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WO2008024746A1 - 4-substituted phenoxyphenylacetic acid derivatives - Google Patents

4-substituted phenoxyphenylacetic acid derivatives Download PDF

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Publication number
WO2008024746A1
WO2008024746A1 PCT/US2007/076378 US2007076378W WO2008024746A1 WO 2008024746 A1 WO2008024746 A1 WO 2008024746A1 US 2007076378 W US2007076378 W US 2007076378W WO 2008024746 A1 WO2008024746 A1 WO 2008024746A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
group
methyl
phenyl
Prior art date
Application number
PCT/US2007/076378
Other languages
French (fr)
Inventor
George Doherty
Adam Cook
Original Assignee
Array Biopharma, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to RS20120563A priority Critical patent/RS52627B/en
Priority to US12/438,112 priority patent/US8183289B2/en
Priority to JP2009525728A priority patent/JP5582634B2/en
Priority to PL07814294T priority patent/PL2057115T3/en
Priority to NZ575507A priority patent/NZ575507A/en
Priority to UAA200902429A priority patent/UA96459C2/en
Priority to ES07814294T priority patent/ES2396715T3/en
Application filed by Array Biopharma, Inc. filed Critical Array Biopharma, Inc.
Priority to SI200731117T priority patent/SI2057115T1/en
Priority to EP07814294A priority patent/EP2057115B9/en
Priority to AU2007286829A priority patent/AU2007286829B2/en
Priority to DK07814294.0T priority patent/DK2057115T3/en
Priority to KR1020097005733A priority patent/KR101397352B1/en
Priority to CA2661164A priority patent/CA2661164C/en
Priority to MX2009001876A priority patent/MX2009001876A/en
Priority to BRPI0715617-0A2A priority patent/BRPI0715617A2/en
Publication of WO2008024746A1 publication Critical patent/WO2008024746A1/en
Priority to IL197135A priority patent/IL197135A/en
Priority to US13/448,689 priority patent/US8492437B2/en
Priority to HRP20130004TT priority patent/HRP20130004T8/en

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    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly it relates to certain 4-substituted phenoxyphenylace ⁇ c acid derivatives useful in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D 2 (PGD 2 ).
  • PPD 2 prostaglandin D 2
  • the present invention provides a compound of general formula (1):
  • R' is Ar'-L'-W-l ⁇ ;
  • 0008] L 2 is -(CR 0 RV; [0009] W is -CONR 38 - or -NR 3b CO-; [0010] R 3a and R 3b are each H or methyl;
  • each R ⁇ R b , R c and R d is independently H, F, OH, methyl or cyclopropyl, or R° and R b or
  • R c and R d together with the carbon to which they are attached form a cyclopropyl ring
  • Ar 1 is phenyl or naphthyl, each of which is unsubstituted or substituted with one or more substituents selected independently from F, Cl, CN, CF 3 , CHF 2 , CH 2 F, SF 5 , methyl, ethyl, cyclopropyl, t-butyl or OMc, or Ar 1 is 1,2,3,4-tctrahydronaphthyl which is unsubstituted or substituted by mcthoxy,
  • R 2 is H, Ci-C 6 alkyl, a residue of an amino acid or dipeptide, or CHR e (CH 2 ) q R f ;
  • R c is H, methyl or ethyl
  • R f is NR 8 R h in which R 8 and R h each independently represents a hydrogen atom or a Ci-
  • R 4 " and R 4b arc each H or methyl
  • R 5 is Ci-C 6 alkyl, CpC 6 alkoxy, C 3 -C 6 cycloalkyl, hetAr 1 , or Ar 2 ;
  • R 6 is C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , Ar 3 , or hetAr;
  • hetAr 1 is a 6 membered hetcroaryl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom and a group of formula -NR 5a R 5b in which each of R 5a and R 5b independently represents a hydrogen atom or a (1 -4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholino group;
  • hetAr 2 is a 5-6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from C 1 -C4 alkyl;
  • Ar 2 is phenyl which is unsubstituled or substituted with one or more groups independently selected from a halogen atom, CN, SF 5 , cyclopropyl, a Ci-C 4 alkyl group, a C 1 -C4 alkoxy group and a fluoroCrC.4 alkyl group;
  • Ar 3 is as defined for Ar 2 ;
  • R 7 and R 8 are independently H, methyl, or F;
  • R 9 is H or methyl
  • R 10 is H or F.
  • the compound of Formula I has the Formula Ia
  • R 1 is Ar 1 -L 1 -W-L 2 -;
  • L 2 is -(CR c R d ) mS
  • W is -CONR 3 ⁇ - or -NR 3b CO-;
  • R 3 " and R 3b are each H or methyl
  • n and m arc independently 0, 1 or 2;
  • each R 0 , R b , R c and R d is independently H, F, methyl or cyclopropyl, or R" and R b or R c and R d together with the carbon to which they are attached form a cyclopropyl ring;
  • Ar 1 is phenyl or naphthyl, each of which is unsubstituted or substituted with one or more substituents selected independently from F, Cl, CN, CF 3 , CHF 2 , CH 2 F, SF 5 , methyl, ethyl, cyclopropyl, provided that when Ar 1 is naphthyl then n is 0;
  • R 2 is H, Ci-C 6 alkyl, a residue of an amino acid or dipeptide, or CHR c (CH 2 ) q R f ; [0041] q is 1 to 6; [0042] R c is H, methyl or ethyl;
  • R f is NR B R h in which R 8 and R h each independently represents a hydrogen atom or a Ci- C A alkyl group, or R g and R h together with the nitrogen atom to which they are attached form a 5-6 membercd heterocyclic ring optionally containing a second ring heteroatom selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from CpC ⁇ alkyl;
  • R 4a and R 4b arc each H or methyl
  • R 5 is Ci-C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, hctAr 1 , or Ar 2 ; 10047] R 6 is C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyi) 2 , Ar 3 , or hetAr 2 ; 4
  • hetAr 1 is a 6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom and a group of formula -NR 5a R 5b in which each of R 5a and R Sb independently represents a hydrogen atom or a (1-4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholino group;
  • hctAr 2 is a 5-6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from C 1 -C4 alkyl;
  • Ar 2 is phenyl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom, CN, SF 5 , cyclopropyl, a C 1 -C 4 alkyl group, a Ci-C 4 alkoxy group and a fluoroCi-C4 alkyl group;
  • Ar 3 is as defined for Ar 2 ;
  • R 7 and R 8 are independently H, methyl.
  • Compounds according to the present invention have been found to be DF2 modulators and are useful in the treatment of immunologic diseases such as asthma and allergic inflammation.
  • certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
  • the compounds of Formula I include pharmaceutically acceptable salts thereof.
  • the compounds of Formula 1 also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating cnantiomers of compounds of Formula I.
  • halogen as used herein includes F, Cl, Br and I.
  • CpC 4 alkyl and C)-C 6 alkyl refer to a saturated linear or branchcd-chain monovalent hydrocarbon radical of one to four or one to six carbon atoms, respectively.
  • alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl,
  • heteroaryl refers to a monovalent aromatic radical of a 5-, 6-, or 7-membercd ring.
  • heteroaryl groups include, but are not limited to, pyridinyl, 5 imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, and pyrrolyl.
  • fluoroCi-C 4 alkyl refers to a Ci-C 4 alkyl group wherein one or more of the hydrogens is replaced by a fluorine atom. Examples include CF 3 , CH 2 F, CHF 2 ,
  • Ci-C 6 alkoxy refers to a Ci-C 6 alkyloxy group.
  • exemplary alkoxy groups include mcthoxy, ethoxy, propoxy, isopropoxy, butoxy. t-butoxy, and isobutoxy.
  • W is -CONR 3 "-.
  • An example of a particular value for K u is hydrogen.
  • W is -NR 3h CO-.
  • R 3h is hydrogen.
  • R 3b is methyl. Examples of particular values for W arc CONH, NHCO and N(CH 3 )CO.
  • L 1 is -(CR a R b ) n -. Examples of particular values for n are 0, 1 and 2.
  • L 1 is a bond
  • L 1 is -(CR°R b ).
  • R° and R b are hydrogen.
  • R° is OH.
  • R° and R b together with the carbon atom to which are attached form a cyclopropylidine ring.
  • L 1 is -(CR°R b ) 2 .
  • R" and R b are hydrogen.
  • R" and R b together with the carbon atom to which are attached form a cyclopropylidine ring. In certain embodiments, R" and R b are attached to the same carbon. In other embodiments, R" and R b arc attached to different carbon atoms.
  • L 1 examples of particular values for L 1 are a bond, -CH 2 -, -CH 2 CH 2 - and cyclopropylidcneCH 2 .
  • L 1 includes CH(OH)CH 2 .
  • V include cyclopropylidine groups, which can be represented by the following structures:
  • L 1 is -O(CR°R b )-.
  • An exemplary embodiment is -OCH 2 -.
  • examples of particular values for m are 0 and 1.
  • examples of particular values for L 2 are a bond and -CH 2 -.
  • the sum of m and n is 0, 1 and 2. Particular mention is made of compounds in which the sum of m and n is 0 or 2.
  • Examples of values for -L'-W-l ⁇ include -CONH-, -CH 2 CONH-, -CH 2 CH 2 CONH-,
  • Ar 1 is a naphthyl group or a phenyl group that is substituted by one or two substituents independently selected from F, Cl CF 3 , OMe, Me, and t-Bu.
  • Ar 1 is a naphthyl group or a phenyl group that is unsubstituted or substituted by one or tvvo substituents selected independently from F, Cl and CF 3 .
  • Ar 1 is a naphthyl group or a phenyl group that is substituted by one or two substituents independently selected from OMe, Me, and t-Bu.
  • Ar' is 1,2,3,4-tetrahydronaphthyl which is unsubstituted or substituted with OMe.
  • A is selected from the structures:
  • Ar 1 examples of particular values for Ar 1 are naphthyl, phenyl, 4-fluorophenyl, 3,4- di fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-chloro-3- fluorophcnyl, 3-chloro-4-fIuorophcnyl, 4-trifluoromethylphcnyl, 3-fluoro-4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxyphcnyl, 4- ⁇ crtbulylphenyl, 3-fluorophenyl, 4-methylphenyI, l,2,3,4-tetrahydronaphth-2-yl and 6-methoxy- l,2,3,4-tetrahydronaphth-2-yl.
  • Ar 1 is selected from naphthyl, phenyl, 4-fluorophenyl, 3,4- di fluorophenyl, 2-chlorophcnyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-chloro-3- fluorophcnyl, 3-chloro-4-fluorophenyl, 4-lrifluoromethylphenyl and 3-fluoro-4- tri fluoromethy (phenyl .
  • Ar 1 is selected from 3-trifluoromethylphenyl, 2,6- dichlorophenyl, 2,4-dichlorophenyl, 3-methoxyphenyI, 4-methoxyphenyl, 4-tertbutylphenyl, 3-fluorophenyl and 4-methylphenyl, and l,2,3,4-tetrahydronaphth-2-yl and 6-methoxy- 1,2,3,4- tetrahydronaphth-2-yl.
  • A is CN.
  • A is H. 7
  • A is selected from F, Br and Cl.
  • A is selected from (l-4C)alkyl. Particular examples include methyl and ethyl.
  • A is cyclopropyl
  • A is selected from CH 2 NH 2 , CH 2 NH(I-C alkyl), and CH 2 N(MC alkyl) 2 .
  • Particular examples include CH 2 NH 2 and CH 2 NMe 2 .
  • A is thienyl. In a particular embodiment, A is 2-lhienyI.
  • A is phenyl which is unsubstitutcd or substituted with SO 2 Me.
  • Particular examples include phenyl, 3-mcthylsulfonyIphenyI, and 4-mcthylsulfonylphenyl.
  • A is C H 2 N R 411 C( 3 O)R 5 .
  • An example of a particular value for R 4 * is hydrogen.
  • R 5 is hetAr 1 .
  • An example of a particular value for a heteroaryl group represented by hetAr 1 is a pyridyl group. Examples of optional subs ⁇ tucnts on the heteroaryl group are NH 2 , Cl, and pyrrolidinyl.
  • R 5 is Ci-Ce alkyl; CpC 6 alkoxy; C 3 -C 6 cycloalkyl; pyridyl which is unsubstituted or substituted by a halogen atom or a group of formula -NR 5 "R Sh in which each of
  • R 5 " and R 5b independently represents a hydrogen atom or a (1 -4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholino group; or a phenyl group that is unsubstiluted or substituted by one or two halogen atoms.
  • R 5 examples of particular values for R 5 are methyl, mclhoxy, cyclohcxyl, pyrid-2-yl, pyrid-
  • R 5 6-dimethylaminopyrid-3-yl.
  • A is CH 2 NR*SO 2 R ⁇ .
  • An example of a particular value for R 4b is hydrogen.
  • K 6 is hetAr 2 .
  • Examples of particular values for a heteroaryl group represented by hetAr arc an imidazolyl and a pyridyl group.
  • Examples for optional substituents on the heteroaryl group are Ci -C 4 alkyl, for example methyl.
  • R 6 is Ci-C 6 alkyl, NH(Ci-C 6 alkyl), N(Ci-C 6 alkyl) 2 , a phenyl group that is unsubstituted or substituted by one or two halogen atoms, pyridyl or imidazolyl that is unsubstituled or substituted with a C1-C 3 alkyl group.
  • R 6 examples of particular values for R 6 arc methyl, dimethylamino, 4-fluorophenyl, 2,4- dichlorophenyl, pyrid-3-yl and l-methylimidazol-5-yl.
  • An additional example of R 6 is pyrid-4-yl.
  • Examples of particular values for A are acetamidomcthyl, cyclohexylamidomethyl, methoxycarbonylaminomcthyl, picolinamidomethyl, nicotinamidomethyl, isonicotinamidomethyl, 6- chloropyrid-3-ylamidomethyl, 6-aminopyrid-3-ylamidomethyl, 6-pyrroIidin-l-ylpyrid-3- ylamidomelhyl, 4-fluorobenzamidometh ⁇ i, methylsulfonamidomethyl, N,N- dimcthylsulfamoylamino, 4-fluorophcnylsulfonamidomethyl, 2,4-dichlorophenyl- sulfonamidomcthyl, l-methylimidazol-5-ylsulfonamidomethyl and pyrid-3-ylsulfonamidomethyl, which can be represented by the following
  • Particular values for A also include 6-dimeuiylamtnopyrid-3-ylamidomethyI, 2-(4-fluorophenylsulfonamido)acetamidomethyl, dimethylaminomethyl and (N- methylmethylsulfonamido)methyl, which can be represented by the following structures, respectively:
  • R 2 when it represents a CpC 6 alkyl group examples are methyl, ethyl, propyl, isopropyl and t-butyl.
  • R 2 is CHR c (CH 2 ) q R r .
  • values for R c are hydrogen and methyl.
  • R r is di(l-4C)alkylamino, morpholino, or piperazinyl optionally substituted with (l-4C)alkyl.
  • Examples of particular values for R r are dimethylamino, diethylamino, morpholino, piperazinyl and 1-mcthylpiperazinyl. Additional examples include NH 2 and NHMe. [00102
  • R 2 is hydrogen
  • both R 7 and R s are H. In certain embodiments, R 7 is H and R 8 is methyl. In other embodiments, each of R 7 and R s is methyl.
  • the present invention provides a process for the preparation a compound of formula (I) or a salt thereof as defined hcreinabove, which comprises:
  • R l0 ° is H or F in the presence of a base
  • R 8 are independently H or Me, reducing a corresponding compound formula (IV) 10
  • E is an electron withdrawing group, in the presence of a base; and if desired removing said electron withdrawing group; or
  • the leaving atom or group represented by Z 1 may be, for example, a halogen atom such as a fluorine atom.
  • the carboxyl protecting group may be any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting
  • carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl.
  • the base may be, for example, an alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate or potassium carbonate, or a tertian' amine, such as triethylamine or N,N-diisopropylethylamine.
  • Convenient solvents include amides, sulfoxides and nitriles, such as DMF, DMSO or acetonitrile.
  • the reaction can be performed at an elevated temperature, such as in the range of from 50 to 150 0 C.
  • the compound of formula (IV) can be reduced by hydrogenation in the presence of a Group VIII metal catalyst, such as Rancy Ni with mcthanol/ammonia.
  • the reaction can be conducted at a temperature in the range of from 0 to 100 0 C.
  • the dioxoisoindolinyl group can be cleaved using HBr and acetic acid or hydrazine.
  • XII in the presence of a base, in which Z 4 represents a leaving atom or group, such as a fluorine atom, and R lx represents an electron withdrawing group convertible into a group R 1 , for example a nitro group that can be reduced to an amino group and then acylated.
  • the base may be, for example, an 15 alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate or potassium carbonate.
  • Compounds of formula (IX) can be prepared by reacting 4-hydroxyphenylacetic acid with 2-(hydroxymethyl)isoindoline-l,3-dione in the presence of a sulfonic acid, such as methancsulfonic acid, and followed if desired by introducing a protecting group P 3 .
  • a sulfonic acid such as methancsulfonic acid
  • the leaving atom or group represented by Z 2 and Z 3 may be, for example, a halogen atom such as a fluorine atom.
  • the reaction can be performed in the presence of a base, for example a tertiary amine such as diisopropylethylamine or pyridine.
  • Convenient solvents include halogcnated hydrocarbons, such as methylene chloride.
  • the reaction can be conducted at a temperature in the range of from 0 to 100 0 C.
  • the coupling of the compound of formula (VII) with a compound of formula (VlII) may be performed using conventional amide bond formation conditions, for example by reacting an amine with a reactive derivative of a carboxylic acid, for example an acid halidc, such as an acid chloride.
  • a reactive derivative of a carboxylic acid for example an acid halidc, such as an acid chloride.
  • An example of A 1 when it represents a protected form of A is a group of formula -CH 2 NR 4 P 6 in which P 6 represents an amine protecting group.
  • the amine protecting group may be any convenient amine protecting group, for example as described in
  • amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl
  • examples of electron withdrawing groups include NO 2 .
  • this group can be removed, if desired, by reducing the nitro group to an amino group using any convenient reducing conditions (for example, Zn and NH 4 Cl) followed by cleavage of the amino group (for example, by treating the amino compound with isobutyl nitrite).
  • the base may be, for example, an alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate or potassium carbonate.
  • the Z 4 group represents a suitable leaving atom or group, such as a fluorine atom, and R lx represents an electron withdrawing group convertible into a group R 1 , for example a nitro group that can be reduced to an amino group and then acylaled.
  • the leaving atom or group represented by Z 5 may be, for example, a halogen atom such as a fluorine atom.
  • the base may be, for example, an alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate, or potassium carbonate.
  • Convenient solvents include sulfoxides such as DMSO.
  • the reaction can be performed at elevated temperatures, ibr example in the range of 50- 100 "C, for example at 85 0 C.
  • the carbonyl group can 16 be converted to a carboxyl group by treating the coupling product with methylsulfonyl/methylthiomcthane to provide an intermediate having the formula (XVIII)
  • the halide represented by X can be F, Cl or Br.
  • Convenient solvents include ethers such as THF or dioxanc.
  • Suitable palladium (0) catalysts include Pd(PPIb) 4 and bis(tri-t-butylphosphinc)palladium (0).
  • a convenient base when compound (XVI) is reacted with a boronic acid reagent includes DBU. The reaction can be performed at elevated temperatures, for example in the range of 50-100 0 C, for example 60 0 C.
  • reaction is conveniently performed in the presence of an amine base, for example pyridine.
  • an amine base for example pyridine.
  • the reaction is conveniently performed in the presence of a base, for example a hydride such as sodium cyanoborohydride in an alcohol solvent such as methanol.
  • a base for example a hydride such as sodium cyanoborohydride in an alcohol solvent such as methanol.
  • the reaction is preferably performed in the presence of a catalytic amount of acid, for example acetic acid.
  • the reaction is conveniently performed at ambient temperature.
  • Compounds which are modulators of DP2 are useful in the treatment of diseases or disorders mediated by PGD 2 , for example, diseases or disorders associated with overproduction or dysregulation Of PGD 2 .
  • treatment includes prophylaxis as well as treatment of an existing condition.
  • disorders or diseases that may be treated with compounds according to the invention include immunologic diseases. 17
  • immunologic diseases include allergic inflammatory diseases, such as asthma, atopic dermatitis, allergic rhinitis, seasonal allergies, food allergies, contact hypersensitivity (e.g., nickel sensitivity), hypcr-cosinophilic syndromes, and allergic conjunctivitis.
  • allergic inflammatory diseases such as asthma, atopic dermatitis, allergic rhinitis, seasonal allergies, food allergies, contact hypersensitivity (e.g., nickel sensitivity), hypcr-cosinophilic syndromes, and allergic conjunctivitis.
  • Additional diseases or disorders which may be treated with the compounds of this invention include inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, ileitis and enteritis, vasculitis, Behcet's syndrome, psoriasis and inflammatory dermatoses such as dermatitis, eczema, urticaria, viral cutaneous pathologies such as those derived from human papillomavirus, HIV or RLV infection, bacterial, fungal and other parasital cutaneous pathologies, and cutaneous lupus erythematosus, respiratory allergic diseases such as persensitivity lung diseases, chronic obstructive pulmonary disease and the like, autoimmune diseases, such as arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, glomerulonephritis and the like, graft rejection (including allograft rejection
  • another aspect of this invention provides a method of treating diseases or medical conditions in a mammal mediated by PGD2, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat or prevent said disorder.
  • the phrase "effective amount” means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder mediated by PGD2, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. 18
  • the amount of a compound of Formula 1 that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • the term "mammal” refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
  • This invention also provides compounds of Formula I for use in the treatment of PGD2- mediatcd conditions.
  • An additional aspect of the invention is the use of a compound of Formula I in the preparation of a medicament for therapy, such as for the treatment or prevention PGD2 -mediated conditions.
  • the compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-inflammatory compound that works by a different mechanism of action.
  • the compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rcclally or orally), the nose, lungs, musculature or vasculature or transdermally.
  • the compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc.
  • Such compositions ma)' contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
  • the present invention provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinabove.
  • the pharmaceutical composition includes the compound of formula (I) together with a pharmaceutically acceptable diluent or carrier.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to (real an immunologic disorder, as defined hereinabove. 19
  • the coding sequence of human DP2 was introduced into the human Leukemic cell line K562 by electroporation and stable clones expressing DP2 were obtained by limiting dilution followed by cell surface staining with a rat monoclonal antibody specific for human DP2.
  • Membranes were prepared from one of these DP2 expressing clones and used to determine the ability of the compounds of the present invention to inhibit binding of prostaglandin D2 (PGD2) to its receptor DP2 by the following procedure.
  • Membranes (1.25 Og ⁇ vell) were mixed with 3 H- labeled PGD 2 and various concentrations of test compounds in 150 ⁇ L of binding buffer (50 mM Tris-HCl, pH 7.4, 40 mM MgCl 3 , 0.1% bovine serum albumin, 0.1% NaN 3 ) in 96-well U-bottom polypropylene plates. After incubation for 60 minutes at room temperature, the assay was transferred to a filtration plate (#MAFB; Milliporc Corporation, Bedford, MA), and washed three times with binding buffer. Radioactivity was measured by a scintillation counter (TopCount; PerkinElmer Life Sciences, Boston, MA).
  • binding buffer 50 mM Tris-HCl, pH 7.4, 40 mM MgCl 3 , 0.1% bovine serum albumin, 0.1% NaN 3
  • Nonspecific binding was determined by incubations in the presence of 1 ⁇ M unlabeled PGD 2 or 5 DM of a known DP2 antagonist.
  • IC 50 values for inhibition of binding are determined for each compound tested from the inflexion point of a standard 4-parameter logistical curve fitted to the values obtained. All compounds disclosed herein had IC 50 values less than 1 micromolar. 20
  • Step A 2-(4-hydrox> ⁇ henyl)acetic acid (7.0 g, 46 mmol) was diluted with methane sulfonic acid (100 mL) and cooled to -10 0 C.
  • Step B The product of step A (6.7 g, 22 mmol) was diluted with HBr (21 g, 258 mmol) and acetic acid (20 mL). The reaction mixture was heated to reflux and stirred overnight. The reaction mixture was then cooled to 0 0 C and was neutralized with solid NaOH pellets to pH ⁇ 10, affording a solution of 2-(3-(aminomethyl)-4-hydroxyphenyI)acetic acid which was used in the next step without further purification.
  • Step C To 2-(3-(aminomethyl)-4-hydroxyphenyl)acctic acid (3.9 g, 21.5 mmol) was added BOC2O (5.40 g, 24.8 mmol) in 30 mL of dioxane. After stirring for 4 hours, the reaction was diluted with ethyl acetate and IN HCl. The organic layer was dried over MgSO 4 and concentrated. The solid was taken up in minimal methylene chloride, filtered and rinsed with methylene chloride. The filtrate was concentrated to yield 3.0 g of 2-(3-((tert-butoxycarbonyl)aminomethyl)-4- hydroxyphenyl)acctic acid as a white foam.
  • Step D 2-(3-((tert-Butoxycarbonyl)aminomethyl)-4-hydroxyphenyl)acetic acid (1.6 g, 5.69 mmol) was diluted with THF ( 10 mL) and methanol (5 mL) followed by the addition of TMSCHN 2 (14.2 mL, 28.4 mmol) dropwise. The reaction mixture was stirred for 30 minutes and then diluted with ethyl acetate and water. The layers were separated and the organic layer was dried 21 over MgSQi, filtered and concentrated. The material was purified using a biotagc 4OS cartridge eluting with hexanes:ethyl acetate (4: 1) yield 860 nig of clear oil that later solidified to methyl 2-(3-
  • Step E Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-hydrox ⁇ 'phenyl)acetate (200 mg, 0.677 mmol) was diluted with ACN (2 rnL) followed by the addition of K 2 CO 3 (206 mg, 1.49 mmol) and l-fluoro-4-nitrobenzene (0.103 mL, 0.948 mmol). The reaction mixture was heated to reflux (at about 82 0 C) and stirred for 5 hours. The reaction mixture was then diluted with ethyl acetate and water. The layers were separated and the organic layer was dried over MgSO.4, filtered and concentrated. The material was purified using a biotage 4OS eluting with hcxancs/cthyl acetate
  • Step F Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-ni ⁇ Ophenoxy) phenyOacetate (242 mg, 0.581 mmol) was diluted with THF (3 mL) followed by the addition of Zn dust (38.0 mg, 0.581 mmol). About 2 mL of saturated ammonium chloride was added dropwise.
  • reaction mixture was diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over
  • Step G Methyl 2-(4-(4-aminophenoxy)-3-((tert-butoxycarbonyl)aminomcthyl) phenyOacetate (100 mg, 0.259 mmol) was diluted with methylene chloride (3 mL) followed by the addition of 3,4-dichlorobenzoyl chloride (81.3 mg, 0.388 mmol) and N,N-diisopropylethyl amine
  • Step H Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-(3,4- dichlorobenzamido)phenoxy)phenyl)acetatc (130 mg, 0.232 mmol) was treated with HCl (0.581 mL,
  • Step I The product of step H (30 mg, 0.065 mmol) was diluted with methylene chloride
  • Step J Methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fiuorophenyl- sulfonamido)mcthyl)phenyl)acetate (40 mg, 0.065 mmol) was diluted with MeOH (1 mL) followed by the addition of NaOH (0.32 mL, 1.3 mmol). After stirring for I hour, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO 4 , filtered and concentrated.
