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WO2012027965A1 - Novel compounds - Google Patents

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Publication number
WO2012027965A1
WO2012027965A1 PCT/CN2011/001481 CN2011001481W WO2012027965A1 WO 2012027965 A1 WO2012027965 A1 WO 2012027965A1 CN 2011001481 W CN2011001481 W CN 2011001481W WO 2012027965 A1 WO2012027965 A1 WO 2012027965A1
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Prior art keywords
phenyl
chlorophenyl
thiazol
stirred
mixture
Prior art date
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PCT/CN2011/001481
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French (fr)
Inventor
Yonghui Wang
Wei Cai
Qian Liu
Jia-Ning Xiang
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel retinoid-related orphan receptor gamma (RORy) modulators and their use in the treatment of diseases mediated by RORy.
  • RORy retinoid-related orphan receptor gamma
  • RORs Retinoid-related orphan receptors
  • the ROR family consists of three members, ROR alpha (RORa), ROR beta (RORp) and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB and RORC, respectively).
  • RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2).
  • RORy is a term used to describe both RORyl and/or RORyt.
  • Thl7 cells are a subset of T helper cells which produce IL- 17 and other proinflammatory cytokines. Thl7 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA).
  • EAE experimental autoimmune encephalomyelitis
  • CIA collagen-induced arthritis
  • Thl7 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept. Signal. 7: e003; Manel et al. (2008) Nat. Immunol. 9:641-649).
  • the pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues.
  • Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman (2008) J. Exp. Med. 205:1517- 1522; Leung et al. (2010) Cell. Mol. Immunol. 7: 182-189). There is evidence that Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al. (2009) Annu. Rev.
  • RORyt plays a critical role in the pathogenic responses of Thl7 cells (Ivanov et al. (2006) Cell 126:1121-1133). RORyt deficient mice show very little Thl7 cells. In addition, RORyt deficiency resulted in amelioration of EAE. Further support for the role of RORyt in the pathogensis of autoimmune or inflammatory diseases can be found in the following references: Jetten & Joo (2006) Adv.Dev.Biol. 16:313-355; Meier et al. (2007) Immunity 26:643-654; Aloisi & Pujol-Borrell (2006) Nat. Rev. Immunol. 6:205-217; Jager et al. (2009) J. Immunol. 183:7169-7177; Serafmi et al. (2004) Brain Pathol ⁇ 4 ⁇ 64 ⁇ 4; Magliozzi et al. (2007) Brain 130: 1089-1104; Barnes (2008)
  • the invention is directed to novel RORy modulators and their use in the treatment of diseases mediated by RORy. Specifically, the invention is directed to compounds according to Formula I.
  • Rl, R2, R3, R4 and R5 are defined below, and to pharmaceutically-acceptable salts thereof.
  • this invention provides for the use of the compounds of Formula I for the treatment of diseases mediated by RORy.
  • diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma.
  • the invention is directed to methods of treating such diseases.
  • Figure 1(A) shows the inhibitory effect of the RORy modulator Example 9 on the production of IL-17 by ELISA.
  • Figure 1(B) shows the inhibitory effect of the RORy modulator Example 9 on the production of IL-17 by intracellular staining.
  • Figure 2 shows the mean clinical scores of control and EAE mice treated with the RORy modulator Example 9.
  • Figure 3(A) shows the mean clinical scores of control and CIA mice treated with the RORy modulator Example 9.
  • Figure 3(B) shows the foot volume of control and CIA mice treated with the RORy modulator Example 9.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • C1-C6 alkyl refers to an alkyl group having from 1 to 6 member atoms.
  • Alkyl groups may be optionally substituted with one or more substituent as defined herein.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • Alkoxy refers to the group -O-R where R is alkyl having the specified number of member atoms. Alkoxy includes methoxy, ethoxy and propoxy.
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee,and greater than 90% ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%). "Enantiomerically pure” refers to products whose enantiomeric excess is 99% ee or greater.
  • Half-life refers to the time required for half of a quantity of a substance to be converted to another chemically distinct species in vitro or in vivo.
  • Halo refers to the halogen radicals fluoro, chloro, bromo, and iodo.
  • Heteroatom refers to a nitrogen, sulphur, or oxygen atom.
  • Heterocycloalkyl refers to a saturated or unsaturated ring containing from 1 to 4.
  • heteroatoms as member atoms in the ring.
  • heterocycloalkyl rings are not aromatic.
  • Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocycloalkyl rings have from 5 to 7 member atoms. Bicyclic
  • heterocycloalkyl rings have from 7 to 11 member atoms.
  • heterocycloalkyl is saturated.
  • heterocycloalkyl is unsaturated but not aromatic.
  • Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azetidinyl,
  • Member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • Optionally substituted indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent as defined.
  • RORy refers to all isoforms encoded by the O C gene which include RORyl and RORyt.
  • RORy modulator refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy.
  • RORy modulators include antagonists and inverse agonists of RORy.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituent, one or more (as appropriate) member atom within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
  • the present invention provides, in a first aspect, a compound of Formula I or a
  • l is phenyl optionally substituted with one to three substituents selected from the group consisting of:
  • Ra is H or C1-C3 alkyl
  • R3 is H or Cl-C6 alkyl
  • R4 is H or Cl-C6 alkyl
  • R5 is C1-C6 alkyl optionally substituted with one to three F;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R2 when said R2 is other than 1,3-benzodioxol, then at least one of Rl and R2 is phenyl having at least one substituent.
  • the present invention relates to compounds of Formula I wherein Rl is phenyl substituted with halo.
  • the present invention relates to compounds of Formula I wherein Rl is phenyl substituted with CN, C1-C3 alkoxy, CF 3 , OH or heterocycloalkyl.
  • the present invention relates to compounds of Formula I wherein Rl is unsubstituted phenyl.
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein Rl is 3-chlorophenyl or 3-fluorophenyl.
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein Rl is 3-cyanophenyl or 3- (trifluoromethyl)phenyl.
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein R2 is phenyl substituted with halo. In one embodiment, the invention also relates to compounds of any of the above embodiments wherein R2 is 2-chlorophenyl or 2- fluorophenyl. In another embodiment, the invention also relates to compounds of any of the above embodiments wherein R2 is 3-chlorophenyl or 3-fluorophenyl. The present invention also relates to compounds of Formula I or any of the above embodiments wherein R2 is phenyl substituted with C1-C3 alkyl or C1-C3 alkoxy.
  • the invention also relates to compounds of any of the above embodiments wherein R2 is 2-methylphenyl or 2-methoxyphenyl
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein R2 is phenyl substituted with hydroxyl substituted C1-C3 alkyl.
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein R3 is H.
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein R4 is H.
  • the present invention also relates to compounds of Formula I or any of the above embodiments wherein R5 is C1-C3 alkyl. In one embodiment, the invention also relates to compounds of any of the above embodiments wherein R5 is methyl. In another embodiment, the invention also relates to compounds of any of the above embodiments wherein R5 is ethyl. In one embodiment, the compound of the present invention is not a compound of Formula I wherein R2 is 4-chlorophenyl. In one embodiment, the compound of the present invention is not a compound of Formula I wherein R2 is 4-fluorophenyl.
  • the compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
  • compounds according to Formula I may contain an acidic functional group. In certain other embodiments, compounds according to Formula I may contain a basic functional group.
  • pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts may impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to the use of pharmaceutically-acceptable salts of the compounds according to Formula I.
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • the term "compounds of the invention” means both the compounds according to Formula I and the pharmaceutically-acceptable salts thereof.
  • the term "a compound of the invention” also appears herein and refers to both a compound according to Formula I and its pharmaceutically-acceptable salts.
  • the invention also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride).
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Hydrates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, I spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • Suitable synthetic routes are depicted below in the following general reaction scheme.
  • the skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Scheme 1 represents a general reaction scheme for preparing compounds of Formula I.
  • Starting material substituted a-bromo ketones 1.2 can be obtained commercially or synthesized using methyl ketones 1.1.
  • Protected carbamothioyl amides 1.4 can be obtained by condensation of acyl chlorides 1.3, thiocyanates and bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine or N-2-propen-l-yl-2- propen-1 -amine (commercially available).
  • Treatment of 1.2 with 1.4 gives protected thiazole ketones 1.5. Deprotection of 1.5 affords the amines 1.6, which are then condensed with an appropriate acid in the presence of HOBt and EDC to obtain compounds of Formula I.
  • Mobile phase water containing 0.05% TFA / acetonitrile.
  • Mobile phase water containing 0.04% ammonia/ acetonitrile.
  • Step 1 A mixture of l-[4-(methyloxy)phenyl]methanamine (40 g) and 4- (methyloxy)benzaldehyde (40.5 g) in methanol (220 mL) was heated to reflux for 3 hours. After cooling to 0 °C, NaBH 4 (14.34 g) was added portionwise within 30 min and the resulting mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc for 3 times. The combined organic layers were washed with water and brine, then dried over anhydrous Na 2 SC>4.
  • Step 2 To a solution of benzoyl chloride (2.50 g) in acetone (36 mL) cooled at 0 °C was added ammonium thiocyanate (2.71 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine (5.49 g) was added and stirred for an additional 30 mins.
  • Step 1 A solution of sodium nitrite (18.4 g) in 133 mL of water was added dropwise at 0 °C, while stirring, to a suspension of (4-aminophenyl)acetic acid (40.2 g) in 133 mL of water and 54 mL of concentrated hydrochloric acid. After the addition was complete, the reaction mixture was stirred at the same temperature for 45 minutes. This solution of cold diazonium salt was then added dropwise at room temperature to a mixture of potassium ethylxanthate (49.4 g), 80 mL of water and 200 mL of 2 M sodium carbonate solution. The mixture was heated to 45 °C and stirred at this temperature until gas evolution stops.
  • Step 2 (4- ⁇ [(Ethyloxy)carbonothioyl]thio ⁇ phenyl)acetic acid (90 g) was taken up in 340 mL of ethanol, and a solution of 70 g of potassium hydroxide in 340 mL of water was added. Boiling at reflux was effected for 20 hours. The major portion of ethanol was subsquently removed by the distillation under reduced pressure. The aqueous phase was cooled with ice, and acidified with concentrated hydrochloric acid while stirring. The obtained solution was extracted with diethyl ether (500 mL).
  • Step 3 To a solution of (4-mercaptophenyl)acetic acid (33 g) in N,N-dimethylformamide (DMF) (240 mL) was added K 2 CO 3 (108 g) and bromoethane (64.1 g). The reaction mixture was stirred at T. After 2.5 hours, the starting material was totally consumed. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL).
  • DMF N,N-dimethylformamide
  • Step 4 A solution of ethyl [4-(ethylthio)phenyl] acetate (34 g) in dichloromethane (DCM) (500 mL) was cooled to 0 °C with an ice bath. MCPBA (78 g) was added in portions, and the reaction mixture was stirred at T overnight. The obtained suspension was filtered. The filtrate was washed with sat. sodium carbonate solution (400 mL x 2), water (500 mL), then brine (250 mL). The obtained solution was dried over sodium sulphate, filtered, and concentrated.
