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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to 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 7-phenoxychroman carboxylic acid derivatives useful in the treatment and prevention of immunologic diseases and 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 compounds of formula I may also be useful in treating diseases or medical conditions involving the Th2 T cell via production of IL-4, IL-5 and/or IL-13.
• DP2 is a G-protein coupled receptor that is selectively expressed on cell types that mediate allergic inflammation including mast cells, basophils, eosinophils and Th2 cells and there is growing evidence that it plays a critical role in the pathophysiology of allergy (Hirai et. al., Journal of Experimental Medicine (2001) 193:255-261).
• the endogenous ligands for DP2 (PGD2 and its active metabolites) are made by activated mast cells and by Th2 cells, and can be readily detected at sites of allergic disease.
• Agonism of DP2 promotes the migration and or activation of basophils, eosinophils and Th2 cells in vitro and in vivo (Kostenis and Ulven, Trends in Molecular Medicine (2006) 12:1471-148-158), suggesting that this receptor may drive disease processes in vivo.
• mice made deficient in DP2 by gene inactivation through homologous recombination show evidence of reduced allergic responses in pre-clinical models of asthma and atopic dermatitis. Similar results have been reported using selective small molecule inhibitors of DP2 (reviewed in Pettipher, et. al., Nature Reviews Drug Discovery (2007) 6:313-325).
• Ramatroban (BAY u34505). Ramatroban was originally developed as a Thromboxane A2 (TP) receptor antagonist but showed unexpected clinical activity in allergy, which could not be readily explained by its activity against TP. It has recently been shown that Ramatroban is also an inhibitor of DP2 and its activity in pre-clinical models of allergy can be recapitulated using selective inhibitors of DP2 but not of TP (Sugimoto et. al., Journal of Pharmacology and Experimental Therapeutics (2003) 305:347-352; Takeshiti et al., International Immunology (2004) 16:947-959). These findings support the view that the clinical efficacy seen with Ramatroban in allergic disease is due to its activity against DP2.
• TP Thromboxane A2
• Ramatroban is currently approved in Japan for the treatment of seasonal allergic rhinitis. Based on the validation of DP2 as a drug target in allergy many companies have sought to develop inhibitors of DP2 for the treatment of allergic disease, and the first of these has now entered clinical development.
• the present invention provides a compound of general
• A is H, CN, Cl, F, cyclopropyl, (1-4 C) alkyl or OMe
• a 1 is H, Cl, Br, F, cyclopropyl, (1-4 C) alkyl or OMe
• R 1 is -W-l ⁇ hetAr 1
• W is -CONR 3a - or -NR 3b CO-
• R 3a and R 3b are each H or methyl
• L 1 is a -(CR a R b ) n - or ⁇ — / ; [0015] n is 0 or 2; [0016] R a and R b are independently H, F, methyl, or cyclopropyl, or [0017] R a and R b together with the carbon to which they are attached form a cyclopropyl ring;
• hetAr 1 is heteroaryl ring selected from the structures:
• hetAr 1 is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the ring is optionally substituted with one or more substituents independently selected from (l-4C)alkyl and phenyl which is optionally substituted with one or more substituents independently selected from halogen, -O(l-6Calkyl), (l-6C)alkyl and CF 3 ;
• hetAr 1 is a 5,6-bicyclic heteroaryl having two ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein said ring is optionally substituted with one or more substituents independently selected from -O(l-6Calkyl), (l-6C)alkyl, halogen and CF 3 ;
• hetAr 1 is 2-oxopyridin-l(2H)-yl optionally substituted with halogen;
• one or two of D 1 , D 2 and D 3 is N, the remainder being CH;
• each R c is independently selected from halogen, CF 3 , (l-6C)alkyl, -0(1 -6C alkyl), cyclopropyl, -0-(CH 2 CH 2 )OMe, -S(I -6C alkyl), di(l-6C alkyl)amino, and a 5-6 membered azacycle;
• Ar is phenyl optionally substituted with one or more R d substituents
• each R d is independently selected from (l-6C)alkyl, -O(l-6C)alkyl, halogen,
• hetAr 2 is pyridyl optionally substituted with one or more substituents independently selected from CF 3 and -0(1 -6C alkyl);
• R 7a , R 7b and R 8 are independently H or methyl
• R 10 is H, Me or NH 2 .
• the present invention provides a compound of Formula I
• A is H, CN, Cl, F, cyclopropyl, (1-4 C) alkyl or OMe;
• a 1 is H, Cl, Br, F, cyclopropyl, (1-4 C) alkyl, or OMe;
• R 1 is -W-l ⁇ hetAr 1 ;
• W is -CONR 3a - or -NR 3b CO-;
• R 3a and R 3b are each H or methyl
• L 1 is -(CR a R b ) n -;
• n is 0 or 2;
• R a and R b are independently H, F, methyl, or cyclopropyl, or
• R a and R b together with the carbon to which they are attached form a cyclopropyl ring
• hetAr 1 is heteroaryl ring selected from the structures:
• hetAr 1 is a C-linked 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the ring is optionally substituted by 1-2 substituents independently selected from (1-4C) alkyl and phenyl which is optionally substituted with one or more substituents independently selected from halogen and OMe;
• one or two of D 1 , D 2 and D 3 is N, the remainder being CH;
• each R c is independently selected from halogen, CF 3 , (l-6C)alkyl, -0(1 -6C alkyl), cyclopropyl, -0-(CH 2 CH 2 )OMe, -S(1-6C alkyl) and di(l-6C alkyl)amino;
• Ar is phenyl optionally substituted with one or more R d substituents;
• each R d is independently selected from (l-6C)alkyl, -O(l-6C)alkyl, halogen,
• hetAr 2 is pyridyl optionally substituted with one or more substituents independently selected from CF 3 and -0(1 -6C alkyl);
• R 7a , R 7b and R 8 are independently H or methyl;
• R 10 is H, Me or NH 2 .
• Compounds according to the present invention have been found to be DP2 antagonists and are useful in the treatment of immunologic diseases such as asthma and allergic inflammation.
• immunologic diseases such as asthma and allergic inflammation.
• allergic inflammation includes asthma, atopic dermatitis, and allergic rhinitis, among other inflammatory diseases and disorders.
• 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 compound of Formula I is a racemic mixture.
• the compound of Formula I is an isolated enantiomer.
• the compounds of Formula I include pharmaceutically acceptable salts thereof. Examples of salts of Formula I include alkali metal salts, such as lithium, sodium or potassium salts, or alkaline earth metal salts, such as calcium salts. A particular example is a sodium salt of a compound of Formula I.
• the compounds of Formula I 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 enantiomers of compounds of Formula I.
• the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly any such solvate is included within the scope of the present invention.
• prodrugs of the compound of Formula I are also provided herein.
• a "prodrug" is a compound that may be converted under physiological conditions or by so lvo lysis to the specified compound or to a salt of such compound.
• the compounds of Formula I also include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds of the invention include compounds wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• (l-6C)alkyl and "(l-4C)alkyl” as used herein refer to a saturated linear or branched-chain monovalent hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, respectively.
• alkyl groups include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2 -methyl- 1 -propyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3- methyl-1 -butyl, 2 -methyl- 1 -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.
• O(l-6Calkyl) refers to a saturated linear or branched-chain monovalent hydrocarbon alkoxy radical of one to six carbon atoms, respectively, wherein the radical is on the oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
• halogen as used herein includes F, Cl, Br and I.
• W is -CONR 3a -.
• R 3a is hydrogen.
• W is -NR 3b CO-.
• R 3b is hydrogen.
• R 3b is methyl. Examples of particular values for W are CONH, NHCO and N(CH 3 )CO.
• L 1 is -(CR a R b ) n - where n is 0, that is, L 1 is a bond.
• L 1 is -(CR a R b ) n - where n is 2.
• R b are hydrogen. In one embodiment, R a and R b together with the carbon atom to which are attached form a cyclopropylidine ring. In one embodiment, R a and R b are attached to the same carbon. In other embodiments, R a and R b are attached to different carbon atoms. [0070] In one embodiment, L 1 is a group having the formula: j* [0071] In certain embodiment, L 1 is selected from a bond, -CH 2 CH 2 -,
• L 1 is selected from a bond, -CH 2 CH 2 -, and
• L 1 Particular values for L 1 are -CH 2 CH 2 - and -cyclopropylideneCH 2 -.
• hetAr 1 is a heteroaryl ring having the structure:
• D 1 , D 2 and D 3 are as defined herein.
• values for hetAr 1 include optionally substituted quinolinyl, isoquinolinyl, quinoxalinyl, and quinazolinyl rings.
• hetAr 1 is optionally substituted with one or more R c substituents independently selected from halogen, CF 3 , (1-6C) alkyl and -0(1 -6C alkyl).
• R c substituents include Cl, CF3, Me, and OMe.
• hetAr 1 is optionally substituted with one or two R c substituents.
• Particular values for hetAr 1 include the structures:
• hetAr 1 is a heteroaryl ring having the structure:
• hetAr 1 examples include pyridyl, pyridazinyl, pyrimidyl and pyrazinyl rings. In one embodiment, the hetAr 1 ring is optionally substituted with one or more R c substituents.
• R c substituents include Cl, CF 3 , tert-butyl, isobutyl, cyclopropyl,
• R c is selected from Cl, CF 3 , tert-butyl, isobutyl, cyclopropyl, -OMe, -OEt, -SC(CH 3 ) 3 , -NMe 2 and -OCH 2 CH 2 OMe.
• hetAr 1 is optionally substituted with one or two R c substituents.