  • Step A 4-Aminophenol (1.9 g, 17 mmol) was diluted with DMF (40 mL) followed by the addition of pyridine (0.978) (1.4 mL, 17 mmol) and 3,4-dichlorobenzoyl chloride (3.0 g, 14 mmol) in 5 mL of DMF. After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The aqueous layer was extracted once with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO 4 , filtered and concentrated onto silica gel.
  • the material was purified using a biotage 4OM column eluting with hexanes:cthyl acetate (9: 1) using 2 L and then (60:40) IL to yield 3,4-dichloro-N-(4-hydroxyphenyl)-benzamide ( 1.5 g, 37% yield) as a white solid.
  • Step B tert-Butyl 2-(3-cyano-4-fluorophenyl)acetate (2.0 g, 8.5 mmol) and the product of step A (2.9 g, 10 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.4 g, 10 mmol). The reaction was heated to 125 0 C and stirred for 12 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated.
  • Step C The product of step B (100 mg, 0.201 mmol) was diluted with 7N ammonia/methanol (10 mL), followed by addition of ethyl acetate (10 mL). Once the material dissolved, Raney Nickel (1.72 mg, 0.0201 mmol) was added and die reaction was purged three times with a balloon of hydrogen.
  • Step D The product of step C (0.050 g, 0.997 mmol) was dissolved into I mL of DCM in a small test tube. Pyridine (0. 017 g, 0.219 mmol) and nicotinoyl chloride (0.0195 g, 0.110 mmol) were added, and the reaction mixture was stirred for 12 hours. The reaction mixture was then diluted with methylene chloride and water.
  • Step E The product of step D (44 mg ; 0.073 mmol) was diluted with methylene chloride:TFA (1 : 1 ) and stirred for 3 hours. The reaction mixture was concentrated, taken up in ether and sonicated. The solid was filtered, rinsed with ether and dried under vacuum to yield the title compound (35 mg, 88% yield) as white solid.
  • 1 H NMR 400 MHz, CDCI 3 /CD 3 OD) 8.75 (m, IH), 8.65 (m, IH), 8.15 (m, IH), 8.
  • Step A tert-Butyl 2-(3-cyano-4-fluorophenyl)acetatc (2.6 g, 11.1 mmol) and methyl 4- hydroxybenzoate (3.36 g, 22.1 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.83 g, 13.3 mmol). The reaction mixture was heated to 125 0 C and stirred for 5 hours. The reaction mixture was diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO 4 , filtered and concentrated.
  • Step B The product of step A (2.5 g, 6.80 mmol) was diluted with TN ammonia/niethanol (30 mL) followed by the addition of Raney Nickel (0.0583 g, 0.680 mmol). The reaction mixture was purged three times with hydrogen and stirred for 12 hours. The reaction mixture was then filtered through a GF/F filter and concentrated.
  • Step C The product of step B ( 1.87 g, 5.03 mmol) was diluted with methylene chloride (2 mL) followed by the addition of pyridine (0.489 mL, 6.04 mmol) and methanesulfonyl chloride (0.779 mL, 10.1 mmol).
  • Step D The product of step C (900 mg, 2.00 mmol) was diluted with dioxane (10 mL) followed by the addition of LiOH-H 2 O (126 mg, 3.00 mmol) dissolved in water (2 mL). After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSU4, filtered and concentrated.
  • the material was purified using a biotage 4OM cartridge cluting with methylene chloridc:MeOH (95:5) to yield 4- (4-(2-tert-butox)'-2-oxoethyl)-2-(mcthylsulfonamido-melhyl)phenoxy)bcnzoic acid (710 mg, 81.4% yield) as a clear oil.
  • Step E The product of step D (62 mg, 0.14 mmol) was diluted with methylene chloride (1 mL) followed by the addition of oxalyl dichloride (0.093 mL, 0.19 mmol) and 1 drop of DMF. The reaction was stirred for 30 minutes followed by the addition of 3,4-dichlorobenzenamine (46 mg, 0.28 mmol). The reaction was allowed to stir for 1 hour.
  • reaction mixture was loaded directly onto a 12i sim and purified on the horizon eluting with methylene chloride:MeOH (99.5-0.5 to 95:5) to yield 30 mg of tert-butyl 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3- (metliylsulfonamidomethyl)phenyl)acetate as a clear oil.
  • Step F The product of step E (22 mg, 0.038 mmol) was diluted with methylene chloride (1 mL) followed by the addition of TFA (1 mL). After stirring for 1 hour, the reaction was concentrated, diluted with ether, sonicated and concentrated to yield 2-(4-(4-((3,4- dichlorophenyl)carbamoyl)phenoxy)-3-(metliylsulfonamidomethyl)phenyl)acetic acid (15 mg, 75% 30 yield) as a white solid.
  • Step A 2-(3-Chloro-4-hydroxyphenyI)acetic acid (5.0 g, 26.8 mmol) was dissolved in 30 mL of MeOH and H 2 SO 4 (0.744 ml, 13.4 mmol) was added dropwise at ambient temperature. The reaction was refluxed for four hours and then concentrated in vacuo. The residue was diluted with 150 mL of EtOAc and washed sequentially with saturated NaHCOj, water, and brine, dried over H2SO4, and concentrated in vacuo to provide methyl 2-(3-chloro-4-hydroxyphcnyl)acetate (5.16 g, 96.0% yield) as a semi-opaque thick oil.
  • Step B Methyl 2-(3-chloro-4-hydroxyphcnyl)acetatc (177 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K 2 CO 3 ( 122 mg, 0.885 mmol) and N-(4- chlorophcncthyl)-4-chloro-3-nitrobcnzamide (300 mg, 0.885 mmol) (synthesized in step C). The reaction was heated to 85 0 C and stirred for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over H 2 SO4, filtered and concentrated.
  • Step C 2-(4-Chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 niL) followed by the addition of DlEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyl chloride (3.0 g, 14 mmol) in 10 mL of DCM. After stirring for 30 minutes the reaction was loaded directly onto a biotage 4OM cartridge and elutcd with hexanes:ethyl acetate (2: 1) to yield N-(4-chlorophenethyI)-4- chloro-3-nitrobenzamide (4.0 g, 86% yield) as a white solid.
  • Step D Methyl 2-(4-(4-((4-chlorophenethyl)carbamwl)-2-nilrophenoxy)-3- chlorophenyOacetatc (1 10 mg, 0.219 mmol) was diluted with THF ( I mL) followed by the addition of Zn dust (14.3 mg, 0.219 mmol) and saturated NH 4 CI (1 mL). After stirring for 1 hour, the reaction was diluted DCM and 10% aq. sodium carbonate.
  • Step E Isobutyl nitrite (0.0751 ml, 0.634 mmol) was diluted with DMF (1 mL), placed under nitrogen and heated to 60 0 C.
  • Step F Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetate (33 mg, 0.0720 mmol) was diluted with THF (500 ⁇ L) followed by the addition NaOH (0.144 ml, 0.720 mmol) and 100 ⁇ L of water. After stirring for 2 hours, the reaction was diluted with DCM and 2N HCI.
  • Step A To a stirred solution of diisopropylaminc (357 ⁇ l, 2.55mmol) in THF (3 ml) at - 78 0 C was added n-butyllithium (2.5M in hcxancs, 1.02 ml, 2.55 mmol). The reaction was stirred for 30 minutes after which time a solution of the acetate (500 mg, 2.13 mmol) in THF (3.5 ml) was added dropwise and stirred for 20 minutes at -78 0 C, then warmed to 0 0 C. MeI (133 ⁇ l, 2.13 mmol) was added and the reaction stirred for an additional 30 minutes.
  • Step B To a stirred solution of 4-aminophenol (2.50 g, 22.9 mmol) in DMF (55 ml) was added pyridine (1.85 ml, 22.9 mmol) followed by 3,4-dichlorobenzoyl chloride (4.0 g, 19.1 mmol) in DMF (7 ml). The reaction stirred at ambient temperature overnight, then diluted with 2M HCl and EtOAc. The aqueous layer was then extracted with EtOAc and the combined organics washed with brine and dried over MgSO 4 . The residue was purified on the Biotage Horizon (65+M 5% to 75% B:EtOAc, 51 ml-2448 ml).
  • Step C To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (360mg, 1.44mmol) from Step A and 3,4-dichloro-N-(4-hydroxyphenyl)benzamide (488 mg, l.73mmol) from Step B in DMSO (4ml) was added K 2 CO 3 (240 mg, 1.73 mmol). The reaction was stirred at 125 °C overnight, then cooled to ambient temperature and diluted with EtOAc and 10% aqueous sodium carbonate.
  • Step D To a stirred solution of tert-butyl 2-(3-cyano-4-(4-(3,4- dichlorobcnzamido)phenoxy)phenyl)propanoate (25 mg, 0.049 mmol) in DCM ( I ml) was added TFA (250 ⁇ l). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified via preparative TLC (5%MeOH/DCM) to give 2-(3-cyano-4-(4-(3,4- 40 dichlorobenzamido)phcnoxy)phcnyl)propanoic acid (0.0174 g, 0.0382 mmol, 78%).
  • Step A To a stirred solution of NaH (60% in oil, 195 mg, 4.88 mmol) in DMF (10 ml) at O 0 C was added a solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (500 mg, 2.125 mmol) and McI (330 ⁇ l, 5.31mmol) in DMF (1 ml) dropwise. The reaction was warmed to ambient temperature, stirred overnight, and then diluted with IN HCl and EtOAc.
  • Step B 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-(me ⁇ ylsulfonamidomethyl) phenyl)-2-methylpropanoic acid was prepared from tert-butyl 2-(3-cyano-4-fluorophenyl)-2 ⁇ methylpropanoate by the method of Example 35 substituting tert-butyl 2-(3-cyano-4- fluorophenyl)propanoatc in Step B with tert-butyl 2-(3-cyano-4-fluorophcnyl)-2-mcthylpropanoate and following steps B,C and F of Example 14.
  • Step A 2-(4-hydroxyphenyl)acetic acid ( 1.0 g, 6.57 mmol) was diluted with THF (4 mL) followed by the addition of Reactant 2 (2.63 g, 13.1 mmol). The reaction was stirred for hours 12 hours. The reaction was filtered and loaded directly onto a biolage 4OM cartridge eluting with hexancsxthyl acetate (3:1) to yield tert-butyl 2-(4-hydroxyphenyl)acctate (800 mg, 58.4% yield) as a clear oil that later solidified to a white solid.
  • Step B 2-(4-chlorophenyl)ethanamine (0.321 ml, 2.27 mmol) was diluted with DCM (10 mL) followed by the addition of DIEA (d 0.742) (0.395 ml, 2.27 mmol) and 4-fluorobenzoyl chloride (0.231 ml, 1.89 mmol). After stirring for 30 minutes the reaction was loaded directly onto a biotage 4OS cartridge and eluted with hexanes:ethyl acetate (2: 1 ) to yield N-(4-chlorophenethyl)-4- fluorobenzamide (393 nig, 74.8% yield) as a white solid.
  • Step C Tert-butyl 2-(4-hydroxyphenyl)acetate (200 mg, 0.960 mmol) was diluted with DMSO (4 mL) followed by the addition of K 2 CO 3 ( 133 mg, 0.960 mmol) and N-(4- ch!orophenethyl)-4-fluorobcnzamide (267 mg, 0.960 mmol). The reaction was stirred at 85 0 C overnight, and then stirred at 138 0 C for 12 hours. The reaction was cooled to ambient temperature, diluted with DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated.
  • Step D Tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyI)phenoxy)phenyl)acetate (20 mg, 0.043 mmol) was diluted with DCM (1 mL) followed by the addition of TFA (1 mL).
  • Step A 2-(3-Fluoro-4-hydroxyphenyl)acetic acid (1.0 g, 5.88 mmol) was diluted with THF:McOH (3: 1) (10 mL) followed by the addition Of TMSCHN 2 (5.88 ml, 11.8 mmol). After 44 stirring for 1 hour, the reaction was quenched with 2N HCl and diluted with DCM. The layers were separated and the organic layer was dried over MgSO 4 , filtered and concentrated.
  • the material was purified by silica gel chromatography, cluting with hexanes:cthyl acetate (2: 1) to yield methyl 2-(3- fluoro-4-hydroxyphenyl)acetate (700 mg, 64.7% yield) as a clear oil.
  • Step B 2-(4-Chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 niL) followed by the addition of DIEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyI chloride (3.0 g, 14 mmol) dropwise in 10 mL of DCM. After stirring for 30 minutes the reaction was loaded directly onto a silica gel column and eluted with hcxancsxthyl acetate (2: 1) to yield N-(4- chlorophcncthyl)-4-chloro-3-nitrobcnzamide (4.0 g, 86% yield) as a white solid.
  • Step C Methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (prepared in Step A; 163 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K 2 CO 3 ( 122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nilrobenzamide (prepared in Step B; 300 mg, 0.885 mmol). The reaction was stirred at 8O 0 C for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over MgSO 4 , filtered and concentrated.
  • Step D Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3- fluorophenyl)acetate (100 mg, 0.205 mmol) was diluted with THF (2 mL) followed by the addition of Zn dust ( 13.4 mg, 0.205 mmol) and saturated aq.
  • Step E Isobutyl nitrile (0.060 ml, 0.51 mmol) was diluted with DMF (2 mL), placed under nitrogen and heated to 6O 0 C followed by the addition of methyl 2-(4-(4-((4- chlorophenethyl)carbamoyI)-2-aminophenoxy)-3-fluorophenyl)acetate (93 mg, 0.20 mmol) in 500 ⁇ L of DMF. The reaction was stirred 30 minutes and then cooled. The reaction was diluted with ethyl acetate and washed with 2N HCI and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over MgSO 4 , filtered and concentrated.
  • Step F Methyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phenoxy)-3- fluorophenyl)acetate (32 mg, 0.072 mmol) was diluted with dioxane ( 1 mL) followed by the addition of NaOH (0.072 ml, 0.36 mmol) and 200 ⁇ L of water.
  • Step A A flask was charged with tert-bulyl 2-(3-cyano-4-fluorophenyl)acetate (9.410 g, 40.00 mmol), methyl 4-hydroxybenzoate (7.303 g, 48.00 mmol), K 3 CO 3 (6.634 g, 48.00 mmol), and DMSO (160 mL). The mixture was heated to 90 0 C under a nitrogen atmosphere for 17 hours. The mixture was cooled to ambient temperature and poured into a mixture of EtOAc (250 mL) and 10% K 2 CO 3 solution (250 mL). The resulting insoluble residue was dissolved in water and added to the EtOAc-aqueous mixture. The mixture was stirred for 1 hour and layers were separated.
  • Step B Methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1 1.60 g, 31.57 mmol) was dissolved in dioxane (160 mL) and the solution was cooled to 10 0 C in an ice bath. LiOH-H 2 O, IM (37.89 ml, 37.89 mmol) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with 2N HCl ( 10OmL) and CH 2 Cb (200 mL). Layers were separated and aqueous layer was extracted with CH 2 Cl 2 .
  • Step C To 4-(4-(2-tert-butoxy-2-oxocthyl)-2-cyanophenoxy)bcnzoic acid (0.34 g, 0.962 mmol), 2-(4-chlorophenyl)ethanamine (0.165 g, 1.06 mmol) in DMF (5 ml) was added diisopropylamine (0.200 ml, 1.15 mmol) and HBTU (0.149 g, 1.15 mmol). The reaction was stirred 46 al ambient temperature for 90 minutes. The reaction was diluted with water and the product extracted into ethyl acetate.
  • Step D To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- cyanophenyl)acetate (0.40 g, 85%) as a white solid after column chromatography.
  • Step D To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- cyanophenyOacetatc (4.40 g, 8.96 mmol) in DCM (20 ml) was treated with TFA (20 ml). After stirring for 2 hours.
  • the reaction mixture was concentrated and the crude material was purified by silica gel chromatography using a gradient of 0.5% McOH/DCM containing 0.5% AcOH to 10% McOH/DCM containing 0.5% AcOH to provide 2-(4-(4-((4-chlorophencthyl)carbamoyl)phcnoxy)- 3-cyanophcnyl)acctic acid (3.30 g, 84.7% yield).
  • Step A N-(4-chlorophenethyl)-4-hydroxybenzamide ( 1.5 g, 5.4 mmol) was diluted with DMSO (15 mL) followed by the addition of K 2 CO 3 (0.89 g, 6.4 mmol) and 3-bromo-4- 47 fluorobenzaldehydc (1.0 g. 4.9 mmol). The reaction was stirred at 85 0 C overnight and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and then concentrated.
  • Step B N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenox>')benzamide (1.6 g, 3.5 mmol) was diluted with THF (10 mL) followed by the addition of N,N,N- trimcthyl(phenyi)methanaminiurn hydroxide (0.79 ml, 1.7 mmol) and mcthylsulfinyl(rnethylthio)methane (0.87 g, 7.0 mmol). The reaction was stirred at 70 0 C for 2 hours.
  • reaction mixture was loaded directly onto a silica gel column and clutcd with DCM:MeOH (98:2) to yield (Z)-N-(4.chlorophcncthyl)-4-(2-bromo-4-(2-(mcthylsulfinyl)-2- (methyithio)vinyl)phenoxy)benzamide (1.9 g, 96% yield).
  • Step C (Z)-N-(4-chlorophencthyl)-4-(2-bromo-4-(2-(methylsulfinyl)-2-(methyithio) vinyl)phcnoxy)benzamide (2.0 g, 3.5 mmol) was treated with HCI (8.9 ml, 18 mmol) in ethanol. The reaction was stirred at 70 0 C for 2 hours.
  • Step D Ethyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phcnoxy)-3-bromophenyl)acetate (30 ing, 0.058 mmol) was diluted with dioxane (500 ⁇ L) followed by the addition of NaOH (0.093 ml, 0.46 mmol) and 200 ⁇ L of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl.
  • Step A Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)pheno ⁇ y)-3-bromophenyl)acetate (Example 46 step C ; 30 mg, 0.058 mmol) was diluted with THF ( 1 mL) followed by the addition of bis(tri-t-but ⁇ lphosphinc)palladium (0) (3.0 mg, 0.0058 mmol) and methylzinc chloride (0.087 ml, 0.17 mmol).
  • Step B Ethyl 2-(4-(4-((4-chlorophcnetliyl)carbamoyl)phcnoxy)-3-mcthylphenyl)acetate (20 mg, 0.0443 mmol) was diluted with dioxane (500 ⁇ L) followed by the addition of NaOH (0.0885 ml, 0.443 mmol) and 200 ⁇ L of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl.
  • Step A Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and 2-thienylzinc bromide (0.23 ml, 0.12 mmol).
  • Step B Ethyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phenoxy)-3-(thiophen-2- yl)phenyl)acctate (20 mg, 0.038 mmol) was diluted with dioxane (500 ⁇ L) followed by the addition of NaOH (0.052 ml, 0.26 mmol) and 200 ⁇ L of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl.
  • Step A Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phcnoxy)-3-bromophcnyl)acctate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-l-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and phenylzinc iodide (0.23 ml, 0.12 mmol).
  • Step B Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phcnoxy)biphenyl-3-yl)acetate (10 mg, 0.0195 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.0389 ml, 0.195 mmol) and 200 ⁇ L of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl.
  • Step A Ethyl 2-(4-(4-((4-chlorophcnethyl)carbamoyl)phenox ⁇ )-3-bromophenyI)acetate (Example 46 step C; 100 mg. 0.193 mmol), 3-(mcthanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K 2 CO 3 (80.2 mg, 0.580 mmol) and Pd(PPh 3 ) 4 (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60 0 C overnight.
  • Step B Ethyl 2-(6-(4-(4-chlorophcnethylcarbamoyl)phenoxy)-3'-
  • Step A A flask was charged with cyclopropyl magnesium bromide (29.6 ml, 14.8 mmol) and placed under nitrogen. Zinc chloride ( 14.8 ml, 14.8 mmol) was added and the reaction was stirred for 20 minutes. 3-Bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol) and bis(tri-t- butylphosphinc)palladium (0) (0.126 g, 0.246 mmol) were diluted in 600 ⁇ L of THF and added to the reaction mixture. After stirring for 4 hours, the reaction was heated to 5O 0 C and stirred overnight. The reaction was cooled and quenched with saturated NH 4 Cl and extracted with DCM.
  • Step B N-(4-Chlorophenethyl)-4-hydroxybenzamide (504 mg, 1.83 mmol) was diluted with DMSO (8 mL) and K 2 CO 3 (379 mg, 2.74 mmol) and 3-cyclopropyl-4-fluorobenza!dehyde (300 mg, 1.83 mmol) were added. The reaction was stirred 85 0 C overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and concentrated.
  • Step C N-(4-Chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 0.381 mmol) was diluted with THF (3 mL) followed by the addition of N,N,N- trirnethyl(phenyl)mcthanaminium hydroxide (0.0866 ml, 0.191 mmol) and methylsulfinyl(mcthy!thio)rnethane (94.7 mg, 0.762 mmol). The reaction was heated to 70 0 C and stirred for 2 hours.
  • Step D (Z)-N-(4-chIorophenetliyl)-4-(2-cyclopropyl-4-(2-(methylsulfinyl)-2-
  • Step E Ethyl 2-(4-(4-((4-chlorophcncthyl)carbamoyl)phcnoxy)-3- cyclopropylphenyl)acetate (70 mg, 0.146 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.293 ml, 1 ,46 mmol) and water (300 ⁇ L). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl.
  • Step A Ethyl 2-(4-(4-((4 ⁇ hlorophencthyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 30 mg, 0.058 mmol) was diluted with THF (1 mL) followed by the addition of l, r-bis(diphcnylphosphino)ferroccncdichloropalladium(II) (4.8 mg, 0.0058 mmol) and diethylzinc (0. 13 ml, 0.15 mmol).
  • Step B Elhyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetate (10 mg, 0.0215 mmol) was diluted with dioxanc (500 ⁇ L) followed by the addition of NaOH (0.0429 ml, 0.215 mmol) and 5 drops of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl, and the layers were separated. The organic layer was dried over MgSO.1, filtered and concentrated.
  • Step A Ethyl 2-(4-(4-((4-chlorophcnctliyl)carbamoyl)phenoxy)-3-bromophenyl)acctate (Example 46 step C; 40 mg, 0.077 mmol), K 2 CO 3 (32 mg, 0.23 mmol) and 4- (methylsulfonyl)phenylboronic acid (23 mg, 0.12 mmol) were diluted with dioxane (1 mL)/water (300 ⁇ L) followed by the addition of Pd(PPh 3 ) 4 (8.9 mg, 0.0077 mmol). The reaction was purged with nitrogen and stirred at 55°C for 12 hours. The reaction was cooled and concentrated.
  • Step B Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4'-
  • Step A A mixture of te/7-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.32 g, 5.59 mmol), N-(4-chlorophenethyl)-4-hydroxybenzamide ( 1.85 g, 671 mmol), and potassium carbonate (0.93 g, 6.70 mmol) in DMSO (10 ml) was stirred at 90 0 C for 1 day. The reaction was cooled, diluted with ethyl acetate, and washed with 10% aqueous NazCC ⁇ . The aqueous layer was back extracted with 55 ethyl acetate.
  • Step B To tert-Butyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phenoxy)-3- cyanophenyl)acetate ( 1.09 g.. 2.22 mmol) in 6 ml of 7 N ammonia in methanol at ambient temperature was added Raney-Ni (0.019 g) and the reaction was stirred under a balloon of hydrogen gas at ambient temperature. The reaction was filtered and concentrated to give /er/-butyl 2-(4-(4- ((4-chlorophcnethyl)carbamoyl)phcnoxy)-3-(aminomcthyl)phenyl)acctate (0. 160 g, 15%).
  • Step C A mixture of ter/-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- (aminomethyl)phenyl)acetale (0.015 g, 0.030 mmol), nicotinoyl chloride hydrochloride (0.007 g, 0.039 mmol), and triethylamine (0.013 ml, 0.091 mmol) in dichloromethane (1 ml) was stirred at ambient temperature for 1 hour.
  • the reaction was loaded onto a silica gel samplet and the product was eluted using a gradient system of 0.5% methanol/ dichloromethane to 5% methanol/dichloromethanc to provide tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- (nicotinamidomethyl)phenyl)acetate (0.005 g, 275%).
  • Step D To a solution of / «?r/-butyl 2-(4-(4-((4-chlorophencthyI)carbamoyl)phenoxy)-3- (nicotinamidomethyl)phenyl)acctate (0.005 g, 0.008 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phcnoxy)-3-(nicotinamidomethyl) phenyOacctic acid (0.005 g). MS -449.1 [M - CO2H],
  • Step A To a stirred solution of tert-butyl 2-(3-(aminonicthyl)-4-(4- (phcnethylcarbamoyl)phenoxy)phenyl)acetatc (0.015 g, 0.030 mmol) in nictlianol (1 ml) was added acetic acid (0.012 ml, 0.212 mmol), sodium cyanoborohydridc (0.010 g, 0.152 mmol) and paraformaldehyde (0.007 g, 0.152 mmol). The reaction was stirred at ambient temperature for 1 hour.
  • reaction was loaded directly onto a silica gel samplct and the product elutcd using a gradient of 0.5% mcthanol/dichloromcthanc to 5% methanol/ dichloromcthanc to provide /er/-butyl 2-(4-(4-((4-chloroplienetliyl)carbamoyl)phenoxy)-3-((dimelhylamino)methyl)phcnyl)acetate (0.005 g, 0.010 mmol).
  • Step B To tert-bulyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-
  • Step A To a stirred solution of tert-buty ⁇ 2-(3-cyano-4-fluorophcnyl)acetatc (1.00 mg, 4.25 mmol) and methyl 4-hydroxybenzoate (776 mg, 5.10 mmol) in DMSO (20 ml) was added K 2 CO 3 (704 mg, 5.10 mmol). The reaction was heated to 90 0 C overnight via an oil bath. The reaction was diluted with ethyl acetate and 10% aqueous sodium carbonate.
  • Step B To a stirred solution of the methyl 4-(4-(2- ⁇ ?rt-buloxy-2-oxoethyl)-2- cyanophcnoxy)bcnzoatc (1.086 mg, 2.96 mmol) in 7N ammonia/mcthanol (30 ml) under nitrogen was added Raney Nickel (25.3 mg, 0.296 mmol). The reaction was purged with a hydrogen balloon and stirred under hydrogen overnight. The reaction was filtered through GF paper and the solid catalyst was rinsed with methanol and ethyl acetate.
  • Step C To a stirred solution of the methyl 4-(2-(aminomcthyl)-4-(2-re «-butoxy-2- oxoethyl)phenoxy)benzoate (690 mg, 1.86 mmol) in dichloromethane (6 ml) was added pyridine (225 ⁇ L, 2.78 mmol) followed by mclhanesulfonyl chloride (287 ⁇ L, 3.71 mmol). The reaction was stirred at ambient temperature for 4 hours, after which time additional pyridine (1.5 eq) and mcthanesulfonyl chloride (2 eq) were added.
  • Step D To a stirred solution of the methyl 4-(4-(2-fm-butoxy-2-oxoethyl)-2- (mcthylsulfonamidomethyl)phenoxy)benzoate (745 mg, 1.65 mmol) in DMF (10 ml) was added McI ( 155 ⁇ L, 2.48 mmol) followed by K2CO3 (343 mg, 2.48 mmol). The reaction was stirred at ambient temperature for 3 hours, then diluted with ethyl acetate and 2M HCI. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried 59 over MgS0.».
