined organic layers were concentrated to 11 mL and cooled to O0C. IN HCl (17 mL) was added dropwise followed by stirring at room temperature for 1 h. The solution was cooled to O0C, basified with solid NaOH pellets to pH 12 and extracted with Et2O (2 X 85 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification with flash column chromatography eluting with 4% 7 N ammonia in MeOH/DCM provided the desired product as pale yellow oil (0.245 g, 23%). 1H NMR (300 MHz, d-CHCl3) δ 0.85 (t, 3H), 1.67 (m, 2H), 3.87 (t, IH), 7.41 (d, 2H), 7.56 (d, 2H). MS: calculated: 203.09, found (MH+): 203.9.
Step F
[00107] (i?)-l-(l-isocyanatopropyl)-4-(trifluoromethyl) benzene. Triphosgene (43.5 mg,
0.15 mmol) in dichloromethane (1 mL) was added dropwise to (S)-l-(4-(trifiuoromethyl) phenyl)propylamine (89.4 mg, 0.44 mmol) in dichloromethane (1 niL). The mixture was stirred at room temperature for 3 h; a precipitate formed. This material was used directly to the next step.
Step G
[00108] (R^N^-chlorobenzy^-N^methyl-N1- [(S)- l-(4-(trifluoromethyl)phenyl) propyl] pyrrolidine-l,2-dicarboxamide. The resulting solution from Step F was added dropwise to a solution of (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride (116 mg, 0.40 mmol) and diisopropylethylamine (175 DL, 1.0 mmol) in dichloromethane (2 mL), then stirred for 10 min, and purified by preparative HPLC to give the title product as white oil (74.0 mg, 38.4%). 1H NMR (300 MHz, d-CHCl3) δ 0.94 (m, 3H), 1.81-1.92 (m, 3H), 2.05 (m, IH), 2.23 (m, 2H), 2.92 (s, IH), 2.99 (s, 2H), 3.44 (m, IH), 3.61 (m, IH), 4.44-4.73 (m, 2H), 4.81 (m, IH), 4.89 (q, IH), 7.08 (d, IH), 7.19 (d, 2H), 7.34 (d, IH), 7.41 (d, 2H), 7.58 (d, 2H). MS: calculated: 481 18, found (MH+): 481.9.
Example 10
Step E Step A
[00109] (5)-2-methyl-iV-[(5)-l-phenyl-2-(triinethylsilyloxy)ethyl]-l-(4-trinuoro- methylphenyl) propan-1-amine. In a 100 niL of round bottom flask (flame-dried) were added anhydrous THF (12.5 mL) and /-PrMgCl (2.0 M in Et2O, 14.4 mL) at -5O0C. (S)-2- (4-(trifluoromethyl)benzylideneamino)-2-phenylethane-trimethylsilyl ether (step B of Ex. 9) (4.1O g, 11.2 mmole) in anhydrous THF (12.5 mL) was added dropwise at -5O0C. The reaction mixture was stirred at -4O0C for 1 h, then at room temperature for 1 h. The mixture was added dropwise to cold, saturated NH4Cl (42 mL) with stirring at O0C. Ethyl ether (63 mL) was added, and the organic layer was separated and concentrated to 12 mL.
Step B
[00110] (5)-2-[(5)-2-methyl-l- (4-trifluoromethylphenyl]propylamino-2- phenylethanol. THF (21 mL) was added to the solution from Step A. The solution was cooled to O0C, and H2SO4 (2.5 M, 12.6 mL) was added dropwise with stirring. After 2 hthe mixture was carefully basified with 2N NaOH at O0C and extracted with Et2O (3 X 50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to obtain the title compound (0.90 g, 25%). 1H NMR (300 MHz, d-CHCl3) δ 0.80 (d, 3H), 1.02 (d, 3H), 1.96 (m, IH), 3.49 (d, IH), 3.55-3.61 (m, IH), 3.68 (t, IH), 3.74-3.79 (m, IH), 7.11-7.14 (m, 2H), 7.21-7.24 (m, 5H), 7.47 (d, 2H). MS: calculated: 337.17, found (MH+): 338.0.
Step C
[00111] (^-l-methyl-l-IΦ^rinuoromethy^phenyllpropan-l-amine. (S)-2-[(S)-2- methyl-l-(4-trifluoromethyl)phenyl]propylamino-2-phenylethanol (0.90 g, 2.67 mmol) was dissolved in EtOH (9 mL), and 10% Pd on active carbon (catalyst) was added to the reaction mixture. After balloon hydrogenation overnight, the reaction mixture was filtered through
Celite and washed with EtOH. The filtrate was concentrated and purified by flash column chromatography, eluted with 7 N ammonia in MeOH/DCM (3%) to afford the title compound as a clear yellow oil.
1K NMR (300 MHz, d-CHCl3) δ 0.80 (d, 3H), 0.98 (d, 3H), 1 79 (brs, 2H), 1.89 (m, IH),
3.72 (d, IH), 7.42 (d, 2H), 7.58 (d, 2H). MS: calculated: 217.11, found (MH+): 217.9.
Step D [00112] (i?)-l-(l-isocyanato-2-methylpropyl)-4-(trifluoromethyl)benzene. Triphosgene (43.5 mg, 0.15 mmol) in dichloromethane (1 niL) was added dropwise to (S)- 2- methyl- 1- [4-(trifluoromethyl)phenyl]propan-l-amine (95.9 mg, 0.44 mmol) in dichloromethane (1 niL). The mixture was stirred at room temperature for 3 h; precipitate formed. This material was used directly to the next step.