• hetAr 1 is a heteroaryl ring having the structure:
• hetAr 1 examples include pyridyl, pyridazinyl, pyrimidyl and pyrazinyl rings. In one embodiment, hetAr 1 is optionally substituted with one or more R c substituents. Examples of R c substituents include halogen and (1-6C alkyl). Particular values of R c substituents include F and methyl.
• Ar is an unsubstituted phenyl.
• Ar is phenyl substituted with one or more R d substituents independently selected from (l-6C)alkyl, halogen, -O(1-6C alkyl), -S(1-6C alkyl), and CF 3 . Particular values include F, Cl CF 3 , OMe, Me, t-Bu and SMe.
• Ar is phenyl optionally substituted with 1-3 R d substituents.
• Ar examples include phenyl, trifluoromethylphenyl, fluorophenyl, methylphenyl, chlorophenyl, methoxyphenyl, chlorotrifluoromethylphenyl, fluorotrifluoromethylphenyl, dichlorophenyl, chloromethoxyphenyl, difluorophenyl, fluoromethylphenyl, tert-butylphenyl, chlorofluorophenyl, dimethylphenyl, methylsulfonylphenyl and methylthiophenyl.
• Ar include phenyl, 3 -trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-fluorophenyl, 3 -methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 4-methyoxyphenyl, 3-trifluoromethyl-4-chlorophenyl, 2,4- dichlorophenyl, 3,4-dichlorophenyl, 2-methoxy-4-chlorophenyl, 3,4-difluorophenyl, 2,4- difluorophenyl, 2,3-difluorophenyl, 3, 5 -difluorophenyl, 3-methyl-4-fluorophenyl, 4-tert- butylphenyl, 3-fluoro-4-chlorophenyl, 2-fluoro-4-chlorophenyl, 3-fluoro-4-methylphenyl, 2,3-dimethylphenyl
• values of hetAr 1 when m is 1 include any of the aforementioned structures with the exception of the following structure:
• hetAr 1 is a heteroaryl ring having the structure:
• heteroaryl ring is optionally substituted with one or more R c substituents.
• m is 0.
• m is 1.
• the hetAr 1 ring is optionally substituted with one to two R c substituents independently selected from halogen and CF 3 , for example Cl and CF 3 .
• hetAr 2 include pyridyl optionally substituted with one or more substituents independently selected from CF3, OMe and OEt.
• examples of hetAr 2 include pyridyl, methoxypyridyl, dimethoxypyridyl, and trifluoromethylpyridyl.
• Particular examples of hetAr 2 include pyridyl, 2-trifluoromethylpyrid-4-yl, 2-methoxypyrid-5-yl, and 2,6- dimethoxypyrid-4-yl.
• hetAr 1 is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the ring is optionally substituted with one or more substituents independently selected from (l-4C)alkyl and phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogen, -0(1- ⁇ Calkyl), (l-6C)alkyl and CF 3 .
• hetAr 1 is a C-linked 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the ring is optionally substituted by 1-2 substituents independently selected from (1-4C) alkyl and phenyl which is optionally substituted with one or more substituents independently selected from halogen and OMe.
• hetAr 1 is a nitrogen-linked 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the ring is optionally substituted by one or more substituents independently selected from (1-4C) alkyl and phenyl which is optionally substituted with one or more substituents independently selected from halogen and OMe.
• Examples of 5-membered heteroaryl rings include pyrrolyl, thiadiazolyl, thiazolyl, isoxazolyl, oxazolyl, and pyrazolyl rings.
• the 5-membered heteroaryl ring is a thiadiazolyl, thiazolyl, isoxazolyl, oxazolyl, or a pyrazolyl ring.
• the 5 membered heteroaryl ring is optionally substituted with one or two substituents independently selected from methyl, ethyl, isopropyl, t-butyl, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, fluorochlorophenyl, dichlorophenyl, methoxyphenyl, methylphenyl and trifluoromethylphenyl.
• the 5 membered heteroaryl ring is optionally substituted with 1-2 substituents independently selected from methyl, ethyl, isopropyl, t- butyl, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, fluorochlorophenyl, dichlorophenyl, and methoxyphenyl.
• hetAr 1 is represented by any of the aforementioned 5- membered heteroaryl rings with the exception of the following structures:
• hetAr 1 is a 5,6-bicyclic heteroaryl having two ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein said ring is optionally substituted with one or more substituents independently selected from -0(l-6Calkyl), (l-6C)alkyl, halogen and CF 3 .
• the 5,6-bicyclic heteroaryl is a 5-membered heteroaryl ring fused to a benzo ring, wherein the 5-membered heteroaryl ring has two ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the bicyclic ring is optionally substituted.
• the bicyclic ring is optionally substituted with one or more substituents independently selected from methyl, CF 3 , F, Cl and methoxy.
• hetAr 1 when represented by a 5,6-bicyclic heteroaryl include the structures:
• hetAr 1 is 2-oxopyridin-l(2H)-yl optionally substituted with halogen, for example chloro.
• halogen for example chloro.
• a particular example of hetAr 1 is the structure:
• A is hydrogen
• A is Cl.
• A is CN
• A is cyclopropyl
• A is F.
• A is (1-3 C) alkyl.
• a particular example is methyl
• A is OMe
• A is CN, Cl, or cyclopropyl.
• a 1 is hydrogen
• a 1 is Cl. [00122] In one embodiment, A 1 is Br.
• a 1 is cyclopropyl
• a 1 is F.
• a 1 is OMe.
• a 1 is H, cyclopropyl, Br, or Cl.
• A is CN, Cl, or cyclopropyl and A 1 is H, cyclopropyl, Br, or CL
• R 7a and R 7b are each hydrogen.
• R 8 is hydrogen
• R 10 is hydrogen
• R 10 is hydrogen
• R 10 is Me.
• R 10 is NH 2 .
• the present invention provides a process for the preparation a compound of Formula I or a pharmaceutically acceptable salt thereof, which comprises:
• E is an electron withdrawing group and Z 2 is a leaving atom, in the presence of a base, and if desired removing said electron withdrawing group; or [00141] (c) for a compound of Formula I in which A is H, Cl, (1-4C alkyl) or cyclopropyl and A 1 is (1-4C alkyl), Cl, Br or cyclopropyl, coupling a corresponding compound having the formula (VI)
• 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 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 tertiary amine, such as triethylamine or N 5 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.
• Compounds of formula (lib) wherein R 8 is Me can be prepared by reacting a corresponding compound of formula (lib) wherein R 8 is H with methyl iodide in the presence of a suitable base, such as an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate or cesium carbonate) or an alkali metal hydride (e.g., sodium hydride).
• a suitable base such as an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate or cesium carbonate) or an alkali metal hydride (e.g., sodium hydride).
• a suitable base for example an amine base such as pyrrolidine.
• the reaction is conveniently preformed at elevated temperatures, such as between 50-100 0 C, for example 80 0 C.
• examples of leaving atoms include F, Cl, Br and I.
• electron withdrawing groups examples 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).
• a base for example an alkali metal hydroxide such as sodium hydroxide.
• suitable copper salts include copper (I) or copper (II) halides, for example copper (I) chloride.
• the copper salt can be used in catalytic, stoichiometric, or greater than stoichiometric amounts. In one embodiment, the reaction is performed using 2 equivalents of the copper salt.
• Suitable palladium catalysts include Pc(O) catalysts, for example Pd(PPh 3 ) 4 .
• Suitable ligands include 2,2,6,6-tetramethyl-3,5- heptanedione, pyridine-type ligands, or phosphine-type ligands. The ligand is suitably used in catalytic amounts.
• the base may be, for example, an alkali metal carbonate, such as cesium carbonate, sodium carbonate, or potassium carbonate.
• Appropriate solvents include aprotic solvents such as N-methylpyrrolidinone, dimethylformamide, dimethylacetamide or dimethyl sulfoxide.
• the reaction is conveniently performed at elevated temperatures, for example between 50 and 200 0 C, for example 100 0 C.
• the leaving atom can be, for example, a halogen, for example, bromide.
• An example of a leaving group is a triflate.
• Suitable palladium catalysts include Pd(PPtLs) 4 , or a palladium (II) catalyst in the presence of a ligand, for example Pd 2 dba 3 , Pd(OAc) 2 , or PdCl 2 in the presence of a ligand, for example a phosphine-type ligand.
• Suitable bases include alkali metal carbonates such as sodium carbonate, potassium carbonate or cesium carbonate.
• Suitable solvents include toluene or ethers (for example, THF or dioxane). The reaction is conveniently performed at temperatures ranging from ambient temperature to about 150 0 C, for example from ambient temperature to 110 0 C, for example 50- 100 0 C.
• the coupling of the compound of formula (VIII) with a compound of formula (IX) 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 halide, such as an acid chloride.
• a reactive derivative of a carboxylic acid for example an acid halide, 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 8 in which P 8 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", John Wiley & Sons, Inc.
• Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC).
• the leaving atom can be, for example, a halogen, for example, bromide.
• An example of a leaving group is a triflate.
• Suitable palladium catalysts include Pd(PPlIs) 4 , or a palladium (II) catalyst in the presence of a ligand, for example Pd 2 dba 3 , Pd(OAc) 2 , or PdCl 2 in the presence of a ligand, for example a phosphine-type ligand such as XPHOS (dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine) or triphenylphosphine.
• Suitable solvents include toluene or ethers (for example, THF or dioxane).
• suitable bases include inorganic bases, for example alkali metal phosphates, such as potassium phosphate.
• Suitable catalysts include palladium catalysts, such as Pd(II) catalysts, for example Pd(OAc) 2 in the presence of a suitable ligand.