  • Step E To a stirred solution of methyl 4-(4-(2-fc ⁇ f-butoxy-2-oxoethyl)-2-((N- mcthyImethan-2-ylsulfonarnido)methyl)phenoxy)benzoate (370 mg, 0.797 mmol) in dioxane (8 ml) was added a solution of LiOH monohydratc (43.5 nig, 1.04 mmol) in water (2 ml) (0.1 M solution 4: 1 dioxane/watcr). The reaction was stirred for 5 hours, then diluted with dichloromethane and 2N HCl.
  • Step F To a stirred solution of 4-(4-(2- ⁇ ?/?-butoxy-2-oxoelhyl)-2-((N-methylmethan-2- ylsulfonamido)methyl)phcnoxy)benzoic acid (50 mg, 0.11 1 mmol) and HATU (46.5 mg, 0.122 mmol) in DMF (1 ml) was added DIEA (23.2 ⁇ L, 0.133 mmol) followed by 2-(4- chlorophenyl)cthanamine (11.2 ⁇ L, 0.11 1 mmol). The reaction was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSCj.
  • Step G To a stirred solution of tert-butyl 2-(4-(4-((4- chlorophcnethyl)carbamoyl)phcnoxy)-3-((N-methylmcthan-2-ylsulfonamido)methyl)phcnyl)acctate (1 1.5mg, 0.019mmol) in dichloromethane (ImI) was added TFA (50OuI). The reaction was stirred at ambient temperature for 4 hours and then concentrated..
  • Step A A mixture of /ert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.122 g), N-(4- chlorophenethyl)-4-hydroxybcnzamide (0.150 g), and potassium carbonate (0.086 g) was dissolved in 2 ml of DMSO and stirred at 90 0 C. After 1 day, the reaction was cooled, loaded onto a silica gel samplct and product eluted with a solvent system gradient of 0.5% methanol/ dichloromethane to 5% methanol/ dichloromethane to give /er/-butyl 2-(3-cyano-4-(4-
  • Step B To a solution of tert-butyl 2-(3-cyano-4-(4-(phcncthylcarbamoyl) phenoxy)phenyl)acctate 0. 120 g) in 2 ml of dichloromethane was added 2 ml of TFA and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated and dried under vacuum to give 2-(3-cyaiio-4-(4-(phenethylcarbamoyl)phenoxy)phcnyl)acctic acid (0.100 g). MS -355.3 [M - CO2H].
  • Step A To a stirred solution of the 4-fluoro-3-(trifluoromethyl)benzaldehyde (177 ⁇ L, 1.30mmol) and N-(4-chlorophenethyl)-4-hydroxybcnzamide (359 mg, 1.30 mmol) in DMSO (3 ml) was added K 2 CO 3 (270 mg, 1.95 tnmol). The reaction was stirred at 95°C for 2 hours and Chen directly purified by silica gel chromatography to give N-(4-chlorophenethyl)-4-(4-formyl-2- (trifluoromethyl)phenoxy)benzamide (0.541 g).
  • Step B To a solution of N-(4-chlorophenethyl)-4-(4-formyl-2-
  • Step C To (Z)-N-(4-chlorophenethyl)-4-(4-(2-(m ⁇ thylsulfinyl)-2-(melhylthio)vinyl)-2- (trifluoromethyl)phenoxy)bcnzamide (0.220 g, 0.397 mmol) was added HCl (in ethanol) (0.993 ml, 1.99 mmol) and the reaction heated to 7O 0 C for 1 hour. The reaction was concentrated, loaded onto silica gel and the product eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes. Isolated ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyI)phenoxy)-3-
  • Step D To a solution of ethyl 2-(4-(4-((4-chIorophcnethyl)carbamoyl)phenoxy)-3- (trifluoromethyl)phenyl)acetate (0. 165 g, 0.326 mmol) in methanol/THF (1: 1), 5 ml was added LiOH-H 2 O (0.0684 g, 1.63 mmol) and 3 drops of water, and the reaction was stirred for 1 hour The reaction was diluted with ethyl acetate, washed with 2N HCl and brine, dried over magnesium sulfate and concentrated.
  • Step A To a stirred solution of diisopropylamine in 2 ml of THF at -78 0 C was added n- butyl lithium (0.61 ml). The reaction was stirred for 30 minutes after which time a solution of tert- butyl 2-(3-cyano-4-fluorophenyl)acetate (0.300 g) in THF (2 ml) was added dropwise over 20 minutes at -78 0 C. The reaction was warmed to 0 0 C and then transferred a flask containing 2 ml THF and MeI (0.080 ml). The reaction was acidified with 2M HCl and extracted with ethyl acetate.
  • Step B A flask was charged with ten-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.070 g), N-(4-chlorophenethyl)-4-hydroxybcnzamide (0.105 g), and potassium carbonate (0.047 g) in 1 ml of DMSO and stirred at 95 0 C for one day. The reaction was taken up in dichloromcthanc and washed with water. The organic layer was collected, dried over MgSCU filtered, and concentrated.
  • Step C A flask was charged with ⁇ ?r/-butyl 2-(4-(4-((4- chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)propanoate (0.098 g) in 1 ml of dichloromethane and 1 ml of TFA, and the reaction was stirred for 1 hour. The reaction was concentrated and dried under vacuum. Isolated 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- cyanophenyOpropanoic acid (0.080 g). MS +449.1 [M +1J.
  • Step A Methyl 2-(4-hydroxy-3-mctho ⁇ yphenyl)acetate (0.204 g, 1.04 mmol), N-(4- chlorophcncthyl)-4-iodobenzamidc (0.200 g, 0.519 mmol), 2,2,6,6-tetramethyl-3,5-heptanedionc 63
  • Step B To a solution of methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- methoxyphenyl)acetate (0.065 g, 0.143 mmol) in methanol/THF (1: 1, 3 ml) was added NaOH (0.100 ml, 0.500 mmol). After 5 minutes, reaction was quenched with 10 ml of 2N HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated.
  • the crude material was purified by silica gel chromatography, cluting with a gradient of 0.5% methanol/dichloromcthane (containing 0.5% AcOH) to 7.5% methanol/dichloromethane containing (0.5% AcOH) to provide 2-(4-(4-((4- chlorophenethyI)carbamoyl)phenoxy)-3-mcthoxyphcnyl)acctic acid (0.041 g, 65.1% yield) as a white solid.
  • Step A To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (200mg, 1.28mmol) in DMF (3 ml) at ambient temperature were added HATU (536 mg, 1.41 mmol) and DIEA (268 ⁇ L, 1.54 mmol). The reaction was stirred for 30 minutes and then 2-(2,4-dichlorophenyl)ethanamine (193 ⁇ L, 1.28 mmol) was added. The reaction was stirred overnight, then concentrated and diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography) to give N-(2,4-dichlorophenelhyl)-2-fluoro-4- hydroxybcnzamide (0.420 g).
  • Step B To a stirred solution of N-(2,4-dichlorophenethyl)-2-fluoro-4- hydroxybenzamide (420 mg, 1.28 mmol) and rm-butyl 2-(3-cyano-4-fluorophenyl)acetate (361 mg, 64
  • Step C To a stirred solution of /e «-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3- fluorophenoxy)-3-cyanophenyl)acetatc (15 mg, 0.0276 mmol) in dichloromcthanc was added TFA. The reaction was stirred for 2 hours and then concentrated.
  • Step A TFP Resin ( 1.33 mmol/g; 2.872 g, 3.820 mmol) was placed in a vessel and DMA (5 mL) was added to swell the resin. The vessel was placed on a shaker for 15 minutes, and 4-(4-(2-/e/v-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (1.500 g, 4.245 mmol), DIC (0.7311 ml, 4.669 mmol), and DMAP (0.5704 g, 4.669 mmol) were added to the mixture and the vessel was placed on the shaker.
  • Step B TFP resin bound ester (4-(4-(2-t ⁇ rt-butoxy-2-oxoethyl)-2- cyanophenoxy)benzoate) (0.1968 g, 0.09840 mmol) was added to a vial. THF (2 ml) was added and the resin was allowed to swell. 2-(2,6-Dichlorophenyl)ethanamine, (IM in THF; 0.08200 ml, 0.082 mmol) was added to the vial and the vial was place on a shaker. After 16 hours, the mixture was 65 decanted and the resin was rinsed with THF (3 X 2ml). The combined THF solution was concentrated under reduced pressure.
  • Step C tert-Butyl 2-(4-(4-((2,6-dichlorophenethyl)carbamoyl)phenoxy)-3- cyanophcnyl)acetate (34 mg, 0.065 mmol) was dissolved in dichloromethane (ImI) and TFA (ImI) was added. After stirring for 45 minutes, the mixture was concentrated under reduced pressure to give 2-(3-cyano-4-(4-(2,6-dichlorophencthyIcarbamoyl)phenoxy)phenyl)acctic acid (0.034 g).
  • Step A tert-Butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phcnoxy)-3-cyanophenyl) acetate (0.400 g) and 4-methylbenzencsulfonyl azide (0.193 g) were dissolved in 5 ml of acetonitrile and treated with DBU (0.152 ml) The reaction was stirred for 4 hours, then concentrated, diluted with ethyl acetate and washed with water.
  • Step B A flask was charged with /er/-butyl 2-(4-(4-(4- chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)-2-diazoacetate (0.108 g), 5 ml of ether and HF pyridine (0.30 g). The reaction was stirred at 40 0 C for 30 minutes. The reaction mixture was diluted with ethyl acetate and neutralized with saturated aqueous bicarbonate solution. The organic layer was separated and washed with brine, dried, filtered and concentrated onto silica gel.
  • Step C A flask was charged with rm-butyl 2-(4-(4-((4- chlorophencthyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetate (0.026 g), 0.5 ml of dichloromcthanc and 0.2 ml of TFA.

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Abstract

Compounds of Formula (I): in which R1, R2, R7, R8, R9, R10 and A have the meanings given in the specification, are DP2 receptor modulators useful in the treatment of immunologic diseases.

Description

4-SUBST1TUTED PHENOXYPHENYLACETIC ACID DERIVATIVES [0001J This application claims the benefit of United States provisional patent applications Serial No. 60/839,018 filed on August 21, 2006 and Serial No. 60/851 ,385 filed October 13, 2006, which are incorporated herein by reference in their entirety.
[0002) The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly it relates to certain 4-substituted phenoxyphenylaceϋc acid derivatives useful in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D2 (PGD2). |0003] International patent application, publication number WO 2004/058164 discloses inter alia, certain 2-substitutcd phenoxyphcnylacetic acid derivatives that modulate the PGDj-sclective receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), now more commonly referred to as DP2. The compounds arc said to be useful in the treatment of immunologic diseases such as asthma and allergic inflammation.
[0004] Il has now been found that certain 4-substituted phenoxy phenyl acetic acid derivatives bearing a particular substituent meta to the acetic acid moiety arc DP2 receptor modulators. As used herein, the term "modulator" includes antagonists.
[0005) According to one aspect, the present invention provides a compound of general formula (1):
Figure imgf000002_0001
(I)
[0006] or a salt thereof, wherein: [0007] R' is Ar'-L'-W-lΛ; |0008] L2 is -(CR0RV; [0009] W is -CONR38- or -NR3bCO-; [0010] R3a and R3b are each H or methyl;
[0011] L1 is -(CR8RV, -(CH=CH)-, or -O(CR"Rb) provided that when W is -NR3CO- then L1 is not -(CH=CH)-; [0012] n and m are independently 0, 1 or 2; 2
[0013] each R\ Rb, Rc and Rd is independently H, F, OH, methyl or cyclopropyl, or R° and Rb or
Rc and Rd together with the carbon to which they are attached form a cyclopropyl ring;
[0014] Ar1 is phenyl or naphthyl, each of which is unsubstituted or substituted with one or more substituents selected independently from F, Cl, CN, CF3, CHF2, CH2F, SF5, methyl, ethyl, cyclopropyl, t-butyl or OMc, or Ar1 is 1,2,3,4-tctrahydronaphthyl which is unsubstituted or substituted by mcthoxy,
[0015] provided that when Ar1 is naphthyl or 1 ,2,3,4-tetrahydronaphthyl then n is 0;
[0016] R2 is H, Ci-C6 alkyl, a residue of an amino acid or dipeptide, or CHRe(CH2)qRf ;
[0017] q is 1 to 6;
[0018] Rc is H, methyl or ethyl;
[0019] Rf is NR8Rh in which R8 and Rh each independently represents a hydrogen atom or a Ci-
C4 alkyl group, or R8 and Rh together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally containing a second ring heteroatom selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from Ci-Ce alkyl;
[0020] A is CN, CH2NH2, CH2NR4oC(=O)Rs, or CH2NR411SO2R6, Cl, OMc, ( MQalkyl, cyclopropyi, H, F, Br, CH2NH(I -4C alkyl), CH2N(I -4C alkyl)2) thienyl, or phenyl which is unsubstituted or substituted with SO2Me;
[0021] R4" and R4b arc each H or methyl;
[0022] R5 is Ci-C6 alkyl, CpC6 alkoxy, C3-C6 cycloalkyl, hetAr1, or Ar2;
[0023] R6 is C1-C6 alkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, Ar3, or hetAr;
[0024) hetAr1 is a 6 membered hetcroaryl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom and a group of formula -NR5aR5b in which each of R5a and R5b independently represents a hydrogen atom or a (1 -4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholino group;
[0025J hetAr2 is a 5-6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from C1-C4 alkyl;
[0026] Ar2 is phenyl which is unsubstituled or substituted with one or more groups independently selected from a halogen atom, CN, SF5, cyclopropyl, a Ci-C4 alkyl group, a C1-C4 alkoxy group and a fluoroCrC.4 alkyl group;
[00271 Ar3 is as defined for Ar2;
[0028] R7 and R8 are independently H, methyl, or F;
[0029] R9 is H or methyl; and
[0030] R10 is H or F. [0031) In certain embodiments, the compound of Formula I has the Formula Ia
Figure imgf000004_0001
Ia wherein:
[0032] R1 is Ar1 -L1 -W-L2-;
[0033] L2 is -(CRcRd)mS
[0034] W is -CONR3β- or -NR3bCO-;
10035} R3" and R3b are each H or methyl;
[0036) L1 is -(CR0RV1 -(CH=CH)-, or -O(CR°Rb) provided that when W is -NR3CO- then L1 is not -(CH=CH)-;
[0037] n and m arc independently 0, 1 or 2;
[0038] each R0, Rb, Rc and Rd is independently H, F, methyl or cyclopropyl, or R" and Rb or Rc and Rd together with the carbon to which they are attached form a cyclopropyl ring; [0039] Ar1 is phenyl or naphthyl, each of which is unsubstituted or substituted with one or more substituents selected independently from F, Cl, CN, CF3, CHF2, CH2F, SF5, methyl, ethyl, cyclopropyl, provided that when Ar1 is naphthyl then n is 0;
[0040] R2 is H, Ci-C6 alkyl, a residue of an amino acid or dipeptide, or CHRc(CH2)qRf ; [0041] q is 1 to 6; [0042] Rc is H, methyl or ethyl;
|0043) Rf is NRBRh in which R8 and Rh each independently represents a hydrogen atom or a Ci- CA alkyl group, or Rg and Rh together with the nitrogen atom to which they are attached form a 5-6 membercd heterocyclic ring optionally containing a second ring heteroatom selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from CpCβ alkyl;
[0044) A is CN, CH2NH2, CH2NR4aC(=O)R5, or CH2NR^SO2R6, Cl, OMe, ( l-4C)alkyl, cyclopropyl;
[0045] R4a and R4b arc each H or methyl;
[0046] R5 is Ci-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hctAr1, or Ar2; 10047] R6 is C1-C6 alkyl, NH(C1-C6 alkyl), N(C1-C6 alkyi)2, Ar3, or hetAr2; 4
[0048} hetAr1 is a 6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom and a group of formula -NR5aR5b in which each of R5a and RSb independently represents a hydrogen atom or a (1-4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholino group;
(0049] hctAr2 is a 5-6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from C1-C4 alkyl;
[0050] Ar2 is phenyl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom, CN, SF5, cyclopropyl, a C1-C4 alkyl group, a Ci-C4 alkoxy group and a fluoroCi-C4 alkyl group;
[00511 Ar3 is as defined for Ar2; and
[0052] R7 and R8 are independently H, methyl.
[0053) Compounds according to the present invention have been found to be DF2 modulators and are useful in the treatment of immunologic diseases such as asthma and allergic inflammation.
|0054] It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.
[0055] It will further be appreciated that the compounds of formula (I) or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention.
[0056] The compounds of Formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula 1 also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating cnantiomers of compounds of Formula I.
[0057] The term "halogen" as used herein includes F, Cl, Br and I.
[0058] The terms "CpC4 alkyl" and "C)-C6 alkyl" as used herein refer to a saturated linear or branchcd-chain monovalent hydrocarbon radical of one to four or one to six carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl,
2-propyl, 1-butyl, 2-mcthyl-l-propyl, 2-butyi, 2-ιnethyI-2-propyl, 2,2-dimethylpropyl, 1-pentyl,
2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methy 1-2 -butyl, 3-methyI- 1-butyl, 2-methyl- 1-butyl, 1-hexyl,
2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-penlyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl,
2-methyi-3-pentyl, 2,3-diniethyl-2-buryl, and 3,3-dimethyl-2-butyl.
[0059] The term "heteroaryl" as used herein refers to a monovalent aromatic radical of a 5-, 6-, or 7-membercd ring. Examples of heteroaryl groups include, but are not limited to, pyridinyl, 5 imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, and pyrrolyl.
[0060] The term "fluoroCi-C4 alkyl" as used herein refers to a Ci-C4 alkyl group wherein one or more of the hydrogens is replaced by a fluorine atom. Examples include CF3, CH2F, CHF2,
CH2CH2F, CH2CH2F2, CH2CF3, CH2CH2 CH2F, CH2CH2 CHF2, CH2CH2CF3, CHF(CH3J2,
CH2CHF(CH3)2j and (he like.
[0061] The term "Ci-C6 alkoxy" as used herein refers to a Ci-C6 alkyloxy group. Exemplary alkoxy groups include mcthoxy, ethoxy, propoxy, isopropoxy, butoxy. t-butoxy, and isobutoxy.
[0062] In one embodiment, W is -CONR3"-. An example of a particular value for Ku is hydrogen. In one embodiment, W is -NR3hCO-. In one embodiment R3h is hydrogen. In another embodiment, R3b is methyl. Examples of particular values for W arc CONH, NHCO and N(CH3)CO.
[0063] In one embodiment, L1 is -(CRaRb)n-. Examples of particular values for n are 0, 1 and 2.
[0064] In one embodiment, L1 is a bond.
[0065] In one embodiment, L1 is -(CR°Rb). In certain embodiments, R° and Rb are hydrogen. In certain embodiments, R° is OH. In certain embodiments, R° and Rb together with the carbon atom to which are attached form a cyclopropylidine ring.
[0066] In one embodiment, L1 is -(CR°Rb)2. In certain embodiments, R" and Rb are hydrogen.
In certain embodiments, R" and Rb together with the carbon atom to which are attached form a cyclopropylidine ring. In certain embodiments, R" and Rb are attached to the same carbon. In other embodiments, R" and Rb arc attached to different carbon atoms.
[0067] Examples of particular values for L1 are a bond, -CH2-, -CH2CH2- and cyclopropylidcneCH2.
(0068] A further example of L1 includes CH(OH)CH2.
[0069] Further examples of V include cyclopropylidine groups, which can be represented by the following structures:
X x
[0070] In one embodiment, L1 is -O(CR°Rb)-. An exemplary embodiment is -OCH2-.
[0071] Referring to L2, examples of particular values for m are 0 and 1. Examples of particular values for L2 are a bond and -CH2-.
[0072] In certain embodiments, the sum of m and n is 0, 1 and 2. Particular mention is made of compounds in which the sum of m and n is 0 or 2.
[00731 Examples of values for -L'-W-lΛ include -CONH-, -CH2CONH-, -CH2CH2CONH-,
-CONHCHr, -CH2CONHCH2-, -NHCO-, -CH2NHCO-, -NHCOCH2-= -CH2CH2NHCO-, 6
-CH2NHCOCH2-, -CH2CH2NHCOCH2-, -CH2N(CH3)COCH2-, cyclopropylidcncCH2NHCO and
-CH2ONHCO-.
|00741 Further examples of values for -L1 -W-L2- include -CH(OH)CH2NHCO- and
-cyclopropylidineNHCO-.
100751 Particular values of -L'-W-lA are -CONH-, -NHCO-, -CH2NHCO-, -NHCOCH2-,
-CH2CH2NHCO-, -CH2NHCOCH2-, -CH2CH2NHCOCH2-, -CH2N(CHj)COCH2-, cyclopropylidcncCH2NHCO, -CH(OH)CH2NHCO- and -cyclopropylidineNHCO-.
(0076] In one embodiment, Ar1 is a naphthyl group or a phenyl group that is substituted by one or two substituents independently selected from F, Cl CF3, OMe, Me, and t-Bu.
[0077] In one embodiment, Ar1 is a naphthyl group or a phenyl group that is unsubstituted or substituted by one or tvvo substituents selected independently from F, Cl and CF3.
[0078] In one embodiment, Ar1 is a naphthyl group or a phenyl group that is substituted by one or two substituents independently selected from OMe, Me, and t-Bu.
[0079] In one embodiment, Ar' is 1,2,3,4-tetrahydronaphthyl which is unsubstituted or substituted with OMe. In a particular embodiment, A is selected from the structures:
Figure imgf000007_0001
[0080] Examples of particular values for Ar1 are naphthyl, phenyl, 4-fluorophenyl, 3,4- di fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-chloro-3- fluorophcnyl, 3-chloro-4-fIuorophcnyl, 4-trifluoromethylphcnyl, 3-fluoro-4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxyphcnyl,
Figure imgf000007_0002
4-ιcrtbulylphenyl, 3-fluorophenyl, 4-methylphenyI, l,2,3,4-tetrahydronaphth-2-yl and 6-methoxy- l,2,3,4-tetrahydronaphth-2-yl.
[0081] In certain embodiments, Ar1 is selected from naphthyl, phenyl, 4-fluorophenyl, 3,4- di fluorophenyl, 2-chlorophcnyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-chloro-3- fluorophcnyl, 3-chloro-4-fluorophenyl, 4-lrifluoromethylphenyl and 3-fluoro-4- tri fluoromethy (phenyl .
[0082] In certain embodiments, Ar1 is selected from 3-trifluoromethylphenyl, 2,6- dichlorophenyl, 2,4-dichlorophenyl, 3-methoxyphenyI, 4-methoxyphenyl, 4-tertbutylphenyl, 3-fluorophenyl and 4-methylphenyl, and l,2,3,4-tetrahydronaphth-2-yl and 6-methoxy- 1,2,3,4- tetrahydronaphth-2-yl. [0083] In one embodiment, A is CN. [0084] In one embodiment, A is H. 7
[0085) In one embodiment, A is selected from F, Br and Cl.
|0086] In one embodiment, A is selected from (l-4C)alkyl. Particular examples include methyl and ethyl.
[0087] In one embodiment, A is cyclopropyl.
[0088] In one embodiment, A is selected from CH2NH2, CH2NH(I-C alkyl), and CH2N(MC alkyl)2. Particular examples include CH2NH2 and CH2NMe2.
[0089] In one embodiment, A is thienyl. In a particular embodiment, A is 2-lhienyI.
[0090] In one embodiment, A is phenyl which is unsubstitutcd or substituted with SO2Me.
Particular examples include phenyl, 3-mcthylsulfonyIphenyI, and 4-mcthylsulfonylphenyl.
[0091] In one embodiment, A is C H2N R411C(3O)R5. An example of a particular value for R4* is hydrogen. In one embodiment, R5 is hetAr1. An example of a particular value for a heteroaryl group represented by hetAr1 is a pyridyl group. Examples of optional subsϋtucnts on the heteroaryl group are NH2, Cl, and pyrrolidinyl.
[0092] In another embodiment, R5 is Ci-Ce alkyl; CpC6 alkoxy; C3-C6 cycloalkyl; pyridyl which is unsubstituted or substituted by a halogen atom or a group of formula -NR5"RSh in which each of
R5" and R5b independently represents a hydrogen atom or a (1 -4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or morpholino group; or a phenyl group that is unsubstiluted or substituted by one or two halogen atoms.
[0093] Examples of particular values for R5 are methyl, mclhoxy, cyclohcxyl, pyrid-2-yl, pyrid-
3-yl, pyrid-4-yl, 6-chloro-pyrid-3-yl, 6-amino-pyrid-3-yl, 6-pyrrolidin-l-ylpyrid-3-yl or 4- fluorophenyl. An additional example of R5 is 6-dimethylaminopyrid-3-yl.
|0094] In one embodiment, A is CH2NR*SO2Rδ. An example of a particular value for R4b is hydrogen. In one embodiment, K6 is hetAr2. Examples of particular values for a heteroaryl group represented by hetAr arc an imidazolyl and a pyridyl group. Examples for optional substituents on the heteroaryl group are Ci -C4 alkyl, for example methyl.
[0095] In another embodiment, R6 is Ci-C6 alkyl, NH(Ci-C6 alkyl), N(Ci-C6 alkyl)2, a phenyl group that is unsubstituted or substituted by one or two halogen atoms, pyridyl or imidazolyl that is unsubstituled or substituted with a C1-C3 alkyl group.
[0096J Examples of particular values for R6 arc methyl, dimethylamino, 4-fluorophenyl, 2,4- dichlorophenyl, pyrid-3-yl and l-methylimidazol-5-yl. An additional example of R6 is pyrid-4-yl.
[0097] Examples of particular values for A are acetamidomcthyl, cyclohexylamidomethyl, methoxycarbonylaminomcthyl, picolinamidomethyl, nicotinamidomethyl, isonicotinamidomethyl, 6- chloropyrid-3-ylamidomethyl, 6-aminopyrid-3-ylamidomethyl, 6-pyrroIidin-l-ylpyrid-3- ylamidomelhyl, 4-fluorobenzamidometh\i, methylsulfonamidomethyl, N,N- dimcthylsulfamoylamino, 4-fluorophcnylsulfonamidomethyl, 2,4-dichlorophenyl- sulfonamidomcthyl, l-methylimidazol-5-ylsulfonamidomethyl and pyrid-3-ylsulfonamidomethyl, which can be represented by the following structures, respectively:
Figure imgf000009_0001
(0098J Particular mention is made of acetamidomethyl, cyclohexylamidomethyl, methoxycarbonylaminomethyl, picolinamidomethyl, nicotinamidomethyl, isonicotinamidomethyl, 4- fluorobenzamidomethyl, methylsulfonamidomethyl, N,N-dimethylsulfamoylamino, 4- fluorophenylsulfonamidomethyl, 2,4-dichlorophenylsulfonamidomcthyl and pyrid-3- ylsulfonamidomethyl.
[0099J Particular values for A also include 6-dimeuiylamtnopyrid-3-ylamidomethyI, 2-(4-fluorophenylsulfonamido)acetamidomethyl, dimethylaminomethyl and (N- methylmethylsulfonamido)methyl, which can be represented by the following structures, respectively:
Figure imgf000009_0002
(00100) Examples of particular values for R2 when it represents a CpC6 alkyl group are methyl, ethyl, propyl, isopropyl and t-butyl.