  • DCM dichloromethane
  • reaction mixture was partitioned between DCM and water.
  • aqueous phase was extracted with
  • Step 1 see step 1 for preparing intermediate lb.
  • Step 2 To a solution of 4-chlorobenzoyl chloride (1.2 g) in acetone (18 mL) cooled at 0 °C was added ammonium thiocyanate (1.044 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine (2.70 g) was added at the same
  • Step 1 see step 1 for preparing intermediate lb.
  • Step 1 see step 1 for preparing intermediate lb.
  • Step 2 To a solution of 3-cyanobenzoyl chloride (620 mg) in acetone (10 mL) cooled at 0 °C was added ammonium thiocyanate (570 mg). The resulting mixture was strried at this temperature for 1.5 hours. Then bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine (1060 mg) was added to the above mixture and stirred for an addtional 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The aqueous phase was washed with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na 2 SC>4.
  • Step 1 see step 1 for preparing intermediate lb.
  • Step 1 see step 1 for preparing intermediate lb.
  • Step 2 To a solution of 3-(trifluoromethyl)benzoyl chloride (1.3 g) in acetone (15 mL) cooled at 0 °C was added ammonium thiocyanate (0.949 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine (1.925 g) was added and the reaction mixture was stirred for an additional 30 mins. The reaction mixture was allowed to warm to room temperature and stirred overnight.
  • Step 1 To a solution of 4-chlorobenzoyl chloride (3.81 mL) in acetonitrile (50 mL) stirred in air at RT was added solid KSCN (4.37 g). After stirring for 45 mins, the mixture was filtered, and the filtrate was used direcly in the next step.
  • Step 1 to 2 see steps 1&2 for preparing intermediate Id.
  • Step 4 A mixture of methyl 2-(4-mercaptophenyl)acetate (1.2 g), l,l,l-trifluoro-2-iodoethane (1.4 g) and K 2 CO 3 (2.4 g) in NN-dimethylformamide (DMF) (30 mL) was stirred at room temperature
  • Step 6 A mixture of methyl 2-(4-(2,2,2-trifluoroethylsulfonyl)phenyl)acetate (1.1 g) and cone. HC1 (30 mL) in acetic acid (30 mL) was stirred at 105 °C for 1.5 hours. Solvent was removed under reduce pressure. Water (30 mL) and DCM (30 mL) was added. The aqueous was washed with DCM (15 mL x 3). The combined organic phases were dried over Na 2 S0 4 , filtered, and concentrated to give the title product 2-(4-(2,2,2-trifluoroethylsulfonyl)phenyl)acetic acid (700 mg) as a white solid.
  • Step 1 To a solution of 3-bromobenzoyl chloride (2.5 g) in acetone (25 mL) cooled at 0 °C was added ammonium thiocyanate (1.734 g). The resulting mixture was strried at this temperature for 1.5 hours. Then bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine (3.22 g, synthesis of this starting material, see step 1 for preparing intermediate lb) was added to the above mixture and stirred for an addtional 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the resulting residue was dissovled in EtOAc and washed with water and brine, dried over anhydrous Na 2 SC>4.
  • Step 2 A solution of 2-bromo-l-phenylethanone (0.502 g) and N-[(bis ⁇ [4- (methyloxy)phenyl]methyl ⁇ amino)carbonothioyl]-3-bromobenzamide (1.2 g) in NN- dimethylformamide (DMF) (6 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na 2 SC>4. After filtration, solvent was removed in vacuo to affrod [2-(bis ⁇ [4-
  • Step 3 A mixture of [2-(bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amino)-4-(3-bromophenyl)-l,3- thiazol-5-yl](phenyl)methanone (350 mg), morpholine (203 mg), palladium(II) acetate (26.2 mg), BINAP (72.7 mg) and CS2CO3 (951 mg) in toluene (3.5 mL) was bubbled with N 2 , and then stirred at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered through silica gel and celite. The solid was washed with DCM and EtOAc. The filtrate was collected and concentrated under reduced pressure.
  • Step 1 To a solution of 2-phenylethyl acetate (5 g) in dichloromethane (DCM) (200 mL) was added aluminium chloride (4.06 g) and the mixture was cooled to 0 °C. Then acetyl chloride (2.382 mL) was added dropwise, followed by addition of more aluminium chloride (4.06 g). The resulting mixture was stirred at 0 °C for 1.5 hours. The mixture was poured into ice/water and 5 mL of cone. HC1 was added. The organic layer was separated, washed with brine and dried over anhydrous Na 2 S0 4 .
  • DCM dichloromethane
  • Step 2 To a solution of 2-(4-acetylphenyl)ethyl acetate (260 mg) in diethyl ether (5 mL) cooled at 0 °C was added bromine (0.068 mL) dropwise. The resulting mixture was stirred at room temperature for 1.5 hours. Solvent was removed in vacuo to afford 2-[4-(2-bromoacetyl)phenyl]ethyl acetate (362 mg) as a yellow oil. MS(ES + ) m/z 285 (MH + ).
  • Step 3 A solution of 2-[4-(2-bromoacetyl)phenyl]ethyl acetate (362 mg) and N- [(bis ⁇ [4- (methyloxy)phenyl]methyl ⁇ amino)carbonothioyl]benzamide (intermediate lb, 320 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times.
  • DMF NN- dimethylformamide
  • Step 4 A mixture of 2- ⁇ 4-[(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl ⁇ ethyl acetate
  • Step 1 Acetyl chloride (13.66 g) was added into a solution of 3 -phenyl- 1-propanol (15.8 g), Et 3 N (32.3 mL) and DMAP (1.417 g) in dichloromethane (DCM) (250 mL) at 0 °C dropwise. The resultant mixture was stirred at the same temperature. After 1 hour, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with 1 M HC1 and brine. The organic phase was then dried over anhydrous Na 2 SC>4. After filtration, the filtrate was concentrated in vacuo to afford 3-phenylpropyl acetate (11.8 g) as a yellow oil.
  • DCM dichloromethane
  • Step 2 Acetyl chloride (2.64 g) was added into a mixture of aluminium chloride (3.74 g) and
  • Step 3 Bromine (0.234 mL) was added into a solution of 3-(4-acetylphenyl)propyl acetate (1 g) in diethyl ether (5 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to afford 3-[4-(2- bromoacetyl)phenyl]propyl acetate (1.1 g) as a yellow oil. MS(ES + ) m/z 299 (MH + ).
  • Step 4 A mixture of 3-[4-(2-bromoacetyl)phenyl]propyl acetate (224 mg) and N- [(bis ⁇ [4- (methyloxy)phenyl]methyl ⁇ amino)carbonothioyl]benzamide (intermediate lb, 300 mg) in NN- dimethylformamide (DMF) (5 mL) was heated to 85 °C for 45 mins under N 2 . Solvent was removed under reduced pressure. The residue was dissolved into TFA (4 mL) and the resultant solution was heated to 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was basified with sat. NaHCC>3 solution, and then extracted with EtOAc for 3 times.
  • DMF NN- dimethylformamide
  • Step 5 A mixture of 3- ⁇ 4-[(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl ⁇ propyl acetate (100 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 66.0 mg), HOBt (53.3 mg) and EDC (76 mg) in dichloromethane (DCM) (5 mL) was stirred at room temperature overnight under N 2 . The reaction mixture was washed with 2 M HCl, sat. NaHCC>3 solution and brine successively. The organic layer was dried over anhydrous Na 2 SC>4.
  • Step 1 To a solution of 3-phenylpropanoic acid (10 g) in methanol (100 mL) was added thionyl chloride (0.05 mL) dropwise. The resulting mixture was stirred at room temperature overnight. Solvent was removed in vacuo to afford methyl 3-phenylpropanoate (10.896 g) as a light yellow liquid. MS(ES + ) m/z 165 (MH + ).
  • Step 2 To a solution of methyl 3-phenylpropanoate (5 g) in dichloromethane (DCM) (200 mL) was added aluminium chloride (4.06 g) and the mixture was cooled to 0 °C. Then acetyl chloride (2.60 mL) was added dropwise and more aluminium chloride (4.06 g) was added, the resulting mixture was stirred at 0 °C for 6.5 hours. Then the mixture was poured into ice/water and 5 mL of cone. HCl was added. The organic layer was separated, washed with brine and dried over anhydrous Na 2 S0 4 .
  • DCM dichloromethane
  • Step 3 To a solution of methyl 3-(4-acetylphenyl)propanoate (1.5 g) in diethyl ether (35 mL) stirred at 0 °C was added bromine (0.393 mL) dropwise. The resulting mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated in vacuo to afford methyl 3-[4- (bromoacetyl)phenyl]propanoate (2.019 g) as a brown solid. MS(ES + ) m/z 285 (MH + ).
  • Step 4 A solution of methyl 3-[4-(bromoacetyl)phenyl]propanoate (224 mg) and N-[(bis ⁇ [4-
  • Step 1 SOCl 2 (8.10 mL) was added to a solution of 3-[(methyloxy)carbonyl]benzoic acid (1 g) in dichloromethane (DCM) (15 mL) and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in dry DCM. Solvent was evapourated again to afford the acyl chloride as a light yellow solid. This acyl chloride was dissolved in acetone (15 mL) and cooled to 0 °C, to which ammonium thiocyanate (0.845 g) was added. The mixture was then stirred at this temperature for 1.5 hours.
  • DCM dichloromethane
  • Step 2 A solution of 2-bromo-l-phenylethanone (175 mg) and methyl 3-( ⁇ [(bis ⁇ [4-
  • the aqueous phase was extracted with DCM for 3 times. The combined organic layers were washed with 2 M HCl, sat. NaHCOs, and then brine. The solution was dried over Na 2 S0 4 . After removal of solvent, the residue was redissolved in tetrahydrofuran (THF) (2.5 mL) and water (0.8 mL), to which lithium hydroxide monohydrate (79 mg) was added and the mixture was stirred at room temperature overnight. The mixture was acidified with 2 M HCl, and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc for 3 times. The combined organic layers were washed with brine and concentrated under reduced pressure.
  • THF tetrahydrofuran
  • Step 1 Bromine (0.518 mL) was added into a solution of l-(2-bromophenyl)ethanone (2 g) in diethyl ether (20 mL) at 0 °C dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to afford 2-bromo-l-(2- bromophenyl)ethanone (2.9 g) as a yellow oil. MS(ES + ) m/z 276 (MH + ).
  • Step 2 A mixture of 2-bromo-l-(2-bromophenyl)ethanone (1 g) and N-[(bis ⁇ [4- (methyloxy)phenyl]methyl ⁇ amino)carbonothioyl]benzamide (intermediate lb, 1.664 g) in NN- dimethylformamide (DMF) (10 mL) was heated to 85 °C for 45 mins. After cooling to RT, the mixture was poured into brine, and extracted with EtOAc for 3 times. The combined organic layers were dried over anhydrous Na 2 SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was redissolved into TFA (4 mL), and the resultant solution was heated to 80 °C overnight.