• the ligand can be a phosphine ligand, such as tricyclohexylphosphine. 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).
• Suitable solvents include xylene and toluene. The reaction is conveniently performed at the reflux temperature of the solvent.
• L 1 is a -(CR a R b ) n - or [00186] n is 0 or 2; . [00187] R a and R b are independently H, F, methyl, or cyclopropyl, or
• hetAr 1 is heteroaryl ring selected from the structures:
• hetAr 1 is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein the ring is optionally substituted with one or more substituents independently selected from (l-4C)alkyl and phenyl which is optionally substituted with one or more substituents independently selected from halogen, -O(l-6Calkyl), (l-6C)alkyl and CF 3 ;
• hetAr 1 is a 5,6-bicyclic heteroaryl having two ring heteroatoms independently selected from N, O and S, wherein at least one of said heteroatoms is N, wherein said ring is optionally substituted with one or more substituents independently selected from -O(l-6Calkyl), (l-6C)alkyl, halogen and CF 3 ;
• hetAr 1 is 2-oxopyridin-l(2H)-yl optionally substituted with halogen;
• one or two of D 1 , D 2 and D 3 is N, the remainder being CH;
• D 4 , D 5 and D 6 are N, the remainder being CH;
• each R c is independently selected from halogen, CF 3 , (l-6C)alkyl, -0(1 -6C alkyl), cyclopropyl, -0-(CH 2 CH 2 )OMe, -S(I -6C alkyl), di(l-6C alkyl)amino, and a 5-6 membered azacycle;
• Ar is phenyl optionally substituted with one or more R d substituents
• each R d is independently selected from (l-6C)alkyl, -O(l-6C)alkyl, halogen, -
• hetAr 2 is pyridyl optionally substituted with one or more substituents independently selected from CF 3 and -0(1 -6C alkyl);
• R 7a , R 7b and R 8 are independently H or methyl
• R 10 is H, Me or NH 2 .
• the ability of test compounds to act as DP2 receptor inhibitors may be demonstrated by the assays described in Example A.
• Compounds which are inhibitors 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 .
• the compounds which are inhibitors of DP2 are useful in the treatment of diseases and disorders mediated by metabolites of PGD2 and other prostaglandins (and their corresponding metabolites) that may be acting via the DP2 receptor.
• treatment includes prophylaxis as well as treatment of an existing condition.
• compounds of the invention may be useful for treating inflammatory diseases and disorders.
• Compounds of the invention may also be useful for treating itching/pruritis.
• immunologic diseases include allergic inflammatory disease such as asthma, dermatitis, allergic rhinitis, urticaria, anaphylaxis, angioedema, allergies, contact hypersensitivity (e.g., nickel sensitivity), drug hypersensitivity, and allergic conjunctivitis in addition to inflammatory autoimmune diseases such as hyper-eosinophilic syndromes, psoriasis, systemic mast cell disorders, chronic obstructive pulmonary disease, inflammatory bowel disease, and arthritis.
• allergic inflammatory disease such as asthma, dermatitis, allergic rhinitis, urticaria, anaphylaxis, angioedema, allergies, contact hypersensitivity (e.g., nickel sensitivity), drug hypersensitivity, and allergic conjunctivitis in addition to inflammatory autoimmune diseases such as hyper-eosinophilic syndromes, psoriasis, systemic mast cell disorders, chronic obstructive pulmonary disease, inflammatory bowel disease, and arthritis.
• inflammatory autoimmune diseases such as hyper
• immunologic diseases include allergic inflammatory diseases, such as asthma, atopic dermatitis, allergic rhinitis, seasonal allergies, food allergies, contact hypersensitivity (e.g., nickel sensitivity), hyper-eosinophilic syndromes, and allergic conjunctivitis.
• allergic inflammatory diseases such as asthma, atopic dermatitis, allergic rhinitis, seasonal allergies, food allergies, contact hypersensitivity (e.g., nickel sensitivity), hyper-eosinophilic syndromes, and allergic conjunctivitis.
• allergic inflammatory diseases include asthma (including mild-to-moderate asthma, severe asthma, refractory asthma, steroid-resistant asthma, teroid- insensitive asthma, and exercise-induced asthma), allergies such as severe allergy/anaphylaxis, food allergies, plant allergies, drug allergies, latex allergy, allergic reactions to venomous stings, seasonal allergic rhinitis, and perennial allergic rhinitis, chronic rhinosinusitis, cystic fibrosis, eosinophilic diseases and disorders (including eosinophilic gastroenteritis, eosinophilic esophagitis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, pulmonary eosinophilia (Loeffler's Disease), eosinophilia-myalgia syndrome, Chrug-Strauss syndrome, eosinophilic fasciitis, familial eosinophilic cellulitis, cutaneous eos
• asthma including mild-
• allergic inflammatory diseases include severe allergy/anaphylaxis, eosinophilic gastroenteritis, eosinophilic esophagitis, severe asthma, refractory asthma, steroid-resistance asthma, allergic diseases of the gastrointestinal tract, celiac sprue, gluten enteropathy, gluten intolerance, acute hypersensitivy reaction, and delayed hypersensitivity reaction.
• 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
• Additional diseases or disorders which may be treated with compounds of this invention include inflammatory bowel diseases such as IgA deficiency, inflammatory dermatoses such as chronic urticaria, acute urticaria, seborrheic dermatitis, contact dermatitis, pemphigus, and exfoliative dermatitis (etythroderma), dermatitis herpetiformis, trichinosis, visceral larva migraines, trichuriasis, ascariasis, strongyloidiasis, hookworm infection, clonorchiasis, pragonimiasis, fascioliasis, cysticerosis, echinococcosis, f ⁇ lariasis, schistocomiasis, brucellosis, cat scratch fever, infectious lymphocytosis, acute coccidiodomycosis, infectious mononucleosis, mycobacterial disease, scarlet fever, tuberculosis, and cutaneous lupus
• 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.
• Another aspect of this invention provides a method of treating diseases or medical conditions in a mammal mediated by the DP2 receptor 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.
• Another aspect of this invention provides a method of treating diseases or medical conditions in a mammal involving the Th2 T cell via production of IL-4, IL-5 and/or IL- 13 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.
• Another aspect of this invention provides a method of treating diseases or medical conditions in a mammal involving the activation and trafficking of granulocytes (mast cell, eosinophil, neutrophil, basophil, etc.) 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.
• granulocytes mast cell, eosinophil, neutrophil, basophil, etc.
• phrases "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.
• the amount of a compound of Formula I 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.
• the compounds of the present invention can be used in combination with one or more additional drugs that work by the same or a different mechanism of action.
• anti-inflammatory compounds examples include steroids (e.g., dexamethasone, cortisone and fluticasone), NSAIDs (e.g., ibuprofen, indomethacin, and ketoprofen), anti-histamines, and anti-leukotrienes (e.g., Singulair®).
• steroids e.g., dexamethasone, cortisone and fluticasone
• NSAIDs e.g., ibuprofen, indomethacin, and ketoprofen
• anti-histamines e.g., Singulair®
• anti-leukotrienes e.g., Singulair®
• the compounds of the invention may be administered by any convenient route, e.g., by dermal application (i.e., topical application to the skin), transdermally, or into the gastrointestinal tract (e.g. rectally or orally), nose, lungs (e.g., via inhalation), musculature or vasculature.
• a compound of Formula I is administered topically to the skin or by inhalation.
• the compounds may be administered in any convenient administrative form, e.g., creams, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, and drug delivery devices such as patches, etc.
• Such compositions may 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
• 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 treat a PGU 2 -mediated condition, for example an immunologic disorder, as defined hereinabove.
• Particular compounds of the invention include:
• 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 in the presence of one or more of the following serum protein concentrations, 0.1% BSA, 1% HSA or 4% HSA, by the following procedure.
• Membranes (1.25 ⁇ g/well for 0.1% BSA and 6 ⁇ g/well for 1% or 4% HSA) 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 2 , 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; Millipore 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 ⁇ M unlabeled PGD 2 or 5 ⁇ M of a known DP2 antagonist.
• IC50 values for inhibition of binding were determined for each compound tested from the inflexion point of a standard 4-parameter logistical curve fitted to the values obtained.
• Compounds of the invention had IC50 values less than 5 micromolar in one or more of the binding assays.
• Certain compounds of the invention had IC 50 values less than 1 micromolar in one or more of the binding assays.
• Certain compounds of the invention had IC 50 values less than 0.5 micromolar in one or more of the binding assays.
• Certain compounds of the invention had IC50 values less than 0.25 micromolar in one or more of the binding assays.
• Step A Preparation of ethyl 6,8-dichloro-7-hydroxychroman-4-carboxylate:
• Step B Preparation of ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8- dichlorochroman-4-carboxylate : A mixture of ethyl 6,8-dichloro-7-hydroxychroman-4- carboxylate (2.50 g, 8.59 mmol), tert-butyl 4-fluoro-3-nitrobenzoate (2.20 g, 9.12 mmol) and potassium carbonate (1.8 g, 13 mmol) in 50 mL of NMP was degassed with argon for 10 minutes and was heated at 80 0 C overnight. After stirring overnight the reaction mixture was cooled to ambient temperature and diluted with 600 mL of water.
• Step C Preparation of ethyl 7-(2-amino-4-(tert-butoxycarbonvDphenoxy)-6,8- dichlorochroman-4-carboxylate : To a mixture of ethyl 7-(4-(tert-butoxycarbonyl)-2- nitrophenoxy)-6,8-dichlorochroman-4-carboxylate (2.70 g, 5.27 mmol) in 25 mL of THF and 25 mL of saturated ammonium chloride was added zinc dust (3.45 g, 52.7 mmol) under argon. After 1 hour at ambient temperature, the reaction was diluted with ethyl acetate and filtered.