(00101) In one embodiment, R2 is CHRc(CH2)qRr. Examples of values for Rc are hydrogen and methyl. In one embodiment, Rr is di(l-4C)alkylamino, morpholino, or piperazinyl optionally substituted with (l-4C)alkyl. Examples of particular values for Rrare dimethylamino, diethylamino, morpholino, piperazinyl and 1-mcthylpiperazinyl. Additional examples include NH2 and NHMe. [00102| Examples of particular values for R2 when it represents CHRc(CH2)qRf are:
Figure imgf000010_0001
[00103] In one embodiment, R2 is hydrogen.
(00104] On one embodiment, both R7 and Rs are H. In certain embodiments, R7 is H and R8 is methyl. In other embodiments, each of R7 and Rs is methyl.
[00105J According to another aspect, the present invention provides a process for the preparation a compound of formula (I) or a salt thereof as defined hcreinabove, which comprises:
[00106J (a) for a compound of formula (I) in which A is CN, R7 and R8 are independently H or Me, and R10 is H or F3 reacting a corresponding compound having the formula:
Figure imgf000010_0002
in which P1 represents a hydrogen atom or a carboxyl protecting group and Z1 represents a leaving atom or group, with a corresponding compound having the formula
Figure imgf000010_0003
in which Rl0° is H or F in the presence of a base; or
[00107] (b) for a compound of formula (I) in which A is -CH2NH2, R10 is H, and R7 and
R8 are independently H or Me, reducing a corresponding compound formula (IV) 10
Figure imgf000011_0001
(IV) in which P2 is as defined for P"; or
[OOIOS] (c) for a compound of formula (I) in which A is -CH2NH2, R7 and R8 are independently H or Me, and R10 is H, cleaving a corresponding compound of formula (V)
Figure imgf000011_0002
(V) in which P3 is as defined for P1; or
(00109| (d) for a compound of formula (I) in which A is CH2NR4C(=O)R3 or CH2NR4SO2R6, R7 and R8 are independently H or Me, and R10 is H, reacting a corresponding compound of formula (VI)
Figure imgf000011_0003
(VI) in which P4 is as defined for P1; with a compound of formula R3COZ2 or R6SOjZ3, respectively, in which Z2 and Z3 each represents a leaving atom or group; or
[00110] (e) for a compound of formula (I) in which R7 and R8 are independently H or Me, and R10 is H, coupling a compound of formula (VII) 1 1
Figure imgf000012_0001
(VII) in which P5 is as defined for P1, A2 represents A or a protected form thereof and Rla represents H-X0- L2- in which X0 represents HN or OC(=O), or a reactive derivative thereof; with a compound of formula (VHI)
Ar'-L'-XNH
(VlII) in which Xb represents C(=O)O or NH, or a reactive derivative thereof; or [00111) (0 for a compound of formula (I) in which A is H, F or Cl, R7 and R8 are independently H or Me, and R10 is H, coupling a corresponding compound having the formula OX)
Figure imgf000012_0002
(IX) in which A3 is H, F or Cl, and P6 is as defined for P1, with a corresponding compound having the formula (X)
Figure imgf000012_0003
wherein E is an electron withdrawing group, in the presence of a base; and if desired removing said electron withdrawing group; or
|00112] (g) for a compound of formula (I) in which A is OMe or (l-4C)alkyI, R7 and R8 are independently H or Me, and R10 is H, coupling a corresponding compound having the formula (XI) 12
Figure imgf000013_0001
(XI) in which A4 is OMc or (l-4C)alkyl, respectively, and P7 is as defined for P1, with a corresponding compound having the formula (XII)
Figure imgf000013_0002
in the presence of a base, in which Z4 represents a leaving atom or group, and Rlx represents an electron withdrawing group convertible into a group R1; or
[00113] (h) for a compound of formula (I) in which A is Br or cyclopropyl, R7 and R8 are
H, and R . 10 is H, coupling a corresponding compound having the formula (XIV)
Figure imgf000013_0003
in which Z5 is a leaving group or atom, with a compound having the formula (XV)
Figure imgf000013_0004
in the presence of a base, followed by converting the carbonyl group to a carboxyl group; or [00114) (i) for a compound of formula (I) in which A is methyl, thienyl, phenyl, or phenyl substituted with SO2Me, R9 is H. R7 and R8 are independently H or Me, and R10 is H, reacting a corresponding compound having the formula (XVI) 13
Figure imgf000014_0001
(XVI) with a compound having the formula A5-ZnX, in the presence of a palladium (O) catalyst, or with a compound having the formula A5B(OH)2 in the presence of a base and a palladium (O) catalyst, where A5 is methyl, Ihienyl, phenyl, or phenyl substituted with SC^Me and X is a halide; or [00115] (j) for a compound of formula O) in which R7 is F, R8 is H, and R10 is H, treating a corresponding compound having the formula (XVII)
Figure imgf000014_0002
(XVII) with hydrogen fluoride;
(00116| (k) for a compound of Formula (I) in which A is CH2NH(I -4C alkyl) or , CH2N(I - 4C alkyl)2s R7 and R8 are independently H or Me, and R10 is H, reacting a corresponding compound having the formula
Figure imgf000014_0003
14 with an aldehyde having the formula HC(O)(I -4C alkyl); and removing any protecting group or groups and, if desired, forming a salt.
(001171 Referring to process (a), the leaving atom or group represented by Z1 may be, for example, a halogen atom such as a fluorine atom. The carboxyl protecting group may be any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting
Groups in Organic Synthesis", John Wiley & Sons, Inc. Examples of carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl. The base may be, for example, an alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate or potassium carbonate, or a tertian' amine, such as triethylamine or N,N-diisopropylethylamine. Convenient solvents include amides, sulfoxides and nitriles, such as DMF, DMSO or acetonitrile. The reaction can be performed at an elevated temperature, such as in the range of from 50 to 150 0C.
(00118 J Compounds of formula (II) arc known or can be prepared from the corresponding 3-halo compound, such as a 3-bromo compound, by treatment with CuCN.
[00119] Referring to process (b), the compound of formula (IV) can be reduced by hydrogenation in the presence of a Group VIII metal catalyst, such as Rancy Ni with mcthanol/ammonia. The reaction can be conducted at a temperature in the range of from 0 to 100 0C.
[00120] Referring to process (c), the dioxoisoindolinyl group can be cleaved using HBr and acetic acid or hydrazine.
[00121] Compounds of formula (V) can be prepared by reacting a compound of formula (XIII)
Figure imgf000015_0001
(XIII) with a compound of formula (XIl)
Figure imgf000015_0002
(XII) in the presence of a base, in which Z4 represents a leaving atom or group, such as a fluorine atom, and Rlx represents an electron withdrawing group convertible into a group R1, for example a nitro group that can be reduced to an amino group and then acylated. The base may be, for example, an 15 alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate or potassium carbonate.
|00122] Compounds of formula (IX) can be prepared by reacting 4-hydroxyphenylacetic acid with 2-(hydroxymethyl)isoindoline-l,3-dione in the presence of a sulfonic acid, such as methancsulfonic acid, and followed if desired by introducing a protecting group P3.
[00123] Referring to process (d), the leaving atom or group represented by Z2 and Z3 may be, for example, a halogen atom such as a fluorine atom. The reaction can be performed in the presence of a base, for example a tertiary amine such as diisopropylethylamine or pyridine. Convenient solvents include halogcnated hydrocarbons, such as methylene chloride. The reaction can be conducted at a temperature in the range of from 0 to 100 0C.
[00124| Referring to process (e), the coupling of the compound of formula (VII) with a compound of formula (VlII) may be performed using conventional amide bond formation conditions, for example by reacting an amine with a reactive derivative of a carboxylic acid, for example an acid halidc, such as an acid chloride. An example of A1 when it represents a protected form of A is a group of formula -CH2NR4P6 in which P6 represents an amine protecting group. The amine protecting group may be any convenient amine protecting group, for example as described in
Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", JoIm Wiley & Sons, Inc. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl
(BOC).
[00125] Referring to process (f), examples of electron withdrawing groups include NO2. In embodiments wherein the electron withdrawing group is NOa, this group can be removed, if desired, by reducing the nitro group to an amino group using any convenient reducing conditions (for example, Zn and NH4Cl) followed by cleavage of the amino group (for example, by treating the amino compound with isobutyl nitrite).
[00126] Referring to process (g), the base may be, for example, an alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate or potassium carbonate. The Z4 group represents a suitable leaving atom or group, such as a fluorine atom, and Rlx represents an electron withdrawing group convertible into a group R1, for example a nitro group that can be reduced to an amino group and then acylaled.
[00127] Referring to process (h), the leaving atom or group represented by Z5 may be, for example, a halogen atom such as a fluorine atom. The base may be, for example, an alkali metal hydride or carbonate, such as sodium hydride, sodium carbonate, or potassium carbonate.
Convenient solvents include sulfoxides such as DMSO. The reaction can be performed at elevated temperatures, ibr example in the range of 50- 100 "C, for example at 85 0C. The carbonyl group can 16 be converted to a carboxyl group by treating the coupling product with methylsulfonyl/methylthiomcthane to provide an intermediate having the formula (XVIII)
Figure imgf000017_0001
(XVIII) followed by converting the intermediate (XVIlI) to the corresponding methyl ester upon treatment with HCI in methanol. The ester can be converted to the corresponding acid under standard hydrolysis conditions.
|00128) Referring to process (i), the halide represented by X can be F, Cl or Br. Convenient solvents include ethers such as THF or dioxanc. Suitable palladium (0) catalysts include Pd(PPIb)4 and bis(tri-t-butylphosphinc)palladium (0). A convenient base when compound (XVI) is reacted with a boronic acid reagent includes DBU. The reaction can be performed at elevated temperatures, for example in the range of 50-100 0C, for example 60 0C.
(00129] Referring to process (j), the reaction is conveniently performed in the presence of an amine base, for example pyridine.
[00130] Referring to process (k), the reaction is conveniently performed in the presence of a base, for example a hydride such as sodium cyanoborohydride in an alcohol solvent such as methanol. The reaction is preferably performed in the presence of a catalytic amount of acid, for example acetic acid. The reaction is conveniently performed at ambient temperature. [00131] The ability of test compounds to act as DP2 receptor modulators may be demonstrated by the assay described in Example A.
[00132] Compounds which are modulators of DP2 are useful in the treatment of diseases or disorders mediated by PGD2, for example, diseases or disorders associated with overproduction or dysregulation Of PGD2.
[00133] As used herein, the term treatment includes prophylaxis as well as treatment of an existing condition.
[00134] Examples of disorders or diseases that may be treated with compounds according to the invention include immunologic diseases. 17
[00135| Examples of immunologic diseases include allergic inflammatory diseases, such as asthma, atopic dermatitis, allergic rhinitis, seasonal allergies, food allergies, contact hypersensitivity (e.g., nickel sensitivity), hypcr-cosinophilic syndromes, and allergic conjunctivitis. [00136) Additional diseases or disorders which may be treated with the compounds of this invention include inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, ileitis and enteritis, vasculitis, Behcet's syndrome, psoriasis and inflammatory dermatoses such as dermatitis, eczema, urticaria, viral cutaneous pathologies such as those derived from human papillomavirus, HIV or RLV infection, bacterial, fungal and other parasital cutaneous pathologies, and cutaneous lupus erythematosus, respiratory allergic diseases such as persensitivity lung diseases, chronic obstructive pulmonary disease and the like, autoimmune diseases, such as arthritis (including rheumatoid and psoriatic), systemic lupus erythematosus, type I diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, glomerulonephritis and the like, graft rejection (including allograft rejection and graft-v-host disease), e.g., skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection, fever, cardiovascular disorders such as acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary artery disease, restenosis, thrombosis and vascular stenosis, cerebrovascular disorders such as traumatic brain injury, stroke, ischemic rcperfusion injury and aneurysm, cancers of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood and lymphatic system, fibrosis, connective tissue disease and sarcoidosis, genital and reproductive conditions such as erectile dysfunction, gastrointestinal disorders such as gastritis, ulcers, nausea, pancreatitis and vomiting; neurologic disorders, such as Alzheimer's disease, sleep disorders such as insomnia, narcolepsy, sleep apnea syndrome and Pickwick Syndrome, pain, renal disorders, ocular disorders such as glaucoma, infectious diseases, viral infections such as HIV, and bacterial infections such as sepsis, inflammation, flushing, nasal congestion, and otitis media. [00137J Accordingly, another aspect of this invention provides a method of treating diseases or medical conditions in a mammal mediated by PGD2, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt or prodrug thereof in an amount effective to treat or prevent said disorder.
(00138] The phrase "effective amount" means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat or prevent a particular disease, condition, or disorder mediated by PGD2, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. 18
[00139| The amount of a compound of Formula 1 that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
(00140] As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
(00141) This invention also provides compounds of Formula I for use in the treatment of PGD2- mediatcd conditions.
(00142) An additional aspect of the invention is the use of a compound of Formula I in the preparation of a medicament for therapy, such as for the treatment or prevention PGD2 -mediated conditions.
[00143] The compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-inflammatory compound that works by a different mechanism of action.
[00144] The compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rcclally or orally), the nose, lungs, musculature or vasculature or transdermally. The compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions ma)' contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
[00145] According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinabove. In one embodiment, the pharmaceutical composition includes the compound of formula (I) together with a pharmaceutically acceptable diluent or carrier.
[00146| According to another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.
[00147] According to a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to (real an immunologic disorder, as defined hereinabove. 19
[00148] The following examples illustrate the invention. In the examples described below, unless otherwise indicated all temperatures arc set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridgc, and were used without further purification unless otherwise indicated. Tctrahydrofuran (THF), dichloromethane (DCM, methylene chloride), toluene, and dioxane were purchased from Aldrich in Sure seal bottles and used as received.
[00149] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
[00150] 1HNMR spectra were obtained as CDCl3, CD3OD, D2O or (I6-DMSO solutions (reported in ppm), using tetramcthylsilane (0.00 ppm) or residual solvent (CDCI3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; dό-DMSO: 2.50 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations arc used: s (singlet), d (doublet), t (triplet), m (multiple.), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
Example A
DP-2 binding Inhibition Assay
[00151] The coding sequence of human DP2 was introduced into the human Leukemic cell line K562 by electroporation and stable clones expressing DP2 were obtained by limiting dilution followed by cell surface staining with a rat monoclonal antibody specific for human DP2. Membranes were prepared from one of these DP2 expressing clones and used to determine the ability of the compounds of the present invention to inhibit binding of prostaglandin D2 (PGD2) to its receptor DP2 by the following procedure. Membranes (1.25 OgΛvell) were mixed with 3H- labeled PGD2 and various concentrations of test compounds in 150 μL of binding buffer (50 mM Tris-HCl, pH 7.4, 40 mM MgCl3, 0.1% bovine serum albumin, 0.1% NaN3) in 96-well U-bottom polypropylene plates. After incubation for 60 minutes at room temperature, the assay was transferred to a filtration plate (#MAFB; Milliporc Corporation, Bedford, MA), and washed three times with binding buffer. Radioactivity was measured by a scintillation counter (TopCount; PerkinElmer Life Sciences, Boston, MA). Nonspecific binding was determined by incubations in the presence of 1 μM unlabeled PGD2 or 5 DM of a known DP2 antagonist. IC50 values for inhibition of binding are determined for each compound tested from the inflexion point of a standard 4-parameter logistical curve fitted to the values obtained. All compounds disclosed herein had IC50 values less than 1 micromolar. 20
Example 1
2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-((4-fluorophenylsulfonamido)tnethyl)-
Figure imgf000021_0001
[00152] Step A: 2-(4-hydrox>φhenyl)acetic acid (7.0 g, 46 mmol) was diluted with methane sulfonic acid (100 mL) and cooled to -10 0C. 2-(Hydroxymcthyl)isoindoline-I,3-dionc (8.2 g, 46 mmol) was added portionwisc over 15 minutes. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured onto ice and stirred for 1 hour. The reaction mixture was filtered and rinsed with water. The material was air dried overnight and then placed under high vacuum for 5 hours. The material was then taken up in DMF using heat to ensure all the material was in solution. Small amounts of water were added until a precipitate persisted. The mixture was filtered and the solid material corresponded to bis alkylated material. Additional water was added to crash out the 2-(3-((l,3-dioxoisoindolin-2-yl)methyl)-4-hydroxyphenyl)acetic acid which was filtered and dried. This material was carried on to the next step without further purification.
[00153] Step B: The product of step A (6.7 g, 22 mmol) was diluted with HBr (21 g, 258 mmol) and acetic acid (20 mL). The reaction mixture was heated to reflux and stirred overnight. The reaction mixture was then cooled to 0 0C and was neutralized with solid NaOH pellets to pH~10, affording a solution of 2-(3-(aminomethyl)-4-hydroxyphenyI)acetic acid which was used in the next step without further purification.
[00154] Step C: To 2-(3-(aminomethyl)-4-hydroxyphenyl)acctic acid (3.9 g, 21.5 mmol) was added BOC2O (5.40 g, 24.8 mmol) in 30 mL of dioxane. After stirring for 4 hours, the reaction was diluted with ethyl acetate and IN HCl. The organic layer was dried over MgSO4 and concentrated. The solid was taken up in minimal methylene chloride, filtered and rinsed with methylene chloride. The filtrate was concentrated to yield 3.0 g of 2-(3-((tert-butoxycarbonyl)aminomethyl)-4- hydroxyphenyl)acctic acid as a white foam.
[00155] Step D: 2-(3-((tert-Butoxycarbonyl)aminomethyl)-4-hydroxyphenyl)acetic acid (1.6 g, 5.69 mmol) was diluted with THF ( 10 mL) and methanol (5 mL) followed by the addition of TMSCHN2 (14.2 mL, 28.4 mmol) dropwise. The reaction mixture was stirred for 30 minutes and then diluted with ethyl acetate and water. The layers were separated and the organic layer was dried 21 over MgSQi, filtered and concentrated. The material was purified using a biotagc 4OS cartridge eluting with hexanes:ethyl acetate (4: 1) yield 860 nig of clear oil that later solidified to methyl 2-(3-
((tcrt-butoxycarbonyl)aminomethyl)-4-hydro.vyphenyl)acetate.
|00156] Step E: Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-hydrox\'phenyl)acetate (200 mg, 0.677 mmol) was diluted with ACN (2 rnL) followed by the addition of K2CO3 (206 mg, 1.49 mmol) and l-fluoro-4-nitrobenzene (0.103 mL, 0.948 mmol). The reaction mixture was heated to reflux (at about 82 0C) and stirred for 5 hours. The reaction mixture was then diluted with ethyl acetate and water. The layers were separated and the organic layer was dried over MgSO.4, filtered and concentrated. The material was purified using a biotage 4OS eluting with hcxancs/cthyl acetate
(3: 1) to yield 242 mg of methyl 2-(3-((tcrt-butoxycarbonyl)aminomcthyl)-4-(4-nitrophcnoxy) phenyl)acctate as a clear oil.
100157] Step F: Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-niϋOphenoxy) phenyOacetate (242 mg, 0.581 mmol) was diluted with THF (3 mL) followed by the addition of Zn dust (38.0 mg, 0.581 mmol). About 2 mL of saturated ammonium chloride was added dropwise.
After stirring the reaction for 10 minutes, the reaction mixture was diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over
MgSO4, filtered and concentrated to yield 225 mg of methyl 2-(4-(4-aminophenoxy)-3-((tert- butoxycarbonyl)aminomelhyl)phenyl)acetate.
|00158] Step G: Methyl 2-(4-(4-aminophenoxy)-3-((tert-butoxycarbonyl)aminomcthyl) phenyOacetate (100 mg, 0.259 mmol) was diluted with methylene chloride (3 mL) followed by the addition of 3,4-dichlorobenzoyl chloride (81.3 mg, 0.388 mmol) and N,N-diisopropylethyl amine
(0.0451 mL, 0.259 mmol). The reaction was stirred for 3 hours. The reaction mixture was diluted with methylene chloride and water. The layers were separated and the organic layer was dried over
MgSO4, filtered and concentrated. The material was purified using a biotagc 12i eluting with hexanes:cthyl acetate (3: 1) to yield 130 mg of methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-
(4-(3,4-dichlorobenzamido)phcnoxy)phenyl)acctatc.
]00159] Step H: Methyl 2-(3-((tert-butoxycarbonyl)aminomethyl)-4-(4-(3,4- dichlorobenzamido)phenoxy)phenyl)acetatc (130 mg, 0.232 mmol) was treated with HCl (0.581 mL,
2.32 mmol), After stirring for 3 hours, the material was concentrated to yield 100 mg of methyl 2-
(3-(aminomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate.
[00160] Step I: The product of step H (30 mg, 0.065 mmol) was diluted with methylene chloride
(1 mL) followed by the addition of 4-fluorobenzene-l-sulfonyl chloride (15 mg, 0,078 mmol) and
DlEA (0.024 mL, 0.14 mmol). After stirring the reaction for 4 hours, the reaction mixture was placed directly onto a preparative tic plate 0.5 mm and eluted with hexanesxthyl acetate (3: 1) to 22 yield 30 mg of methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fluorophenyl- sulfonamido)methyl)phenyl)acetate.
|00161] Step J: Methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fiuorophenyl- sulfonamido)mcthyl)phenyl)acetate (40 mg, 0.065 mmol) was diluted with MeOH (1 mL) followed by the addition of NaOH (0.32 mL, 1.3 mmol). After stirring for I hour, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative plate cliiUng with methylene chloridc:MeOH:AcOH (90:9: 1) to yield 12 mg of the title compound as a solid. 1H NMR (400 MHz, CDCI3/CD3OD) 8.1 (m, IH), 7.85 (m, I H), 7.8 (m, 2H), 7.7 (d, IH), 7.6 (d, IH), 7.25 (s, 1 H), 7.2 (m, 3H), 6.85 (d, 2H), 6.7 (d, IH), 4.15 (s, 2H), 3.55 (s, 2H).
Example 2 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000023_0001
[00162] Prepared by the method of Example 1, substituting 4-fluorobenzene- l-sulfonyl chloride in Step H with methanesulfonyl chloride. 1H NMR (400 MHz, ^-DMSO) 12.4 (s, IH), 10.4 (s, IH), 8.20 (m, 1 H): 7.95 (m, IH), 7.85 (d, IH), 7.75 (d, 2H), 7.55 (t, IH), 7.4 (m, I H), 7.19 (m, IH), 7.05 (d, 2H), 6.8 (d, IH), 4.2 (d, 2H), 3.55 (s, 2H), 2.85 (s, 3H).
Example 3
2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-((2,4-dichlorophenylsulfonamido)methyl)- phenyl)acetic acid
Figure imgf000023_0002
(00163] Prepared by the method of Example 1 , substituting 4-fluorobenzene- l-sulfonyl chloride in Step H with 2..4-dichiorobcnzyl-l-sulfonyl chloride. 1H NMR (400 MHz, CDCl3,CDjOD) 8.1 (s, IH), 7.85 (m, 2H), 7.65 (m, 3H), 7.50 (m, IH), 7.35 (d, IH), 7.2 (s, IH), 7. 10 (d, I H), 6.90 (d, 2H), 6.60 (d, IH), 4.20 (s, 2H), 3.45 (s, 2H). 23
Example 4 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-(nicotinamidomethyl)phenyl)acetic acid
Figure imgf000024_0001
(00164] Step A: 4-Aminophenol (1.9 g, 17 mmol) was diluted with DMF (40 mL) followed by the addition of pyridine (0.978) (1.4 mL, 17 mmol) and 3,4-dichlorobenzoyl chloride (3.0 g, 14 mmol) in 5 mL of DMF. After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The aqueous layer was extracted once with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, filtered and concentrated onto silica gel. The material was purified using a biotage 4OM column eluting with hexanes:cthyl acetate (9: 1) using 2 L and then (60:40) IL to yield 3,4-dichloro-N-(4-hydroxyphenyl)-benzamide ( 1.5 g, 37% yield) as a white solid.
[00165| Step B: tert-Butyl 2-(3-cyano-4-fluorophenyl)acetate (2.0 g, 8.5 mmol) and the product of step A (2.9 g, 10 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.4 g, 10 mmol). The reaction was heated to 125 0C and stirred for 12 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 4OM column eluting with hexancsicthyl acetate (8:2) to yield tert-butyl 2-(3-cyano-4-(4-(3,4- dichlorobcnzamido)phenoxy)phenyl)acetatc (2.5 g, 59% yield) as a white solid. (00166| Step C: The product of step B (100 mg, 0.201 mmol) was diluted with 7N ammonia/methanol (10 mL), followed by addition of ethyl acetate (10 mL). Once the material dissolved, Raney Nickel (1.72 mg, 0.0201 mmol) was added and die reaction was purged three times with a balloon of hydrogen. After stirring for 12 hours, the reaction mixture was filtered through a GF/F filter and concentrated. The residue was purified using a biotage 12i column eluting with methylene chloride:MeOH:NH4OH (90:9: 1) to yield tert-butyl 2-(3-(aminomethyl)-4-(4-(3,4- dichlorobcnzamido)phenoxy)phcnyl)acetate (100 mg, 99.2% yield) as a clear oil. 24
[00167] Step D: The product of step C (0.050 g, 0.997 mmol) was dissolved into I mL of DCM in a small test tube. Pyridine (0. 017 g, 0.219 mmol) and nicotinoyl chloride (0.0195 g, 0.110 mmol) were added, and the reaction mixture was stirred for 12 hours. The reaction mixture was then diluted with methylene chloride and water. The methylene chloride layer was separated and loaded directly onto a biotagc 12i column cluting with methylene chloridc:MeOH (95:5) to yield tert-buryl 2-(4-(4-(3,4-dichlorobenzamido)phcnoxy)-3-(nicotinamidomethyl)phenyl)-acetate (44 mg, 73% yield) as a clear oil.
[00168] Step E: The product of step D (44 mg; 0.073 mmol) was diluted with methylene chloride:TFA (1 : 1 ) and stirred for 3 hours. The reaction mixture was concentrated, taken up in ether and sonicated. The solid was filtered, rinsed with ether and dried under vacuum to yield the title compound (35 mg, 88% yield) as white solid. 1H NMR (400 MHz, CDCI3/CD3OD) 8.75 (m, IH), 8.65 (m, IH), 8.15 (m, IH), 8. 10 (m, IH), 8.0 (m, IH), 7.60 (m, 3H), 7.45 (m, IH), 7.20 (m, IH), 6.95 (d, 2H), 6.90 (d, IH), 4.65 (m, 2H), 3.62 (s, 2H).
Example 5
2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-((N,N-dimethylsulfamoylamino)methyl)-
Figure imgf000025_0001
[00169] Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with dimcthylsulfamoyl chloride. 1H NMR (400 MHz, CDC13/CD3OD) 8.05 (s, IH), 7.80 (m, IH), 7.65 (m,2H), 7.55 (d, IH), 7.35 (m, IH), 7.18 (m, IH), 7.00 (d, 2H), 6.82 (d, IH), 4.25 (s, 2H), 3.60 (s, 2H), 2.75 (s, 6H).