Step E
[00113] (R)-N2-(4-chlorobenzyl)-N2-methyl-N1-{(S)-2-methyl-l-[4-(trifluoromethyl) phenyl]propyl}pyrrolidine-l,2-dicarboxamide. The resulting solution from Step D was added dropwise to a solution of (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2- carboxamide hydrochloride (116 mg, 0.40 mmol) and DIEA (175 DL, 1.0 mmol) in DCM (2 mL). The mixture was stirred for 10 min. then purified by preparative HPLC to afford the title product as white oil (106.3 mg, 54%). 1H NMR (300 MHz, d-CHCh) δ 0.91 (m, 6H), 1.93 (m, IH), 2.11 (m, IH), 2.24 (m, 2H), 2.91-2.99 (m, 3H), 3.47 (m, IH), 3.65 (m, IH), 4.49 (m, 2H), 4.67-4.90 (m, 4H), 7.06 (d, IH), 7.17-7.20 (m, 2H), 7.32-7.38 (m, 3H), 7.57 (d, 2H). MS. calculated: 495.19, found (MH+): 495.9.
Example 11
Step A
[00114] 5',5'-dimethyl-Λr-[4-(trinuoromethyl)phenyl]sulfiliinine. Sulfur trioxide (1.94 g,
24.8 mmol) in DCM (4 mL) was added to DMSO (1.8 mL, 24.8 mmol) in DCM (4 mL) at - 5 to O0C. When the addition was complete 4-(trifluoromethyl)aniline (1.54 mL, 12.4 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature. After about 1 h the mixture was diluted with dichloro methane (32 mL) and washed with sodium hydroxide (1 N, 40 mL), dried and evaporated to give the title product as a solid (1.63 g, 60%). 1H NMR (300 MHz, d-CHCl3) δ 2.88 (s, 6H), 6.95 (d, 2H), 7.39 (d, 2H).
Step B
[00115] 2-[(methyltMo)methyl]-4-(trifluoromethyl)benzenamine. Sodium methoxide in methanol (1.6 g, 25%, 7.40 mmol) was added to the product from Step A (1.63 g, 7.37 mmol) in toluene (12 mL). The mixture was warmed to about 8O0C. After 1 h the mixture was allowed to cool and was poured into water (80 mL). The mixture was extracted with ethyl acetate (2 X 80 mL) and the combined extracts were dried and evaporated to give the title product as a solid (1.38 g, 85%). Recrystallized from hexanes.
1H NMR (300 MHz, d-CHCl3) δ 2.00 (s, 3H), 3.74 (s, 2H), 6.84 (d, IH), 7.29 (s, IH), 7.38
(d, IH). MS: calculated: 221.05, found (MH+): 222.2.
Step C
[00116] 2-methyl-4-(trifluoromethyl)benzenamine. A solution of 2- [(methylthio) methyl]-4-(trifluoromethyl)benzenamine (0.57 g, 2.58 mmol) in EtOH (19 mL) was hydro genated (55 pounds per square inch, psi) over Raney Ni (wet, 8 g) at room temperature for 48 h. Raney Ni was removed by filtration and washed with EtOH. The filtrate was concentrated in vacuo to obtain the desired product as a colorless oil (0.39 g, 86%). 1H NMR (300 MHz, d-CHCl3) δ 2.25 (s, 3H), 3.79 (brs, 2H), 6.61 (d, IH), 7.34 (s, 2H). MS: calculated: 175.06, found (MH+): 176.2.
Step D
[00117] l-isocyanato-2-inethyl-4-(trifluoroinethyl)beiizene. Tπphosgene (44.5 mg, 0.15 mmol) in DCM (1 mL) was added dropwise to 2-methyl-4-(trifluoromethyl) benzenamine (79 mg, 0.45 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 3 h; precipitate formed. This material was used directly in the next step. [00118] (i?)-iV2-(4-chlorobenzyl)-iV2-methyl- Λ^l-methyl-^tiifluoromethyl) phenyl]pyrτolidine-l,2-dicarboxamide. The resulting solution from Step D was added dropwise to a solution of (R)-N-(4-chlorobenzyl)-N-methylpyrrolidine-2-carboxamide hydrochloride (116 mg, 0.40 mmol) and DIEA (175 DL, 1.0 mmol) in DCM (2 mL), stirred for 10 min, and purified by preparative HPLC to give the title product as light yellow oil (57.3 mg, 32%). 1H NMR (300 MHz, d-CHCl3) δ 1.97-2.02 (m, IH), 2.10-2.14 (m, IH), 2.24-2.35 (m, 5H), 2.99 (s, IH), 3.06 (s, 2H), 3.54 (m, IH), 3.70 (m, IH), 4.59-4.67 (m, 2H), 4.89-4.98 (m, IH), 7.17 (d, IH), 7.24-7.38 (m, 3H), 7.44 (d, 2H), 7.81 (t, IH). MS: calculated: 453.14, found (MH+): 453.9.
Step A
[00119] l,2,4,5-tetrafluoro-3-isocyanato-6-(trifluoromethyl)benzene. A solution of 2,3,5,6-tetrafluoro-4-(trifluoromethyl)-benzenamine (140 mg, 0.6 mmol), DIEA (1.2 eq, 126 μL) in dichloromethane (0.5 mL) was added to a solution of triphosgene (0.37 eq, 66 mg) in DCM (0.5 mL) over 30 min via syringe pump. It was used without work-up.