• Step D Preparation of ethyl 7-(4-(tert-butoxycarbonvDphenoxy)-6,8- dichlorochroman-4-carboxylate : To a solution of ethyl 7-(2-amino-4-(tert- butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate (2.1 g, 4.4 mmol) in 20 niL of DMF at 70 0 C was added isobutyl nitrite (1.29 rnL, 10.9 mmol) dropwise over ten minutes. After an additional 15 minutes the reaction was cooled to ambient temperature and poured into 600 mL of water.
• Step E Preparation of 4-(6,8-dichloro-4-(ethoxycarbonyl)chroman-7- yloxy)benzoic acid: To a solution of ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6,8- dichlorochroman-4-carboxylate (1.85 g, 3.96 mmol) in 20 mL of DCM was added trifluoroacetic acid (10 mL). After stirring at ambient temperature for 1 hour, the mixture was concentrated to a sticky residue. The residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate and filtered.
• Step A Preparation of 3-chloro-l-(5-chloro-2,4-dihydroxyphenyl)propan-l- one: A 2-liter 4-neck round-bottom flask was charged with trifluoromethanesulfonic acid (500 g, 3.33 mol) and the flask contents were cooled below 10 0 C. 4-Chlororesorcinol (100 g, 0.69 mol) was added in portions over 20-30 minutes, maintaining the temperature at 4 to 8°C. The reaction mixture was stirred at or below 10 0 C until a clear solution formed (40 minutes).
• 3-Chloropropanoic acid (78.8 g, 0.73 mol) was warmed until melted and then added in liquid form dropwise over 45 minutes to the flask, maintaining the temperature at or below 10°C.
• the reaction mixture was stirred for an additional 10 minutes at or below 10 0 C, then slowly heated to 50-55 0 C and maintained there for 6 hours.
• the reaction mixture was cooled to ambient temperature and added dropwise to water (1.1 L) contained in a 3 -liter 4-neck round- bottom flask. The resulting mixture was stirred at ambient temperature for 30 minutes.
• Step B Preparation of 6-chloro-7-hvdroxychroman-4-one: A 20-liter 4-neck round-bottom flask was charged with water (10 L) and 3-chloro-l-(5-chloro-2,4- dihydroxyphenyl)propan-l-one (1.62 kg, 6.89 mol), and the resulting mixture was stirred and cooled to 10 0 C. A solution of sodium hydroxide (606.5 g, 15.16 mol) in water (2.96 L) was added dropwise over 40-60 minutes, maintaining the temperature at 10-15 0 C. The resulting mixture was stirred at ambient temperature for a further 30 minutes, then cooled to 5 0 C.
• Step C Preparation of 6-chloro-4,7-bis(trimethylsilyloxy)chroman-4- carbonitrile: (CAUTION: Hydrogen cyanide gas is produced in this reaction; take appropriate precautions).
• CAUTION Hydrogen cyanide gas is produced in this reaction; take appropriate precautions.
• a 20-liter 4-neck round-bottom flask was charged with dichloromethane (12.5 L), iodine (32 g, 0.13 mol) and 6-chloro-7-hydroxychroman-4-one (1.25 kg, 6.30 mol). The resulting mixture was stirred under nitrogen and cooled to 10 0 C. Trimethylsilyl cyanide (2.36 L, 18.88 mol) was added dropwise over 30 minutes, maintaining the temperature at or below 10 0 C.
• reaction mixture was stirred at ambient temperature for 10-11 hours, then cooled below 20 0 C.
• a solution of sodium thiosulfate (59.5 g, 0.38 mol) in water (500 mL) was added dropwise, maintaining the temperature below 20 0 C, and the resulting mixture was stirred for 20 minutes while maintaining the temperature below 20 0 C.
• Solid sodium sulfate anhydrous (3.75 kg) was added, and the resulting mixture was stirred for 30 minutes while maintaining the temperature below 20 0 C.
• the reaction mixture was filtered through a HyFloTM bed, and the bed was washed with dichloromethane.
• Step D Preparation of 6-chloro-7-hvdroxychroman-4-carboxylic acid: A 20- liter 4-neck round-bottom flask was charged with glacial acetic acid (2.04 L), 6-chloro-4,7- bis(trimethylsilyloxy)chroman-4-carbonitrile (2.2 kg, 5.94 mol), and tin(II) chloride dihydrate (3.35 kg, 14.85 mol) and the resulting mixture was stirred at ambient temperature.
• Step E Preparation of ethyl 6-chloro-7-hvdroxychroman-4-carboxylate: A 20- liter 4-neck round-bottom flask was charged with ethanol (8.6 L) and crude 6-chloro-7- hydroxychroman-4-carboxylic acid (1.70 kg, 7.44 mol) and the resulting mixture was stirred at ambient temperature. Concentrated sulfuric acid (397 mL) was added over 10 minutes. The resulting mixture was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (9.0 mL). The resulting mixture was washed with brine (2 x 12 L).
• Step F Preparation of ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6- chlorochroman-4-carboxylate : Tert-butyl 4-bromobenzoate (210.4 g, 818.2 mmol) was dissolved in 1 L of dioxane, which was previously degassed with argon, in a 4-neck 5 L round bottom flask equipped with a mechanical stirrer and a reflux condenser.
• Step G Preparation of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7- yloxy)benzoic acid: Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4- carboxylate (221 g, 0.511 mol) was dissolved in hydrogen chloride in ethyl acetate (2.4 N, 1.6 L, 3.84 mol) and the resulting solution was stirred at ambient temperature for 16 hours. The solution was concentrated to give 198 g of crude 4-(6-chloro-4- (ethoxycarbonyl)chroman-7-yloxy)-benzoic acid.
• Step A Preparation of 7-fluoro-4-(trimethylsilyloxy)chroman-4-carbonitrile :
• Step C Preparation of methyl 7-fluoro-3,4-dihydro-2H-chromene-4- carboxylate: 7-Fluoro-3,4-dihydro-2H-chromene-4-carboxylic acid (346 mg, 1.76 mmol) was diluted with THF (2 mL), methanol (2 mL) and 4 drops of sulfuric acid. The reaction was heated at 55°C and stirred for 12 hours. The reaction was cooled to ambient temperature, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated to yield the title compound (366 mg, 98.7% yield).
• Step D Preparation of methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4- carboxylate: Methyl 7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (336 mg, 1.60 mmol) was diluted with DMF (5 mL) followed by the addition of N-bromosuccinimide (313 mg, 1.76 mmol). The reaction was heated at 50 0 C and stirred for 2.5 hours. The reaction was cooled, diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The material was purified by silica gel chromatography using a Biotage 4OM cartridge (gradient 5% ethyl acetate/hexane) to 50% to yield the title compound (415 mg, 89.8% yield).
• Step E Preparation of methyl 6-cvano-7-fluorochroman-4-carboxylate:
• Methyl 6-bromo-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (415 mg, 1.44 mmol) was diluted with N-methylpyrrolidone (5 mL) followed by the addition of Cu(I)CN (643 mg, 7.18 mmol). The reaction was bubbled with argon for 20 minutes, then heated at 160 0 C under a slight argon bubble for 6 hours. The reaction was cooled to ambient temperature and loaded directly onto a Biotage 25 column (silica gel), eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (260 mg, 77.0% yield).
• Step F Preparation of methyl 7-(4-carbamoylphenoxy)-6- cyanochroman-4-carboxylate : Methyl 6-cyano-7-fluorochroman-4-carboxylate (300 mg, 1.28 mmol), 4-hydroxybenzamide (227 mg, 1.66 mmol) and potassium carbonate (423 mg, 3.06 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 110 0 C for 12 hours.
• Step G Preparation of 7-(4-((5-(trifluoromethv0pyridin-2-v0carbamovQ phenoxy)-6-cyanochroman-4-carboxylate: Methyl 7-(4-carbamoylphenoxy)-6- cyanochroman-4-carboxylate (58 mg, 0.17 mmol), 2-chloro-5-(trifluoromethyl)pyridine (0.021 mL, 0.17 mmol), cesium carbonate (75 mg, 0.23 mmol), (R)-(-)-l-[(S)-2- (dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (4.6 mg, 0.0083 mmol) and palladium(II) acetate (1.9 mg, 0.0083 mmol) were diluted with DME (1 mL).
• the reaction was heated to 90 0 C and stirred for 5 hours.
• the reaction was loaded directly onto a biotage 25 cartridge (silica gel), eluting with 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes to afford methyl 7-(4-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenoxy)-6- cyanochroman-4-carboxylate (9 mg, 11% yield) as a white solid.
• Step F Preparation of 7-(4-((5-(trifluoromethv0pyridin-2-v0carbamov0 phenoxy)-6-cvanochroman-4-carboxylic acid: Methyl 7-(4-((5-(trifluoromethyl)pyridin-2- yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (9 mg, 0.018 mmol) was diluted with THF (500 ⁇ L) followed by the addition of sodium hydroxide (0.11 mL, 0.11 mmol) and methanol (100 ⁇ L). After stirring for 2 hours, the reaction was diluted with ethyl acetate and IN HCl.
• Step A Preparation of 6-cvano-7-fluoro-3,4-dihydro-2H-chromene-4- carboxylic acid: Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (3.3g, 14.0 mmol) and LiOH-H 2 O (5.89 g, 140 mmol) were stirred together in THF (25 mL) and water (25 mL) at ambient temperature for 1 hour. The reaction was diluted with ether and water, and filtered to remove undissolved solids. The filtrate was collected and the aqueous layer was washed with additional ether.