25
Example 6 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000026_0001
[00170] Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with methanesulfonyl chloride. 1H NMR (400 MHz, αk-DMSO) 12.4 (s, IH), 10.4 (s, I H), 8.20 (m, IH), 7.95 (m, IH), 7.85 (d, IH), 7.75 (d, 2H), 7.55 (t, I H), 7.4 (m, IH), 7.19 (m, IH), 7.05 (d, 2H), 6.8 (d, IH), 4.2 (d, 2H), 3.55 (s, 2H), 2.85 (s, 3H).
Example 7
2-(3-(Cyclohexanecarboxamidomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)-acetic acid
Figure imgf000026_0002
(001711 Prepared by method of Example 4, substituting nicotinoyl chloride in Step D with cyclohexanccarbonyl chloride. 1H NMR (400 MHz, CDC13,CD3OD) 8.10 (m, IH), 7.80 (m, IH), 7.65 (d, 2H), 7.55 (d, IH), 7.25 (m, I H), 7. 15 (d, I H), 6.95 (d, 2H), 6.85 (d, IH), 2.10 (m, IH), 1.6- 1.8 (m, 5H), 1.2-1.4 (m, 6H).
Example 8 2-(3-(Acetamidomethyl)-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetic acid 26
Figure imgf000027_0001
|00172) Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with acetyl chloride. 1H NMR (400 MHz, CDCI3/CD3OD) 8.10 (m, IH), 7.80 (m, IH), 7.60 (m, 3H), 7.30 (m, IH), 7.15 (m. IH), 6.95 (d, 2H), 6.85 (d, I H), 4.42 (s, 2H), 3.40 (s, 2H), 1.95 (s, 3H).
Example 9 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-(isonicotinamidomethyl)phenyl)acetic acid
Figure imgf000027_0002
[00173] Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with isonicotinoyl chloride. 1H NMR (400 MHz, CDCI3/CD3OD) 8.62 (m, IH), 8.05 (m, IH), 7.88 (m, IH), 7.80 (m, I H), 7.65 (m, 2H), 7.58 (m, 3H), 7.35 (m, IH), 7.20 (m, I H), 6.95 (d5 2H), 6.90 (d, IH), 4.65 (d, 2H), 3.62 (s, 2H).
27
Example 10 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-((4-f1uorobenzamido)methyl)phenyl)acetic acid
Figure imgf000028_0001
|00I74) Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with 4- fiuorobenzoyl chloride. 1H NMR (400 MHz, CD3OD) 8.10 (s, IH), 7.85 (m, IH), 7.80 (m, 2H), 7.70 (d, I H), 7.62 (d, 2H), 7.35 (s, IH), 7.25 (d, IH), 7.35 (m, 2H), 6.95 (d, 2H), 6.90 (d, IH), 4.62 (s, 2H), 3.60 (s, 3H).
Example 11 2-(4-(4-(3,4-Dichlorob hyl)phenyl)acetic acid
Figure imgf000028_0002
[0017Sj Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with picolinoyl chloride. 1 H NMR (400 MHz, CD3OD) 8.60 (d, IH), 8.10 (m, I H), 8.05 (m, IH), 7.95 (m, IH), 7.85 (m, I H), 7.70 (d, IH), 7.60 (d, 2H), 7.55 (m, IH), 7.35 (m, I H), 7.20 (d, IH), 7.00 (d, 2H), 6.85 (d, IH), 4.64 (s, 2H), 3.60 (s, 2H).
Example 12
2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-((methoxycarbonylamino)methyl)phenyl)-acetic acid
Figure imgf000028_0003
28
[00176| Prepared by the method of Example 4, substituting nicotinoyl chloride in Step D with methyl chloroformate. 1H NMR (400 MHz, CDCl3) 8.10 (m, IH), 7.80 (m, IH), 7.65 (m, 2H), 7.58 (m, IH)1 7.30 (m, IH), 7.19 (m, IH), 6.95 (m, 2H), 6.85 (m, IH), 4.40 (s, 2H), 3.65 (s5 3H), 3.60 (s, 2H).
Example 13
2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-((pyridine-3-sulfonamido)methyl)phenyl)-acetic acid
Figure imgf000029_0001
[00177] Prepared by the method of Example 4. substituting nicotinoyl chloride in Step D with pyridine-3-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) 8.95 (s, IH), 8.60 (m, IH), 8.10 (m, IH), 8.05 (d, IH)5 7.80 (d, IH), 7.60 (m, 3H), 7.35 (m, I H), 7.22 (m, I H), 7.05 (d, I H), 6.80 (d, 2H), 6.62 (d, IH), 4.25 (s, I H), 3.55 (s, 2H).
Example 14
2-(4-(4-(3,4-Dichlorophenylcarbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)-acetic acid
Figure imgf000029_0002
[00178] Step A: tert-Butyl 2-(3-cyano-4-fluorophenyl)acetatc (2.6 g, 11.1 mmol) and methyl 4- hydroxybenzoate (3.36 g, 22.1 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.83 g, 13.3 mmol). The reaction mixture was heated to 125 0C and stirred for 5 hours. The reaction mixture was diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 4OM column eluting with hexanes:ethyl 29 acetate (9: 1) to yield methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (2.65 g, 65.3% yield) as a clear oil.
|00179] Step B: The product of step A (2.5 g, 6.80 mmol) was diluted with TN ammonia/niethanol (30 mL) followed by the addition of Raney Nickel (0.0583 g, 0.680 mmol). The reaction mixture was purged three times with hydrogen and stirred for 12 hours. The reaction mixture was then filtered through a GF/F filter and concentrated. The residue was purified using a biotage 4OM column cluting with methylene chloride:MeOH:NH,OH (90:9: 1) to yield methyl 4-(2- (aminomcmyl)-4-(2-tert-butθλy-2-oxocthyl)phenoxy)benzoatc (1.87 g, 74.0% yield) as a clear oil. [00180] Step C: The product of step B ( 1.87 g, 5.03 mmol) was diluted with methylene chloride (2 mL) followed by the addition of pyridine (0.489 mL, 6.04 mmol) and methanesulfonyl chloride (0.779 mL, 10.1 mmol). After stirring for 12 hours, the reaction mixture was diluted with methylene chloride and 2N HCl, the layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 4OM cartridge eluting with hcxancsxthyl acetate (1: 1) to yield methyl 4-(4-(2-tcrt-buloxy-2-oxoethyl)-2- (methylsulfonamidomethyl)phcnoxy)bcnzoate (1.53 g, 67.6% yield) as a clear oil. ]0018l] Step D: The product of step C (900 mg, 2.00 mmol) was diluted with dioxane (10 mL) followed by the addition of LiOH-H2O (126 mg, 3.00 mmol) dissolved in water (2 mL). After stirring for 12 hours, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSU4, filtered and concentrated. The material was purified using a biotage 4OM cartridge cluting with methylene chloridc:MeOH (95:5) to yield 4- (4-(2-tert-butox)'-2-oxoethyl)-2-(mcthylsulfonamido-melhyl)phenoxy)bcnzoic acid (710 mg, 81.4% yield) as a clear oil.
[00182] Step E: The product of step D (62 mg, 0.14 mmol) was diluted with methylene chloride (1 mL) followed by the addition of oxalyl dichloride (0.093 mL, 0.19 mmol) and 1 drop of DMF. The reaction was stirred for 30 minutes followed by the addition of 3,4-dichlorobenzenamine (46 mg, 0.28 mmol). The reaction was allowed to stir for 1 hour. The reaction mixture was loaded directly onto a 12i sim and purified on the horizon eluting with methylene chloride:MeOH (99.5-0.5 to 95:5) to yield 30 mg of tert-butyl 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3- (metliylsulfonamidomethyl)phenyl)acetate as a clear oil.
[00183] Step F: The product of step E (22 mg, 0.038 mmol) was diluted with methylene chloride (1 mL) followed by the addition of TFA (1 mL). After stirring for 1 hour, the reaction was concentrated, diluted with ether, sonicated and concentrated to yield 2-(4-(4-((3,4- dichlorophenyl)carbamoyl)phenoxy)-3-(metliylsulfonamidomethyl)phenyl)acetic acid (15 mg, 75% 30 yield) as a white solid. 1H NMR (400 MHz, CDCyCD3OD) 7.92 (m, I H), 7.90 (d, 2H), 7.59 (m, IH), 7.42 (m, 2H), 7.25 (m, IH), 7.10 (d, 2H), 6.90 (d, IH), 4.28 (s, 2H), 3.62 (s, 2H), 2.85 (s, 3H).
Example 15
2-(4-(4-(3,4-DichlorophenethylcarbamoyI)phenoxy)-3-(methylsulfonainidomethyl)- phenyl)acetic acid
Figure imgf000031_0001
[00184] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with 2-(3,4-dichlorophenyl)cthanamine. 1H NMR (400 MHz, CDCIvCD1OD) 7.75 (d, 2H), 7.35 (m, 3H), 7.22 (d, IH), 7.10 (d, IH), 6.95 (d, 2H), 6.90 (d, IH), 4.25 (s, 2H), 3.62 (m, 4H), 3.40 (s, 2H), 2.90 (t, 2H), 2.85 (s, 3H).
Example 16 2-(3-(MethyIsulfonamidomethyl)-4-(4-(naphthalen-2-ylcarbamoyl)phenoxy)phenyl)-acetic acid
Figure imgf000031_0002
[00185] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with napthaien-2-amine. 1H NMR (400 MHz, CDC13/CD3OD) 8.35 (s, I H), 7.96 (d, 2H), 7.83 (m, 3H), 7.70 (d, IH), 7.45 (m, 3H), 7.25 (d, I H), 7.05 (d, 2H), 6.95 (d, I H), 4.30 (d, 2H), 3.62 (s, 2H), 2.85 (s, 3H). 31 Example 17
2-(4-(4-(4-Fluorophenethylcarbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)-acetic acid
Figure imgf000032_0001
[00186] Prepared by the method of Example 14, substituting 3,4-dichlorobenzcnamine in Step E with 2-(4-fluorophenyl)ethanamine. 1H NMR (400 MHz, CDCI3/CD3OD) 7.70 (d, 2H), 7.40 (m, IH), 7.22 (m, 3H), 7.10 (m, 2H), 6.90 (d, 2H), 6.70 (d, IH), 4.30 (s, 2H), 3.65 (m, 4H), 2.90 (t, 2H), 2.85 (s, 3H).
Example 18
2-(3-(Methylsulfonamidoniethyl)-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000032_0002
[00187] Prepared by the method of Example 14, substituting 3,4-dichlorobcnzcnamine in Step E with phencthylainine. 1H NMR (400 MHz, CDCyCD3OD) 7.70 (d, 2H), 7.40 (m, IH), 7.31 (m, IH), 7.25 (m, 5H), 6.95 (d, 2H), 6.90 (d, IH), 4.30 (s, 2H), 3.68 (t, 2H), 3.61 (s, 2H), 2.90 (t, 2H), 2.85 (s, 3H).
Example 19 2-(3-(Methylsulfonamidomethyl)-4-(4-(phenylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000032_0003
32
[00188] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with aniline. 1 H NMR (400 MHz, CDCI3/CD3OD) 7.92 (d, 2H)5 7.65 (d, 2H), 7.45 (s, IH), 7.38 (m, 2H), 7.25 (d, IH), 7.18 (m, I H), 7.05 (d, 2H), 6.95 (d, IH), 4.30 (s, 2H), 3.65 (s, 2H), 2.85 (s, 3H).
Example 20 2-(4-(4-(Benzylcarbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000033_0001
|00189] Prepared by the method of Example 14, substituting 3,4-dichlorobcnzcnamine in Step E with benzyl amine. 1H NMR (400 MHz, CDCl3ZCD3OD) 7.80 (d, 2H), 7.40 (m, IH), 7.35 (m, 4H), 7.22 (d, IH), 6.95 (m, 3H), 6.90 (d, IH), 4.62 (d, 2H), 4.30 (s, 2H), 3.62 (s, 2H), 2.85 (s, 3H).
Example 21
2-(4-(4-(4-Chloι ophenethylcarbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)-acetic acid
Figure imgf000033_0002
(00190] Prepared by the method of Example 14, substituting 3,4-diclilorobcnzcnamine in Step E with 2-(4-chlorophenyI)cthanamine. 1H NMR (400 MHz, CDCI3/CD3OD) 7.7 (d. 2H), 7.4 (s, IH), 7.25 (d, 2H), 7.22 (d, I H), 7.18 (d, 2H), 6.95 (d, 2H), 6.90 (d, IH), 6.82 (br t, IH), 4.3 (s, 2H), 3.65 (t, 2H), 3.4 (br s, 2H), 2.9 (t, 2H), 2.85 (s, 3H).
Example 22
2-(4-(4-(2-(4-Chlorobenzylamino)-2-oxoethyl)phenoxy)-3-(methylsulfonamidomethyl)-
Figure imgf000033_0003
33
J00191| Prepared by the method of Example 14, substituting methyl 4-hydroxybenzoate in Step A with methyl 2-(4-hydroxylphenyl)acetate and substituting 3,4-dichlorobenzenaminc in Step E with 4-chlorobenzyl amine. 1H NMR (400 MHz, CDCVCD3OD) 7.38 (m, IH), 7.25 (m, 4H), 7.20 (m, 3H), 6.95 (d, 2H); 6.85 (d, IH), 4.38 (m, 2H), 4.32 (s, 2H), 3.61 (s, 2H)1 3.55 (s, 2H), 2.85 (s, 3H).
Example 23
2-(4-(4-(2-(Benzylamino)-2-oxoethyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)-acetic acid
Figure imgf000034_0001
|00192] Prepared by the method of Example 14, substituting methyl 4-hydroxybcnzoate in Step A with methyl 2-(4-hydroxylphenyl)acetate and substituting 3,4-dichlorobenzcnaminc in Step E with benzylaminc. 1H NMR (400 MHz, CDCI3/CD3OD) 7.38 (m, IH), 7.15-7.30 (m, 8H), 6.95 (d, 2H), 6.85 (d, IH), 4.40 (d, 2H), 4.32 (s, 2H), 3.61 (s, 2H), 3.56 (s, 2H), 2.82 (s, 3H).
Example 24
2-(3-(Methylsulfonamidoniethyl)-4-(4-(2-oxo-2-(phenethylamino)ethyl)phenoxy)phenyl)-acetic acid
Figure imgf000034_0002
[00193| Prepared by the method of Example 14, substituting methyl 4-hydroxybenzoate in Step A with methyl 2-(4-hydroxylphenyl)acetate and substituting 3,4-dichlorobenzenaminc in Step E with phenethylamine. 1H NMR (400 MHz, CDCI3/CD3OD) 7.38 (m, IH), 7.28 (m, I H), 7.25 (m, IH), 7.18-7.22 (111, 2H), 7.15 (d, 2H), 7.10 (d, IH), 6.92 (d, 2H), 6.82 (d, IH), 4.38 (s, 2H), 3.62 (s, 2H), 3.48 (m, 4H), 2.82 (s, 3H), 2.75 (t, 2H). 34
Example 25
2-(4-(4-(2-(Benzyl(methyl yIsulfonaitiidomethyl)-
Figure imgf000035_0001
[00194 j Prepared by the method of Example 14, substituting methyl 4-hydroxybenzoatc in Step A with methyl 2-(4-hydroxylphenyl)acelate and substituting 3,4-dichlorobcnzenamine in Step E with N-methylbcnzj'lamine. 1H NMR (400 MH7, CDCI3/CD3OD) 7. 10-7.40 (m, 9H), 6.94 (m, 2H), 6.82 (m, I H), 4.60 (d, 2H), 4.35 (m, 2H), 3.75 (d, 2H), 3.62 (m, 2H), 2.97 (d, 3H), 2.82 (s, 3H).
Example 26
2-(3-(Methylsulfonamidomethyl)-4-(4-(2-oxo-2-(phenylamino)ethyl)phenoxy)phenyl)-acetic acid
Figure imgf000035_0002
|00195) Prepared by the method of Example 14, substituting methyl 4-hydroxybcnzoate in Step A with methyl 2-(4-hydroxylphenyl)acetate and substituting 3,4-dichlorobcnzenamine in Step E with aniline. 1H NMR (400 MHz, CDCI3/CD3OD) 7.55 (d, 2H), 7.30-7.35 (m, 5H), 7.18 (m, IH), 7.10 (m, I H), 6.95 (d, 2H), 6.85 (d, IH), 4.35 (s, 2H), 3.68 (s, 2H), 3.60 (s, 2H), 2.85 (s, 3H).
Example 27 2-(4-(4-Benzamidophenoxy)-3-((4-fluoι ophenylsulfonamido)methyl)phenyl)acetic acid
Figure imgf000035_0003
[00196] Prepared by the method of Example 1 substituting 3,4-dichlorobenzoyl chloride in Step G with benzoyl chloride. MS+ 534.9 |M + IJ. 35 Example 28
2-(4-(4-(4-Chlorobenzamido)phenoxy)-3-((4-fluorophenylsulfonamido)methyl)phenyl)-acetic acid
Figure imgf000036_0001
f00197J Prepared by the method of Example 1 substituting 3,4-dichlorobcnzoyl chloride in Step G with 4-chlorobenzoyl chloride. 1H NMR (400 MHz, CD3OD) 7.85 (d, 2H), 7.70 (m, IH), 7.45- 7.55 (m, 5H), 7.35 (m, IH), 7.15 (m, 2H), 6.60-6.70 (m, 3H), 4.55 (s, 2H), 3.58 (s, 2H).
Example 29
2-(4-(4-(3-Chlorobenzamido)phenoxy)-3-((4-fluorophenylsulfonamido)methyl)phenyl)-aceϋc
Figure imgf000036_0002
J00198) Prepared by the method of Example 1 substituting 3,4-dichlorobenzoyl chloride in Step G with 3-chlorobenzoyl chloride 1H NMR (400 MHz, CD3OD) 7.90 (s, IH), 7.80 (d, IH), 7.65 (m, IH), 7.52 (m, 4H), 7.45 (t, IH), 7.35 (m, IH), 7.15 (m, 2H), 6.60 (m, 4H), 4.45 (s, 2H), 3.50 (br s, 2H).
Example 30
2-(4-(4-(3,4-Difluorobenzamido)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000036_0003
36
[00199| Prepared by the method of Example 1 substituting 3,4-dichlorobenzoyl chloride in Step G with 3,4-difluorobenzoyl chloride and substituting 4-fluorobenzenc- 1-sulfonyl chloride in Step I with mcthanesulfonyl chloride. 1H NMR (400 MHz, CD3OD) 7.88 (m IH), 7.80 (m, IH), 7.65 (d, 2H), 7.42 (m, 2H), 7.20 (m, 2H), 7.00 (d, 2H), 6.82 (m, I H), 4.33 (s, 2H), 3.62 (s, 2H), 2.85 (s, 3H).
Example 31 2-(4-(4-(2-Chlorobenzamido)phenoxy)-3-(methylsuIfonamidoniethyl)phenyl)acetic acid
Figure imgf000037_0001
[00200| Prepared by the method of Example 1 substituting 3,4-dichlorobenzoyl chloride in Step G with 2-chlorobenzoyl chloride and substituting 4-fluorobcnzcnc- 1-sulfonyl chloride in Step I with methancsulfonyl chloride. 1H NMR (400 MHz, CD3OD) 7.68 (d, 2H), 7.40-7.55 (m, 5H), 7.20 (d, IH), 7.05 (d, 2H), 6.85 (d, I H), 4.35 (s, 2H), 3.65 (br s, 2H), 2.85 (s, 3H).
Example 32 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-methoxyphenyl)acetic acid.
Figure imgf000037_0002
[00201] Prepared according to Steps E, F, G and J of Example, 1, substituting methyl 2-(3-((tert- butoxycarbonyl)aminomethyl)-4-hydroxyphenyl)acetate in Step E with methyl 2-(4-hydroxy-3- methoxyphenyl)acetate. 1H NMR (400 MHz, CDCl3) 9.64 (s, IH), 8.17 (d, IH), 7.97 (dd, IH), 7.72- 7.75 (m, 4H), 7.13 (d, IH), 6.99 (d, IH), 6.93 (d, IH), 6.87 (m, 2H), 3.80 (s, 3H), 3.66 (s, 2H). 37
Example 33 2-(4-(4-(benzyloxycarbamoyl)phenoxy)-3-(methylsulfonamidomethyI)phenyl)acetic acid
Figure imgf000038_0001
|00202] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with O-benzylhydroxylamine hydrochloride. 1H NMR (400 MHz, CD3OD) 7.76 (d, J=8.6 Hz, 2H), 7.50 (t, J = 6.3 Hz, IH), 7.33-7.48 (m, 5H), 7.23 (d, J=6.3 Hz, IH), 6.99 (d, J=8.7 Hz, 2H), 6.91 (d, J= 8.4 Hz, 2H), 4.91 (s, 2H), 4. 10 (d, J=6.3 Hz, 2H), 3.60 (s, 2H), 2.85 (s, 3H).
Example 34 2-(3-Chloι o-4-(4-(4-chlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000038_0002
(00203| Step A: 2-(3-Chloro-4-hydroxyphenyI)acetic acid (5.0 g, 26.8 mmol) was dissolved in 30 mL of MeOH and H2SO4 (0.744 ml, 13.4 mmol) was added dropwise at ambient temperature. The reaction was refluxed for four hours and then concentrated in vacuo. The residue was diluted with 150 mL of EtOAc and washed sequentially with saturated NaHCOj, water, and brine, dried over H2SO4, and concentrated in vacuo to provide methyl 2-(3-chloro-4-hydroxyphcnyl)acetate (5.16 g, 96.0% yield) as a semi-opaque thick oil.
(00204] Step B: Methyl 2-(3-chloro-4-hydroxyphcnyl)acetatc (177 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 ( 122 mg, 0.885 mmol) and N-(4- chlorophcncthyl)-4-chloro-3-nitrobcnzamide (300 mg, 0.885 mmol) (synthesized in step C). The reaction was heated to 85 0C and stirred for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over H2SO4, filtered and concentrated. The material was purified using a biotage 4OS cartridge eluϋng with DCM:MeOH (99: 1) to yield methyl 2-(4-(4-((4- chlorophcncthyl)carbamoyl)-2-nitrophenoxy)-3-chlorophcnyl)acctate (206 mg, 46.3% yield). 38
[00205| Step C: 2-(4-Chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 niL) followed by the addition of DlEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyl chloride (3.0 g, 14 mmol) in 10 mL of DCM. After stirring for 30 minutes the reaction was loaded directly onto a biotage 4OM cartridge and elutcd with hexanes:ethyl acetate (2: 1) to yield N-(4-chlorophenethyI)-4- chloro-3-nitrobenzamide (4.0 g, 86% yield) as a white solid.
[00206] Step D: Methyl 2-(4-(4-((4-chlorophenethyl)carbamwl)-2-nilrophenoxy)-3- chlorophenyOacetatc (1 10 mg, 0.219 mmol) was diluted with THF ( I mL) followed by the addition of Zn dust (14.3 mg, 0.219 mmol) and saturated NH4CI (1 mL). After stirring for 1 hour, the reaction was diluted DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSC>4, filtered and concentrated to yield methyl 2-(4-(4-((4- chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-chlorophenyl)acetate (102 mg, 98.6% yield). (00207) Step E: Isobutyl nitrite (0.0751 ml, 0.634 mmol) was diluted with DMF (1 mL), placed under nitrogen and heated to 60 0C. Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2- aminophenoxy)-3-chlorophenyl)acetatc (100 mg, 0.21 1 mmol) in DMF (1 mL) was added dropwise and the reaction was stirred for 1 hour. The reaction was cooled, diluted with ethyl acetate and washed with 2N HCl, saturated sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i column, cluting with DCM: MeOH (99: 1) to yield methyl 2-(4-(4-((4-chlorophcncthyl)carbamoyl)phcnoxy)-3- chlorophenyOacctate (70 mg, 72.3% yield).
[00208] Step F: Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetate (33 mg, 0.0720 mmol) was diluted with THF (500 μL) followed by the addition NaOH (0.144 ml, 0.720 mmol) and 100 μL of water. After stirring for 2 hours, the reaction was diluted with DCM and 2N HCI. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetic acid (19 mg, 59.4% yield) as a white solid. 1H NMR (400 MHz, CDC13/CD3OD) δ 7.65 (d, 2H), 7.42 (m, IH), 7.25 (d, 2H), 7.20 (d, IH), 7.15 (d, 2H), 7.05 (d, IH), 6.85 (d, 2H), 3.65 (t, 2H), 3.60 (s, 2H), 2.90 (t, 2H).
Example 35 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)propanoic acid
Figure imgf000039_0001
39
[00209| Step A: To a stirred solution of diisopropylaminc (357 μl, 2.55mmol) in THF (3 ml) at - 78 0C was added n-butyllithium (2.5M in hcxancs, 1.02 ml, 2.55 mmol). The reaction was stirred for 30 minutes after which time a solution of the acetate (500 mg, 2.13 mmol) in THF (3.5 ml) was added dropwise and stirred for 20 minutes at -78 0C, then warmed to 0 0C. MeI (133 μl, 2.13 mmol) was added and the reaction stirred for an additional 30 minutes. The reaction was acidified with 2M HCl and extracted with EtOAc. The combined organics were then washed with brine and dried over MgSO4. The residue was purified on the Biotage Horizon (40+M, 5%to 50% BiEtOAc, 21 ml-1008 ml) to give tcrt-butyl 2-(3-cyano-4-fluorophcnyl)propanoatc (0.368 g, 1.48 mmol, 70%). 1H NMR (400 MHz, CDCl3 ) δ 7.50-7.60 (m, 2H), 7.17 (t, J=8.7 Hz, I H), 3.63 (q, J=7.1 Hz, IH), 4.60 (d, J=7.2 Hz, 3H), 1.40 (s, 9H).
[00210] Step B: To a stirred solution of 4-aminophenol (2.50 g, 22.9 mmol) in DMF (55 ml) was added pyridine (1.85 ml, 22.9 mmol) followed by 3,4-dichlorobenzoyl chloride (4.0 g, 19.1 mmol) in DMF (7 ml). The reaction stirred at ambient temperature overnight, then diluted with 2M HCl and EtOAc. The aqueous layer was then extracted with EtOAc and the combined organics washed with brine and dried over MgSO4. The residue was purified on the Biotage Horizon (65+M 5% to 75% B:EtOAc, 51 ml-2448 ml). 3,4-Dichloro-N-(4-hydroxyphenyl)bcnzamide was collected as a white solid (3.91 g, 13.9 mmol, 73%). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1 H)S 7.84 (d, J=8.5 Hz, IH), 7.67 (d, J=8.6 Hz, IH), 7.45 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H).
[00211 | Step C: To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (360mg, 1.44mmol) from Step A and 3,4-dichloro-N-(4-hydroxyphenyl)benzamide (488 mg, l.73mmol) from Step B in DMSO (4ml) was added K2CO3 (240 mg, 1.73 mmol). The reaction was stirred at 125 °C overnight, then cooled to ambient temperature and diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organics washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified on a Biotage Horizon (40+M 5%to50% B:EtOAc, 21 ml-1008 ml). The appropriate fractions were then combined and concentrated to give tcrt-butyl 2-(3-cyano-4-(4-(3,4- dichlorobcnzamido)phenoxy)phenyl)propanoate (0.476 g, 0.797 mmol, 55%). 1H NMR (400 MHz, CDCl3 ) δ 7.99 (s, IH), 7.84 (bs, N-H), 7.72 (d, J=9.3 Hz, IH), 7.67 (d, J=8.7 Hz, 2H), 7.60 (m, 2H), 7.42 (d, J=8.6 Hz, IH), 7.11 (d, J=7.7, 2H), 6.83 (d, J=8.7 Hz, IH), 3.61 (q, J=7.1 Hz, IH), 1.45 (d, J=7.5 Hz, 3H), 1.42 (s, 9H).