  • DMF NN- dimethylformamide
  • Step 3 A mixture of (2-amino-4-phenyl-l,3-thiazol-5-yl)(2-bromophenyl)methanone (200 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 140 mg), HOBt (113 mg) and EDC (160 mg) in dichloromethane (DCM) (5 mL) was stirred at room temperature under N 2 overnight. The mixture was washed with 1 M HCl, sat. NaHCC>3 and brine successively. The organic layer was dried over anhydrous Na 2 SC>4.
  • Step 4 A mixture of N- ⁇ 5-[(2-bromophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl ⁇ -2-[4- (ethylsulfonyl)phenyl]acetamide (100 mg), iodocopper (3.34 mg) and cyanocopper (31.5 mg) in N- methyl-2-pyrrolidone (NMP) (4 mL) was heated to 120 °C for 1 hour. The mixture was poured into water, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na 2 SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • NMP N- methyl-2-pyrrolidone
  • Step 1 see step 1 for preparing intermediate lb.
  • Step 2 To a solution of 3-chlorobenzoyl chloride (2 g) in acetone (30 mL) cooled at 0 °C was added ammonium thiocyanate (1.74 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis ⁇ [4-(methyloxy)phenyl]methyl ⁇ amine (3.53 g) was added at this temperature and stirred for an additional 30 mins.
  • Step 1 To a mixture of methyl 3-formylbenzoate (950 mg) and dimethylamine hydrochloride (613 mg) in dichloromethane (DCM) (40 mL) at 0 °C was added NaBH(OAc) 3 (1.859 g) portionwise. The mixture was warmed to room temperature and stirred at room temperature for 18 hours. The mixture was washed with sat, NaHCOs solution (20mL x 2) and then brine (40 mL). The organic phase was dried over Na 2 SC>4, filtered and concentrated to yield the crude methyl 3- ((dimethylamino)methyl)benzoate (1.23 g) as a yellow solid. MS(ES + ) m/z 194 (MH + ).
  • Step 2 To a mixture of methyl 3-((dimethylamino)methyl)benzoate (1.2 g) in methanol (10 mL) was added a solution of LiOH (0.294 g) in water (5 mL). The mixture was stirred at 30 °C overnight. After removal of methanol in vacuo, the pH of the mixture was adjusted to 2.0 with 2 M HC1 solution. The mixture was extracted with butan-l-ol (20mL x 3). The combined organic phase was concentrated to yield 3-((dimethylamino)methyl)benzoic acid (900 mg) as a white solid. MS(ES ) m/z 180 (MH + ).
  • Step 3 A mixture of 3-((dimethylamino)methyl)benzoic acid (900 mg) and oxalyl dichloride (574 mg) in dichloromethane (DCM) (20 mL) was stirred at 45 °C for 3 hours. The mixture was concentrated in vacuo, and then dry DCM (30 mL) was added. The mixture was concentrated again to afford 3-((dimethylamino)methyl)benzoyl chloride (1 g) as a light yellow solid.
  • DCM dichloromethane
  • Step 4 3-((Dimethylamino)methyl)benzoyl chloride (1 g) was dissolved in acetone (30 mL) and cooled to 0 °C, to which ammonium thiocyanate (1.48 g) was added. The mixture was then stirred at this temperature for 2 hours. To the above mixture bis(4-methoxybenzyl)amine (1.224 g) was added at the same temperature and stirred for an additional 2 hours. The mixture was
  • Step 5 A solution of N-(bis(4-methoxybenzyl)carbamothioyl)-3-
  • Step 6 A mixture of (2-(bis(4-methoxybenzyl)amino)-4-(3-((dimethylamino)methyl) phenyl) thiazol-5-yl)(phenyl)methanone (520 mg) in 2,2,2-trifluoroacetic acid (6686 ⁇ ) was stirred at 85 °C for 18 hours. Most of TFA was evaporated in vacuo. The residue was dissolved in DCM (30 mL) and then washed with sat. NaHCC>3 solution (20mL x 2) and brine (40 mL). The organic phase was dried over Na 2 SC>4, filtered and concentrated to yield (2-amino-4-(3-
  • Step 7 A mixture of (2-amino-4-(3-((dimethylamino)methyl)phenyl)thiazol-5- yl)(phenyl)methanone (260 mg), 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 460 mg), BOP (579 mg) and Et 3 N (0.281 mL) in dichloromethane (DCM) (10 mL) was stirred at 40 °C for 18 hours. As the reaction was not finished, more 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 460 mg) was added and the mixture was stirred at room temperature for another 18 hours until almost full conversion.
  • DCM dichloromethane
  • Step 1 To a solution of methyl 3-(trifluoromethyl)benzoate (2.8 g) in methanol (10 mL) was added NaOH (17.14 mL). The mixture was stirred at RT overnight. After removal of methanol in vacuo, HC1 (2 M) was added to adjust the above mixture to pH 2. The resulting white solid was filtered, washed with water and dried in vacuo to afford 3-(trifluoromethyl)benzoic acid (2.8 g) as a white solid. MS(ES + ) m/z 191 (MH + ).
  • Step 2 To a mixture of 3-(trifluoromethyl)benzoic acid (1.6 g) in dichloromethane (DCM) (20 mL) was added sulfurous di chloride (3.00 g) dropwise. The mixture was then stirred at 40 °C for 2 hours. The mixture was evaporated in vacuo, and then dry DCM (20 mL) was added. The mixture was concentrated again to give 3-(trifluoromethyl)benzoyl chloride (1.38 g) as a light yellow oil.
  • DCM dichloromethane
  • Step 3 The above 3-(trifluoromethyl)benzoyl chloride (1.38 g) was dissolved in acetone (30 mL) and cooled to 0 °C, to which ammonium thiocyanate (993 mg) was added. The mixture was then stirred at this temperature for 2 hours. To the mixture bis(4-methoxybenzyl)amine (4.26 g) was added at the same temperature and stirred for an additional 1 hour. The mixture was concentrated under reduced pressure.
  • Step 4 A solution of N-(bis(4-methoxybenzyl) carbamothioyl)-3-(trifluoromethyl) benzamide
  • Step 5 A mixture of (2-(bis(4-methoxybenzyl)amino)-4-(3-(trifluoromethyl)phenyl)thiazol-5- yl)(3-fluorophenyl)methanone (1.5 g) in TFA (9.53 mL) was stirred at 80 °C overnight. MeOH (10 mL) was added to the reaction and the mixture was left at T overnight. The resulting solid was collected by filtration and dried in vacuo to afford (2-amino-4-(3-(trifluoromethyl)phenyl)thiazol-5- yl)(3 -fluorophenyl) methanone (570 mg) as a yellow solid.
  • Step 6 A mixture of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 187 mg), (2- amino-4-(3-(trifluoromethyl)phenyl)thiazol-5-yl)(3-fluorophenyl) methanone (200 mg), HOBt (167 mg), EDC (209 mg) and DIPEA (0.286 mL) in dichloromethane (DCM) (30 mL) was stirred at 40 °C for 18 hours.
  • DCM dichloromethane
  • the compounds according to Formula I are RORy modulators, and are useful in the treatment of diseases mediated by RORy.
  • the biological activities of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a RORy modulator, as well as tissue and in vivo models. Dual Fluorescence Energy Transfer (FRET) Assay
  • This assay is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand dependent manner.
  • RORy is a typical nuclear receptor in that it has an AF2 domain in the ligand binding domain (LBD) which interacts with co-activators.
  • LBD ligand binding domain
  • the sites of interaction have been mapped to the LXXLL motifs in the co-activator SRC1(2) sequences. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length co-activator.
  • the assay measures ligand-mediated interaction of the co-activator peptide with the purified bacterial-expressed RORy ligand binding domain (RORy-LBD) to indirectly assess ligand binding.
  • RORy has a basal level of interaction with the co-activator SRC 1(2) in the absence of ligand, thus it is possible to find ligands that inhibit or enhance the RORy/SRCl(2) interaction.
  • RORy-LBD Human RORy Ligand Binding Domain
  • BL21(DE3) as an amino-terminal polyhistidine tagged fusion protein.
  • DNA encoding this recombinant protein was sub-cloned into a modified pET21a expression vector (Novagen).
  • a modified polyhistidine tag (MKKHHHHHHLVPRGS) was fused in frame to residues 263-518 of the human RORy sequence.
  • E.coli cell pellet was resuspended in 300 ml of lysis buffer (30 mM imidazole pH 7.0 and 150 mM NaCl). Cells were lysed by sonication and cell debris was removed by centrifugation for 30 minutes at 20,000g at 4°C. The cleared supernatant was filtered through a 0.45 uM cellulose acetate membrane filter. The clarified lysate was loaded onto a column (XK-26) packed with ProBond Nickel Chelating resin (InVitrogen), pre-equilibrated with 30 mM imidazole pH 7.0 and 150 mM NaCl.
  • the column was developed with a gradient from 30 to 500 mM imidazole pH 7.0. Column fractions containing the RORy-LBD protein were pooled and concentrated to a volume of 5 mis. The concentrated protein was loaded onto a Superdex 200 column pre-equilibrated with 20 mM Tris-Cl pH 7.2 and 200 mM NaCl. The fractions containing the desired RORy-LBD protein were pooled together.
  • Purified RORy-LBD was buffer exchanged by exhaustive dialysis [3 changes of at least 20 volumes (>8000x)] against PBS [lOOmM NaPhosphate, pH 8 and 150mM NaCl].
  • concentration of RORy-LBD was approximately 30uM in PBS.
  • Five-fold molar excess of NHS-LC-Biotin (Pierce) was added in a minimal volume of PBS. This solution was incubated with occasional gentle mixing for 60 minutes at ambient room temperature.
  • the modified RORy-LBD was dialyzed against 2 buffer changes - TBS pH 8.0 containing 5mM DTT, 2mM EDTA and 2% sucrose - each at least 20 times of the volume.
  • the modified protein was distributed into aliquots, frozen on dry ice and stored at -80°C.
  • the biotinylated RORy-LBD was subjected to mass spectrometric analysis to reveal the extent of modification by the biotinylation reagent. In general, approximately 95% of the protein had at least a single site of biotinylation and the overall extent of biotinylation followed a normal distribution of multiple sites ranged from one to five.
  • biotinylated SRC 1(2) solution was prepared by adding an appropriate amount of biotinylated SRC 1(2) from the lOOuM stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM.
  • An appropriate amount of Europium labeled Streptavidin was then added to the biotinylated SRC 1(2) solution in a tube to give a final concentration of 10 nM. The tube was inverted gently and incubated for 15 minutes at room temperature. Twenty-fold excess biotin from the 10 mM stock solution was added and the tube was inverted gently and incubated for 10 minutes at room temperature.
  • biotinylated RORy-LBD solution was prepared by adding an appropriate amount of biotinylated RORy-LBD from the stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM.
  • An appropriate amount of APC labeled Streptavidin was then added to the biotinylated RORy-LBD solution in a tube to give a final concentration of 20 nM. The tube was inverted gently and incubated for 15 minutes at room temperature. Twenty- fold excess biotin from the 10 mM stock solution was then added and the tube was inverted gently and incubated for 10 minutes at room temperature.