• Step B Preparation of tert-butyl 6-cvano-7-fluoro-3,4-dihydro-2H-chromene-
• Step C Preparation of tert-Butyl 7-(4-carbamoylphenoxy)-6-cvanochroman-
• 4-carboxylate tert-butyl 6-cyano-7-fluorochroman-4-carboxylate (290 mg, 1.05 mmol), 4- hydroxybenzamide (172 mg, 1.25 mmol) and potassium carbonate (347 mg, 2.51 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 120 0 C for 12 hours under a slight argon bubble. The reaction was cooled and loaded directly onto a biotage 40 M cartridge, eluting with 20% ethyl acetate/hexanes to 100% ethyl acetate to yield 1 g of the crude product which was found to contain NMP.
• Step D Preparation of tert-butyl 7-(4-(5-chloropyridin-2- ylcarbamoyl)phenoxy)-6-cvanochroman-4-carboxylate: tert-Butyl 7-(4-carbamoylphenoxy)- 6-cyanochroman-4-carboxylate (30 mg, 0.076 mmol), 2,5-dichloropyridine (12 mg, 0.084 mmol), XPHOS (7.3 mg, 0.015 mmol), palladium (II) acetate (1.7 mg, 0.0076 mmol) and cesium carbonate (62 mg, 0.19 mmol) were diluted with dioxane (600 ⁇ L) in a 1 mL vial.
• the reaction was purged with argon for 3 minutes, capped and heated at 80 0 C for 12 hours.
• the reaction was cooled and loaded directly onto a biotage 25 column and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield tert-butyl 7-(4-(5-chloropyridin- 2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (5 mg, 0.0099 mmol, 13 % yield).
• Step A Preparation of methyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6- cyanochroman-4-carboxylate : To methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4- carboxylate (3.04 g, 12.9 mmol), tert-butyl 4-hydroxybenzoate (3.10 g, 16.0 mmol) and potassium carbonate (4.47 g, 32.3 mmol) in 20 mL of NMP was added oven dried powdered 4 Angstrom sieves (2.5 gm), the reaction was degassed with argon for 15 minutes then heated at 110 0 C overnight.
• the reaction was diluted with ethyl acetate and water.
• the organic layer was dried, concentrated and the residue flashed with 4:1 hexanes/ethyl acetate to 3:1 hexanes/ethyl acetate to provide the desired product (2.3 g, 44%).
• Step B Preparation of 4-(6-cvano-4-(methoxycarbonyl)chroman-7- yloxy)benzoic acid: Methyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-cyanochroman-4- carboxylate (350 mg, 0.855 mmol) was diluted with dichloromethane (2 mL) and treated with TFA (2 mL). After stirring for 3 hours, the reaction was concentrated.
• the crude material was purified using a biotage 4OM cartridge eluting with 0.5% methanol/dichloromethane to 10%methanol/dichloromethane to yield 4-(6-cyano-4-(methoxycarbonyl)chroman-7- yloxy)benzoic acid (280 mg, 92.7% yield).
• Step C Preparation of methyl 7-(4-((6-(trifluoromethv0pyridin-3- yl)carbamoyl)phenoxy)-6-cvanochroman-4-carboxylate: 4-(6-cyano-4-(methoxycarbonyl) chroman-7-yloxy)benzoic acid (100 mg, 0.283 mmol) was diluted with dichloromethane (1 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (0.156 mL, 0.311 mmol) and 1 drop of DMF.
• Step D Preparation of 7-(4-((6-(trifluoromethv0pyridin-3- yl)carbamoyl)phenoxy)-6-cvanochroman-4-carboxylic acid: Methyl 7-(4-((6-
• Step A Preparation of methyl 6-cyano-7-(4-(8-methoxyquinolin-3- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Dissolved 4-(6-cyano-4-
• Step B Preparation of 6-cvano-7-(4-(8-methoxyquinolin-3- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a solution of methyl 6-cyano-7-(4-(8- methoxyquinolin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.061 g, 0.120 mmol) in THF (2 mL) was added LiOH-H 2 O (0.239 mL, 0.239 mmol) and added a few drops of methanol to ensure a homogeneous solution. The reaction was stirred at ambient temperature for 3 hours.
• Step A Preparation of methyl 7-(4-(6-bromopyridin-2- ylcarbamoyl)phenoxy)-6-cvanochroman-4-carboxylate: To a solution of 4-(6-cyano-4- (methoxycarbonyl)chroman-7-yloxy)benzoic acid (1.00 g, 2.83 mmol) and a drop of DMF in DCE (10 ml) was added oxalyl chloride in dichloromethane (2M) (1.55 mL, 3.11 mmol).
• Step B Preparation of methyl 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-
• 2-ylcarbamoyl)phenoxy)chroman-4-carboxylate A vial was charged with methyl 7-(4-(6- bromopyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (51 mg, 0.100 mmol), 3,4-dimethylphenylboronic acid (19.5 mg, 0.130 mmol), Na 2 CO 3 (31.9 mg, 0.300 mmol), toluene (1 mL) and water (0.1 mL). The mixture was degassed with Argon for few minutes, and then Pd(PPh 3 ) 4 (5.8 mg, 0.005 mmol) was added. The vial was sealed and heated at 100 0 C for 16 hours.
• Step C Preparation of 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: A mixture of methyl 6-cyano-7-(4-(6- (3 ,4-dimethylphenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (51.1 mg, 0.096 mmol), LiOH-H 2 O-IM-H 2 O (191.5 ⁇ L, 0.1915 mmol), and THF (1.5 mL) was stirred at ambient temperature for 3 days.
• Step A Preparation of methyl 7-(4-(tert-butoxycarbonyl)-2-methylphenoxy)-
• 6-cyanochroman-4-carboxylate Methyl 6-cyano-7-fluorochroman-4-carboxylate (0.200 g, 0.850 mmol), tert-butyl 4-hydroxy-3-methylbenzoate (0.195 g, 0.935 mmol) and potassium carbonate (0.141 g, 1.02 mmol) were dissolved in 4 mL of dry DMSO and degassed with argon. The solution was heated in a microwave oven at 150 0 C for 15 minutes, then at 170 0 C for 15 additional minutes.
• the reaction was poured into 10% HCl/water (IL), extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to a yellow film.
• the crude product was adsorbed onto silica gel and purified by column using 20-30% ethyl acetate/hexanes to provide the desired product (0.133 g, 37%) as a light yellow foam.
• Step B Preparation of 4-(6-cvano-4-(methoxycarbonyl)chroman-7-yloxy)-3- methylbenzoic acid: Methyl 7-(4-(tert-butoxycarbonyl)-2-methylphenoxy)-6-cyanochroman- 4-carboxylate was taken up in dichloromethane (10 mL). To the solution was added 2 ml TFA and the solution was stirred at ambient temperature for 2 hours. The reaction was concentrated and the crude material was purified over silica gel, eluting with 2-3% methanol/dichloromethane, to provide the desired product (0.103 g, 89%). [00507] Step C: Preparation of methyl 6-cyano-7-(2-methyl-4-(6-
• 6-(Trifluoromethyl)pyridin-3 -amine (0.136 g, 0.841 mmol), pyridine (0.0567 mL, 0.701 mmol) and DMAP (0.0034 g, 0.0280 mmol) were added and the solution was stirred at ambient temperature overnight.
• the reaction was poured into water, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated.
• the crude material was purified by silica gel column chromatography, eluting with 30-50% ethyl acetate/hexanes, followed by a second silica gel chromatography eluting with 30% acetone/hexanes to provide the desired product (0.097 g, 68%).
• Step D Preparation of 6-cvano-7-(2-methyl-4-(6-(trifluoromethyl)pyridin-3- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a solution of methyl 6-cyano-7-(2- methyl-4-(6-(trifluoromethyl)pyridin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.097 g, 0.190 mmol) in 2 mL of THF containing 200 ⁇ L methanol was added LiOH-H 2 O (0.379 niL, 0.379 mmol) and the solution was stirred at ambient temperature for 12 hours.
• Step A Preparation of 3-chloro-l-(5-chloro-2,4-dihydroxyphenyl)propan-l- one: A solution of 4-chlorobenzene-l,3-diol (100 g, 692 mmol) and 3-chloropropanoic acid (75.1 g, 692 mmol) in trifluoromethanesulfonic acid (295 mL) was stirred at 75 0 C for 30 minutes. The reaction was cooled to ambient temperature and slowly poured into a 2L beaker filled with ice. To the slurry was added ethyl acetate (1200 mL) with stirring until all solids dissolved.
• the mixture was poured into a separatory funnel, the aqueous layer was removed and the organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated.
• the crude material was purified by silica gel column chromatography eluting with a solvent system mixture of 15% ethyl acetate/hexanes to provide the desired product (162.6 g, 86%).
• Step B Preparation of 6-chloro-7-hvdroxychroman-4-one: 3-Chloro-l-(5- chloro-2,4-dihydroxyphenyl)propan-l-one (140 g, 596 mmol) was dissolved in a 2M aqueous NaOH solution (2085 mL) at 0 0 C, and then the reaction was warmed to ambient temperature over 2 hours. The reaction was acidified by the addition of 6M H 2 SO 4 to a pH of ⁇ 2. The resulting solids were removed by filtration and dried under high vacuum. The resulting solid was dissolved in THF (600 mL) and washed with water. The organic layer and was dried over magnesium sulfate, filtered, and concentrated.