Step B
[00120] ^-Λ^ ^-chlorobenzy^-Λ^-methyl-^ ^^^^-tetranuoro-Φ (trifluoroinethyl)phenyl)pyrrolidine-l,2-dicarboxamide. The above reaction mixture was added dropwise to a solution of (i?)-iV-(4-chlorobenzyl)-iV-methylpyrrolidine-2- carboxamide hydrochloride (87 mg, 0.30 mmol) and diisopropylethylamine (116 μL, 2.2 eq) in dichloromethane (0.5 mL), then stirred for 10 min, and purified with preparative HPLC to give the title product as a white oil (48.4 mg, 31.5%). 1H NMR (300MHz, d- CHCl3) δ 1.86-2.28 (m, 4H), 2.89 (s, IH), 2.99 (s, 2H), 3.57-3.65 (m, IH), 3.71-3.74 (m, IH), 4.51-4.62 (m, 2H), 4.82-4.91 (m, IH), 7.09-7.32 (m, 4H). MS: calculated: 511.82, found (MH+): 511.9.
Example 13
Step A
[00121] l-(2-isocyanatopropan-2-yl)benzene. Cumylamine (50 mg, 0.37 mmol) was dissolved in dichloromethane (3.0 mL), and DIEA (130 μL, 2 eq) and triphosgene (44 mg, 0.4 eq) were added. The reaction mixture was stirred for 10 mm. It was used without workup.
Step B
[00122] ^-Λ^ ^-chlorobenzy^-Λ^-methyl-iV'^l-phenylpropan-l-y^pyrroUdine- 1,2- dicarboxamide. To the above reaction mixture, DIEA (130 μL, 2 eq) and (R)-N-(4- chlorobenzyl)-iV-methylpyrrolidine-2-carboxamide hydrochloride (110 mg, 1 eq) were added, then stirred for 10 min, and purified with preparative HPLC to give the title product as white foam (101.6 mg, 66.3%).
1H NMR (300MHz, d-CHCl3) δ 1.68-1.74 (m, 6H), 1.88-2.24 (m, 4H), 2.93 & 2.96 (2 s,
3H), 3.38-3.50 (m, IH), 3.54-3.66 (m, IH), 4.46-4.50 (m, 2H), 4.70-4.90 (m, 2H), 7.12 (t,
2H), 7.21-7.34 (m, 5H), 7.41 (t, 2H). MS: calculated: 413.94, found (MH+): 413.9.
Example 14
major isomer minor isomer
major isomer
Step A
[00123] (5r,£)-2-((3-methyl-5-phenyIisoxazol-4-yl)methyleneamino)-2-phenylethanol.
To a flame-dried 100 mL round bottom flask were added 3-methyl-5-phenylisoxazole-4- carbaldehyde (2.0 g, 10.68 mmol), (S)-2 (+)-phenylglycinol (1.462 g, 1 eq) Na2SO4 (1.0 g) and dichloromethane (20.8 mL), which were then stirred overnight under argon. The Na2SO4 was filtered off and rinsed with 5 mL of dichloromethane. The filtrate was collected into a 100 mL round bottom flask, which contained the desired product, used in the next step without further work-up. 1H NMR (300MHz, d-CHCl3) δ 2.62 (s, 3H), 3.87 (d, 2H), 4.39 (t, IH), 7.24-7.43 (m, 5H), 7.46-7.7.50 (m, 3H), 7.65-7.68 (m, 2H), 8.49 (s, IH).
Step B
[00124] (5r,£)-Λr-((3-methyl-5-phenylisoxazol-4-yl)methylene)-l-phenyl-2- (trimethylsilyloxy)ethanamine. The above filtrate was cooled in an ice bath, then NEt3 (4.5 mL, 3 eq) and chlorotrimethylsilane (TMSCl) (2.0 mL, 1.5 eq) were added dropwise. The mixture was warmed slowly to room temperature, then stirred over a weekend under argon. The solvent was removed, hexanes (87 mL) were added and stirred for 30 min., the residue was passed through a silica gel column and rinsed with 2% NEt3 in 10%
EtO Ac/he xane (200 mL) to give 3.0 g of the desired product (yield: 74% for 2 steps).
1K NMR (300MHz, d-CHCl3) δ 0.04 (s, 9H), 2.62 (s, 3H), 3.69-3.82 (m, 2H), 4.28-4.31 (m,
IH), 7.27 (m, IH), 7.32-7.37 (m, 2H), 7.46-7.50 (m, 5H), 7.70-7.73 (m, 2H), 8.44 (s, IH).
Step C
[00125] (5)- iV-((5)-l-(3-methyl-5-phenyUsoxazol-4-yl)ethyl)-l-phenyl-2- (trimethylsilyloxy)ethanamine. To a flame dried 50 mL round bottom flask at -4O0C under argon was added Et2O (1.0 mL) and EtMgBr (3.0M in Et2O, 1.4 mL). (S,E)-N-((3- methyl-5-phenylisoxazol-4-yl)methylene)- l-phenyl-2-(trimethylsilyloxy) ethanamine (0.8 g) in Et2O (2.7 mL) was added dropwise, and slowly warmed to room temperature. The reaction was followed with 1H NMR until completion, which took about 45 min. The reaction mixture was cooled to O0C and sat. NH4Cl (4.3 mL) was added dropwise. The reaction mixture was then extracted with Et2O (16 mL X 3). The organic layers were combined and concentrated.