[00212] Step D: To a stirred solution of tert-butyl 2-(3-cyano-4-(4-(3,4- dichlorobcnzamido)phenoxy)phenyl)propanoate (25 mg, 0.049 mmol) in DCM ( I ml) was added TFA (250 μl). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified via preparative TLC (5%MeOH/DCM) to give 2-(3-cyano-4-(4-(3,4- 40 dichlorobenzamido)phcnoxy)phcnyl)propanoic acid (0.0174 g, 0.0382 mmol, 78%). 1H NMR (400 MHz, CDCI3 ): 8.04 (bs, N-H), 7.96 (s, IH), 7.64-7.71 (m, 3H), 7.61 (s, IH), 7.55 (d, J=7.7 Hz, IH)5 7.44 (dd, J=8.6: 2.2 Hz, I H), 7.08 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.5 Hz, 1 H), 3.74 (q, J=7.4 Hz, 1H): 1.53 (d, J=6.9 Hz, 3H).
Example 36 2-(4-(4-(3,4-diclilorobenzamido)phenoxy)-3-(methylsulfonamidomethyl)phenyl)propanoic acid
Figure imgf000041_0001
[00213] Prepared by the method of Example 14 substituting methyl 4-(4-(2-tert-butoxy-2- oxocthyl)-2-cyanophenoxy)bcnzoate in Step B with tert-butyl 2-(3-cyano-4-(4-(3,4- dichlorobcnzamido)phenoxy)phenyl)propanoatc and following steps C and F. 1H NMR (400 MHz, CDiOD): 8.10 (s, IH), 7.85 (s, IH), 7.60-7.70 (m, 3H), 7.50 (s, IH), 7.20 (d, IH), 7.1 (d, 2H), 6.80 (d, IH), 4.30 (s, 2H), 3.75 (q, IH), 2.80(2, 3H), 1.45 (d, 3H).
Example 37
2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-(methylsulfonamidomethyl)phenyl)-2- methylpropanoic acid
Figure imgf000041_0002
[00214| Step A: To a stirred solution of NaH (60% in oil, 195 mg, 4.88 mmol) in DMF (10 ml) at O 0C was added a solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (500 mg, 2.125 mmol) and McI (330 μl, 5.31mmol) in DMF (1 ml) dropwise. The reaction was warmed to ambient temperature, stirred overnight, and then diluted with IN HCl and EtOAc. The aqueous was extracted with EtOAc and the combined organics washed with brine and dried over MgSOφ The crude concentrated product was then purified on the Biotage Horizon (40+M 5%to 50% BiEtOAc, 18 ml- 864 ml) to give tert-butyl 2-(3-cyano-4-fIuorophenyl)-2-methylpropanoate (0.423 g, 1.602 mmol, 75%). 1H NMR (400 MHz, CDCI3) δ 7.56-7.63 (m, 2H), 7.17 (t, J=8.1 Hz, IH), 1.54 (s, 6H), 1.38 (s, 9H). 41
[002l5| Step B: 2-(4-(4-(3,4-Dichlorobenzamido)phenoxy)-3-(meΛylsulfonamidomethyl) phenyl)-2-methylpropanoic acid was prepared from tert-butyl 2-(3-cyano-4-fluorophenyl)-2τ methylpropanoate by the method of Example 35 substituting tert-butyl 2-(3-cyano-4- fluorophenyl)propanoatc in Step B with tert-butyl 2-(3-cyano-4-fluorophcnyl)-2-mcthylpropanoate and following steps B,C and F of Example 14. 1H NMR (400 MHz, CD3OD): 8.15 (s, IH), 7.85 (d, IH)5 7.65-7.75 (m, 3H), 7.55 (s, I H), 7.30 (d, IH), 7.05 (d, 2H), 6.80 (d, IH), 4.35 (s, 2H), 2.80 (s, 3H), 1.55 (s, 6H).
Example 38
2-(3-(Methylsulfonamidomethyl)-4-(4-(4- (trifluoromethyl)phenylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000042_0001
|00216] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with 4-trifluoromcthylbenzenamine. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.95 (d, 2H), 7.82 (d, 2H), 7.62 (d, IH), 7.45 (s, I H), 7.25 (d, IH), 7.05 (d, 2H), 6.95 (d, IH), 4.30 (s, 2H), 3.62 (s, 2H), 2.82 (s, 3H).
Example 39
2-(3-(MethyIsulfonamidomethyl)-4-(4-(3- (trifluoromethyl)ρhenylcarbamoyl)phenoχy)phenyl)acetic acid
Figure imgf000042_0002
(00217) Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with 3-trifluoromethylbenzenamine. 1H NMR (400 MHz, CD3CI3, CD3OD) 8.05 (s, IH), 7.90 (m, 3H), 7.50 (m, IH), 7.45 (s, IH), 7.40 (m, I H), 7.25 (d, I H), 7.05 (d, 2H), 6.85 (d, IH), 4.30 (s, 2H), 3.65 (s, 2H)1 2.85 (s, 3H). 42 Example 40
2-(4-(4-(4-chloro-3-fluorophenylcarbamoyl)phenoxy)-3- (methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000043_0001
(00218] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with 4-chloro-3-fluorobenzenamine. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.90 (d, 2H), 7.75 (m, IH), 7.30-7.45 (m, 3H), 7.25 (d, 1 H), 7.05 (d, 2H), 6.95 (d, I H), 4.3 (s, 2H), 3.65 (s, 2H), 2.85 (s, 3H).
Example 41
2-(4-(4-(3-chloro-4-fluoi*ophenylcnrban>oyl)phenoxy)-3- (methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000043_0002
[00219] Prepared by the method of Example 14, substituting 3,4-dichlorobenzenamine in Step E with 3-chloro-4-fluorobenzenamine. 'H NMR (400 MHz, CD3Cl3, CD3OD) 7.93 (d, 2H), 7.85 (m, IH), 7.55 (m, IH), 7.45 (s, IH), 7.25 (d, IH), 7. 15 (t, IH), 7.05 (d, 2H), 6.85 (d, IH), 4.30 (s, 2H), 3.65 (s, 2H)1 2.85 (s, 3H).
Example 42
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000043_0003
43
[00220| Step A: 2-(4-hydroxyphenyl)acetic acid ( 1.0 g, 6.57 mmol) was diluted with THF (4 mL) followed by the addition of Reactant 2 (2.63 g, 13.1 mmol). The reaction was stirred for hours 12 hours. The reaction was filtered and loaded directly onto a biolage 4OM cartridge eluting with hexancsxthyl acetate (3:1) to yield tert-butyl 2-(4-hydroxyphenyl)acctate (800 mg, 58.4% yield) as a clear oil that later solidified to a white solid.
[00221 ] Step B: 2-(4-chlorophenyl)ethanamine (0.321 ml, 2.27 mmol) was diluted with DCM (10 mL) followed by the addition of DIEA (d 0.742) (0.395 ml, 2.27 mmol) and 4-fluorobenzoyl chloride (0.231 ml, 1.89 mmol). After stirring for 30 minutes the reaction was loaded directly onto a biotage 4OS cartridge and eluted with hexanes:ethyl acetate (2: 1 ) to yield N-(4-chlorophenethyl)-4- fluorobenzamide (393 nig, 74.8% yield) as a white solid.
[00222] Step C: Tert-butyl 2-(4-hydroxyphenyl)acetate (200 mg, 0.960 mmol) was diluted with DMSO (4 mL) followed by the addition of K2CO3 ( 133 mg, 0.960 mmol) and N-(4- ch!orophenethyl)-4-fluorobcnzamide (267 mg, 0.960 mmol). The reaction was stirred at 850C overnight, and then stirred at 138 0C for 12 hours. The reaction was cooled to ambient temperature, diluted with DCM and 10% aq. sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography, eluting with hexanesxthyl acetate (4: 1) to yield tert-butyl 2-(4-(4-((4- chlorophcnethyl)carbamoyl)phcnoxy)phenyl)acetate (20 mg, 4.47% yield) as an off white solid. [00223] Step D: Tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyI)phenoxy)phenyl)acetate (20 mg, 0.043 mmol) was diluted with DCM (1 mL) followed by the addition of TFA (1 mL). After stirring for 2 hours, the reaction was concentrated, diluted with ether and concentrated to yield 2-(4- (4-((4-chlorophcnethyl)carbamoyl)phenoxy)phenyl)acetic acid (17 mg, 97% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.30 (m, 4H), 7.19 (m, 2H), 7.00 (m, 4H), 3.62 (m, 4H), 2.90 (t, 2H).
Example 43 2-(4-(4-(4-chlorophenethylcarbamoyl)pheπoxy)-3-fluorophenyl)acetic acid
Figure imgf000044_0001
[00224] Step A: 2-(3-Fluoro-4-hydroxyphenyl)acetic acid (1.0 g, 5.88 mmol) was diluted with THF:McOH (3: 1) (10 mL) followed by the addition Of TMSCHN2 (5.88 ml, 11.8 mmol). After 44 stirring for 1 hour, the reaction was quenched with 2N HCl and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, cluting with hexanes:cthyl acetate (2: 1) to yield methyl 2-(3- fluoro-4-hydroxyphenyl)acetate (700 mg, 64.7% yield) as a clear oil.
[00225] Step B: 2-(4-Chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 niL) followed by the addition of DIEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyI chloride (3.0 g, 14 mmol) dropwise in 10 mL of DCM. After stirring for 30 minutes the reaction was loaded directly onto a silica gel column and eluted with hcxancsxthyl acetate (2: 1) to yield N-(4- chlorophcncthyl)-4-chloro-3-nitrobcnzamide (4.0 g, 86% yield) as a white solid. [00226] Step C: Methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (prepared in Step A; 163 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 ( 122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nilrobenzamide (prepared in Step B; 300 mg, 0.885 mmol). The reaction was stirred at 8O0C for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was pun Tied by silica gel chromatography, eluting with hcxane: acetone (2: 1) to yield methyl 2-(4-(4-((4- chlorophenetliyI)carbamoyl)-2-nitrophenoxy)-3-fluorophenyl)acetate (200 mg, 46.4% yield). |00227] Step D: Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3- fluorophenyl)acetate (100 mg, 0.205 mmol) was diluted with THF (2 mL) followed by the addition of Zn dust ( 13.4 mg, 0.205 mmol) and saturated aq. NH4C1 ( I mL). After stirring for 1 hour, the reaction was diluted with ethyl acetate and 10%aq sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield methyl 2-(4-(4-((4- chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-fluorophenyl)acetate (93 mg, 99.1% yield). [00228] Step E: Isobutyl nitrile (0.060 ml, 0.51 mmol) was diluted with DMF (2 mL), placed under nitrogen and heated to 6O0C followed by the addition of methyl 2-(4-(4-((4- chlorophenethyl)carbamoyI)-2-aminophenoxy)-3-fluorophenyl)acetate (93 mg, 0.20 mmol) in 500 μL of DMF. The reaction was stirred 30 minutes and then cooled. The reaction was diluted with ethyl acetate and washed with 2N HCI and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluling with hexancs:ethyl acetate (2: 1) to yield methyl 2-(4-(4-((4- chlorophenethyOcarbamoyOphenoxy^S-fluorophenyOacetate (35 mg, 39% yield). [00229] Step F: Methyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phenoxy)-3- fluorophenyl)acetate (32 mg, 0.072 mmol) was diluted with dioxane ( 1 mL) followed by the addition of NaOH (0.072 ml, 0.36 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was 45 diluted with ethyl acetate and 2N HCl. The organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophcnethyl)carbamoyl)phenoxy)-3-fluorophenyl)acetic acid (15 mg, 48% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.25 (d, 2H), 7.19 (m, 3H), 7.10 (m, 2H), 6.95 (d, 2H), 3.65 (m, 4H), 2.90 (t, 2H).
Example 44 2-(3-cyano-4-(4-(4-chlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000046_0001
[00230] Step A: A flask was charged with tert-bulyl 2-(3-cyano-4-fluorophenyl)acetate (9.410 g, 40.00 mmol), methyl 4-hydroxybenzoate (7.303 g, 48.00 mmol), K3CO3 (6.634 g, 48.00 mmol), and DMSO (160 mL). The mixture was heated to 90 0C under a nitrogen atmosphere for 17 hours. The mixture was cooled to ambient temperature and poured into a mixture of EtOAc (250 mL) and 10% K2CO3 solution (250 mL). The resulting insoluble residue was dissolved in water and added to the EtOAc-aqueous mixture. The mixture was stirred for 1 hour and layers were separated. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with saturated KjCO3, water, and brine, dried over MgSO4, filtered through a Celite pad, and concentrated under reduced pressure to give 14.7 g of crude product as an oil. The crude material was purified by silica gel chromatography to provide methyl 4-(4-(2-tert-butoxy-2-oxocthyl)-2-cyanophcnoxy)benzoate (11.6 g, 79%) as a white solid.
(00231] Step B: Methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1 1.60 g, 31.57 mmol) was dissolved in dioxane (160 mL) and the solution was cooled to 100C in an ice bath. LiOH-H2O, IM (37.89 ml, 37.89 mmol) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with 2N HCl ( 10OmL) and CH2Cb (200 mL). Layers were separated and aqueous layer was extracted with CH2Cl2. The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered through a Celite pad and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to provide 4- (4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (7.29 g) as a white solid. [00232] Step C: To 4-(4-(2-tert-butoxy-2-oxocthyl)-2-cyanophenoxy)bcnzoic acid (0.34 g, 0.962 mmol), 2-(4-chlorophenyl)ethanamine (0.165 g, 1.06 mmol) in DMF (5 ml) was added diisopropylamine (0.200 ml, 1.15 mmol) and HBTU (0.149 g, 1.15 mmol). The reaction was stirred 46 al ambient temperature for 90 minutes. The reaction was diluted with water and the product extracted into ethyl acetate. The combined organic layers were dried (MgSOa), filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- cyanophenyl)acetate (0.40 g, 85%) as a white solid after column chromatography. [00233] Step D: To tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- cyanophenyOacetatc (4.40 g, 8.96 mmol) in DCM (20 ml) was treated with TFA (20 ml). After stirring for 2 hours. The reaction mixture was concentrated and the crude material was purified by silica gel chromatography using a gradient of 0.5% McOH/DCM containing 0.5% AcOH to 10% McOH/DCM containing 0.5% AcOH to provide 2-(4-(4-((4-chlorophencthyl)carbamoyl)phcnoxy)- 3-cyanophcnyl)acctic acid (3.30 g, 84.7% yield). 1H NMR (400 MHz, CD3OD) 7.85 (d, 2H), 7.65 (s, IH), 7.45 (d, IH), 7.35 (s, IH), 7.25 (d, 2H), 7.20 (d, 2H), 7.10 (d, 2H), 6.95 (d, IH), 3.62 (m, 4H), 2.90 (t, 2H).
Example 45
2-(3-cyano-4-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000047_0001
[00234] Prepared by the method of Example 44 substituting 2-(2,4-dichlorophcnyl)ethanamine for 2-(4-chlorophcnyl)cthanaminc in Step D. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.79 (d, 2H), 7.65 (m, IH), 7.45 (d, IH), 7.40 (m, IH), 7.21 (m, 2H), 7.10 (d, 2H), 6.85 (d, IH), 3.65 (m. 4H), 3.05 (t, 2H).
Example 46 2-(3-bromo-4-(4-(2,4-dichIorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000047_0002
[002351 Step A: N-(4-chlorophenethyl)-4-hydroxybenzamide ( 1.5 g, 5.4 mmol) was diluted with DMSO (15 mL) followed by the addition of K2CO3 (0.89 g, 6.4 mmol) and 3-bromo-4- 47 fluorobenzaldehydc (1.0 g. 4.9 mmol). The reaction was stirred at 850C overnight and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and then concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (1 :1) and then 100% ethyl acetate to yield N-(4-chlorophcnethyl)-4-(2-bromo-4-formylphenoxy)benzamide (1.6 g, 71% yield). [00236] Step B: N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenox>')benzamide (1.6 g, 3.5 mmol) was diluted with THF (10 mL) followed by the addition of N,N,N- trimcthyl(phenyi)methanaminiurn hydroxide (0.79 ml, 1.7 mmol) and mcthylsulfinyl(rnethylthio)methane (0.87 g, 7.0 mmol). The reaction was stirred at 70 0C for 2 hours. The reaction mixture was loaded directly onto a silica gel column and clutcd with DCM:MeOH (98:2) to yield (Z)-N-(4.chlorophcncthyl)-4-(2-bromo-4-(2-(mcthylsulfinyl)-2- (methyithio)vinyl)phenoxy)benzamide (1.9 g, 96% yield).
[00237] Step C: (Z)-N-(4-chlorophencthyl)-4-(2-bromo-4-(2-(methylsulfinyl)-2-(methyithio) vinyl)phcnoxy)benzamide (2.0 g, 3.5 mmol) was treated with HCI (8.9 ml, 18 mmol) in ethanol. The reaction was stirred at 70 0C for 2 hours. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:cthyl acetate (3: 1) to yield ethyl 2-(4-(4-((4- chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate.
|00238] Step D: Ethyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phcnoxy)-3-bromophenyl)acetate (30 ing, 0.058 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.093 ml, 0.46 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbaιnoyl)phenoxy)-3-bromophenyl)acetic acid (24 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.60 (s, IH), 7.22-7.32 (m, 3H), 7.19 (d, 2H), 7.05 (d, IH), 6.90 (d, 2H), 3.62 (m, 4H), 2.90 (l, 2H).
Example 47
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)3,5-dimethylphenyl)acetic acid
Figure imgf000048_0001
[00239] Prepared by the method of Example 46 substituting 4-fluoro-3,5-dimethylbcnzaldehyde for 3-bromo-4-fluorobenzaldehyde in step A. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.60 (d, 2H), 48
7.25 (d, 2H), 7.15 (d, 2H), 7.05 (s, 2H), 6.78 (d, 2H), 3.65 (t, 2H), 3.58 (s, 2H), 2.90 (t, 2H), 2.15 (s, 6H).
Example 48 2-(4-(4-(4-chIorophenethylcarbamoyl)phenoxy)3-methylphenyl)acetic acid
Figure imgf000049_0001
[00240] Step A: Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)pheno\y)-3-bromophenyl)acetate (Example 46 step C ; 30 mg, 0.058 mmol) was diluted with THF ( 1 mL) followed by the addition of bis(tri-t-butγlphosphinc)palladium (0) (3.0 mg, 0.0058 mmol) and methylzinc chloride (0.087 ml, 0.17 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column, cluting with hexanesxthyl acetate (3:1) to yield ethyl 2-(4-(4-((4- chlorophcncthyl)carbarnoyl)phcnoxy)-3-mcthylphcnyl)acetatc (20 mg, 76% yield) as a clear oil. (00241] Step B: Ethyl 2-(4-(4-((4-chlorophcnetliyl)carbamoyl)phcnoxy)-3-mcthylphenyl)acetate (20 mg, 0.0443 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.0885 ml, 0.443 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO.), filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- mcthylphcnyOacctic acid (16.0 mg, 85.3% yield). 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.62 (d, 2H), 7.30 (d, 2H), 7.10-7.22 (m, 4H), 6.92 (d, IH), 6.85 (d, 2H), 3.65 (t, 2H), 3.60 (s, 2H), 2.90 (U 2H), 2.15 (s, 3H).
Example 49
2-(4-(4-(4-chlorophenethylcarbamoyl)plienoxy)3-(thiophen-2-yl)phenyl)acetic acid
Figure imgf000049_0002
49
[00242| Step A: Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and 2-thienylzinc bromide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was purified by silica gel chromatography, cluting with hexanes:ethyl acetate (3: 1) to yield ethyl 2-(4-(4-((4-chlorophenethyl) carbamoy])phcnoxy)-3-(thiophen-2-yl)phenyl)acetate (20 mg, 83% yield) as a clear oil. [00243] Step B: Ethyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phenoxy)-3-(thiophen-2- yl)phenyl)acctate (20 mg, 0.038 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.052 ml, 0.26 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO.>, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- (thiophen-2-yl)phenyl)acetic acid (7 mg, 37% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.69 (s, IH), 7.64 (d, 2H), 7.45 (d, IH), 7.30 (d, 2H), 7.22 (d, IH), 7.15 (d, 2H), 6.98-7.05 (m, 2H), 6.90 (d, 2H), 3.65 (m, 4H)1 2.90 (t, 2H).
Example 50 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetic acid
Figure imgf000050_0001
[00244] Step A: Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phcnoxy)-3-bromophcnyl)acctate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-l-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and phenylzinc iodide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column and eluted with hexanesiethyl acetate (3: 1) to yield Ethyl 2-(6-(4-(4- chlorophcnethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (15 mg, 63% yield) as a clear oil. [00245] Step B: Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phcnoxy)biphenyl-3-yl)acetate (10 mg, 0.0195 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.0389 ml, 0.195 mmol) and 200 μL of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetic acid (1.6 mg, 16.9% yield) as a white solid. MS ESl negative M-H = 485. 50
Example 51 2-(6-(4-(4-chIorophenethylcarbamoyl)phenoxy)-3'-(methylsulfonyl)biphenyl-3-yl)acetic acid
Figure imgf000051_0001
[00246] Step A. Ethyl 2-(4-(4-((4-chlorophcnethyl)carbamoyl)phenoxγ)-3-bromophenyI)acetate (Example 46 step C; 100 mg. 0.193 mmol), 3-(mcthanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K2CO3 (80.2 mg, 0.580 mmol) and Pd(PPh3)4 (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60 0C overnight. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:ethyl acetate (2: 1) to yield ethyl 2-(6-(4-(4-chlorophenethyIcarbamoyl)phenoxy)-3'- (methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 69.8% yield).
(00247) Step B: Ethyl 2-(6-(4-(4-chlorophcnethylcarbamoyl)phenoxy)-3'-
(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 0.135 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.270 ml, 1.35 mmol) and 300 μL of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated The material was purified using a biotage 12i cartridge eluting with 1-4% methanol/DCM to yield 2-(6-(4-(4- chlorophenclhylcarbamoyl)phcnoxy)-3'-(mcthylsulfonyl)biphcnyl-3-yl)acetic acid (5 mg, 6.56% yield). 1H NMR (400 MHz, CD3Cb, CD3OD) 8.05 (s, IH), 7.81 (d, IH), 7.78 (d, IH), 7.50-7.60 (m, 3H), 7.42 (s, I H), 7.38 (d, IH), 7.25 (d, 2H), 7.19 (d, 2H), 7.05 (d, IH), 6.85 (d, IH), 3.75 (s, 2H), 3.62 (q, 2H), 3.0 (s, 3H), 2.90 (t, 2H).
Example 52
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyclopropyIphenyl)acetic acid
Figure imgf000051_0002
51
|00248] Step A: A flask was charged with cyclopropyl magnesium bromide (29.6 ml, 14.8 mmol) and placed under nitrogen. Zinc chloride ( 14.8 ml, 14.8 mmol) was added and the reaction was stirred for 20 minutes. 3-Bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol) and bis(tri-t- butylphosphinc)palladium (0) (0.126 g, 0.246 mmol) were diluted in 600 μL of THF and added to the reaction mixture. After stirring for 4 hours, the reaction was heated to 5O0C and stirred overnight. The reaction was cooled and quenched with saturated NH4Cl and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotagc 4OM cartridge cluting with hcxanesxthyl acetate (4: 1) to yield 3-cyclopropyl-4- fluorobenzaldchyde (400 mg, 49.5% yield)
[00249] Step B: N-(4-Chlorophenethyl)-4-hydroxybenzamide (504 mg, 1.83 mmol) was diluted with DMSO (8 mL) and K2CO3 (379 mg, 2.74 mmol) and 3-cyclopropyl-4-fluorobenza!dehyde (300 mg, 1.83 mmol) were added. The reaction was stirred 85 0C overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and concentrated. The crude material was purified by silica gel chromatography eluting with hexanes.ethyl acetate (3: 1) to provide N-(4-chlorophenethyl)-4-(2-cyclopropyl-4- formylphcnoxy)benzamide (160 mg, 20.9% yield).
|002501 Step C: N-(4-Chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 0.381 mmol) was diluted with THF (3 mL) followed by the addition of N,N,N- trirnethyl(phenyl)mcthanaminium hydroxide (0.0866 ml, 0.191 mmol) and methylsulfinyl(mcthy!thio)rnethane (94.7 mg, 0.762 mmol). The reaction was heated to 700C and stirred for 2 hours. The reaction was cooled and loaded directly onto a silica gel column, eluting with ethyl acetate to yield (Z)-N-(4-chloropheneUiyl)-4-(2-cyclopropyl-4-(2-(methylsulfιnyl)-2- (methylthio)vinyl)phenoxy)benzamide (100 mg, 49.9% yield).
1002511 Step D: (Z)-N-(4-chIorophenetliyl)-4-(2-cyclopropyl-4-(2-(methylsulfinyl)-2-
(methylthio)vinyl)phenoxy)benzamide (100 mg, 0.190 mmol) was diluted with HCl (0.950 ml, 1.90 mmol), heated to 7O0C and stirred for 4 hours. The reaction was cooled and loaded directly onto a biotage 25 cartridge and eluted with hexanes:ethyl acetate (3: 1) to yield ethyl 2-(4-(4-((4- chlorophenethyl)carbamoyl)phcnoxy)-3-cyclopropylphcnyl)acctatc (70 mg, 77.0% yield) as a white solid.
[00252] Step E: Ethyl 2-(4-(4-((4-chlorophcncthyl)carbamoyl)phcnoxy)-3- cyclopropylphenyl)acetate (70 mg, 0.146 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.293 ml, 1 ,46 mmol) and water (300 μL). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl) 52 carbamoyl)phenoxy)-3-cyclopropylphenyl)acetic acid (50 mg, 75.9% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.65 (ds 2H), 7.30 (d, 2H), 7.15 (d, 2H), 7.10 (d, IH), 6.90 (m, 4H), 3.65 (t, 2H), 3.60 (s, 2H), 2.00 (t, 2H); 2.05 (m, I H), 0.80 (m, 2H), 0.62 (m, 2H).
Example 53 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-ethylphenyl)acetic acid
Figure imgf000053_0001
|00253] Step A: Ethyl 2-(4-(4-((4<hlorophencthyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 30 mg, 0.058 mmol) was diluted with THF (1 mL) followed by the addition of l, r-bis(diphcnylphosphino)ferroccncdichloropalladium(II) (4.8 mg, 0.0058 mmol) and diethylzinc (0. 13 ml, 0.15 mmol). After stirring for 4 hours, the reaction loaded directly onto a silica gel column, eluϋng with 5-50% ethyl acetate/hexane to yield ethyl 2-(4-(4-((4- chlorophcnethyl)carbamoyl)phenoxy)-3-ethylphcnyl)acctate (10 mg, 37% yield). [00254] Step B: Elhyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetate (10 mg, 0.0215 mmol) was diluted with dioxanc (500 μL) followed by the addition of NaOH (0.0429 ml, 0.215 mmol) and 5 drops of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl, and the layers were separated. The organic layer was dried over MgSO.1, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with 10%MeOH/DCM to yield 2-(4-(4-((4-chlorophencthyl)carbamoyl)phcnoxy)-3- ethylphenyOacetic acid (2 mg, 21.3% yield). (400 MHz, CD3Cl3, CD3OD) 7.65 (d, 2H), 7.30 (d, 2H), 7.10-7.25 (m, 4H), 6.90 (m, 3H), 3.62 (m, 2H), 3.40 (s, IH), 2.90 (t, 2H), 2.55 (q, 2H), 1.15 (t, 3H).