  • Equal volumes of the above-described Europium labeled SRC 1(2) peptide and the APC labeled RORy-LBD were gently mixed together to give 20nM RORy-LBD, ⁇ APC-Strepavidin, 20nM SRC 1(2) and 5nM Europium- Streptavidin.
  • the reaction mixtures were incubated for 5 minutes.
  • 25 ul of the reaction mixtures per well was added to the 384-well assay plates containing lul of test compound per well in 100% DMSO. The plates were incubated for lhour and then read on ViewLux in Lance mode for EU/APC.
  • RORy is known to bind to a CNS (conserved non-coding sequences) enhancer element in the IL17 promoter.
  • RORy activity is indirectly assessed using a luciferase reporter construct which contains the human IL17 promoter having the RORy-specific CNS enhancer element.
  • the 3 Kb human IL17 promoter containing the RORy- specific CNS enhancer element was PCR amplified from human genomic DNA and cloned into a pGL4-Luc2/hygro reporter plasmid sequencially as Xhol-Hindlll (1.1 Kb) and Kpnl-Xhol (1.9 Kb) fragments.
  • PCR was used to amplify human IL17 proximal promoter region from genomic DNA of 293T cells using primers as follows: forward primer, 5'- CTCGAGTAGAGCAGGACAGGGAGGAA-3' (Xhol site is underlined) and reverse primer, 5'- AAGCTTGGATGGATGAGTTTGTGCCT-3 ' (Hindlll site is underlined).
  • forward primer 5'- CTCGAGTAGAGCAGGACAGGGAGGAA-3'
  • reverse primer 5'- AAGCTTGGATGGATGAGTTTGTGCCT-3 ' (Hindlll site is underlined).
  • the 1.1 kb DNA bands were excised, purified, and inserted into pMD19-T Simple Vector (Takara).
  • PCR was used to amplify human IL17 promoter region from genomic DNA using primers as follows: forward primer,5'- GGTACCTGCCCTGCTCTATCCTGAGT-3' (Kpnl site is underlined) and reverse primer, 5'-
  • the luciferase reporter plasmid and the RORyt overexpression plasmid were transfected into Jurkat cell line and a stable clone was identified.
  • the stable clone was grown in 10% dialyzed FBS in RPMI (1640) with 800ug/ml geneticin and 400ug/ml hygromecin.
  • ELISA CD4+ cells were isolated from splenocytes of C57BL/6 (B6) mice (Shanghai Laboratory
  • CD4+ T Cell Isolation II Kit Animal Resource Center
  • 96 well plates were pre-coated with anti-CD3 antibody.
  • CD4+ cells were resuspended in RPMI complete medium and were added to the 96-well plates at 3xl0 5 cells/well, with the total volume of each well being 90 ul.
  • a cytokine cocktail (90 ul) was then added to stimulate Thl7 differentiation.
  • the final concentrations of antibodies (R&D Systems) and cytokines (R&D Systems) were: anti-mCD3, 5ug/ml; anti-mCD28, 2ug/ml; anti-mlFNy, lOug/ml; anti-mIL4, lOug/ml; mIL-6, 20ng/ml; mIL-23, lOng/ml; mIL- ⁇ , lOng/ml; TGF- ⁇ , lOng/ml.
  • the cell culture was incubated at 37°C for 3 days. Supernatants were collected and IL-17 concentration was determined by ELISA, performed according to manufacturer's instructions (R&D Systems).
  • the optical density (OD) at 405 nm were measured with a microplate reader (BioRad) and the IL-17 quantity were extrapolated from the standard curve.
  • the percentage of IL-17 inhibition was calculated by referring to the positive control (100%) and the pIC50 were determined by GraphPad. Intracellular staining
  • Thl7 differentiation cell culture described above was maintained for 5 days instead of 3 days.
  • the effect of compounds on the production of IL-17 and IFN- ⁇ in the cells was determined by intracellular staining according to manufacturer's instructions (BD Biosciences).
  • the RORy modulator of Example 9 significantly reduced IL-17 production in Thl7 cells ( Figure 1).
  • the data described below represents a mean pIC50 value of multiple test results if the test was performed more than once. It is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the testing.
  • Example 27 All exemplified compounds except Example 27 were tested in the dual FRET assay described above. All tested compounds except Examples 5, 14, 18, 31, 41 and 42 were found to have a pIC50 between 6 and 9. Example 31 was tested three times and had a pIC50 below 6 in each test. Examples 5, 14, 18, 41 and 42 were tested multiple times and each compound had at least one result indicating it enhanced the RORy/SRCl(2) interaction in the assay; however, all of them were found to inhibit RORy activity in the Jurkat cell luciferase assay and the Thl7 ELISA assay described above.
  • Examples 1-44 All exemplified compounds (Examples 1-44) were tested in the Jurkat cell luciferase assay described above. All tested compounds except Examples 37 and 38 were found to have a pIC50 between 6 and 9. Example 37 was tested twice and Example 38 was tested once, and all showed a pIC50 below 5, the detection limit of the assay.
  • Wild-type mice of the C57BL/6 (B6) strain were obtained from Shanghai Laboratory Animal Resource Center. EAE was induced by intravenous injections of 100 ng of pertussis toxin (List Biological Laboratories) and then subcutaneous immunization with 200 ⁇ of an emulsion composed of MOG 35 .55 peptide (300 ⁇ g/mouse) in PBS and an equal volume of complete Freund's adjuvant containing 5 mg/ml heat-killed Mycobacterium tuberculosis H37Ra (Difco Laboratories) on day 0, followed by another intravenous injections of 100 ng of pertussis toxin on day 2 as described previously (Wang et al. (2006) J. Clin. Invest.
  • mice were scored for disease severity daily using a EAE scoring system (Wang et al. (2006) J. Clin. Invest. 116: 2434-2441): 0, no overt signs of disease; 1, limp tail or hind limb weakness but not both; 2, limptail and paraparesis (weakness, incomplete paralysis of one or two hind limbs); 3, paraplegia (complete paralysis of two hind limbs); 4, paraplegia with forelimb weakness or paralysis; and 5, moribund state or death. Clinical score data were expressed as means ⁇ s.e.m.
  • the RORy modulator of Example 9 delayed EAE onset.
  • Collagen-induced arthritis was induced in 8-week old male DBA/1 mice via an initial intradermal (i.d.) injection of an emulsion consisting of bovine type II collagen in CFA. Mice were intraperitoneally (i.p.) injected with bovine type II collagen 21 days later to boost the immune system, resulting in chronic inflammation in both the hind and the front paws. Each compound was given to the mice at lOOmg/kg twice a day starting from day 20 after the first immunization. Mice were examined for onset and severity of disease in a blinded manner.
  • the RORy modulator of Example 9 reduced disease severity in CIA mice.
  • the compounds of the invention are modulators of RORy and can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases.
  • the Inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, asthma, chronic obstructive pulmonary disease and allergy. Accordingly, in another aspect the invention is directed to methods of treating such diseases.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
  • treat in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.1 mg to 1000 mg.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the invention relates to the use of the compounds of the invention in the preparation of a medicament for the treatment of diseases mediated by RORy. In another embodiment, the invention relates to the compounds of the invention for use in the treatment of diseases mediated by RORy.
  • Such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease and type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, asthma, chronic obstructive pulmonary disease and allergy.
  • autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease and type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, asthma, chronic obstructive pulmonary disease and allergy
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 0.1 mg to 1000 mg.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically- acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

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Abstract

Disclosed are retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.

Description

NOVEL COMPOUNDS
The present invention relates to novel retinoid-related orphan receptor gamma (RORy) modulators and their use in the treatment of diseases mediated by RORy.
Background of the Invention
Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 16:313-355). The ROR family consists of three members, ROR alpha (RORa), ROR beta (RORp) and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB and RORC, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2). RORy is a term used to describe both RORyl and/or RORyt.
While RORyl is expressed in a variety of tissues including thymus, muscle, kidney and liver, RORyt is exclusively expressed in the cells of the immune system. RORyt has been identified as a key regulator of Thl7 cell differentiation. Thl7 cells are a subset of T helper cells which produce IL- 17 and other proinflammatory cytokines. Thl7 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Thl7 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept. Signal. 7: e003; Manel et al. (2008) Nat. Immunol. 9:641-649). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Thl7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman (2008) J. Exp. Med. 205:1517- 1522; Leung et al. (2010) Cell. Mol. Immunol. 7: 182-189). There is evidence that Thl7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al. (2009) Annu. Rev.
Immunol. 27:485-517). RORyt plays a critical role in the pathogenic responses of Thl7 cells (Ivanov et al. (2006) Cell 126:1121-1133). RORyt deficient mice show very little Thl7 cells. In addition, RORyt deficiency resulted in amelioration of EAE. Further support for the role of RORyt in the pathogensis of autoimmune or inflammatory diseases can be found in the following references: Jetten & Joo (2006) Adv.Dev.Biol. 16:313-355; Meier et al. (2007) Immunity 26:643-654; Aloisi & Pujol-Borrell (2006) Nat. Rev. Immunol. 6:205-217; Jager et al. (2009) J. Immunol. 183:7169-7177; Serafmi et al. (2004) Brain Pathol Α4Α64ΑΊ 4; Magliozzi et al. (2007) Brain 130: 1089-1104; Barnes (2008)
Nat.Rev. Immunol. 8:183-192.
In light of the role RORy plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORy activity, which can be used in the treatment of diseases mediated by RORy.
Summary of the Invention
The invention is directed to novel RORy modulators and their use in the treatment of diseases mediated by RORy. Specifically, the invention is directed to compounds according to Formula I.
Figure imgf000003_0001
Formula I
wherein Rl, R2, R3, R4 and R5 are defined below, and to pharmaceutically-acceptable salts thereof.
In another aspect, this invention provides for the use of the compounds of Formula I for the treatment of diseases mediated by RORy. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma. In yet another aspect, the invention is directed to methods of treating such diseases. Brief Description of the Figures
Figure 1(A) shows the inhibitory effect of the RORy modulator Example 9 on the production of IL-17 by ELISA.
Figure 1(B) shows the inhibitory effect of the RORy modulator Example 9 on the production of IL-17 by intracellular staining.
Figure 2 shows the mean clinical scores of control and EAE mice treated with the RORy modulator Example 9.
Figure 3(A) shows the mean clinical scores of control and CIA mice treated with the RORy modulator Example 9.
Figure 3(B) shows the foot volume of control and CIA mice treated with the RORy modulator Example 9.
Detailed Description of the Invention
Terms and Definitions
In describing the invention, chemical elements are identified in accordance with the Periodic Table of the Elements.
"Alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be optionally substituted with one or more substituent as defined herein. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
"Alkoxy" refers to the group -O-R where R is alkyl having the specified number of member atoms. Alkoxy includes methoxy, ethoxy and propoxy.
"Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee,and greater than 90% ee.
"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%). "Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or greater.
"Half-life" refers to the time required for half of a quantity of a substance to be converted to another chemically distinct species in vitro or in vivo.