• Step C Preparation of 6-chloro-7-hydroxy-4-(trimethylsilyloxy)chroman-4- carbonitrile: To a solution of 6-chloro-7-hydroxychroman-4-one (85.7 g, 432 mmol) in trimethylsilanecarbonitrile (134 mL, 1008 mmol) was added zinc(II) iodide (6.89 g, 21.6 mmol). The reaction began to warm and was cooled with an ice bath as necessary.
• Step D Preparation of 6-chloro-7-hvdroxychroman-4-carboxylic acid: A solution of 6-chloro-7-hydroxy-4-(trimethylsilyloxy)chroman-4-carbonitrile (129 g, 433 mmol) and SnCl 2 dihydrate (293 g, 1299 mmol) in concentrated HCl (435 mL) and glacial acetic acid (435 mL) was heated to 125°C and stirred for 12 hours. The reaction was taken up in ethyl acetate (500 mL) and washed with water, dried over magnesium sulfate, filtered and concentrated to provide the desired product (99 g, 100%).
• Step E Preparation of 6-chloro-7-hvdroxychroman-4-carboxylate: To a solution of 6-chloro-7-hydroxychroman-4-carboxylic acid (99 g, 433 mmol) in ethanol (650 mL) was added sulfuric acid (1.2 mL) and the reaction was stirred at 60 0 C for 24 hours. The reaction was cooled to ambient temperature and the resulting solids were removed by filtration and discarded. The filtrate was diluted with ethyl acetate (700 mL), washed with water, dried over magnesium sulfate and concentrated.
• the crude material was purified by silica gel column chromatography eluting with a solvent system of 20% ethyl acetate/hexanes to give ethyl 6-chloro-7-hydroxychroman-4-carboxylate (46 g, 41%).
• Step F Preparation of ethyl 7-(4-carbamoyl-2-nitrophenoxy)-6- chlorochroman-4-carboxylate : To a stirred solution of ethyl 6-chloro-7-hydroxychroman-4- carboxylate (6.40 g, 24.9 mmol) and 4-chloro-3-nitrobenzamide in N,N'-dimethylformamide (75 mL) at ambient temperature was added potassium carbonate (8.61 g, 62.3 mmol). An argon balloon with purge valve was attached, and the stirred mixture was evacuated and purged 5 times with argon. The mixture was stirred in an oil bath at 90 0 C under argon.
• Step G Preparation of ethyl 7-(2-amino-4-carbamoylphenoxy)-6- chlorochroman-4-carboxylate : To a stirred solution of ethyl 7-(4-carbamoyl-2- nitrophenoxy)-6-chlorochroman-4-carboxylate (7.74 g, 18.4 mmol) in THF (130 rnL) at ambient temperature was added zinc dust followed by saturated ammonium chloride solution (50 mL). The resulting mixture was stirred at ambient temperature. After 30 minutes the reaction was filtered through a glass microfibre filter and the insoluble material was washed twice with THF.
• Step F Preparation of ethyl 7-(4-carbamoylphenoxy)-6-chlorochroman-4- carboxylate: To a solution of isobutyl nitrite (3.92 g, 15.2 mmol) in DMF (100 mL) at 66°C was added a solution of ethyl 7-(2-amino-4-carbamoylphenoxy)-6-chlorochroman-4- carboxylate (5.94 g, 15.2 mmol) in DMF (30 mL) dropwise over 14 minutes. The temperature rose to 70 0 C during the addition and gas began to evolve.
• Step G Preparation of ethyl 6-chloro-7-(4-(6-chloroquinoxalin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Ethyl 7-(4-carbamoylphenoxy)-6- chlorochroman-4-carboxylate (750 mg, 2.00 mmol), 2,6-dichloroquinoxaline (437 mg, 2.20 mmol), XPHOS (95.1 mg, 0.200 mmol), Pd(OAc) 2 (22.4 mg, 0.0998 mmol) and cesium carbonate (1626 mg, 4.99 mmol) were diluted with dioxane (6 mL) in a vial.
• the reaction was purged with argon for 3 minutes, capped and heated at 80 0 C for 12 hours.
• the reaction was cooled and loaded directly onto a biotage 25 column (silica gel) and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(6- chloroquinoxalin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (540 mg, 1.00 mmol, 50.3 % yield).
• Step H Preparation of 6-chloro-7-(4-(6-chloroquinoxalin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Ethyl 6-chloro-7-(4-(6-chloroquinoxalin- 2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (540 mg, 1.00 mmol) was diluted with THF (8 mL) followed by the addition of NaOH (5015 ⁇ L, 5.02 mmol) and ethanol (4 mL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5 M HCl.
• Step A Preparation of ethyl 7-(4-(tert-butoxycarbonvDphenoxy)-6- chlorochroman-4-carboxylate : tert-Butyl 4-iodobenzoate (25.9 g, 85.2 mmol) and 2,2,6,6- tetramethyl-3,5-heptanedione (7.01 mL, 34.1 mmol) were diluted with NMP (70 mL) and bubbled with Argon for 20 minutes.
• the crude material was purified by silica gel column chromatography, eluting with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to provide the desired product (14 g, 32.3 mmol, 38.0 % yield) as a viscous oil.
• Step B Preparation of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7- yloxy)benzoic acid: Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4- carboxylate (8.62 g, 19.91 mmol) was diluted with DCM (40 mL) followed by portionwise addition of TFA (30 mL). After stirring for 1 hour, the reaction was concentrated and placed under vacuum over the weekend. The residue was taken up in DCM and washed with saturated bicarbonate and IN HCl.
• Step C Preparation of 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: 4-(6-Chloro-4-(ethoxycarbonyl)chroman-7- yloxy)benzoic acid (1.00 g, 2.65 mmol) was diluted with DCE (10 mL) followed by the addition of oxalyl chloride in DCM (2M) (1.46 mL, 2.92 mmol) and DMF (1 drop).
• Step D Preparation of 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To ethyl 6-chloro-7-(4-(6-chloroquinolin- 2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (1.31 g, 2.44 mmol) in THF (12 mL) and ethanol (6 mL) was added NaOH (6.09 mL, 12.2 mmol) and the reaction stirred at ambient temperature for 3 hours. The reaction was diluted with ethyl acetate (25 mL) and IN aqueous HCl (20 mL).
• Step A Preparation of ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-
• 6-chlorochroman-4-carboxylate 4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (1 g, 2.65 mmol) was diluted with DCM (10 mL) followed by the addition of oxalyl chloride in DCM (2M) (1.46 mL, 2.92 mmol) and DMF (1 drop). After stirring for 20 minutes, 6-bromopyridin-2-amine (0.505 g, 2.92 mmol) and DIEA (1.16 mL, 6.64 mmol) were added and the reaction was stirred overnight at ambient temperature. The reaction was loaded directly onto a biotage 40 cartridge and eluted with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to provide the desired product.
• Step B Preparation of 6-chloro-7-(4-(6-(4-chlorophenv0pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Ethyl 7-(4-(6-bromopyridin-2- ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4- chlorophenylboronic acid (19 mg, 0.12 mmol), Na 2 CO 3 (30 mg, 0.28 mmol) and Pd(PPh 3 ) 4 (11 mg, 0.0094 mmol) were place in a 1 mL vial and diluted with toluene (600 ⁇ L) and water (60 ⁇ L).
• the vial was purged with argon, sealed and heated to 100 0 C. After stirring for 12 hours, the reaction was cooled and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes to provide the desired product (40 mg, 0.071 mmol, 76 % yield).
• Step A Preparation of tert-butyl 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: To 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.980 g, 1.924 mmol) suspended in toluene (2 mL) was added N,N-dimethylformamide di-tert-butyl acetal (4.613 mL, 19.24 mmol) and the reaction heated to 60 0 C for 2 hours under a positive pressure of nitrogen.
• the reaction was cooled and diluted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over magnesium sulfate and concentrated. The resulting oil was loaded onto a silica gel samplet with DCM and the product eluted using a gradient of 5% to 40% ethyl acetate/hexanes to provide racemic tert-butyl 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.91 g, 1.609 mmol, 83.64 % yield) as a foam.
• the enantiomers were separated by column chromatography using a cellulose tris(4- methylbenzoate) coated silica gel column (OJ column, 20 mm x 250 mm; Chiral Technologies, West Chester, PA), eluting with 75% acetonitrile/25% methanol.
• Step B Preparation of 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid, Enantiomer 1 : To a solution of racemic tert-butyl 6-chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate, Enantiomer 1 (0.068 g, 0.12 mmol) in 2 mL of DCM was added 0.5 mL of TFA and the reaction was allowed to stand at ambient temperature. After stirring for 3 hours, the reaction was concentrated to a solid and taken up in 3 mL of DCM.
• Enantiomer 1 (0.061 g, 98%) as an off white powder.
• Step A Preparation of tert-butyl 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: To 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.980 g, 1.924 mmol) suspended in toluene (2 mL) was added N,N-dimethylformamide di-tert-butyl acetal (4.613 mL, 19.24 mmol) and the reaction heated to 60 0 C for 2 hours under a positive pressure of nitrogen.
• the reaction was cooled and diluted with ethyl acetate (30 mL). The organic layer was washed with water and brine. The organic layer was separated, dried over magnesium sulfate and concentrated. The resulting oil was loaded onto a silica gel samplet with DCM and the product eluted using a gradient of 5% to 40% ethyl acetate/hexanes to provide racemic tert- butyl 6-chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.91 g, 1.609 mmol, 83.64 %) as a foam.
• the enantiomers were separated by column chromatography using a cellulose tris(4-methylbenzoate) coated silica gel column (OJ column, 20 mm x 250 mm; Chiral Technologies, West Chester, PA), eluting with 75% acetonitrile/25% methanol.