Step D
[00126] (5)-2-((5)-l-(3-methyl-5-phenyIisoxazol-4-yl)ethylamino)-2-phenylethanoL
Et2O (4.6 mL) was added to the above residue and cooled to O0C. HCl (3N, 6.2 mL) was added dropwise with stirring and the mixture was then stirred at O0C for an additional 10 min. The mixture was basified with 50% NaOH to pH 14, at O0C and extracted with Et2O (3
X 25 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified with a silica gel column, eluted with 7N ammonia in
MeOH/DCM (0-2.5%) to give 147.6 mg of the title compound and 26.8 mg of the other isomer.
The major product:
1H NMR (300MHz, d-CHCl3) δ 1.43 (d, 3H), 2.35 (s, 3H), 3.52-3.58 (m, IH), 3.64-3.70 (m,
IH), 3.76-3.82 (m, IH), 4.05 (q, IH), 7.14-7.18 (m, 2H), 7.28-7.31 (m, 3H), 7.33-7.39 (m,
5H). MS: calculated: 322.17, found (MH+): 323.4.
The minor product - (5r)-2-((i?)-l-(3-methyl-5-phenyIisoxazol-4-yl)ethylamino)-2- phenylethanol: 1H NMR (300 MHz, d-CHCl3) δ 1.42 (d, 3H), 2.42 (s, 3H), 3.49-3.62 (m,
3H), 3.94 (q, IH), 6.98-7.01 (m, 2H), 7.17-7.19 (m, 3H), 7.29-7.39 (m, 5H). MS: calculated:
322.17, found (MH+): 323.5. Step E
[00127] (S)-l-(3-methyl-5-phenyUsoxazol-4-yl)ethanamine. 40% MeNH2 in water (0.69 niL, 30 eq) was added to a solution of (S)-2-((S)-l-(3-methyl-5-phenylisoxazol-4- yl)ethylamino)-2-phenylethanol (80.3 mg, 0.249 mmol) in MeOH (0.99 niL). At O0C, H5IO6 (0.37 g, 6 eq) in water (0.61 mL) was added dropwise. White precipitates were formed. The resulting reaction mixture was stirred at room temperature overnight. Et2O (8.5 mL) and water (2 mL) were added. The organic layer was separated, and the aqueous layer was extracted with Et2O (8.5 mL x 3). Combined organic layers were dried over Na2SO4 and concentrated. The residue was purified with preparative thin-layer chromatography (TLC), and developed with 4% MeOH/DCM to provide the desired product as pink oil (13.2 mg, 26%). 1H NMR (300 MHz, d-CHCl3) δ 1.46 (d, 3H), 1.52 (brs, 2H), 2.49 (s, 3H), 4.41 (q, IH), 7.46-7.50 (m, 3H), 7.61-7.64 (m, 2H). MS: calculated: 202.11, found (MH+): 204.1. [00128] (i?)-l-(3-methyl-5-phenylisoxazol-4-yl)ethanamine was made the same way, from (5)-2-((i?)-l-(3-methyl-5-phenylisoxazol-4-yl)ethylamino)-2-phenylethanol. 1H NMR (300MHz, d-CHCl3) δ 1.47 (d, 3H), 1.55 (brs, 2H), 2.49 (s, 3H), 4.41 (q, IH), 7.46-7.50 (m, 3H), 7.61-7.65 (m, 2H). MS: calculated: 202.11, found (MH+): 203.0/204.1.
Step F
[00129] (i?)-4-(l-isocyanatoethyl)-3-methyl-5-phenyIisozazole. Triphosgene (7.2 mg) in dichloromethane (0.6 mL) was added to a solution of (iS)-l-(3-methyl-5-phenylisoxazol-4- yl)ethanamine (13.2 mg, 0.0653 mmol) and DIEA (23.2 μL) in dichloromethane (0.6 mL).
The mixture was stirred at room temperature for 15 nun. The product was used directly to the next step without further work-up.
[00130] (5)-4-(l-isocyanatoethyl)-3-methyl-5-phenylisozazole was made the same way from (R)- l-(3-methyl-5-phenylisoxazol-4-yl)ethanamine.
Step G
[00131] ^-Λ^ ^-chlorobenzy^-Λ^-methyl-V-^-l p-methyl-S-phenyUsoxazol^- yl)ethyl)pyrτolidine-l,2-dicarboxamide. To the resulting solution from Step F were added DIEA (23.2 μL) and (i?)-iV-(4-chlorobenzyl)-iV-methylpyrrolidine-2-carboxamide hydrochloride (19 mg), then stirred for 10 nun and purified with preparative HPLC to give the title product as a colorless oil (20.9 mg, 67%). 1H NMR (300MHz, d-CHCl3) δ 1.48 (d, 3H), 1.85-1.99 (m, 2H), 2.11-2.17 (m, 2H), 2.41 (m, 3H), 2.90 (s, IH), 2.96 (s, 2H), 3.15-3.27 (m, 2H), 4.51 (s, IH), 4.58-4.68 (m, IH), 4.72-4.83 (m, IH), 5.06-5.08 (m, IH), 7.08-7.32 (m, 5H), 7.45-7.48 (m, 2H), 7.62-7.65 (m, 2H). MS: calculated. 480.19, found (MH+): 481.0.
[00132] ^-Λ^ ^-chlorobenzy^-Λ^-methyl-^^^-i p-methyl-S-phenyUsoxazol^- yl)ethyl)pyrτolidine-l,2-dicarboxamide was made the same way from (S)-4-(l- isocyanatoethyl)-3-methyl-5-phenylisozazole. 1H NMR (SOOMHZ, d-CHCl3) δ 1.49 (d, 3H), 1.83-1.93 (m, 2H), 2.13 (m, 2H), 2.40 (m, 3H), 2.91-2.98 (m, 4H), 3.39 (m, IH), 4.44-4.62 (m, 3H), 4.70-4.79 (m, IH), 5.12 (m, IH), 7.12-7.31 (m, 5H), 7.46-7.48 (m, 2H), 7.66-7.82 (m, 2H). MS- calculated: 480.19, found (MH+): 481.0.