"Halo" refers to the halogen radicals fluoro, chloro, bromo, and iodo.
"Heteroatom" refers to a nitrogen, sulphur, or oxygen atom.
"Heterocycloalkyl" refers to a saturated or unsaturated ring containing from 1 to 4
heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic.
Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituent as defined herein. Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocycloalkyl rings have from 5 to 7 member atoms. Bicyclic
heterocycloalkyl rings have from 7 to 11 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azetidinyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, and oxabicylo[2.2.1]heptyl.
"Member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
"Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent as defined.
"RORy" refers to all isoforms encoded by the O C gene which include RORyl and RORyt.
"RORy modulator" refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy. RORy modulators include antagonists and inverse agonists of RORy.
"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
"Substituted" in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituent, one or more (as appropriate) member atom within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
Compounds
The present invention provides, in a first aspect, a compound of Formula I or a
pharmaceutically acceptable salt thereof.
Figure imgf000006_0001
Formula I
wherein:
l is phenyl optionally substituted with one to three substituents selected from the group consisting of:
- halo;
- CN;
- (CH2)nOH;
- C1-C3 alkoxy;
- (CH2)nCOOH;
- C1-C4 alkyl optionally substituted with one to three F; - heterocycloalkyl; and
- NRaRa wherein Ra is H or C1-C3 alkyl;
R2 is
- 1,3-benzodioxol or
- phenyl optionally substituted with one to three substituents selected from the group consisting of:
- halo;
- CN;
- (CH2)nOH;
- C1-C3 alkoxy;
- C1-C4 alkyl optionally substituted with one to three F; and
- (CH2)nCOOH;
R3 is H or Cl-C6 alkyl;
R4 is H or Cl-C6 alkyl;
R5 is C1-C6 alkyl optionally substituted with one to three F;
n is 0, 1, 2, 3, 4, 5 or 6; and
wherein when said R2 is other than 1,3-benzodioxol, then at least one of Rl and R2 is phenyl having at least one substituent. In one embodiment, the present invention relates to compounds of Formula I wherein Rl is phenyl substituted with halo. In another embodiment, the present invention relates to compounds of Formula I wherein Rl is phenyl substituted with CN, C1-C3 alkoxy, CF3, OH or heterocycloalkyl. In yet another embodiment, the present invention relates to compounds of Formula I wherein Rl is unsubstituted phenyl. The present invention also relates to compounds of Formula I or any of the above embodiments wherein Rl is 3-chlorophenyl or 3-fluorophenyl. The present invention also relates to compounds of Formula I or any of the above embodiments wherein Rl is 3-cyanophenyl or 3- (trifluoromethyl)phenyl.
The present invention also relates to compounds of Formula I or any of the above embodiments wherein R2 is phenyl substituted with halo. In one embodiment, the invention also relates to compounds of any of the above embodiments wherein R2 is 2-chlorophenyl or 2- fluorophenyl. In another embodiment, the invention also relates to compounds of any of the above embodiments wherein R2 is 3-chlorophenyl or 3-fluorophenyl. The present invention also relates to compounds of Formula I or any of the above embodiments wherein R2 is phenyl substituted with C1-C3 alkyl or C1-C3 alkoxy. In one embodiment, the invention also relates to compounds of any of the above embodiments wherein R2 is 2-methylphenyl or 2-methoxyphenyl The present invention also relates to compounds of Formula I or any of the above embodiments wherein R2 is phenyl substituted with hydroxyl substituted C1-C3 alkyl.
The present invention also relates to compounds of Formula I or any of the above embodiments wherein R3 is H.
The present invention also relates to compounds of Formula I or any of the above embodiments wherein R4 is H.
The present invention also relates to compounds of Formula I or any of the above embodiments wherein R5 is C1-C3 alkyl. In one embodiment, the invention also relates to compounds of any of the above embodiments wherein R5 is methyl. In another embodiment, the invention also relates to compounds of any of the above embodiments wherein R5 is ethyl. In one embodiment, the compound of the present invention is not a compound of Formula I wherein R2 is 4-chlorophenyl. In one embodiment, the compound of the present invention is not a compound of Formula I wherein R2 is 4-fluorophenyl.
The meaning of any functional group or substituent thereon at any one occurrence in Formula I, or any subformula thereof, is independent of its meaning, or any other functional group's or substituent's meaning, at any other occurrence, unless stated otherwise.
The compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
The compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
In certain embodiments, compounds according to Formula I may contain an acidic functional group. In certain other embodiments, compounds according to Formula I may contain a basic functional group. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts may impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to the use of pharmaceutically-acceptable salts of the compounds according to Formula I.
As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
As used herein, the term "compounds of the invention" means both the compounds according to Formula I and the pharmaceutically-acceptable salts thereof. The term "a compound of the invention" also appears herein and refers to both a compound according to Formula I and its pharmaceutically-acceptable salts. The invention also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride).
The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates.
The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, I spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
Compound Preparation The compounds according to Formula I are prepared using conventional organic syntheses.
Suitable synthetic routes are depicted below in the following general reaction scheme. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
Scheme 1
Figure imgf000011_0001
Formula I
[Conditions: a) bromine, Et20; b) bis {[4-(methyloxy)phenyl]methyl} amine, NH4SCN, acetone (for PMB protection); or N- 2-propen-l-yl-2-propen-l -amine , KSCN, acetonitrile (for allylic protection); c) DMF, 85 °C; d) TFA, 80 °C (for PMB protection); or AyV-dimethylbarbituric acid, Pd(PPh3)4, 1,4-dioxane (for allylic protection); e) HOBt (or pyridine), EDC, acid, DCM]
Scheme 1 represents a general reaction scheme for preparing compounds of Formula I. Starting material substituted a-bromo ketones 1.2 can be obtained commercially or synthesized using methyl ketones 1.1. Protected carbamothioyl amides 1.4 can be obtained by condensation of acyl chlorides 1.3, thiocyanates and bis {[4-(methyloxy)phenyl]methyl} amine or N-2-propen-l-yl-2- propen-1 -amine (commercially available). Treatment of 1.2 with 1.4 gives protected thiazole ketones 1.5. Deprotection of 1.5 affords the amines 1.6, which are then condensed with an appropriate acid in the presence of HOBt and EDC to obtain compounds of Formula I.
Examples
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
Abbreviations
BINAP 2,2 ' -bis(diphenylphosphino)- 1 , 1 ' -binaphthyl
DCM dichloromethane
DMF NN-dimethylformamide
DMSO dimethylsulphoxide
EA ethyl acetate
EDC N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
ES Electrospray
HOBt Hydroxybenzotriazole
IPA isopropylalcohol
LCMS Liquid Chromatography Mass Spectrometry
MDAP mass directed automated preparative liquid chromatography.
MS mass spectrometry
PE petroleum ether
PG protecting group
PMB />-methoxybenzyl
T room temperature
sat. saturated
TFA trifluoroacetic acid
THF tetrahydrofuran Chromato graphy
Unless stated otherwise, all chromatography was carried out using silica columns.
LCMS Conditions:
1) Acidic conditions:
Mobile phase: water containing 0.05 % TFA / acetonitrile
Column: XBridgeTM CI 8 30 x 100 mm - 5 microns
Detection: MS and photodiode array detector (PDA)
2) Basic conditions:
Mobile phase: water containing 0.08 % NH4HCO3 / acetonitrile Column: XBridgeTM CI 8 30 x 100 mm - 5 microns;
Detection: MS and photodiode array detector (PDA)
MDAP Conditions:
1) Acidic conditions:
Instrument: Waters instrument
Column: Sunfire Prep CI 8 column (5 um, 19 x 50 mm)
Mobile phase: water containing 0.05% TFA / acetonitrile.
2) Basic conditions:
Instrumnet: Waters instrument
Column: Xbridge Prep CI 8 column (5 um, 19 x 50 mm)
Mobile phase: water containing 0.04% ammonia/ acetonitrile.
Example 1
/V-{5-[(2,6-dichlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000013_0001
Intermediate la: 2-bromo-l-(2,6-dichlorophenyl)ethanone
Figure imgf000013_0002
Bromine (0.818 mL) was added into a solution of l-(2,6-dichlorophenyl)ethanone (3 g) in diethyl ether (20 mL) at 0 °C dropwise. After the additon was complete, the reaction mixture was allowed to warm to room temperature, and stirred at this temperature for 2 hours. Solvent was removed in vacuo to afford 2-bromo-l-(2,6-dichlorophenyl)ethanone (4.2 g) as a yellow oil. MS(ES+) m/z 267 (MH+).
Intermediate lb: N-[(bis{[4-(methyloxy)phenyllmethyl}amino)carbonothioyllbenzamide
Figure imgf000014_0001
Step 1: A mixture of l-[4-(methyloxy)phenyl]methanamine (40 g) and 4- (methyloxy)benzaldehyde (40.5 g) in methanol (220 mL) was heated to reflux for 3 hours. After cooling to 0 °C, NaBH4 (14.34 g) was added portionwise within 30 min and the resulting mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc for 3 times. The combined organic layers were washed with water and brine, then dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford bis {[4-(methyloxy)phenyl]methyl} amine (75.9 g) as a colorless oil. MS(ES+) m/z 258 (MH+). Step 2: To a solution of benzoyl chloride (2.50 g) in acetone (36 mL) cooled at 0 °C was added ammonium thiocyanate (2.71 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis {[4-(methyloxy)phenyl]methyl} amine (5.49 g) was added and stirred for an additional 30 mins. The mixture was concentrated under reduced pressure then purified directly by chromatography (EtOAc : PE = 0-10 %) to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (7.1 g) as a yellow solid. MS(ES ) m/z All (MH+).
Intermediate lc: (2-amino-4-phenyl-l,3-thiazol-5-yl (2,6-dichlorophenyl methanone
Figure imgf000014_0002
A solution of 2-bromo-l-(2,6-dichlorophenyl)ethanone (intermediate la, 191 mg) and N- [(bis{[4-(methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC03, and then extracted with
EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by chromatography (EtOAc : PE = 0-50 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)(2,6-dichlorophenyl)methanone (180 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Intermediate Id: |"4-(ethylsulfonyl)phenyllacetic acid
Figure imgf000015_0001
Step 1: A solution of sodium nitrite (18.4 g) in 133 mL of water was added dropwise at 0 °C, while stirring, to a suspension of (4-aminophenyl)acetic acid (40.2 g) in 133 mL of water and 54 mL of concentrated hydrochloric acid. After the addition was complete, the reaction mixture was stirred at the same temperature for 45 minutes. This solution of cold diazonium salt was then added dropwise at room temperature to a mixture of potassium ethylxanthate (49.4 g), 80 mL of water and 200 mL of 2 M sodium carbonate solution. The mixture was heated to 45 °C and stirred at this temperature until gas evolution stops. After cooling to room temperature, pH was adjusted to 1 with concentrated hydrochloric acid and the oiled xanthogenate ester was extracted with ether. Solvent was evaporated to give a dark red liquid (4-{[(ethyloxy)carbonothioyl]thio}phenyl)acetic acid (90 g). MS(ES+) m/z 257 (MH+).