Example 54 2-(6-(4-(4-chIorophenethylcarbamoyl)phenoxy)-4'-(methylsulfonyl)biphenyl-3-yl)acetic acid 53
Figure imgf000054_0001
[00255] Step A: Ethyl 2-(4-(4-((4-chlorophcnctliyl)carbamoyl)phenoxy)-3-bromophenyl)acctate (Example 46 step C; 40 mg, 0.077 mmol), K2CO3 (32 mg, 0.23 mmol) and 4- (methylsulfonyl)phenylboronic acid (23 mg, 0.12 mmol) were diluted with dioxane (1 mL)/water (300 μL) followed by the addition of Pd(PPh3)4 (8.9 mg, 0.0077 mmol). The reaction was purged with nitrogen and stirred at 55°C for 12 hours. The reaction was cooled and concentrated. The residue was taken up in minimal DCM and purified by silica gel chromatography, eluting with hexanes:ethyl acetate ( 1 : 1) to yield ethyl 2-(6-(4-(4-chlorophencthylcarbamoyI)phenoxy)-4'- (methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 44% yield) as a clear oil.
[00256] Step B: Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-4'-
(methylsulfonyl)biphenyl-3-yl)acetate (20 mg, 0.0338 mmol) was diluted with dioxane ( 1 mL) followed by the addition of NaOH (0.0676 ml, 0.338 mmol) and 300 μL of water. After stirring for 3 hours, Uic reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(6-(4-(4- chlorophenethylcarbamoyl)phenoxy)-4'-(methylsulfonyl)biphenyl-3-yl)acetic acid (10 mg, 52.5% yield). (400 MHz, CD3Cl3, CD3OD) 7.90 (d, 2H), 7.70 (d, 2H), 7.60 (d, 2H), 7.40 (s, IH), 7.35 (d, IH), 7.25 (d, 2H), 7.15 (d, 2H), 7.05 (d, I H), 6.85 (d, 2H), 6.55 (t, IH), 3.63 (m, 4H), 3.05 (s, 3H), 2.90 (t, 2H).
Example 55
2-(3-(methylsulfonamidomethyl)-4-(4-(3- (trifluoromethyl)phenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000054_0002
[00257] Prepared by the method of Example 14, substituting 3,4-dichlorobcnzenamine in Step E with 2-(3-trifluoromethylphenyI)ethyanamine. MS+ 551.1 [M + I]. 54 Example 56
2-(3-(methylsulfonamidomethyl)-4-(4-(4- trifluoromethyl)phenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000055_0001
[00258| Prepared by ϋie rnelliod of Example 14, substituting 3,4-dichlorobenzenainine in Step E with 2-(4-trifluoromethylphenyl)ethyanamine. MS+ 550.9 [M + I].
Example 57
2-(4-(4-((l-(4-chlorophenyl)cyclopropyl)methylcarbamoyl)phenoxy)-3- (methylsulfonamidomethyl)phenyl)acetic acid
Figure imgf000055_0002
[00259] Prepared by the method of Example 14, substituting 3.4-dichlorobenzenamine in Step E with (l-(4-chlorophenyl)cycloproyl)methanamine. MS - 541.1 [M - 1].
Example 58 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-(nicotinamidomethyl)phenyl)acetic acid
Figure imgf000055_0003
[00260] Step A: A mixture of te/7-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.32 g, 5.59 mmol), N-(4-chlorophenethyl)-4-hydroxybenzamide ( 1.85 g, 671 mmol), and potassium carbonate (0.93 g, 6.70 mmol) in DMSO (10 ml) was stirred at 90 0C for 1 day. The reaction was cooled, diluted with ethyl acetate, and washed with 10% aqueous NazCC^. The aqueous layer was back extracted with 55 ethyl acetate. The organic washes were combined, washed with 10% NajCOs and brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography, cluting with a gradient of 5% ethyl acetatc/hexanes to 60% ethyl acetatc/hexanes gave /er/-butyl 2- (4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 40%). (00261] Step B: To tert-Butyl 2-(4-(4-((4-chlorophencthyl)carbamoyl)phenoxy)-3- cyanophenyl)acetate ( 1.09 g.. 2.22 mmol) in 6 ml of 7 N ammonia in methanol at ambient temperature was added Raney-Ni (0.019 g) and the reaction was stirred under a balloon of hydrogen gas at ambient temperature. The reaction was filtered and concentrated to give /er/-butyl 2-(4-(4- ((4-chlorophcnethyl)carbamoyl)phcnoxy)-3-(aminomcthyl)phenyl)acctate (0. 160 g, 15%). [00262] Step C: A mixture of ter/-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- (aminomethyl)phenyl)acetale (0.015 g, 0.030 mmol), nicotinoyl chloride hydrochloride (0.007 g, 0.039 mmol), and triethylamine (0.013 ml, 0.091 mmol) in dichloromethane (1 ml) was stirred at ambient temperature for 1 hour. The reaction was loaded onto a silica gel samplet and the product was eluted using a gradient system of 0.5% methanol/ dichloromethane to 5% methanol/dichloromethanc to provide tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- (nicotinamidomethyl)phenyl)acetate (0.005 g, 275%).
|00263| Step D: To a solution of /«?r/-butyl 2-(4-(4-((4-chlorophencthyI)carbamoyl)phenoxy)-3- (nicotinamidomethyl)phenyl)acctate (0.005 g, 0.008 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phcnoxy)-3-(nicotinamidomethyl) phenyOacctic acid (0.005 g). MS -449.1 [M - CO2H],
Example 59
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-((pyridine-3- sulfonamido)niethyl)phenyl)acetic acid
Figure imgf000056_0001
(00264] Prepared by the method of Example 58, substituting nicotinoyl chloride hydrochloride in Step C with pyridine-3-sulfonyl chloride hydrochloride. MS -578.1 [M - 1].
Example 60
2-(4-(4-(4-chlυroplienethylcarbamoyl)plieπυxy)-3-((l-methyl-l//-imidazole-5- sulfonamido)methyl)phenyl)acetic acid 56
Figure imgf000057_0001
[00265] Prepared by the method of Example 58, substituting nicotinoyl chloride hydrochloride in Step C with 1 -methyl- 1 H-imidazole-4-sulfonyl chloride. MS -581.2 [M - I].
Example 61
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-((6- dimethylamino)nicotinamido)methyl)phenyl)acetic acid
Figure imgf000057_0002
[00266] Prepared by the method of Example 58, substituting nicotinoyl chloride hydrochloride in Step C with 6-(dimethylamino)nicotinic acid. MS -585.2 [M - 1].
Example 62
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-((2-(4- fluorophenylsulfonamido)acetamido)methyl)phenyl)acetic acid
Figure imgf000057_0003
[00267] Prepared by the method of Example 58, substituting nicotinoyl chloride hydrochloride in Step C with 2-(4-fluorophenylsulfonamido)acetic acid. MS -608.4 [M - CO2H].
Example 63
2-(3-((6-aminonicotinamido)methyl)-4-(4-(4- chloroplienethylcarbamoyl)phenoxy)phenyl)acetic acid 57
Figure imgf000058_0001
[00268] Prepared by the method of Example 58, substituting nicotinoyl chloride hydrochloride in Step C with 6-aminonicotinic acid. MS -557.1 [M - 1].
Example 64 2-(4-(4-(4-chloi ophenethycnrbnmoyl)phenoxy)-3-((dimethylnminno)methyl)phenyl)acetic acid
Figure imgf000058_0002
|00269] Step A: To a stirred solution of tert-butyl 2-(3-(aminonicthyl)-4-(4- (phcnethylcarbamoyl)phenoxy)phenyl)acetatc (0.015 g, 0.030 mmol) in nictlianol (1 ml) was added acetic acid (0.012 ml, 0.212 mmol), sodium cyanoborohydridc (0.010 g, 0.152 mmol) and paraformaldehyde (0.007 g, 0.152 mmol). The reaction was stirred at ambient temperature for 1 hour. The reaction was loaded directly onto a silica gel samplct and the product elutcd using a gradient of 0.5% mcthanol/dichloromcthanc to 5% methanol/ dichloromcthanc to provide /er/-butyl 2-(4-(4-((4-chloroplienetliyl)carbamoyl)phenoxy)-3-((dimelhylamino)methyl)phcnyl)acetate (0.005 g, 0.010 mmol).
[00270] Step B: To tert-bulyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-
((dimethylamino)methyl)phenyl)acetate (0.005 g, 0.010 mmol) in dichloromethane (1.0 ml) was added TFA (1.0 ml) and the reaction stirred for 1 hour at ambient temperature. The reaction was concentrated to give 2-(4-(4-((4-chlorophenethyl)carbamoyI)phenoxy)-3-
((dimethylamino)mcthyl)phenyl)acctic acid (0.005 g). MS -465.1 [M - I ].
Example 65
2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-((N- methylmethylsulfonamido)methyl)phenyl)acetic acid 58
Figure imgf000059_0001
(00271) Step A: To a stirred solution of tert-buty\ 2-(3-cyano-4-fluorophcnyl)acetatc (1.00 mg, 4.25 mmol) and methyl 4-hydroxybenzoate (776 mg, 5.10 mmol) in DMSO (20 ml) was added K2CO3 (704 mg, 5.10 mmol). The reaction was heated to 90 0C overnight via an oil bath. The reaction was diluted with ethyl acetate and 10% aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified by silica gel chromatography to give methyl 4-(4-(2-ftτv-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1.08 g). [00272] Step B: To a stirred solution of the methyl 4-(4-(2-κ?rt-buloxy-2-oxoethyl)-2- cyanophcnoxy)bcnzoatc (1.086 mg, 2.96 mmol) in 7N ammonia/mcthanol (30 ml) under nitrogen was added Raney Nickel (25.3 mg, 0.296 mmol). The reaction was purged with a hydrogen balloon and stirred under hydrogen overnight. The reaction was filtered through GF paper and the solid catalyst was rinsed with methanol and ethyl acetate. The filtrate was concentrated, and the crude product was purified by silica gel chromatography to give methyl 4-(2-(aminomethyl)-4-(2-/e«- bιιtoxy-2-oxoethyl)phcnoxy)bcnzoate (0.69 g).
(00273) Step C: To a stirred solution of the methyl 4-(2-(aminomcthyl)-4-(2-re«-butoxy-2- oxoethyl)phenoxy)benzoate (690 mg, 1.86 mmol) in dichloromethane (6 ml) was added pyridine (225 μL, 2.78 mmol) followed by mclhanesulfonyl chloride (287 μL, 3.71 mmol). The reaction was stirred at ambient temperature for 4 hours, after which time additional pyridine (1.5 eq) and mcthanesulfonyl chloride (2 eq) were added. The reaction was stirred for an additional hour and then diluted with ethyl acetate and IM HCI. The aqueous layer was extracted with ethyl acetate and the combined organics washed with brine and dried over MgSO4. The crude product was then purified on the Biotagc Horizon (40+M, 5%to75% B:ethyl acetate) to give methyl 4-(4-(2-/e/7-butoxy-2- oxoethyl)-2-(methylsulfonamidomethyl)phenoxy)benzoate (0.754 g).
(00274) Step D: To a stirred solution of the methyl 4-(4-(2-fm-butoxy-2-oxoethyl)-2- (mcthylsulfonamidomethyl)phenoxy)benzoate (745 mg, 1.65 mmol) in DMF (10 ml) was added McI ( 155 μL, 2.48 mmol) followed by K2CO3 (343 mg, 2.48 mmol). The reaction was stirred at ambient temperature for 3 hours, then diluted with ethyl acetate and 2M HCI. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried 59 over MgS0.». The crude mixture was purified by silica gel chromatography to give methyl 4-(4-(2- /m-butoxy-2-oxoethyl)-2-((N-meΛyImeώan-2-ylsulfonamido)methyl)phenoxy)benzoate (0.368 g). |00275] Step E: To a stirred solution of methyl 4-(4-(2-fcτf-butoxy-2-oxoethyl)-2-((N- mcthyImethan-2-ylsulfonarnido)methyl)phenoxy)benzoate (370 mg, 0.797 mmol) in dioxane (8 ml) was added a solution of LiOH monohydratc (43.5 nig, 1.04 mmol) in water (2 ml) (0.1 M solution 4: 1 dioxane/watcr). The reaction was stirred for 5 hours, then diluted with dichloromethane and 2N HCl. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSQi. The crude product was purified by silica gel chromatography to give 4-(4-(2-tert-butoxy-2-oxocthyl)-2-((N-mcthylmethan-2- ylsulfonamido)mcthyl)phcnoxy)bcnzoic acid (0.253 g).
[00276] Step F: To a stirred solution of 4-(4-(2-Λ?/?-butoxy-2-oxoelhyl)-2-((N-methylmethan-2- ylsulfonamido)methyl)phcnoxy)benzoic acid (50 mg, 0.11 1 mmol) and HATU (46.5 mg, 0.122 mmol) in DMF (1 ml) was added DIEA (23.2 μL, 0.133 mmol) followed by 2-(4- chlorophenyl)cthanamine (11.2 μL, 0.11 1 mmol). The reaction was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSCj. The crude product was purified by silica gel chromatography to give /e«-butyl 2-(4-(4-((4- chlorophencthyl)carbamoyl)phcnoxy)-3-((N-methylmethan-2-ylsulfonamido)mcthyl)phenyl)acetate (0.0115 g).
100277] Step G: To a stirred solution of tert-butyl 2-(4-(4-((4- chlorophcnethyl)carbamoyl)phcnoxy)-3-((N-methylmcthan-2-ylsulfonamido)methyl)phcnyl)acctate (1 1.5mg, 0.019mmol) in dichloromethane (ImI) was added TFA (50OuI). The reaction was stirred at ambient temperature for 4 hours and then concentrated.. The crude product was then purified by preparative TLC (20% methanol/dichloromethane/0.5% AcOH) to give 2-(4-(4-((4- chlorophencthyl)carbamoyl)phcnoxy)-3-((N-methylmethan-2-ylsulfonamido)methyI)phenyl)acetic acid (0.0123 g). MS +531.0 [M + I].
Example 66 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000060_0001
60
[00278] Step A: A mixture of /ert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.122 g), N-(4- chlorophenethyl)-4-hydroxybcnzamide (0.150 g), and potassium carbonate (0.086 g) was dissolved in 2 ml of DMSO and stirred at 900C. After 1 day, the reaction was cooled, loaded onto a silica gel samplct and product eluted with a solvent system gradient of 0.5% methanol/ dichloromethane to 5% methanol/ dichloromethane to give /er/-butyl 2-(3-cyano-4-(4-
(phcncthylcarbamoyl)phenoxy)phenyl)acctate (0.120 g).
(00279) Step B: To a solution of tert-butyl 2-(3-cyano-4-(4-(phcncthylcarbamoyl) phenoxy)phenyl)acctate 0. 120 g) in 2 ml of dichloromethane was added 2 ml of TFA and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated and dried under vacuum to give 2-(3-cyaiio-4-(4-(phenethylcarbamoyl)phenoxy)phcnyl)acctic acid (0.100 g). MS -355.3 [M - CO2H].
Example 67 2-(4-(4-(4-chlorophenethyIcarbamoyl)-3-(trifluoromethyl)phenyl)acetic acid
Figure imgf000061_0001
[00280] Step A: To a stirred solution of the 4-fluoro-3-(trifluoromethyl)benzaldehyde (177 μL, 1.30mmol) and N-(4-chlorophenethyl)-4-hydroxybcnzamide (359 mg, 1.30 mmol) in DMSO (3 ml) was added K2CO3 (270 mg, 1.95 tnmol). The reaction was stirred at 95°C for 2 hours and Chen directly purified by silica gel chromatography to give N-(4-chlorophenethyl)-4-(4-formyl-2- (trifluoromethyl)phenoxy)benzamide (0.541 g).
[00281] Step B: To a solution of N-(4-chlorophenethyl)-4-(4-formyl-2-
(trifluoromcthyl)phenoxy)benzamide (0.225 g, 0.502 mmol) in THF (5 ml) was added methylsulfinyl(methylthio)methane (0.125 g, 1.00 mmol) followed by benzyltrimethylammonium hydroxide (0.114 ml, 0.251 mmol) and the reaction was stirred at 70 0C forl hour. The reaction was cooled, loaded onto a silica gel samplet and the product was eluted using a gradient of 0.5% methanol/dichloromethane to 15% methanol/dichloromethane. Isolated (Z)-N-(4-chlorophenethyl)- 4-(4-(2-(meUiylsulfinyl)-2-(methylthio)vinyl)-2-(trifluoromethyl)phenoxy)benzamide (0.220 g, 79.0% yield) which by TLC appeared to be a 4: 1 mixture of olefin isomers. The crude material was used directly in the next step. 61
(002821 Step C: To (Z)-N-(4-chlorophenethyl)-4-(4-(2-(mεthylsulfinyl)-2-(melhylthio)vinyl)-2- (trifluoromethyl)phenoxy)bcnzamide (0.220 g, 0.397 mmol) was added HCl (in ethanol) (0.993 ml, 1.99 mmol) and the reaction heated to 7O0C for 1 hour. The reaction was concentrated, loaded onto silica gel and the product eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes. Isolated ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyI)phenoxy)-3-
(trifluoromethyl)phenyl)acetate (0.165 g, 82.1% yield) as a white solid.
[00283] Step D: To a solution of ethyl 2-(4-(4-((4-chIorophcnethyl)carbamoyl)phenoxy)-3- (trifluoromethyl)phenyl)acetate (0. 165 g, 0.326 mmol) in methanol/THF (1: 1), 5 ml was added LiOH-H2O (0.0684 g, 1.63 mmol) and 3 drops of water, and the reaction was stirred for 1 hour The reaction was diluted with ethyl acetate, washed with 2N HCl and brine, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel chromatography, eluting with a gradient of 0.5% methanol/ dichloromethane containing 0.5% AcOH to 7% methanol/ dichloromethane containing 0.5% AcOH to provide 2-(4-(4-((4-chlorophenethyl) carbamoyl)pheno\y)-3-(trifluoromethyl)phenyl)acetic acid (0.112 g). MS +478.3 [M + I]. 1H NMR (400 MHx, CD3OD) δ 8.49 (bt, NH), 7.79 (d, J = 8.7 Hz, 2H), 7.68 (s, I H), 7.53 (d, J - 4.3 Hz, IH), 7.28 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.02-7.06 (m, 3H), 3.71 (s, 2H), 3.56 (t, J = 6.8 Hz, 2H), 2.90 (t, J = 7.3 Hz, 2H).
Example 68 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)propanoic acid
Figure imgf000062_0001
[00284] Step A: To a stirred solution of diisopropylamine in 2 ml of THF at -78 0C was added n- butyl lithium (0.61 ml). The reaction was stirred for 30 minutes after which time a solution of tert- butyl 2-(3-cyano-4-fluorophenyl)acetate (0.300 g) in THF (2 ml) was added dropwise over 20 minutes at -780C. The reaction was warmed to 0 0C and then transferred a flask containing 2 ml THF and MeI (0.080 ml). The reaction was acidified with 2M HCl and extracted with ethyl acetate. The combined organics were then washed with brine and dried over MgSO4. The concentrated product was purified by silica gel chromatography using a solvent system of 5% to 50% ethyl acetate/hexanes to provide re/7-butyl 2-(3-cyano-4-fluorophenyl)propanoate (0.140g). 62
[00285| Step B: A flask was charged with ten-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.070 g), N-(4-chlorophenethyl)-4-hydroxybcnzamide (0.105 g), and potassium carbonate (0.047 g) in 1 ml of DMSO and stirred at 95 0C for one day. The reaction was taken up in dichloromcthanc and washed with water. The organic layer was collected, dried over MgSCU filtered, and concentrated. The crude material was purified by silica gel chromatography, eluting with a solvent system of 5%- 80% ethyl acetate/hexanes gave /cw-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)phenoxy)-3- cyanophcnyOpropanoate (0.102).
(00286) Step C: A flask was charged with Λ?r/-butyl 2-(4-(4-((4- chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)propanoate (0.098 g) in 1 ml of dichloromethane and 1 ml of TFA, and the reaction was stirred for 1 hour. The reaction was concentrated and dried under vacuum. Isolated 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- cyanophenyOpropanoic acid (0.080 g). MS +449.1 [M +1J.
Example 69 2-(3-cyano-4-(2,4-dichlorophenethylcarbamoyl)phenoxy)phenyl)propanoic acid
Figure imgf000063_0001
[00287] Prepared by the method of Example 68 substituting N-(4-chlorophenethyl)-4- hydroxybenzamidc in step B with N-(2,4-dichlorophenelhyl)-4-hydroxybenzarnidc. MS +483.0 [M
+1J-
Example 70 2-(4-(4-(4-chlorophenethyIcarbamoyl)-3-methoxyphenyl)acetic acid
Figure imgf000063_0002
[00288) Step A: Methyl 2-(4-hydroxy-3-mctho\yphenyl)acetate (0.204 g, 1.04 mmol), N-(4- chlorophcncthyl)-4-iodobenzamidc (0.200 g, 0.519 mmol), 2,2,6,6-tetramethyl-3,5-heptanedionc 63
(0.00956 g, 0.0519 mmol), Cu(I)Cl (0.0257 g, 0.259 mmol) and Cs2CO3 (0.338 g, 1.04 mmol) were stirred together in NMP (2 ml) for 1 hour. The reaction was loaded onto silica gel and the product elulcd using a gradient of 5% ethyl acetat^exancs to 100% ethyl acetate/hexancs. Isolated methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methoxyphenyl)acetate (0.105 g, 44.6% yield) as a yellow solid.
[00289} Step B: To a solution of methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3- methoxyphenyl)acetate (0.065 g, 0.143 mmol) in methanol/THF (1: 1, 3 ml) was added NaOH (0.100 ml, 0.500 mmol). After 5 minutes, reaction was quenched with 10 ml of 2N HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude material was purified by silica gel chromatography, cluting with a gradient of 0.5% methanol/dichloromcthane (containing 0.5% AcOH) to 7.5% methanol/dichloromethane containing (0.5% AcOH) to provide 2-(4-(4-((4- chlorophenethyI)carbamoyl)phenoxy)-3-mcthoxyphcnyl)acctic acid (0.041 g, 65.1% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.37-8.41 (bt, NH), 7.70 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.5 Hz5 2H), 7.08 (s, IH), 7.02 (d, J - 8.6 Hz, IH), 6.91 (d, J = 8.6 Hz, 2H), 3.64 (s, 2H), 3.56 (t, , J = 6.8 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H).
Example 71 2-(3-cyano-4-(4-(2,4-dichloi ophenethylcarbamoyl)-3-fluoι ophenoxy)phenyl)acetic acid
Figure imgf000064_0001
(002901 Step A: To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (200mg, 1.28mmol) in DMF (3 ml) at ambient temperature were added HATU (536 mg, 1.41 mmol) and DIEA (268 μL, 1.54 mmol). The reaction was stirred for 30 minutes and then 2-(2,4-dichlorophenyl)ethanamine (193 μL, 1.28 mmol) was added. The reaction was stirred overnight, then concentrated and diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography) to give N-(2,4-dichlorophenelhyl)-2-fluoro-4- hydroxybcnzamide (0.420 g).
[00291] Step B: To a stirred solution of N-(2,4-dichlorophenethyl)-2-fluoro-4- hydroxybenzamide (420 mg, 1.28 mmol) and rm-butyl 2-(3-cyano-4-fluorophenyl)acetate (361 mg, 64
1.54 mmol) in DMSO (6 ml) was added K2CO3 (265 mg, 1.92 mmol). The reaction was heated stirred at 7O0C for one hour. The reaction was then stirred at 9O0C overnight. The reaction was diluted with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% Na^CO3 and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography to give /e/7-butyl 2-(4- (4-((2,4-diclilorophenethyl)carbamoyl)-3-fluorophenoxy )-3-cyanophcny Oacetate (0.0157 g). [00292] Step C: To a stirred solution of /e«-butyl 2-(4-(4-((2,4-dichlorophenethyl)carbamoyl)-3- fluorophenoxy)-3-cyanophenyl)acetatc (15 mg, 0.0276 mmol) in dichloromcthanc was added TFA. The reaction was stirred for 2 hours and then concentrated. The crude material was purified by preparative TLC ( 10%mcthanol/0.5%AcOH/dichloromcthanc). The appropriate section was collected and then purified a second time by preparative TLC to provide 2-(4-(4-((2,4- dichlorophcnethyl)carbamoyl)-3-fluorophenoxy)-3-cyanophenyl)acetic acid (0.0042 g). 1H NMR (400 MHz, CD3OD) δ 7.70-7.74 (m, 2H), 7.61 (d, J = 7.8 Hz, IH), 7.43 (s, IH), 7.33 (d, J = 8.6 Hz, IH), 7.26 (d, J = 7.8 Hz, IH), 7.13 (d, J = 8.7 Hz, IH), 6.88-6.94 (m, 2H), 3.52-3.65 (m, 4H), 3.05 (t, J = 7.0 Hz, 2H).
Example 72 2-(3-cyano-4-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000065_0001
(00293) Step A: TFP Resin ( 1.33 mmol/g; 2.872 g, 3.820 mmol) was placed in a vessel and DMA (5 mL) was added to swell the resin. The vessel was placed on a shaker for 15 minutes, and 4-(4-(2-/e/v-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (1.500 g, 4.245 mmol), DIC (0.7311 ml, 4.669 mmol), and DMAP (0.5704 g, 4.669 mmol) were added to the mixture and the vessel was placed on the shaker. The mixture was filtered, washed with DMA, THF, dichloromethane, and ether, and air-dried to give 3.1 1 g of the resin bound (4-(4-(2-fert-buloxy-2-oxoethyl)-2- cyanophcnoxy)ben/:oate.
[00294] Step B: TFP resin bound ester (4-(4-(2-tørt-butoxy-2-oxoethyl)-2- cyanophenoxy)benzoate) (0.1968 g, 0.09840 mmol) was added to a vial. THF (2 ml) was added and the resin was allowed to swell. 2-(2,6-Dichlorophenyl)ethanamine, (IM in THF; 0.08200 ml, 0.082 mmol) was added to the vial and the vial was place on a shaker. After 16 hours, the mixture was 65 decanted and the resin was rinsed with THF (3 X 2ml). The combined THF solution was concentrated under reduced pressure. The residue was dried under high vacuum to give fen-butyl 2- (4-(4-((2,6-dichlorophcncthyl)carbamoyl)phenoxy)-3-cyanophcnyl)acetatc (0.034 g), which was used in the nest step without further purification.
[00295) Step C: tert-Butyl 2-(4-(4-((2,6-dichlorophenethyl)carbamoyl)phenoxy)-3- cyanophcnyl)acetate (34 mg, 0.065 mmol) was dissolved in dichloromethane (ImI) and TFA (ImI) was added. After stirring for 45 minutes, the mixture was concentrated under reduced pressure to give 2-(3-cyano-4-(4-(2,6-dichlorophencthyIcarbamoyl)phenoxy)phenyl)acctic acid (0.034 g).