Example 15
Step A
[00133] ό-chloro-S-nitro-lH-chromene. 5-chlorosalicylaldehyde (3.40 g), di-rø- butylammonium chloride (1.80 g), /-pentyl acetate (52 mL) and 2-nitroethanol (2.45 niL) were placed in a one- necked 250 mL round bottom flask with a Dean- Stark trap. The mixture was vigorously refluxed with stirring for 8 h and then allowed to cool to room temperature. A dark solid was filtered by suction and thoroughly rinsed with EtOAc. The solvents were combined and then evaporated and the crude material obtained was directly chromatographed on a silica gel column (170 g, eluent: dichloro methane). The fractions containing the desired product were pooled and stirred with charcoal for 2 h. After filtration through a short pad of Celite and removal of the dichloro methane, recrystallization from hexanes afforded pure product (1.055 g, 23%). 1H NMR (300MHz, d-CHCl3) δ 5.26 (s, 2H), 6.88 (d, IH), 7.24-7.31 (m, 2H), 7.72 (s, IH).
Step B [00134] ό-chloro-S^-dihydro-lH-chromen-S-amine. 6-chloro-3-nitro-2H-chromene (1.055 g) was dissolved in Et2O (100 mL). Lithium aluminum hydride (LAΗ) (605 mg, 3.2 eq) was added in several portions. The reaction mixture was refluxed overnight under argon. It was then cooled down, and the reaction quenched by adding dropwise H2O (2 mL), 2 N NaOH (1.25 mL), and more H2O (6 mL). The mixture was filtered and the filtrate was collected. The aqueous phase was extracted with Et2O. The combined organic phase was dried over Na2SO4, and concentrated. The crude material was purified with flash column chromatography (3% 7N ammonia in MeOH/DCM) to obtain the title compound (94.2 mg, 10%). 1H NMR (300MHz, d-CHCl3) δ 1.36 (br, 2H), 2.52 (dd, IH), 2.99 (dd, IH), 3.33 (m, IH), 3.75-3.81 (m, IH), 4.08-4.13 (m, IH), 6.73 (d, IH), 7.00-7.05 (m, 2H). MS: calculated: 183.05, found (MH+): 184.0.
Step C
[00135] ό-chloro-S-isocyanato-S^-dihydro-lH-chromene. 6-chloro-3,4-dihydro-2H- chromen-3-amine (10 mg) was dissolved in dichloromethane (0.45 mL). DIEA (19 μL) and triphosgene (8.1 mg) were added to the reaction mixture, stirred for 10 min, and the crude product was used directly to the next step.
Step D
[00136] (2i?)-7V2-(4-chlorobenzyl)-iV1-(6-chlorochroman-3-yl)-iV2-methylpyiTondine- 1,2-dicarboxamide. To the above reaction mixture were added DIEA (23 μL) and (R)-N- (4-chlorobenzyl)-iV-methylpyrrolidine-2-carboxamide hydrochloride (20 mg). The reaction mixture was stirred for 10 min, then purified with preparative ΗPLC to give the title product as light yellow foam (5.2 mg, 21%). 1H NMR (300MΗz, d-CHCl3) δ 1.87-2.18 (m, 4H), 2.72-3.16 (m, 4H), 3.21-3.32 (m, IH), 3.43-3.53 (m, 2H), 4.13 (m, 2H), 4.39-4.87 (m, 5H), 6.79 (dd, IH), 7.06 (m, 2H), 7.20 (t, 2H), 7.26-7.38 (m, 2H). MS: calculated: 461.13, found (MH+): 461.9.
CCRl binding protocol
[00137] The following protocol was used to test compounds for CCRl binding. A mixture, including scintillation proximity assay (SPA) beads and cell membrane expressing human CCRl, was prepared in assay buffer (130 mM NaCl + 5 niM KCl + ImM MnCl + 50 niM Tris HCl at pH 7.4 + 0.1% bovine serum albumin (BSA)) at the ratio of 50 μg/ml membrane to 10 mg/ml SPA beads. 10 μl of the mixture was transferred to each well of a 384- well assay plate yielding a final concentration for the membrane and SPA beads of 0.5 μg/well and 100 μg/well, respectively
[00138] To generate different concentrations ofthe test compound, compound stocks were prepared using 10 step 1A log dilutions with a high concentration of 10 mM in DMSO and the lowest concentration being DMSO only without compound. An intermediate 4Ox dilution was then prepared in the assay buffer. The compound was then transferred at 10 μl/well to the assay plate. 0.5 nM [1251] -labeled macrophage inflammatory protein- lα (MIP- lα, an endogenous CCRl ligand) in the assay buffer was transferred to the assay plate at 5 μl/well, for a final ligand concentration of 0. InM. The assay plate was then centrifuged at 2500 rpm for 2 minutes and incubated for 4 hours at ambient temperature, at which time the raw data was recorded using microbeta. The IC50 was then calculated using Graphpad Prism.