Step 2: (4-{[(Ethyloxy)carbonothioyl]thio}phenyl)acetic acid (90 g) was taken up in 340 mL of ethanol, and a solution of 70 g of potassium hydroxide in 340 mL of water was added. Boiling at reflux was effected for 20 hours. The major portion of ethanol was subsquently removed by the distillation under reduced pressure. The aqueous phase was cooled with ice, and acidified with concentrated hydrochloric acid while stirring. The obtained solution was extracted with diethyl ether (500 mL). The organic phase was washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated to affored the desired product as a yellow solid (4-mercaptophenyl)acetic acid (33 g). MS(ES+) m/z 169 (MH+).
Step 3: To a solution of (4-mercaptophenyl)acetic acid (33 g) in N,N-dimethylformamide (DMF) (240 mL) was added K2CO3 (108 g) and bromoethane (64.1 g). The reaction mixture was stirred at T. After 2.5 hours, the starting material was totally consumed. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was washed with water (300 mL x 4) and brine (200 mL), dried over sodium sulphate, filtered, and concentrated to give the desired product ethyl [4-(ethylthio)phenyl]acetate (34 g) as a pale yellow solid. MS(ES ) m/z 225 (MH+).
Step 4: A solution of ethyl [4-(ethylthio)phenyl] acetate (34 g) in dichloromethane (DCM) (500 mL) was cooled to 0 °C with an ice bath. MCPBA (78 g) was added in portions, and the reaction mixture was stirred at T overnight. The obtained suspension was filtered. The filtrate was washed with sat. sodium carbonate solution (400 mL x 2), water (500 mL), then brine (250 mL). The obtained solution was dried over sodium sulphate, filtered, and concentrated. The residue was purified by column chromatography (silica gel; EtOAc : PE = 0: 1 to 1 : 1) to afford the target compound ethyl [4- (ethylsulfonyl)phenyl]acetate as a yellow liquid (25 g). MS(ES+) m/z 257 (MH+).
Step 5: To a solution of ethyl [4-(ethylsulfonyl)phenyl]acetate (25 g) in ethanol (180 mL) was added a solution of NaOH (14.28 g) in water (180 mL). The reaction mixture was stirred at room temperature overnight. Ethanol was removed under reduced pressure, and 150 ml of water was added. The aqueous phase was washed with dichloromethane (100 mL x 2), and then acidified with 6 M HC1 to pH = 1. This solution was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with brine (200 mL), dried over sodium sulphate, filtered, and concentrated to give the desired product as a dark red oil, which slowly solidified to give a yellow solid [4- (ethylsulfonyl)phenyl]acetic acid (20 g). ¾-NMR (400 MHz, DMSO- ) δ ppm 1.07 (t, J= 9.6 Hz, 3H), 3.26 (q, J= 9.6 Hz, 2H), 3.72 (s, 2H), 7.53 (d, J= 11.2 Hz, 2H), 7.81 (d, J= 11.2 Hz, 2H), 12.53 (s, 1H); MS(ES+) m/z 229 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 48.0 mg), EDC (57.6 mg) and HOBt (40.6 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins, and then (2-amino-4-phenyl-l,3-thiazol-5-yl)(2,6-dichlorophenyl)methanone
(intermediate lc, 70 mg) was added. The reaction mixure was stirred at room temperature for 1 day.
The reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with
DCM for 3 times. The combined organics were washed with brine and dried over anhydrous Na2SC>4.
After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{5-[(2,6-dichlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4-
(ethylsulfonyl)phenyl]acetamide (35 mg) as a white solid. ¾-NMR (400 MHz, DMSO- 6) δ ppm
1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 7.17-7.20 (m, 2H), 7.24-7.27 (m, 2H), 7.30-7.35 (m, 3H), 7.47 (d, J= 2.4 Hz, 1H), 7.63 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.18 (s, 1H); MS(ES+) m/z 559 (MH+).
Example 2
2-[4-(ethylsulfonyl)phenyl]- V-(5-{[2-(methyloxy)phenyl]carbonyl}-4-phenyl-l,3-thiazol-2- yl)acetamide
Figure imgf000017_0001
Intermediate 2a: 2-amino-4-phenylthiazol-5-yl)(2-methoxyphenyl)methanone
Figure imgf000017_0002
A solution of 2-bromo-l-[2-(methyloxy)phenyl]ethanone (229 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 400 mg) in NN- dimethylformamide (DMF) (4 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (7 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure and the residue was neutralized with sat. NaHC(¾, which was then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-80 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)[2- (methyloxy)phenyl]methanone (238 mg) as a yellow solid. MS(ES+) m/z 311 (MH+).
Preparation of the final product
A mixture of (2-amino-4-phenyl-l,3-thiazol-5-yl)[2-(methyloxy)phenyl]methanone
(intermediate 2a, 60 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 46.3 mg), EDC (48.2 mg) and HOBt (26.1 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford 2-[4-(ethylsulfonyl)phenyl]-N-(5-{[2-(methyloxy)phenyl]carbonyl}-4-phenyl-l,3-thiazol-2- yl)acetamide (35 mg) as a white solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 3.42 (s, 3H), 4.00 (s, 2H), 6.67 (d, J= 8.7 Hz, 1H), 6.85 (t, J= 7.4 Hz, 1H), 7.14 (t, J= 7.3 Hz, 2H), 7.19-7.31 (m, 5H), 7.62 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.00 (s, 1H); MS(ES+) m/z 521 (MH+).
Example 3
2-[4-(ethylsulfonyl)phenyl]- V-{5-[(2-methylphenyl)carbonyl]-4-phenyl-l,3-thiazol-2- yl}acetamide
Figure imgf000018_0001
Intermediate 3a: 2-bromo-l-(2-methylphenyl)ethanone
Figure imgf000018_0002
To a solution of l-(2-methylphenyl)ethanone (2 g) in diethyl ether (50 mL) cooled at 0 °C was added bromine (0.768 mL) dropwise and the resulting mixture was stirred at room temperature for 1.5 hours. Solvent was removed in vacuo to afford 2-bromo-l-(2-methylphenyl)ethanone (3.0 g) as a brown oil. MS(ES+) m/z 213 (MH+).
Figure imgf000018_0003
A solution of 2-bromo-l-(2-methylphenyl)ethanone (intermediate 3a, 152 mg) and N- [(bis { [4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-30 %) to afford (2-amirio-4-pheriyl-l,3-thiazol-5-yl)(2-methylpheriyl)methariorie (170 mg) as a yellow solid. MS(ES+) m/z 295 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 57.0 mg), EDC (59.3 mg) and HOBt (41.8 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. (2-Amino-4-phenyl-l,3-thiazol-5-yl)(2-methylphenyl)methanone (intermediate 3b, 70 mg) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organics were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford 2-[4-(ethylsulfonyl)phenyl]-N-{5-[(2-methylphenyl)carbonyl]-4-phenyl-l,3-thiazol-2- yljacetamide (53 mg) as a white solid. ¾-NM (400 MHz, DMSO- 6) δ ppm 1.11 (t, J= 7.2 Hz, 3H), 2.27 (s, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.00 (s, 2H), 6.94 (t, J= 7.2 Hz, 1H), 7.10 (d, J= 7.2 Hz, 1H), 7.15-7.24 (m, 5H), 7.35-7.37 (m, 2H), 7.62 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.07 (s, 1H); MS(ES+) m/z 505 (MH+).
Example 4
A'-{5-[(2-chlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000019_0001
Intermediate 4a: 2-bromo-l-(2-chlorophenyl)ethanone
Figure imgf000019_0002
To a solution of l-(2-chlorophenyl)ethanone (3 g) in diethyl ether (30 mL) cooled at 0 °C was added bromine (1.000 mL) dropwise and the resulting mixture was stirred at room temperature for 1.5 hours. Solvent was removed in vacuo to afford 2-bromo-l-(2-chlorophenyl)ethanone (4.6 g) as a brown oil. MS(ES+) m/z 233 (MH+).
Figure imgf000020_0001
A solution of 2-bromo-l-(2-chlorophenyl)ethanone (intermediate 4a, 146 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-40 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)(2-chlorophenyl)methanone (150 mg) as a yellow solid. MS(ES+) m/z 315 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 53.3 mg), EDC (55.4 mg) and HOBt (39.1 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. Then (2-amino-4-phenyl-l,3-thiazol-5-yl)(2-chlorophenyl)methanone
(intermediate 4b, 70 mg) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous layer was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{5-[(2-chlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide (24 mg) as a yellow solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.01 (s, 2H), 7.16-7.20 (m, 3H), 7.21-7.31 (m, 3H), 7.35-7.38 (m, 3H), 7.62 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.13 (s, 1H); MS(ES+) m/z 525 (MH+).
Example 5
A'-{5-[(3-chlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000021_0001
Intermediate 5a: 2-bromo-l-(3-chlorophenvDethanone
Figure imgf000021_0002
To a solution of l-(3-chlorophenyl)ethanone (1 g) in diethyl ether (20 mL) cooled at 0 °C was added bromine (0.367 mL) dropwise. The reaction mixture was allowed to warm to room temperature. After stirring for 2 hours, most of the starting materials was consumed. Solvent was removed in vacuo to afford 2-bromo-l-(3-chlorophenyl)ethanone (1.56 g) as a yellow oil. MS(ES+) m/z 233
(MH+).
Intermediate 5b: (2-amino-4-phenyl-l,3-thiazol-5-yl)(3-chlorophenyl)methanone
Figure imgf000021_0003
A solution of 2-bromo-l-(3-chlorophenyl)ethanone (intermediate 5a, 146 mg) and N- [(bis { [4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins to finish the first step ring closure reaction. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in trifluoroacetic acid (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers was washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-30 %) to afford (2-amino-4-phenyl-l,3- thiazol-5-yl)(3-chlorophenyl)methanone (130 mg) as a yellow solid. MS(ES+) m/z 315 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 53.3 mg), EDC (55.4 mg) and HOBt (39.1 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature for 15 mins. Then (2-amino-4-phenyl-l,3-thiazol-5-yl)(3-chlorophenyl)methanone (intermediate 5b, 70 mg) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was then partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organics were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N- {5-[(3- chlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (37 mg) as a yellow solid. ^-NM (400 MHz, DMSO-d6) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 7.17-7.27 (m, 4H), 7.34-7.36 (m, 2H), 7.43-7.46 (m, 3H), 7.64 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 13.12 (s, 1H); MS(ES+) m/z 525 (MH+). Example 6
2-[4-(ethylsulfonyl)phenyl]- V-(4-phenyl-5-{[2-(trifluoromethyl)phenyl]carbonyl}-l,3-thiazol-2- yl)acetamide
Figure imgf000022_0001
Intermediate 6a: 2-bromo-l-(2-(trifluoromethyl)phenyl)ethanone
Figure imgf000022_0002
To a solution of l-[2-(trifluoromethyl)phenyl]ethanone (1 g) in diethyl ether (10 mL) cooled at 0 °C was added bromine (0.288 mL) dropwise. The resulting mixture was allowed to warm to room temperature. After stirring for 2 hours, the reaction was complete. Solvent was removed in vacuo to afford 2-bromo-l-[2-(trifluoromethyl)phenyl]ethanone (1.488 g) as a yellow oil. MS(ES+) m/z 267 (MH+).