Example 73 2-(3-cyano-4-(4-(4-fluorophenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000066_0001
[00296] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(4-fluorophenyl)ethanamine.
Example 74
2-(3-cyano-4-(4-(3-methoxyphenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000066_0002
[00297] Prepared by the method of Example 72 substituting 2-(2,6-dtchlorophenyl)ethanamine in Step B with 2-(3-melhoxyphenyl)cthanaminc.
Example 75 2-(3-cyano-4-(4-(4-terf-butyIphenethylcarbamoyl)phenoxy)phenyl)acetic acid 66
Figure imgf000067_0001
[00298J Prepared by the method of Example 72 substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(4-tørt-butylphenyl)cthanaminc.
Example 76 2-(3-cyano-4-(4-(4-trifluoromethylphenethylcarbamoyl)pheιιoxy)phenyl)acetic acid
Figure imgf000067_0002
(00299| Prepared by the method of Example 72 substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(4-trifluoromethylphcnyl)ethanamine.
Example 77 2-(3-cyano-4-(4-(3-chlorophenethylcarbamoyl)phenoχy)phenyl)acetic acid
Figure imgf000067_0003
[00300] Prepared by the method of Example 72 substituting 2-(2,6-dich!orophenyl)ethanaminc in Step B with 2-(3-chiorophcnyl)ethanamine.
Example 78 2-(3-cyano-4-(4-(3-fluorophenethylcarbamoyl)phenoxy)phenyl)acetic acid 67
Figure imgf000068_0001
[00301] Prepared by the mclhod of Example 72 substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(3-fluorophenyl)cthanamine.
Example 79 2-(3-cyano-4-(4-(4-methoxyphenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000068_0002
[00302] Prepared by the method of Example 72, substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(4-methoxyphenyl)ethanamine.
Example 80
2-(3-cyano-4-(4-(4-methylphenethylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000068_0003
[00303] Prepared by tlie method of Example 72, substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(4-methylphenyl)ethanamine
Example 81 2-(3-cyano-4-(4-(4-methylphenethylcarbamoyl)phenoxy)phenyl)acetic acid 68
Figure imgf000069_0001
[00304J Prepared by the method of Example 72, substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-(3,4-dichlorophenyi)ethanamine.
Example 82 2-(4-(4-(2-(4-chlorophenyl)-2-hydroxyethyIcarbamoyl)phenoxy)-3-cyanophenyl)acetic acid
Figure imgf000069_0002
[00305| Prepared by the method of Example 72 substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with 2-amino- l-(4-chlorophenyl)cthanol hydrochloride.
Example 83 2-(4-(4-(l-(4-chlorophenyl)cyclopropylcarbamoyl)phenoxy)-3-cyanophenyl)acetic acid
Figure imgf000069_0003
[00306] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophenyl)cthanamine in Step B with l-(4-chlorophenyl)cycloproanamine hydrochloride.
Example 84 2-(3-cyano-4-(4-(2-phenylcyclopropylcarbamoyl)phenoxy)phenyl)acetic acid 69
Figure imgf000070_0001
[00307] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophcnyl)ethanamine in Step B with 2-phenyIcyclopropylaminc.
Example 85 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)-2-fIuoroacetic acid
Figure imgf000070_0002
[00308] Step A: tert-Butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phcnoxy)-3-cyanophenyl) acetate (0.400 g) and 4-methylbenzencsulfonyl azide (0.193 g) were dissolved in 5 ml of acetonitrile and treated with DBU (0.152 ml) The reaction was stirred for 4 hours, then concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried, filtered, concentrated onto silica gel and purified by silica gel chromatography to provide tert-butyl 2-(4-(4-(4- chlorophenethylcarbamoyI)phenoxy)-3-cyanophenyl)-2-diazoacelate (0.48 g) as a bright yellow solid.
100309] Step B: A flask was charged with /er/-butyl 2-(4-(4-(4- chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)-2-diazoacetate (0.108 g), 5 ml of ether and HF pyridine (0.30 g). The reaction was stirred at 40 0C for 30 minutes. The reaction mixture was diluted with ethyl acetate and neutralized with saturated aqueous bicarbonate solution. The organic layer was separated and washed with brine, dried, filtered and concentrated onto silica gel. The crude material was purified by silica gel chromatography to provide ten-butyl 2-(4-(4-((4- chlorophencthyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetate (0.026 g) as a colorless oil. [00310] Step C: A flask was charged with rm-butyl 2-(4-(4-((4- chlorophencthyl)carbamoyl)phenoxy)-3-cyanophenyl)-2-fluoroacetate (0.026 g), 0.5 ml of dichloromcthanc and 0.2 ml of TFA. The reaction was concentrated, and the residue was dissolved 70 in a minimal amount of dichloromethane and placed under high vacuum to give a solid. The procedure was repeated to give 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)-2- flυoroacetic acid (0.024 g) as a tan solid.
Example 86 2-(4-(4-((l-(4-chloιophenyl)cyclopropyl)methylcarbamoyl)phenoxy)-3-cyanophenyl)acetic acid
Figure imgf000071_0001
[00311 ] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophenyl)ethanamine in Step B with (l-(4-chlorophneyl)cyclopropyl)mcthanaminc.
Example 87 2-(4-(4-(2-(4-chlorophenyl)cyclopropylcarbamoyl)phenoxy)-3-cyanophenyl)acetic acid
Figure imgf000071_0002
[00312] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophcnyl)ethanamine in Step B with 2-(4-chlorophenyl)cyclopropanamine.
Example 88 2-(3-cyano-4-(4-(l,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000071_0003
[00313] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophcnyl)ethanamine in Step B with l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride. 71
Example 89
2-(3-cyano-4-(4-(6-rnethoxy-l,2,3,4-tetrahydronaphthalen-2- ylcarbamoyl)phenoxy)phenyl)acetic acid
Figure imgf000072_0001
[00314] Prepared by the method of Example 72 substituting 2-(2,6-dichlorophcnyl)ethanamine in Step B with 6-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride.

Claims

72Claims
I. A compound of general formula (I):
Figure imgf000073_0001
(I) or a salt thereof, wherein:
R' is Ar'-L'-W-lΛ; L2 is -(CRCRV; W is -CONR30- or -NR3bC0-; R38 and R3b are each H or methyl; L" is -(CRBRb)n-, -(CH=CH)-, or -0(CR"Rb) provided that when W is -NR3CO- thcn L1 is not -(CH=CH)-; n and m are independently O, 1 or 2; each Ra, Rb, Rc and Rd is independently H, F, OH, methyl or cyclopropyl, or R" and Rb or Rc and Rd together with the carbon to which they are attached form a cyclopropyl ring; Ar1 is phenyl or naphthyl, each of which is unsubstituted or substituted with one or more substituents selected independently from F, Cl, CN, CF3, CHF2, CH2F, SF5, methyl, ethyl, cyclopropyl, t-butyl or OMe, or Ar1 is 1,2,3,4-tctrahydronaphthyl which is unsubstituted or substituted by mcthoxy, provided that when Ar1 is naphthyl or 1,2,3,4-tetrahydronaphthyl then n is O; R2 is H, Ci-C6 alkyl, a residue of an amino acid or dipcptide, or CHRe(CH2)<,Rf ; q is 1 to 6;
Rc is H, methyl or ethyl;
Rf is NR8R*1 in which R8 and Rb each independently represents a hydrogen atom or a C1-C4 alkyl group, or R8 and Rh together with the nitrogen atom to which they are attached form a 5-6 incnibercd heterocyclic ring optionally containing a second ring hetcroatom selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from Ci-Cβ alkyl;
A is CN, CH2NH2, CH2NR40C(O)R5, or CH2NR415SO2R6, Cl, OMe, (l-4C)alkyl, cyclopropyl, H, F, Br, CH2NH( 1-4C alkyl), CH2N(1-4C alkyl)2, thienyl, or phenyl which is unsubstituled or substituted with SO2Me;
73
R4" and R4b arc each H or methyl;
R5 is C1-C6 alkyl, C-C6 alkoxy, C3-C6 cycloalkyl, hetAr1, or Ar; R6 is Ci-C6 alk-yl, NH(C1-C6 alkyl), N(C1-C6 alky I)2, Ar3, or hetAr2; hetAr1 is a 6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom and a group of formula -NR58R51" in which each of R5* and R5b independently represents a hydrogen atom or a (1-4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl or moφholino group; hetAr is a 5-6 membered heteroaryl which is unsubstituted or substituted with one or more groups independently selected from C1-C4 nlkyl;
Ar2 is phenyl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom, CN, SF5, cyclopropyl, a CpC4 alkyl group, a Ci-C4 alkoxy group and a fluoroCi-C4 alkyl group;
Ar3 is as defined for Ar; R7 and R8 are independently H, methyl, or F;
R9 is H or methyl; and R10 is H or F.
2. A compound of claim 1 having the formula Ia
Figure imgf000074_0001
wherein
R1 is Ar'-L'-W-L2-;
L2 is -(CR0RV;
W is -CONR30- or -NR3bC0-; R3a and R3b are each H or methyl;
L1 is -(CR0R1V1 -(CH=CH)-, or -0(CR0R6)-, provided that when W is -NR3CO- then L1 is not -(CH=CH)-; n and m are independently 0, 1 or 2; each R", Rb, Rc and Rd is independently H, F, methyl or cyclopropyl, or R" and Rb or Rc and Rd together with the carbon to which they arc attached form a cyclopropyl ring;
74
Ar1 is phenyl or naphthyl, each of which is unsubstituted or substituted with one or more substituents selected independently from F, Cl, CN, CF3, CHF2, CH2F, SF5, methyl, ethyl and cyclopropyl, provided that when Ar1 is naphthyl then n is 0;
R2 is H, Ci-Ce alkyl, a residue of an amino acid or dipeptide, or CHRc(CH2)qRr ; q is 1 to 6;
Re is H, methyl or ethyl;
Rr is NRBRh in which Rε and Rh each independently represents a hydrogen atom or a Ci-C4 alkyl group, or R8 and Rh together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally containing a second ring hctcroatom selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from Ci -C6 alkyl;
A is CN, CH2NH2, CH2NR4aC(=O)R5, CH2NR4bSO2R6, Cl, OMc, ( l-4C)alkyl, or cyclopropyl;
R40 and R4b are each H or methyl; R5 is C1-C6 alkyl, CrC6 alkoxy, C3-C6 cycloalkyl, hetAr1, or Ar2;
R6 is C1-C6 alkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, Ar3, or hetAr; hetAr1 is a 6 membered hcteroaryl which is unsubstitutcd or substituted with one or more groups independently selected from a halogen atom and a group of formula -NRJaR5b in which each of R5a and R5b independently represents a hydrogen atom or a (1-4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, pipcridinyl or morpholino group; hetAr is a 5-6 membered hcteroaryl which is unsubstituted or substituted with one or more groups independently selected from Ci-C4 alkyl;
Ar2 is phenyl which is unsubstituted or substituted with one or more groups independently selected from a halogen atom, a CN, SFS, cyclopropyl, CpC4 alkyl group, a Ci- C4 alkoxy group and a fluoroCi-C4 alkyl group;
Ar3 is as defined for Ar2; and R7 and R8 are independently H or methyl.
3. A compound according to claim 1 or 2, wherein -L1 -W-L2- is selected from -CONH-, -CH2CONH-, -CH2CH2CONH-, -CONHCH2-, -CH2CONHCH2-, -NHCO-,
-CH2NHCO-, -NHCOCH2-, -CH2CH2NHCO-, -CH3NHCOCH2-, -CH2CH2NHCOCH2-,
-CH2N(CH3)COCH2-, cyclopropylideneCH2NHCO, -CH2ONHCO-, -CH(OH)CH2NHCO- and
-cyclopropylidineNHCO-.
75
4. A compound according to any of claims 1-3, wherein Ar1 is a naphthyl group or a phenyl group that is unsubstituted or substituted by one or two substitucnts selected independently from F, Cl, CF3, OMe, Me, and l-Bu, or a 1,2,3,4-tetrahydronaphthyl group which is unsubstituted or substituted with OMe.
5. A compound as claimed in claim 4, wherein Ar1 is naphthyl, phenyl, 4- fluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl, 3- fluoro-4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2,6-dichlorophenyl, 2,4- dichlorophcnyl, 3-methoxyphcnyl, 4-methoxyphcnyl, 4-tertbulylphcnyl, 3-fluorophenyl and 4- mcthylphenyl, l,2,3,4-tctrahydronaphth-2-yl or 6-mcthoxy- 1 ,2,3,4-tctrahydronaphth-2-yl.
6. The compound according to any of claims 1-5, wherein the 6 membered hetcroaryl group in hctAr1 is a pyridyl group and the 5-6 membered hctcroaryl in hetAr2 is an imidazolyl or pyridyl group.
7. A compound as claimed in claim 6, in which R5 is Ci-C-6 alkyl; Cι-C-6 alkoxy; C3- C6 cycloalkyl; pyridyl which is unsubstituted or substituted by a halogen atom or a group of formula -NR5aR5b in which each of R5a and R5b independently represents a hydrogen atom or a (1-4C) alkyl group, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, pipcridinyl or morpholino group; or a phenyl group that is unsubstituted or substituted by one or two halogen atoms, and R6 is Ci-C6 alkyl, NH(C-C6 alkyl), N(Ci-C6 alky I)2, a phenyl group that is unsubstituted or substituted by one or two halogen atoms, pyridyl or imidazolyl that is unsubstituled or substituted with a C1-C3 alkyl group.
8. A compound as claimed in claim 7, in which R5 is methyl, mclhoxy, cyclohexyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 6-chloro-pyrid-3-yl, 6-amino-pyrid-3-yl, 6-pyrrolidin-l- ylpyrid-3-yl or 4-fluorophenyl and R6 is methyl, dimcthylamino, 4-fluorophenyl, 2,4- dichlorophcnyl, pyrid-3-yl, l-methylimidazol-5-yl, or 6-dimethylaminopyrid-3-yl.
9. A compound as claimed in claims 1-5, in which A is selected from cyano, acetamidomethyl, cyclohexylamidomethyl, methoxycarbonylaminomethyl, picolinamidomethyl, nicolinamidomcthyl, isonicoϋnamidomcthyl, β-chloropyrid-S-ylamidomcthyl, 6-aminopyrid-3- ylamidomethyl, 6-pyrrolidin- l-ylpyrid-3-ylamidomethyl, 4-fluorobenzamidomethyl, methylsulfonamidomethyl, N,N-dimctliylsulfamoylamino, 4-fluorophenylsulfonamidomethyl, 2,4-dichlorophenylsuIfonamidomethyl, l-methyIimidazol-5-ylsulfonamidomcthyl, pyrid-3- ylsulfonamidomcthyl, 6-dimelhylaminopyrid-3-yIamidomethyI, 2-(4-fluorophenylsulfonamido) acetamidomethyl, dimethylaminomethyl, (N-mcthylmcthylsulfonamido)methyl, H, F, Br, Cl,
76 methyl, ethyl, cyclopropyl, CH2NH2, CH2NMe2, thienyl, phenyl, 3-methylsulfonylphenyl, and 4- methylsulfonylphenyl.
10. A compound as claimed in claim 9, in which A is selected from cyano, acetamidomethyl, cyclohexylamidomethyl, methoxycarbonylaminomethyl, picolinamidomethyl, nicotinamidomethyl, isonicotinamidomethyl, 4-fluorobcnzamidomethyl, methylsulfonamido- methyl, N,N-dimcthylsulfamoylamino, 4-fluorophenylsulfonamidomethyl, 2,4-dichIoro- phenylsulfonamidomethyl, pyrid-3-ylsulfonamidomethyl, 6-dimethylaminopyrid-3- ylamidomethyl, 2-(4-fluorophenylsulfonamido)acetamidomethyl, dimethylaminomethyl, (N- mcthylmcthylsulfonamido)melhyl, H, F, Br, Cl, methyl, ethyl, cyclopropyl, CH2NH2, CH2NMe2, thienyl, SO2Me, phenyl, 3-methylsulfonylphcnyl, and 4-methylsulfonylphenyl.
11. A compound as claimed in any one of claims 1 to 10, in which R2 is hydrogen.
12. A compound as claimed in any one of claims 1 to 11, in which R7 and R8 arc H.
13. A compound as claimed in any one of claims 1 or 3- 12, in which R9 is H.
14. A compound as claimed in any one of claims 1 or 3-13, in which R10 is H.
15. A pharmaceutical composition, which comprises a compound of formula (I) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
16. A method of treating an immunologic disorder in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I) as defined in any one of claims I to 14, or a pharmaceutically acceptable salt thereof.
17. The method of claim 16, wherein the immunologic disorder is selected from inflammatory conditions, immune disorders, asthma, allergic rhinitis, eczema, psoriasis, atopic dermatitis, fever, sepsis, systemic lupus erythematosus, diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplant rejection, inflammatory bowel disease, cancer, viral infection, thrombosis, fibrosis, flushing, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, inflammation, pain, conjunctivitis, nasal congestion and urticaria.
18. A compound of formula (1) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in therapy.
19. The use of a compound of formula (I) as defined in any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an immunologic disorder.
20. A process for the preparation a compound as defined in any one of claims 1 to 14, which comprises:
77
(a) for a compound of formula (I) in which A is CN, R7 and R8 are independently H or Me, and R10 is H or F, rcacϋng a corresponding compound having the formula:
Figure imgf000078_0001
in which P1 represents a hydrogen atom or a carboxyl protecting group and Z' represents a leaving atom or group, with a corresponding compound having the formula
Figure imgf000078_0002
in which RIOil is H or F in the presence of a base; or
(b) for a compound of formula (I) in which A is -CH2NH2, R10 is H1 and R7 and R8 are independently H or Mc, reducing a corresponding compound formula (IV)
Figure imgf000078_0003
(IV) in which P2 is as defined for P1; or
(c) for a compound of formula (I) in which A is -CH2NH2, R7 and R8 are independently H or Mc, and R10 is H, cleaving a corresponding compound of formula (V)
Figure imgf000078_0004
(V)
78 in which P3 is as defined for P1; or
(d) for a compound of formula (1) in which A is CH2NR4C(=O)R5 or CH2NR4SO2R6, R7 and Rs arc independently H or Me1 and R10 is H. reacting a corresponding compound of formula (Vl)
Figure imgf000079_0001
in which P4 is as defined for P1; with a compound of formula R'COZ2 or R6SO2Z3 in which Z2 and Z3 each represents a leaving atom or group; or
(e) for a compound of formula (I) in which R7 and R8 arc independently H or Me, and R10 is H, coupling a compound of formula (VII)
Figure imgf000079_0002
(VIl) in which P5 is as defined for P1, A2 represents A or a protected form thereof and Rla represents H-X"-L2- in which X" represents HN or OC(=O), or a reactive derivative thereof; with a compound of formula (VIII)
Ar'-L'-X^H
(VIII) in which Xb represents C(=O)O or NH, or a reactive derivative thereof: or (0 for a compound of formula (I) in which A is H, F or Cl, R7 and R8 are independently H or Mc, and R10 is H, coupling a corresponding compound having the formula (IX)
Figure imgf000080_0001
(IX) in which A3 is H, F or Cl, and P6 is as defined for P', with a corresponding compound having the foπnula (X)
Figure imgf000080_0002
wherein E is an electron withdrawing group, in the presence of a base; and if desired removing said electron withdrawing group; or
(g) for a compound of formula (I) in which A is OMe or (l-4C)alkyl, R7 and R8 are independently H or Mc, and R10 is H, coupling a corresponding compound having the formula (XI)
Figure imgf000080_0003
in which A4 is OMe or (l-4C)alkyl, respectively, and P7 is as defined for P1, with a corresponding compound having the formula (XII)
Figure imgf000080_0004
in the presence of a base, in which Z4 represents a leaving atom or group, and Rtx represents an electron withdrawing group convertible into a group R1; or
(h) for a compound of formula (I) in which A is Br or cyclopropyl, R7 and R8 are H, and R10 is H, coupling a corresponding compound having the formula (XlV)
80
Figure imgf000081_0001
(XIV) in which Z5 is a leaving group or atom, with a compound having the formula
(XV)
Figure imgf000081_0002
in the presence of a base, followed by converting the carbonyl group to a carboxyl group; or
(i) for a compound of formula (I) in which A is methyl, thienyl, phenyl, or phenyl substituted with SO2Me, R9 is H, R7 and R8 are independently H or Me, and R10 is H, reacting a corresponding compound having the formula (XVl)
Figure imgf000081_0003
(XVI) with a compound having the formula A5-ZnX, in the presence of a palladium (0) catalyst, or with a compound having the formula A5B(OH)2 in the presence of a base and a palladium (0) catalyst, where A5 is methyl, thienyl, phenyl, or phenyl substituted with SO2Me and X is a halidc; or
(j) for a compound of formula (I) in which R7 is F5 R8 is H, and R10 is H, treating a corresponding compound having the formula (XVII)
81
Figure imgf000082_0001
(XVII) with hydrogen fluoride; and removing any protecting group or groups and, if desired, forming a salt.
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EP2457900A1 (en) 2010-11-25 2012-05-30 Almirall, S.A. New pyrazole derivatives having CRTh2 antagonistic behaviour
EP2526945A1 (en) 2011-05-25 2012-11-28 Almirall, S.A. New CRTH2 Antagonists
EP2548863A1 (en) 2011-07-18 2013-01-23 Almirall, S.A. New CRTh2 antagonists.
EP2548876A1 (en) 2011-07-18 2013-01-23 Almirall, S.A. New CRTh2 antagonists
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WO2008116145A3 (en) * 2007-03-22 2009-08-27 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
WO2008116145A2 (en) * 2007-03-22 2008-09-25 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
US8362056B2 (en) * 2007-11-05 2013-01-29 Array Biopharma Inc. 4-heteroaryl-substituted phenoxyphenylacetic acid derivatives
US20100273850A1 (en) * 2007-11-05 2010-10-28 Doherty George A 4-heteroaryl-substituted phenoxyphenylacetic acid derivatives
US8338484B2 (en) 2008-02-01 2012-12-25 Panmira Pharmaceuticals, Llc N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors
US8168678B2 (en) 2008-02-01 2012-05-01 Panmira Pharmaceuticals, Inc. N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors
US8362044B2 (en) 2008-02-01 2013-01-29 Panmira Pharmaceuticals, Llc N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors
US8067445B2 (en) 2008-02-01 2011-11-29 Panmira Pharmaceuticals, Llc N,N-disubstituted aminoalkylbiphenyl antagonists of prostaglandin D2 receptors
EP2257536A2 (en) * 2008-02-14 2010-12-08 Amira Pharmaceuticals, Inc. Cyclic diaryl ether as antagonists of prostaglandin d2 receptors
EP2257536A4 (en) * 2008-02-14 2011-03-23 Amira Pharmaceuticals Inc Cyclic diaryl ether as antagonists of prostaglandin d2 receptors
US8242145B2 (en) 2008-02-14 2012-08-14 Panmira Pharmaceuticals, Llc Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors
US8497381B2 (en) 2008-02-25 2013-07-30 Panmira Pharmaceuticals, Llc Antagonists of prostaglandin D2 receptors
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
US9096567B2 (en) 2008-06-25 2015-08-04 Array Biopharma Inc. 6-substituted phenoxychroman carboxylic acid derivatives
US8716498B2 (en) 2008-06-25 2014-05-06 Array Biopharma, Inc. 6-substituted phenoxychroman carboxylic acid derivatives
CN103450138A (en) * 2008-06-25 2013-12-18 阵列生物制药公司 Preparation of intermidiates of 6-substituted phenoxychroman carboxylic acid derivatives
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JP2011526290A (en) * 2008-06-25 2011-10-06 アレイ バイオファーマ、インコーポレイテッド 6-substituted phenoxycyclomancarboxylic acid derivatives
US9556139B2 (en) 2008-06-25 2017-01-31 Array Biopharma Inc. 6-substituted phenoxychroman carboxylic acid derivatives
US8071807B2 (en) 2008-07-03 2011-12-06 Panmira Pharmaceuticals, Llc Antagonists of prostaglandin D2 receptors
US8247602B2 (en) 2008-07-03 2012-08-21 Panmira Pharmaceuticals, Llc Antagonists of prostaglandin D2 receptors
GB2461629B (en) * 2008-07-03 2010-05-26 Amira Pharmaceuticals Inc Antagonists of prostaglandin D2 receptors
GB2461629A (en) * 2008-07-03 2010-01-13 Amira Pharmaceuticals Inc Phenoxy acetic acids as atagonists of prostaglandin D2 receptors
US8049015B2 (en) 2008-09-29 2011-11-01 Panmira Pharmaceuticals, Llc Heteroaryl antagonists of prostaglandin D2 receptors
US8378107B2 (en) 2008-10-01 2013-02-19 Panmira Pharmaceuticals, Llc Heteroaryl antagonists of prostaglandin D2 receptors
US8524748B2 (en) 2008-10-08 2013-09-03 Panmira Pharmaceuticals, Llc Heteroalkyl biphenyl antagonists of prostaglandin D2 receptors
US8383654B2 (en) 2008-11-17 2013-02-26 Panmira Pharmaceuticals, Llc Heterocyclic antagonists of prostaglandin D2 receptors
WO2010075200A1 (en) 2008-12-22 2010-07-01 Array Biopharma Inc. 7-phenoxychroman carboxylic acid derivatives
US8785445B2 (en) 2008-12-22 2014-07-22 Array Biopharma Inc. 7-phenoxychroman carboxylic acid derivatives
WO2010094956A1 (en) 2009-02-17 2010-08-26 Pulmagen Therapeutics (Inflammation) Limited. Triazolopyridine derivatives as p38 map kinase inhibitors
US8785393B2 (en) 2009-07-31 2014-07-22 Panmira Pharmaceuticals, Llc Ophthalmic pharmaceutical compositions of DP2 receptor antagonists
US8815917B2 (en) 2009-08-05 2014-08-26 Panmira Pharmaceuticals, Llc DP2 antagonist and uses thereof
US9688624B2 (en) 2010-01-06 2017-06-27 Brickell Biotech, Inc. DP2 antagonist and uses thereof
JP2013516475A (en) * 2010-01-06 2013-05-13 アミラ ファーマシューティカルズ，インク． DP2 antagonists and uses thereof
WO2012069175A1 (en) 2010-11-25 2012-05-31 Almirall, S.A. New pyrazole derivatives having crth2 antagonistic behaviour
EP2457900A1 (en) 2010-11-25 2012-05-30 Almirall, S.A. New pyrazole derivatives having CRTh2 antagonistic behaviour
EP2526945A1 (en) 2011-05-25 2012-11-28 Almirall, S.A. New CRTH2 Antagonists
WO2013010880A1 (en) 2011-07-18 2013-01-24 Almirall, S.A. New crth2 antagonists
EP2548863A1 (en) 2011-07-18 2013-01-23 Almirall, S.A. New CRTh2 antagonists.
EP2548876A1 (en) 2011-07-18 2013-01-23 Almirall, S.A. New CRTh2 antagonists
WO2013010881A1 (en) 2011-07-18 2013-01-24 Almirall, S.A. NEW CRTh2 ANTAGONISTS
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