Chemotaxis protocol
[00139] Human monocyte cell line THPl and a 5 mM chemotaxis plate from Chemicon were used. Cells were resuspended at 2 x 106 cells/ml in assay buffer (RPMI with 0.1% BSA). Compounds were initially diluted in DMSO and then with the assay buffer. Compounds were preincubated with the cells at 370C for 15 minutes. A solution of 1 nM MIP- lα in the assay buffer was prepared. 150 μl of InM MIP- lα solution was then added to the bottom chamber ofthe assay plate, the insert re-placed into the assay plate and the plate allowed to equilibrate for 15 minutes at 37°C. 100 μl cells +/- compound were added to the appropriate wells. The plate was then incubated at 370C for three hours. The insert was removed from the plate and 25 μl/well was transferred to the 96 well white bottom plate. The cells were quantified by adding 25 μl/well of celltitre followed by measurement of luminescence.
[00140] Using synthetic methods analogous to those described above and the CCRl assay described above, the compounds shown in Table 1 were synthesized and found to be CCRl antagonists in vitro. In Table 1, the number of asterisks below the compound number denote an IC50 as follows: ***, IC50 < 0.05 μM; **, 0.05 μM < IC50 < 0.5 μM; *, 0.5 μM < IC50 < 5.0 μM.
6
77
84
100

Claims

WE CLAIM-
1. A compound of formula
wherein
B is selected from the group consisting of halo-substituted phenyl and halo-substituted monocyclic heteroaryl;
R1 is chosen from the group consisting of (C1-C3 )alkyl, hydro Xy(C1-C3^IkVl and (C1- 3)oxaalkyl;
or R1 is bonded to B so as to form a five- to seven-membered ring which is fused to B;
R2a is H or lower alkyl;
Y is chosen from the group consisting Of-CH2-, -CHOH-, -C(=O)-, -CH(C1 -8alkyl)-, - CHOC(=O)-(C1-8)alkyl, -C(OH)(C1-8alkyl)- and -O-;
R8 is H or methyl;
or Y, R and the carbon atom to which R is attached combine to form a three-membered carbocyclic ring;
X2 is chosen from O, S, CH-NO2 and N-C≡N; and
A is selected from the group consisting of A1, A11, Aπi, Aw and Av, wherein:
A1 is mono- or bicyclic unsaturated aryl which is substituted with from O to 3 substituents;
A11 is mono- or bicyclic unsaturated heteroaryl which is substituted with from O to 3 substituents; A111 is -Ci^alkyl-aryl or -Ci^alkyl-heteroaryl, wherein said aryl and heteroaryl moieties are mono- or bicyclic and are substituted with from 0 to 3 substituents; and wherein in each case said C1-3alkyl moiety is optionally substituted with lower alkyl or phenyl;
AIV is selected from the group consisting of AIVa, A^, AWc and A™, wherein
AIVa is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 member non-aromatic ring, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, -0-C1^ alkyl and perfluoroCi -5 alkyl, the moiety being substituted in the non- aromatic ring portion thereof with from 0-3 substituents selected from Ci^alkyl, OH and -OQ-ealkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety;
AIV is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, - 0-C1 S alkyl and perfluoroC^ alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from Ci^alkyl, OH and -OCi^alkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety through a carbon atom which is not adjacent to the ring heteroatom,
AIVc is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the aromatic ring portion of the moiety 1-3 carbon atoms have been replaced with heteroatoms, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, - 0-C1.6 alkyl and perfluoroCi-6 alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from Ci^alkyl, OH and -OC^ealkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety,
AIV is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the aromatic ring portion of the moiety 1-3 carbon atoms have been replaced with heteroatoms and in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1^ alkyl, -0-C1^ alkyl and perfiuoro C1-6 alkyl, the moiety being substituted in the non-aromatic ring portion thereof with from 0-3 substituents selected from Chalky!, OH and -OC^alkyl, the moiety being connected to the rest of the molecule via the non- aromatic ring portion of the moiety through a carbon atom which is not adjacent to the ring heteroatom; and
A is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted non-aromatic heterocyclyl.
2. A compound according to claim 1 of the formula:
wherein R1 is selected from (C1-3)alkyl and hydro xyl(C2-3)alkyl; and
R >2 is halogen.
3. A compound according to claim 2 of the formula:
4. A compound according to any one of claims 1 to 3 wherein A is a group A1.
5. A compound according to claim 4 wherein said group A1 is substituted with from 1 to 3 electron-withdrawing substituents.
6. A compound according to claim 5, wherein said electron-withdrawing substituents are selected from the group consisting alkyl, aryl, heteroaryl, halogen, perfluoroCi. 6alkyl, -O-C1-6alkyl, -O-perfluoroC^alkyl, -S-C1-6alkyl, -S-perfluoroC1-6alkyl, -SONH2, - SON(C1-6alkyl)2, -CN and -NO2.
7. A compound according to claim 5 wherein said electron-withdrawing substituents are selected from the group consisting of methyl, trifluoromethyl, chloro and fluoro.
8. A compound according to claim 6 or 7 wherein A is 4-chloro-2,6-difiuorophenyl.
9. A compound according to claim 6 or 7 wherein A is 4-trifiuoromethyl-2,6- dimethylphenyl.
10. A compound according to claim 6 or 7 wherein A is 4-trifluoromethylphenyl.
11. A compound according to claim 6 or 7 wherein A is 4-chloro-2- fluorophenyl.
12. A compound according to claim 6 or 7 wherein A is 2-methyl-4- trifiuoromethylphenyl.
13. A compound according to any one of claims 1 to 3 wherein A is a group A11.
14. A compound according to claim 13 wherein said group A11 is substituted by at least one of the following substituents: C^alkyl, F, CF3, and substituted phenyl.