Intermediate 6b: (2-amino-4-phenyl-l,3-thiazol-5-yl)[2-(trifluoromethyl)phenyllmethanone
Figure imgf000022_0003
A solution of 2-bromo-l-[2-(trifluoromethyl)phenyl]ethanone (intermediate 6a, 381 mg) and N- [(bis{[4-(methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 400 mg) in NN-dimethylformamide (DMF) (4 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (7 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-70 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)[2-
(trifluoromethyl)phenyl]methanone (336 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A mixture of (2-amino-4-phenyl-l,3-thiazol-5-yl)[2-(trifluoromethyl)phenyl]methanone (intermediate 6b, 70 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 48.2 mg), EDC (50.1 mg) and HOBt (35.3 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford 2-[4-(ethylsulfonyl)phenyl]-N-(4-phenyl-5-{[2-(trifluoromethyl)phenyl]carbonyl}-l,3-thiazol- 2-yl)acetamide (28 mg) as a white solid. LH-NM (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.01 (s, 2H), 7.16-7.26 (m, 3H), 7.32-7.35 (m, 2H), 7.38-7.44 (m, 2H), 7.50-7.54 (m, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.70 (d, J= 7.9 Hz, 1H), 7.87 (d, J= 8.3 Hz, 2H), 13.16 (s, 1H); 19F-NMPv (376 MHz, DMSO-d6) δ ppm -56.86. MS(ES+) m/z 559 (MH+).
Example 7
2-[4-(ethylsulfonyl)phenyl]- V-{5-[(2-fluorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2- yl}acetamide
Figure imgf000023_0001
Intermediate 7a: 2-bromo-l-(2-fluorophenyl)ethanone
Figure imgf000023_0002
To a solution of l-(2-fluorophenyl)ethanone (1.5 g) in diethyl ether (30 mL) cooled at 0 °C was added bromine (0.587 mL) dropwise. The mixture was allowed to warm to room temperature. After stirring for 1.5 hours, most of the starting material was consumed. Solvent was removed in vacuo to afford 2-bromo-l-(2-fluorophenyl)ethanone (2.432 g) as an orange oil. MS(ES+) m/z 217 (MH+).
Intermediate 7b: (2-amino-4-phenyl-l,3-thiazol-5-yl)(2-fluorophenyl)methanone
Figure imgf000024_0001
A solution of 2-bromo-l-(2-fluorophenyl)ethanone (intermediate 7a, 155 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4.
After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-35 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)(2-fluorophenyl)methanone (150 mg) as a yellow solid. MS(ES+) m/z 299 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 56.2 mg), EDC (58.5 mg) and HOBt (41.2 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. (2-Amino-4-phenyl-l,3-thiazol-5-yl)(2-fluorophenyl)methanone (intermediate 7b, 70 mg) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous
Na2S04. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford 2-[4-(ethylsulfonyl)phenyl]-N-{5-[(2-fluorophenyl)carbonyl]-4-phenyl-l,3-thiazol- 2-yl}acetamide (50 mg) as a yellow solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 6.88-6.93 (m, 1H), 7.05-7.09 (m, 1H), 7.13-7.17 (m, 2H), 7.20-7.24 (m, 1H), 7.32-7.38 (m, 3H), 7.40-7.44 (m, 1H), 7.63 (d, J= 8.0 Hz, 2H), 7.87 (d, J = 2H), 13.12 (s, 1H); 19F-NM (376 MHz, DMSO-d6) δ ppm -114.37; MS(ES+) m/z 509 (MH+).
Example 8
N- [5-(l,3-benzodioxol-5-ylcarbonyl)-4-phenyl-l,3-thiazol-2-yl] -2- [4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000025_0001
Intermediate 8a: l-(l,3-benzodioxol-5-yl)-2-bromoethanone
Figure imgf000025_0002
Bromine (0.628 mL) was added into a solution of l-(l,3-benzodioxol-5-yl)ethanone (2 g) in diethyl ether (20 mL) and methanol (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hours. The formed precipitate was collected by filtration, and washed with diethyl ether. The crude product was further dried in vacuo to afford l-(l,3-benzodioxol-5-yl)-2- bromoethanone (1.5 g) as a yellow solid. MS(ES+) m/z 243 (MH+).
Intermediate 8b: (2-amino-4-phenyl-l,3-thiazol-5-yl)(l,3-benzodioxol-5-yl)methanone
Figure imgf000025_0003
A solution of l-(l,3-benzodioxol-5-yl)-2-bromoethanone (intermediate 8a, 152 mg) and N- [(bis{[4-(methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)(l,3-benzodioxol-5- yl)methanone (150 mg) as a yellow solid. MS(ES+) m/z 325 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 51.7 mg), EDC (53.8 mg) and HOBt (37.9 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. Then (2-amino-4-phenyl-l,3-thiazol-5-yl)(l,3-benzodioxol-5-yl)methanone (intermediate 8b, 70 mg) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous
Na2S04. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-[5-(l,3-benzodioxol-5-ylcarbonyl)-4-phenyl-l,3-thiazol-2-yl]-2-[4- (ethylsulfonyl)phenyl]acetamide (23 mg) as a white solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.28 (q, J= 7.2 Hz, 2H), 4.01 (s, 2H), 6.05 (s, 2 H), 6.76 (d, J= 8.0 Hz, 1H), 7.13-7.17 (m, 2H), 7.23-7.31 (m, 3H), 7.39-7.42 (m, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.03 (s, 1H); MS(ES+) m/z 535 (MH+).
Example 9
A'-{4-(3-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000026_0001
A solution of 2-bromo-l-(2-chlorophenyl)ethanone (intermediate 4a, 155 mg) and N- [(bis { [4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 11a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](2- chlorophenyl)methanone (198 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](2-chlorophenyl)methanone (intermediate 9a, 116 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 83 mg), EDC (89 mg) and HOBt (62.8 mg) in dichloromethane (DCM) (5 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure. The residue was purified by MDAP to afford N-{4-(3-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-
(ethylsulfonyl)phenyl]acetamide (56 mg) as a white solid. ^-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.02 (s, 2H), 7.19-7.36 (m, 7H), 7.41 (dd, J= 1.3 Hz, J= 7.6 Hz, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.17 (s, 1H); MS(ES+) m/z 559 (MH+). Example 10
A'-{4-(3-chlorophenyl)-5-[(2-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000027_0001
Intermediate 10a: [2-amino-4-(3-chlorophenyl)-l ,3-thiazol-5-yll(2-fluorophenyl)methanone
Figure imgf000028_0001
A mixture of 2-bromo-l-(2-fluorophenyl)ethanone (intermediate 7a, 159 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 11a, 278 mg) in NN-dimethylformamide (DMF) (3 mL) was heated to 85 °C under N2 for 40 mins. Most of DMF was removed under reduced pressure. The residue was dissolved into TFA (4 mL) and the obtained solution was heated to reflux overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC03, and then extracted with EtOAc for 3 times. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the solution was concentrated under reduced pressure and further purified by chromatography on silica gel (EtOAc : petroleum ether = 0-30 %) to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](2-fluorophenyl)methanone (160 mg) as a yellow solid. MS(ES+) m/z 333 (MH+).
Preparation of the final product
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](2-fluorophenyl)methanone (intermediate 10a, 70 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 50.4 mg), HOBt (42.6 mg) and EDC (60.5 mg) in dichloromethane (DCM) (3 mL) was stirred at room temperature under N2 for 1 day. Solvent was removed under reduced pressure. The residue was purified by MDAP directly to afford N-{4-(3-chlorophenyl)-5-[(2-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide (36 mg) as a white solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 6.97 (t, J= 8.0 Hz, 1H), 7.09-7.13 (m, 1H), 7.21 (t, J= 8.0 Hz, 1H), 7.28-7.47 (m, 5H), 7.63 (d, J= 8.0 Hz, 2H), 7.87 (d, J= 7.6 Hz, 2H), 13.15 (s, 1H); 19F NMR (376 MHz, DMSO- ) δ ppm -114.50; MS(ES+) m/z 543 (MH+).
Example 11
A'-{4-(3-chlorophenyl)-5-[(3-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000029_0001
Intermediate 11a: 2-bromo-l-(3-fluorophenyl ethanone
Figure imgf000029_0002
To a solution of l-(3-fluorophenyl)ethanone (1.5 g) in diethyl ether (30 mL) cooled at 0 °C was added bromine (0.615 mL) dropwise. The reaction was allowed to warm to room temperature. After stirring for 1.5 hours, most of the starting material was consumed. Solvent was removed in vacuo to afford 2-bromo-l-(3-fluorophenyl)ethanone (2.402 g) as a brown oil. MS(ES+) m/z 217 (MH+).
Intermediate 1 lb: [2-amino-4-(3-chlorophenyl -l,3-thiazol-5-yl (3-fluorophenvnmethanone
Figure imgf000029_0003
A solution of 2-bromo-l-(3-fluorophenyl)ethanone (intermediate 11a, 127 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 11a, 242 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-30 %) to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](3- fluorophenyl)methanone (165 mg) as a yellow solid. MS(ES+) m/z 333 (MH+).
Preparation of the final product A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](3-fluorophenyl)methanone (intermediate l ib, 70 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 50.4 mg), HOBt (42.6 mg) and EDC (60.5 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature for 1 day. Solvent was removed under reduced pressure. The residue was purified by MDAP to afford N- {4-(3-chlorophenyl)-5-[(3-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-
(ethylsulfonyl)phenyl]acetamide (9 mg) as a white solid. Ή-ΝΜΡ (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.03 (s, 2H), 7.21-7.36 (m, 7H), 7.40 (t, J= 1.6 Hz, 2H), 7.63 (d, J= 8.0 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 13.14 (s, 1H); 19F-NM (376 MHz, DMSO-d6) δ ppm -112.82; MS(ES+) m/z 543 (MH+). Example 12
A'-[4-(3-chlorophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000030_0001
Intermediate 12a: [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl (phenyl)methanone
Figure imgf000030_0002
A solution of 2-bromo-l-phenylethanone (116 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 11a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](phenyl)methanone (172 mg) as a yellow solid. MS(ES+) m/z 315 (MH+).
Preparation of the final product
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](phenyl)methanone (intermediate 12a, 80 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 60.9 mg), EDC (63.3 mg) and HOBt (44.6 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 3 days. Solvent was removed under reduced pressure and the residue was purified directly by MDAP to afford N-[4-(3-chlorophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4-
(ethylsulfonyl)phenyl]acetamide (51 mg) as a white solid. ^-NM (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.02 (s, 2H), 7.21-7.35 (m, 5H), 7.42 (t, J= 1.8 Hz, 1H), 7.47 (t, J= 7.4 Hz, 1H), 7.56-7.58 (m, 2H), 7.63 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.10 (s, 1H); MS(ES+) m/z 525 (MH+).