• Step B Preparation of 6-chloro-7-(4-(6-chloroquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid, Enantiomer 2: To a solution of racemic tert-butyl 6-chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate, Enantiomer 2 (0.087 g, 0.015 mmol) in 2 mL of DCM was added 0.5 mL of TFA and the reaction was allowed to stand at ambient temperature. After stirring for 3 hours, the reaction was concentrated to a solid and taken up in 3 rnL of DCM.
• Step A Preparation of methyl 6-cvano-7-(4-(2-(5-(trifluoromethv0pyridin-2- yDethylcarbamoyl) phenoxy)chroman-4-carboxylate : A mixture of 4-(6-cyano-4- (methoxycarbonyl)chroman-7-yloxy)benzoic acid (20 mg, 0.0566 mmol), l-(3- (dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (12.85 mg, 0.0670 mmol), 1- hydroxybenzotriazole monohydrate (10.26 mg, 0.0670 mmol), and 1 ,2-dichloroethane (ImL) was stirred at ambient temperature for 20 minutes.
• Step B Preparation of 6-cvano-7-(4-(2-(5-(trifluoromethv0pyridin-2- yDethylcarbamoyl) phenoxy)chroman-4-carboxylic acid: Methyl 6-cyano-7-(4-(2-(5- (trifluoromethyl)-pyridin-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (14.2 mg, 0.0270 mmol) was dissolved in THF (3 mL) and IM solution of lithium hydroxide monohydrate in water (54.0 ⁇ l, 0.0540 mmol) was added.
• Step A Preparation of methyl 7-(4-(6-bromopyridin-2- ylcarbamoyl)phenoxy)-6-cvanochroman-4-carboxylate: To a solution of 4-(6-cyano-4- (methoxycarbonyl)chroman-7-yloxy)benzoic acid (1.00 g, 2.83 mmol) and a drop of DMF in 1 ,2-dichloroethane (10 mL) was added 2 M solution of oxalyl chloride in dichloromethane (1.556 ml, 3.113 mmol) and the mixture was stirred at ambient temperature for 1 hour. Gas evolution was observed.
• Step B Preparation of methyl 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-
• Step C Preparation of 6-cyano-7-(4-(6-(3,4-dimethylphenyl)pyridin-2- ylcarbamovDphenoxy) chroman-4-carboxylic acid: A mixture of methyl 6-cyano-7-(4-(6- (3 ,4-dimethylphenyl)pyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylate (51.1 mg, 0.09577 mmol), 1.0 M lithium hydroxide monohydrate solution in water (191.5 ⁇ l, 0.1915 mmol), and THF (1.5 ml) was stirred for 3 days at ambient temperature.
• Step A Preparation of 2-(4-chlorophenyl)-3-fluoropyridine: 2-Chloro-3- fluoropyridine (0.4380 g, 3.33 mmol), 4-chlorophenylboronic acid (0.6248 g, 3.996 mmol), palladium tetrakistriphenylphosphine (0.1924 g, 0.1665 mmol), sodium carbonate (0.4235 g, 3.996 mmol), toluene (10 mL), and water (1 mL) were placed in a teflon lined vial. The vial was sealed and stirred at 125 0 C for 21 hour. The mixture was cooled to ambient temperature and the whole mixture was purified on silica gel (EtOAc-hexanes gradient) to provide 569.4 mg of the title compound as white solid (82%).
• Step B Preparation of 2-(4-chlorophenvO-3-fluoropyridine 1 -oxide: To a solution of 2-(4-chlorophenyl)-3-fluoropyridine (208mg, 1.0018 mmol) in dichloromethane ( 3mL) was added 3-chloroperbenzoic acid (370.44 mg, 1.5027 mmol, 70%) in one portion and the mixture was stirred at ambient temperature for 4 days.
• Step C Preparation of 6-chloro-2-(4-chlorophenyl)-3-fluoropyridine: A mixture of 2-(4-chlorophenyl)-3-fluoropyridine 1 -oxide (79.5 mg, 0.3555 mmol) and phosphorus oxychloride (5 ml, 54.620 mmol) was heated under reflux for 20 hours under nitrogen atmosphere. The mixture was cooled to ambient temperature and concentrated.
• Step F Preparation of Sodium 6-chloro-7-(4-(6-(4-chlorophenylV5- fluoropyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylate: 6-Chloro-7-(4-(6-(4- chlorophenyl)-5 -fluoropyridin-2-ylcarbamoyl)phenoxy)-chroman-4-carboxylic acid (16.1 mg, 0.0291 mmol) was dissolved in MeOH-THF (0.5 mL-0.5 mL) and 0.5 M sodium methoxide solution in methanol (58.19 ⁇ l, 0.0291 mmol) was added.
• Step A Preparation of ethyl 7-(4-carbamoylphenoxy)-6-chlorochroman-4- carboxylate: To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 2.46 g, 6.529 mmol) in dichloromethane (32 ml) was added DMF (2 drops) and oxalyl chloride (0.6835 ml, 7.835 mmol). The reaction was stirred for 90 minutes. To this, anhydrous ammonia gas was bubbled into the reaction for 90 minutes.
• Step B Preparation of 8-methylquinoline 1 -oxide: To a solution of 8- methylquinoline (1.00 g, 6.98 mmol) in DCM (21 ml) was added 3-chlorobenzoperoxoic acid (2.35 g, 10.5 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with 20% sodium sulfite, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on the silica gel eluting with a gradient of 1-10% MeOH/DCM to yield the desired compound (0.440 g, 2.76 mmol, 39.6 % yield).
• Step C Preparation of 2-chloro-8-methylquinoline: To a solution of 8- methylquinoline 1-oxide (0.440 g, 2.764 mmol) in toluene (10 ml) was added phosphoryl trichloride (1.265 ml, 13.82 mmol), and the reaction was heated to 80 0 C for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude material was taken up in EtOAc and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.4 g, 2.252 mmol, 81.47 % yield).
• Step D Preparation of ethyl 6-chloro-7-(4-(8-methylquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: To a solution of ethyl 7-(4- carbamoylphenoxy)-6-chlorochroman-4-carboxylate (0.025 g, 0.0665 mmol), 2-chloro-8- methylquinoline (0.0130 g, 0.0732 mmol), X-PHOS (0.0238 g, 0.0732 mmol), and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.00634 g, 0.0133 mmol) in THF (0.6 ml) was added tris(dibenzylideneacetone)dipalladium (0.0030 g, 0.0033 mmol), and the reaction was heated to 60 0 C for 16 hours.
• Step E Preparation of 6-chloro-7-(4-(8-methylquinolin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a solution of ethyl 6-chloro-7-(4-(8- methylquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.024 g, 0.0464 mmol) in 3:1 THF/MeOH (1 ml) was added IM sodium hydroxide (0.0511 ml, 0.0511 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated to dryness and acidified with diluted hydrochloric acid.
• Step A Preparation of ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6- chlorochroman-4-carboxylate : To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7- yloxy)benzoic acid (Preparation B; 1.00 g, 2.654 mmol) in dichloroethane (2.6 ml) and DMF (1 drop) was added oxalyl chloride (0.2778 ml, 3.185 mmol), and the reaction was stirred at ambient temperature for 2 hours.
• the reaction was diluted with pyridine (10 ml), and 6- bromopyridin-2-amine (0.9183 g, 5.308 mmol) was added.
• the reaction was heated to 80 0 C for 16 hours, then cooled to ambient temperature and diluted with EtOAc.
• the reaction was washed with IM hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride.
• the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated.
• the crude material was purified on silica gel eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (1.2 g, 2.257 mmol, 85.02 % yield).
• Step B Preparation of ethyl 6-chloro-7-(4-(6-(3.4-dichlorophenvnpyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: To a solution of ethyl 7-(4-(6-bromopyridin- 2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.050 g, 0.094 mmol), 3,4- dichlorophenylboronic acid (0.023 g, 0.12 mmol), and sodium carbonate (0.030 g, 0.28 mmol) in toluene (1 ml) and water (0.1 ml) degassed with argon was added tetrakis(triphenylphosphine)palladium (0.0054 g, 0.0047 mmol), and the reaction was heated to 100 0 C for 16 hours. The reaction was loaded directly onto silica gel and
• Step C Preparation of 6-chloro-7-(4-(6-(3.4-dichlorophenyr)pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a solution of ethyl 6-chloro-7-(4-(6- (3,4-dichlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.051 g, 0.085 mmol) in 3:1 v/v THF/ethanol (1 ml) was added IM sodium hydroxide (0.20 ml, 0.20 mmol), and the reaction was stirred for 16 hours.
• Step A Preparation of 6-chloro-7-(4-(6'-methoxy-2.3'-bipyridin-6- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Prepared according to the method of Example 52, substituting 6-methoxypyridin-3-ylboronic acid for 3,4-dichlorophenylboronic acid.
• Example 55 Preparation of sodium 6-chloro-7-(4-(6'-methoxy-2,3
• Step A Preparation of ethyl 6-chloro-7-(4-(6-(2-chlorophenv0pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to the method of Example 82, substituting 2-chlorophenylboronic acid for 2,4-difluorophenylboronic acid.
• Step B Preparation of 6-chloro-7-(4-(6-(2-chlorophenyl)pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a solution of ethyl 6-chloro-7-(4-(6-(2- chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.010 g, 0.0177 mmol) in 3:1 THF/ethanol (1 ml) was added IM sodium hydroxide (0.0373 ml, 0.0373 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated and diluted with water.