15. A compound according to claim 13 wherein A11 is 5-(6-fluorophenyl)-isoxazol-4-yl, R1 is methyl, R2 is Cl and R8 is H.
16. A compound according to claim 13 wherein A11 is 2-methyl-6- trifluoromethylpyridin-3-yl.
17. A compound according to claim 13 wherein A11 is 2,6-dichloropyridin-3-yl.
18. A compound according to claim 13 wherein A11 is 3,5-disubstituted-isoxazol-4-yl.
19. A compound according to claim 18 wherein A11 is 3,5-dimethylisoxazol-4-yl.
20. A compound according to any one of claims 1 to 3 wherein A is a group A111
21. A compound according to claim 20 in which A111 is l-[2-chlorophenyl]-ethyl, R1 is methyl, R2 is Cl and R8 is H.
22. A compound according to claim 20 in which A111 is selected from the group
23. A compound according to any one of claims 1 to 3 wherein A is a group A IV
24. A compound according to claim 23, wherein A IV is a group A , IVaa.
25. A compound according to claim 24 wherein said group A IVa is selected from:
1 0 "\ wherein Z , Z and Z are each independently selected from H, halogen, C^ealkyl, C1- δalkoxy, and perfluoroC^alkyl, and m = 0, 1 or 2.
26. A compound according to claim 25 wherein A , IVa is selected from the group consisting of:
27. A compound according to claim 26 wherein A , IVa is 1,2,3,4-tetrahydronapthalen- 1-yl, R1 is methyl, R2 is Cl and R8 is H.
28. A compound according to any one of claim 24 to 27 wherein A , IVa h' as the following
stereochemistry:
29. A compound according to claim 23 wherein A is a group A IVb
30. A compound according to claim 29 wherein A IVb is
wherein one of W1 and W2 is CH2CH2, CH2(CR1R"), (CR'R")CH2, CH2, CR1R" or a bond and the other of W1 and W2 is O, S, or N(loweralkyl), wherein R' and R" are each independently lower alkyl, and Z , Z and Z are each independently selected from H, halogen, Ci^alkyl, Ci^alkoxy, and perfluoroCi ^alkyl.
31. A compound according to claim 30, wherein A JVb is selected from the group consisting of:
32. A compound according to claim 30 wherein A is 6-chlorochroman-3-yl, R is methyl, R2 is Cl and R8 is H.
33. A compound according to claim 30 wherein A IVb is
34. A compound according to claim 23 wherein A is a group A IVc
35. A compound according to claim 34 wherein A IVc is
wherein (a) one of W3 and W4 is N and the other of W3 and W4 is CH, or (b) one of W3 and W4 is NH, O or S and the other of W3 and W4 is a bond, and
Z , Z and Z are each independently selected from H, halogen, Ci^alkyl, Ci^alkoxy, and perfluoroCi ^alkyl.
36. A compound according to claim 35, wherein W3 is CH and W4 is N.
37. A compound according to claim 35 wherein A^0 has the structure:
38. A compound according to claim 23 wherein A is a group A IVd
39, A compound according to claim 38 wherein A IVd is selected from
wherein one of W1 and W2 is O, S or N(loweralkyl), and the other of W1 and W2 is CH2; and wherein (a) one of W3 and W4 is N and the other of W3 and W4 is CH, or (b) one of W3 and W4 is NH, O or S and the other of W3 and W4 is a bond, and
Z1, Z2 and Z3 are each independently selected from H, halogen, and perfluoroQ _5alkyl.
40. A compound according to claim 39 wherein AIvd is 3,4-dihydro-2H-pyrano[2,3- b]pyridine-4-yl.
41. A compound according to any one of claims 1 to 3, wherein A is a Av.
42. A compound according to claim 41 wherein A is cycloalkyl.
43. A compound according to claim 1 or 2 wherein Y is chosen from -CHOH- and -O-.
44. A compound according to claim 1 or 2 wherein Y is -CH2-.
45. A compound according to any preceding claim wherein X2 is O.
46. A compound according to claim 1 wherein A is chosen from (C1-C6) linear alkyl, (C1-C6) branched alkyl, (C3-C1O)CyClOaUCyI and substituted (C3-C1O)CyC loalkyl.
47. A compound according to claim 1 wherein A is chosen from benzene, naphthalene, indane, tetralin and their substituted counterparts.
48. A compound according to claim 1 wherein A is chosen from isoxazole, thiophene, fiiran, pyrrole, pyridine, piperidine, oxazole, thiazole, pyrazole, and their substituted counterparts.
49. A compound according to claim 1 wherein A is chosen from benzopyran, dihydrobenzopyran, indole, benzofuran, benzothiene, quinoline, isoquinoline, naphthyridine, benzimidazole, benzoxadiazole and benzothiadiazole and their substituted counterparts.
50. A compound according to any of claims 1 to 3 wherein A is chosen from
wherein
R3 is chosen from (Ci-C6)alkyl, phenyl, benzyl, -CH2OH, -CF3, -OCF3, Br, Cl, F, CN, NO2, (Ci-C6)alkoxy, phenoxy, -SO2NHR6, -SO2N(R6)2, -C(=O)R6, -COOR6,
R6 is chosen from hydrogen, (C1-C6)alkyl, phenyl, benzyl, and when attached to carbon, - CH2OH;
R7 is chosen from hydrogen, (C1-C6)alkyl, phenyl, benzyl, -C(=O)R6, -COOR6 and SO2R6;
X5 is S or O;
X6 is -CH- or -N-; and
X7 is -CH2- or -O-.
51. A compound according to claim 2 of formula
52. A compound according to claim 51 wherein A is chosen from phenyl, benzyl, indanyl, pyridinyl, cyclohexyl and their mono and di-substituted counterparts.
53. A compound according to claim 52 wherein A is chosen from phenyl and benzyl, each optionally substituted with one or two substituents chosen from halogen, CF3, (C1- C6)alkyl, phenoxy, methylenedioxy, -COOH, -C(=O)OCH3 and (C1-C6)alkoxy.
54. A compound according to any one of claims 1, 2, 4 to 14, 16 to 26, 28 to 31 and 33 to 53 wherein R is methyl.
55. A compound according to any one of claims 2, 4 to 14, 16 to 26, 28 to 31 and 33 to 53 wherein R is chosen from Cl and F.
56. A compound according to claim 55 wherein R2 is 4-Cl.
57. A compound according to any preceding claim wherein R8 is H.
58. A compound according to any preceding claim wherein R2a is H.
59. A compound of formula
wherein
B is halo-substituted phenyl or halo-substituted monocyclic heteroaryl;
R1 is chosen from (Ci-C3)alkyl and hydro xy( C2-C3 )alkyl ,
or R is bonded to B so as to form a five- to seven-membered ring which is fused to B;
R2a is H or lower alkyl;
Y is chosen from -CH2-, -CHOH- and -O-;
R8 is H or methyl;
or Y, R8 and the carbon atom to which R8 is attached combine to form a three-membered carbocyclic ring;
X2 is chosen from O, S, CH-NO2 and N-C≡N; and
A is selected from the group consisting of A1, A11, Aπi, Aw and Av, wherein:
A1 is mono- or bicyclic unsaturated aryl which is substituted with from O to 3 substituents;
A is mono- or bicyclic unsaturated heteroaryl which is substituted with from O to 3 substituents,
A111 is -Ci^alkyl-aryl or -Ci^alkyl-heteroaryl, wherein said aryl and heteroaryl moieties are mono- or bicyclic and are substituted with from O to 3 substituents; and wherein in each case said C1-3alkyl moiety is optionally substituted with lower alkyl or phenyl; AIV is selected from the group consisting of AIVa, Aw , βJVc and A^ , wherein
AIVa is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 member non-aromatic ring, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1^ alkyl, -OC1^ alkyl and perfluoroC^ alkyl, the moiety being substituted in the non- aromatic ring portion thereof with from 0-3 substituents selected from Ci-galkyl, OH and -OC^alkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety;
AIvb is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1-6 alkyl, - 0-C1.6 alkyl and perfluoro C1.6 alkyl, the moiety being substituted in the non- aromatic ring portion thereof with from 0-3 substituents selected from C^alkyl, OH and -OCi^alkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety through a carbon atom which is not adjacent to the ring heteroatom,
AIVc is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the aromatic ring portion of the moiety 1-3 carbon atoms have been replaced with heteroatoms, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1^ alkyl, - O-Ci.6 alkyl and perfluoro C1^ alkyl, the moiety being substituted in the non- aromatic ring portion thereof with from 0-3 substituents selected from Ci^alkyl, OH and -OCi-ealkyl, the moiety being connected to the rest of the molecule via the non-aromatic ring portion of the moiety,
AIV is a bicyclic carbocyclic moiety in which one ring is aromatic and the other ring is a 5- 7 membered non-aromatic ring, wherein in the aromatic ring portion of the moiety 1-3 carbon atoms have been replaced with heteroatoms and in the non-aromatic ring portion of the moiety one carbon atom has been replaced with a heteroatom, the moiety being substituted in the aromatic ring portion thereof with from 0-3 substituents selected from halogen, C1 _6 alkyl, -0-C1^ alkyl and perfluoro C1^ alkyl, the moiety being substituted in the non- aromatic ring portion thereof with from 0-3 substituents selected from C^alkyl, OH and -OC^alkyl, the moiety being connected to the rest of the molecule via the non- aromatic ring portion of the moiety through a carbon atom which is not adjacent to the ring heteroatom; and
Av is selected from the group consisting of optionally substituted cycloalkyl and optionally substituted non-aromatic heterocyclyl.
60. A pharmaceutical formulation comprising a compound according to any of the claims 1 to 59 and a pharmaceutically acceptable carrier.
61. A method of prevention or treatment of inflammatory disease or autoimmune disease comprising administering a compound of claims 1 to 59.
62. A method according to claim 61 wherein said inflammatory disease or autoimmune disease is rheumatoid arthritis or multiple sclerosis.
63. A method of prevention or treatment of endometriosis comprising administering a compound of claims 1 to 59.
64. A method of prevention or treatment of cancer comprising administering a compound of claims 1 to 59.
65. A method according to claim 64 wherein said cancer is multiple myeloma.
66. A method of prevention or treatment of a disease disease or condition selected from the group consisting of hepatocellular carcinoma, respiratory synctial virus (RSV), kidney disease, allergic asthma, Alport disease (which includes glumerulosclerosis and progressive renal fibrosis), prion diseases, sepsis, T-cell mediated liver diseases, severe respiratory viruses, chronic renal injury, and transplant and cardio allograft vascalopathy (chronic rejection) comprising administering a compound of claims 1 to 59.
67. A method according to claim 66 wherein said Alport disease is renal fibrosis.
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IL196510A0 (en) 2009-11-18
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AU2007275415A1 (en) 2008-01-24
WO2008011392A8 (en) 2008-07-24
JP2009544620A (en) 2009-12-17
AU2007275415A2 (en) 2009-03-12

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