• Step A Preparation of 6-p-tolylpyridin-2-amine hydrochloride: To a solution of 6-bromopyridin-2-amine (0.500 g, 2.89 mmol) in toluene (10 ml) was added benzaldehyde (0.313 g, 2.95 mmol), and the reaction was stirred for 30 minutes. To this, /?-tolylboronic acid (0.471 g, 3.47 mmol), sodium carbonate (0.368 g, 3.47 mmol), and water (10 ml) were added, and the reaction was degassed with argon.
• Tetrakis(triphenylphosphine)palladium (0.167 g, 0.144 mmol) was added, and the reaction was heated to 100 0 C for 60 hours.
• the reaction was diluted with 10 ml of toluene and 10 ml of water, and the organic layer was collected.
• the organic layer was treated with 4M hydrogen chloride in dioxane (1.44 ml, 5.78 mmol) dropwise with vigorous stirring.
• the resulting solid was collected via filtration to yield pure 6-/?-tolylpyridin-2-amine hydrochloride (0.564 g, 2.56 mmol, 88.4 % yield).
• Step B Preparation of ethyl 6-chloro-7-(4-(6-p-tolylpyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: To a solution of 4-(6-chloro-4- (ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 56 mg, 0.1486 mmol) in 1,2- dichloroethane (0.15 ml) and DMF (1 drop) was added oxalyl chloride (15.56 ⁇ l, 0.1783 mmol), and the reaction was stirred for 2 hours.
• Step C Preparation of 6-chloro-7-(4-(6-p-tolylpyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: To a solution of ethyl 6-chloro-7-(4-(6-p- tolylpyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.049 g, 0.090 mmol) in 3:1 THF/ethanol (1 ml) was added IM sodium hydroxide (0.19 ml, 0.19 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated to dryness and acidified with IM hydrochloric acid.
• Step A Preparation of ethyl 6-chloro-7-(4-(6-chloropyridazin-3- ylcarbamoyl)phenoxy)chroman-4-carboxylate: To a solution of 4-(6-chloro-4- (ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 0.500 g, 1.334 mmol) in 1,2- dichloroethane (1.3 ml) and DMF (1 drop) was added oxalyl chloride (0.1396 ml, 1.601 mmol), and the reaction was stirred for 1 hour at ambient temperature.
• reaction was concentrated to dryness, taken up in water, and acidified with IM hydrochloric acid.
• the reaction was extracted twice with EtOAc, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.030 g, 0.050 mmol, 92 % yield).
• Step D Preparation of sodium 6-chloro-7-(4-(6-(2-chloro-4-
• Step A Preparation of ethyl 7-(4-(5-bromopyrazin-2-ylcarbamoyl)phenoxy)-
• 6-chlorochroman-4-carboxylate Prepared according to the method of Example 59, step A, using 2-amino-5-bromopyrazine in place of 6-chloropyridazin-3-amine. [00593] Step B: Preparation of sodium 6-chloro-7-(4-(5-(4-
• Step A Preparation of 6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridazin-3- amine: To a solution of 6-chloropyridazin-3-amine (0.300 g, 2.32 mmol), 2-fluoro-4- (trifluoromethyl)phenylboronic acid (0.626 g, 3.01 mmol), cesium fluoride (0.915 g, 6.02 mmol), and ⁇ /-ethyl-iV-isopropylpropan-2-amine (0.449 g, 3.47 mmol) in propanol (17 ml) degassed with argon was added (dppf)palladium(II) chloride dichloromethane adduct (0.0953 g, 0.116 mmol), and the reaction was heated to 100 0 C in a sealed tube for 3 hours.
• the reaction was cooled to ambient temperature, diluted with EtOAc, and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with a linear gradient of 0-10% methano 1/EtOAc to yield the desired compound (0.086 g, 0.334 mmol, 14.4 % yield).
• Step B Preparation of 6-chloro-7-(4-(6-(2-fluoro-4-(trifluoromethvO phenyl)pyridazin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Prepared from 6-(2- fluoro-4-(trifluoromethyl)phenyl)pyridazin-3-amine using the procedure of Example 57, steps B and C.
• Steps A and B Preparation of 6-chloro-7-(4-(6'-methoxy-3,3'-bipyridin-6- ylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Prepared according to the procedure for Example 52 using 5-bromopyridin-2-amine in place of 6-chloropyridin-2-amine, and using 6- methoxypyridin-3-ylboronic acid in place of 3,4-dichlorophenylboronic acid in Step B.
• Step A 6-bromopyridin-3 -amine was used in place of 6-chloropyridin-2- amine, and using 3-(trifluoromethyl)phenylboronic acid in place of 3,4- dichlorophenylboronic acid in Step B.
• MS (apci) m/z 569 (M+H).
• Step A 6-bromopyridin-3 -amine, was used in place of 6-chloropyridin-2-amine, and in Step B, 4-(trifluoromethyl)phenylboronic acid was used in place of 3,4-dichlorophenylboronic acid.
• Step A Ethyl 6-chloro-7-(4-(6-phenylpyrazin-2-ylcarbamoyl) phenoxy)chroman-4-carboxylate : Argon was bubbled through a tetrahydrofuran (665 ⁇ l) solution of ethyl 7-(4-carbamoylphenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.133 mmol; Example 45, step A) and 2-chloro-6-phenylpyrazine (25.4 mg, 0.133 mmol) at ambient temperature in a vial.
• Step B Preparation of 6-chloro-7-(4-(6-phenylpyrazin-2- lcarbamoyl)phenoxy)chroman-4-carboxylic acid : Ethyl 6-chloro-7-(4-(6-phenylpyrazin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate (31 mg, 0.0585 mmol) in 2:1 THF-Ethanol (1.2 ml) was treated with 1.0 N aqueous sodium hydroxide (87.7 ⁇ l, 0.0877 mmol) at ambient temperature.
• Step A Ethyl 6-chloro-7-(4-(6-ethoxypyridin-2-ylcarbamov0 phenoxy)chroman-4-carboxylate : Prepared according to Example 77, Step A, replacing 2- chloro-6-phenylpyrazine with 2-chloro-6-ethoxypyridine, to provide 57 mg (81%) of the title compound.
• Step A Preparation of 2-chloro-6-(4-chlorophenyl)pyrazine: 2,6-
• Step B Preparation of ethyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyrazin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to Example 77, Step A wherein 2-chloro-6-phenylpyrazine was replaced with 2-chloro-6-(4-chlorophenyl)pyrazine to provide 68 mg (91%) of the title compound.
• Step A Preparation of 2-methoxy-3 -(2-nitrovinyl)-6-
• Step B Preparation of 2-(2-methoxy-6-(trifluoromethyl)pyridin-3- yDethanamine: To a suspension of lithium borohydride (71.2 mg, 3.27 mmol) in tetrahydrofuran (5 ml) was added chlorotrimethylsilane (826 ⁇ l, 6.53 mmol) at ambient temperature (exothermic reaction) and the reaction was allowed to stir for 30 minutes. 2- Methoxy-3-(2-nitrovinyl)-6-(trifluoromethyl)pyridine (193 mg, 0.778 mmol) was added, and the reaction was heated to reflux for 6 hours. The reaction was cooled to ambient temperature and quenched by the addition of IM HCl (9 ml).
• Step C Preparation of ethyl 6-chloro-7-(4-(2-(2-methoxy-6-)
• Step D Preparation of 6-chloro-7-(4-(2-(2-methoxy-6-(trifluoromethvO pyridin-3 -yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid: Prepared according to Example 77, Step B to provide the title compound (266 mg, 105%) as a white solid.
• Step E Preparation of sodium 6-chloro-7-(4-(2-(2-methoxy-6-
• Step A Preparation of ethyl 6-chloro-7-(4-(6-(2,4-difluorophenyl)pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to Example 52, Step B substituting the boronic acid of that example with 3,4-difluorophenylboronic acid to provide the title compound (32 mg, 75%).
• Step A Preparation of ethyl 6-chloro-7-(4-(6-(2,4-difluorophenyl)pyridin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Ethyl 7-(4-(6-bromopyridin-2- ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (Example 52, Step A, 40 mg, 0.0752 mmol), 2,4-difluorophenylboronic acid (15.4 mg, 0.0978 mmol), and cesium fluoride (29.7 mg, 0.196 mmol) in i-PrOH (1 ml) were sparged with argon for 2 minutes in a vial.
• Step A Preparation 2-(tert-butylthio)- 6-chloropyridine : A suspension of sodium 2-methylpropane-2-thiolate (188 mg, 1.68 mmol) in DMF was treated with 2,6- dichloropyridine (4865 ⁇ l, 1.46 mmol) at ambient temperature in a vial. The vial was capped and heated to 80° C with rapid stirring of the colorless solution. After 12 hours, the reaction was cooled to ambient temperature and diluted with ethyl acetate. The ethyl acetate solution was washed with brine solution, dried with sodium sulfate, filtered, concentrated and purified on silica gel. Elution with 2% to 10% ethyl acetate/hexanes provided the title compound (271 mg, 1.34 mmol, 92.0 % yield) as a light yellow oil.
• Step A Preparation of ethyl 6-chloro-7-(4-(6-chloropyrazin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to the method of Example 52, Step A, substituting the 6-bromopyridin-2-amine with 2-amino-6-chloropyrazine to provide the title compound (260 mg, 87%) as a white solid.
• Step A Preparation of ethyl 6-chloro-7-(4-(6-chloropyrazin-2- ylcarbamoyl)phenoxy)chroman-4-carboxylate: Prepared according to the method of Example 52, Step A, substituting the 6-bromopyridin-2-amine with 2-amino-5-bromopyrazine to provide the title compound (556 mg, 89%) as a white solid.

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