Example 13
A'-{4-(3-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide
Figure imgf000031_0001
Intermediate 13a: [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl (3-chlorophenyl)methanone
Figure imgf000031_0002
A solution of 2-bromo-l-(3-chlorophenyl)ethanone (intermediate 5a, 155 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 11a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](3- chlorophenyl)methanone (206 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](3-chlorophenyl)methanone (intermediate 13a, 80 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 54.9 mg), EDC (57.1 mg) and HOBt (40.2 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 3 days. Solvent was removed under reduced pressure and the residue was purified directly by MDAP to afford N-{4-(3-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-
(ethylsulfonyl)phenyl]acetamide (50 mg) as a white solid. ^-NM (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.03 (s, 2H), 7.21-7.33 (m, 4H), 7.40 (t, J= 1.8 Hz, 1H), 7.45-7.49 (m, 3H), 7.64 (d, J= 8.3 Hz, 2H), 7.88 (d, J= 8.3 Hz, 2H), 13.15 (s, 1H); MS(ES+) m/z 559 (MH+). Example 14
A'-{4-(3-chlorophenyl)-5-[(4-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000032_0001
Intermediate 14a: [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl (4-fluorophenyl)methanone
Figure imgf000032_0002
A solution of 2-bromo-l-(4-fluorophenyl)ethanone (150 mg) and N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 11a, 300 mg,) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, solvent was removed in vacuo and the residue was stirred in TFA (4.5 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](4-fluorophenyl)methanone (288 mg) as a yellow solid. MS(ES+) m/z 333 (MH+).
Preparation of the final product
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](4-fluorophenyl)methanone (intermediate 14a, 100 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 49.7 mg), EDC (51.7 mg) and HOBt (36.4 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure. The residue was directly purified by MDAP to afford N-{4-(3-chlorophenyl)-5-[(4-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide (39 mg) as a white solid. ^-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J = 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.02 (s, 2H), 7.09-7.14 (m, 2H), 7.24 (t, J= 7.8 Hz, 1H), 7.32-7.35 (m, 2H), 7.41 (t, J= 1.8 Hz, 1H), 7.61-7.65 (m, 4H), 7.88 (d, J= 8.3 Hz, 2H), 13.11 (s, 1H); 19F-NMPv (376 MHz, DMSO- 6) δ ppm -106.38; MS(ES+) m/z 543 (MH+). Example 15
A'-{4-(4-chlorophenyl)-5-[(2-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000033_0001
Intermediate 15a: N-[(bis{[4-(methyloxy)phenyllmethyl}amino)carbonothioyll-4-chlorobenzamide
Figure imgf000033_0002
Step 1: see step 1 for preparing intermediate lb.
Step 2: To a solution of 4-chlorobenzoyl chloride (1.2 g) in acetone (18 mL) cooled at 0 °C was added ammonium thiocyanate (1.044 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis{[4-(methyloxy)phenyl]methyl}amine (2.70 g) was added at the same
temperature and stirred for an additional 30 mins. The mixture was concentrated under reduced pressure, and then purified directly by chromatography (EtOAc : PE = 0-15 %) to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-4-chlorobenzamide (3.484 g) as a brown solid. MS(ES+) m/z 455 (MH+).
Intermediate 15b: [2-amino-4-(4-chlorophenyl -l,3-thiazol-5-yl (2-fluorophenvnmethanone
Figure imgf000034_0001
A solution of 2-bromo-l-(2-fluorophenyl)ethanone (intermediate 7a, 130 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-4-chlorobenzamide (intermediate 15a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-60 %) to afford [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](2- fluorophenyl)methanone (160 mg) as a yellow solid. MS(ES+) m/z 333 (MH+).
Preparation of the final product
A suspension of [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](2-fluorophenyl)methanone (intermediate 15b, 70 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 50.4 mg), EDC (52.4 mg) and HOBt (37.0 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature for 1.5 days. Solvent was removed under reduced pressure and the resulting residue was purified directly by MDAP to afford N-{4-(4-chlorophenyl)-5-[(2-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2- [4-(ethylsulfonyl)phenyl]acetamide (21 mg) as a white solid. ^-NMR (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.02 (s, 2H), 6.94-6.99 (m, 1H), 7.10-7.14 (m, 1H), 7.21-7.23 (m, 2H), 7.35-7.47 (m, 4H), 7.63 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.16 (s, 1H); 19F-NMPv (376 MHz, DMSO- ) δ ppm -114.23; MS(ES+) m/z 543 (MH+).
Example 16
A'-{4-(4-chlorophenyl)-5-[(3-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000035_0001
Intermediate 16a: [2-amino-4-(4-chlorophenyl)-l -thiazol-5-yll(3-fluorophenyl)methanone
Figure imgf000035_0002
A solution of 2-bromo-l-(3-fluorophenyl)ethanone (intermediate 11a, 130 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-4-chlorobenzamide (intermediate 15a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with
EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](3- fluorophenyl)methanone (172 mg) as a yellow solid. MS(ES+) m/z 333 (MH+).
Preparation of the final product
A suspension of [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](3-fluorophenyl)methanone (intermediate 16a, 70 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 50.4 mg), EDC (52.4 mg) and HOBt (37.0 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature for 1.5 days. Solvent was removed under reduced pressure and the resulting residue was purified directly by MDAP to afford N-{4-(4-chlorophenyl)-5-[(3-fluorophenyl)carbonyl]-l,3-thiazol-2-yl}-2- [4-(ethylsulfonyl)phenyl]acetamide (35 mg) as a white solid. Ή-ΝΜΡ (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.02 (s, 2H), 7.26-7.41 (m, 8H), 7.63 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.15 (s, 1H); 19F-NM (376 MHz, DMSO-d6) δ ppm -112.78;
MS(ES+) m/z 543 (MH+). Example 17 A'-{4-(4-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000036_0001
Intermediate 17a: [2-amino-4-(4-chlorophenvn-1 -thiazol-5-yll(3-chlorophenyl methanone
Figure imgf000036_0002
A solution of 2-bromo-l-(3-chlorophenyl)ethanone (intermediate 5a, 155 mg) and N- [(bis { [4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-4-chlorobenzamide (intermediate 15a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-45 %) to afford [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](3- chlorophenyl)methanone (178 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A suspension of [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](3-chlorophenyl)methanone (intermediate 17a, 70 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 48.0 mg), EDC (50.0 mg) and HOBt (35.2 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature
1.5 days. Solvent was removed under reduced pressure. The resulting residue was purified directly by MDAP to afford N-{4-(4-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide (35 mg) as a white solid. ^-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.02 (s, 2H), 7.26-7.32 (m, 3H), 7.38-7.40 (m, 2H), 7.47-7.52 (m, 3H), 7.63 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.15 (s, 1H); MS(ES+) m/z 559 (MH+). Example 18
A'-{4-(2-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000037_0001
Step 1: see step 1 for preparing intermediate lb.
Step 2: To a solution of 2-chlorobenzoyl chloride (2.5 g) in acetone (36 mL) cooled at 0 °C was added ammonium thiocyanate (2.175 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis {[4-(methyloxy)phenyl]methyl} amine (4.41 g) was added and stirred for an additional 30 mins. The mixture was concentrated under reduced pressure, and then purified directly by chromatography (EtOAc : PE = 0-10 %) to afford N-[(bis{[4-
(methyloxy)phenyl]methyl}amino)carbonothioyl]-2-chlorobenzamide (5.4 g) as a yellow solid. MS(ES+) m/z 455 (MH+).
Intermediate 18b: [2-amino-4-(2-chlorophenyl -l,3-thiazol-5-yl (4-chlorophenvnmethanone
Figure imgf000037_0002
A solution of 2-bromo-l-(4-chlorophenyl)ethanone (135 mg) and N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-2-chlorobenzamide (intermediate 18a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed in vacuo and the residue was stirred in trifluoroacetic acid (0.042 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC(¾, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](4- chlorophenyl)methanone (150 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 48.0 mg), EDC (50.0 mg) and HOBt (35.2 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. [2-Amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](4-chlorophenyl)methanone (intermediate 18b, 70 mg) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4-(2-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}- 2-[4-(ethylsulfonyl)phenyl]acetamide (54 mg) as a yellow solid. ¾-NM (400 MHz, DMSO- 6) δ ppm 1.11 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 7.23-7.29 (m, 5H), 7.37-7.40 (m, 1H), 7.47-7.50 (m, 2H), 7.64 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 13.12 (s, 1H); MS(ES+) m/z 559 (MH+).
Example 19
A'-{4-(2-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide
Figure imgf000038_0001
Intermediate 19a: [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl (3-chlorophenyl)methanone
Figure imgf000038_0002
A solution of 2-bromo-l-(3-chlorophenyl)ethanone (intermediate 5a, 135 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-2-chlorobenzamide (intermediate 18a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in trifluoroacetic acid (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](3- chlorophenyl)methanone (146 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 48.0 mg), EDC (50.0 mg) and HOBt (35.2 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. Then [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](3-chlorophenyl)methanone (intermediate 19a, 70 mg) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure. The residue was purified by MDAP to afford N-{4-(2-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}- 2-[4-(ethylsulfonyl)phenyl]acetamide (31 mg) as a yellow solid. ¾-NM (400 MHz, DMSO- 6) δ ppm 1.11 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.03 (s, 2H), 7.19-7.31 (m, 4H), 7.34-7.37 (m, 1H), 7.40-7.44 (m, 3H), 7.64 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 13.14 (s, 1H); MS(ES+) m/z 559 (MH+).
Example 20
A'-[4-(2-chlorophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4- (ethylsulfonyl)phenyl]acetamide
Figure imgf000039_0001
Intermediate 20a: [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yll(phenyl)methanone
Figure imgf000040_0001
A solution of 2-bromo-l-phenylethanone (115 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-2-chlorobenzamide (intermediate 18a, 250 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in trifluoroacetic acid (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC03, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-30 %) to afford [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5- yl](phenyl)methanone (158 mg) as a yellow solid. MS(ES+) m/z 315 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 53.3 mg), EDC (55.4 mg) and HOBt (39.1 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. Then [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](phenyl)methanone (intermediate 20a, 70 mg) was added, and the reaction mixture was stirred at room temperature overnight. The obtained solution was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organics were washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure. The residue was purified by MDAP to afford N-[4-(2-chlorophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4- (ethylsulfonyl)phenyl]acetamide (31 mg) as a yellow solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.11 (t, J = 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.03 (s, 2H), 7.20-7.29 (m, 5H), 7.35-7.42 (m, 2H), 7.49-7.52 (m, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 13.09 (s, 1H); MS(ES+) m/z 525 (MH+).
Example 21
A'-{4-(2-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000041_0001
Intermediate 21a: (2-amino-4-(2-chlorophenvnthiazol-5-vn(2-chlorophenvnmethanone
Figure imgf000041_0002
A solution of 2-bromo-l -(2-chlorophenyl)ethanone (intermediate 4a, 132 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl} amino)carbonothioyl]-2-chlorobenzamide (intermediate 18a, 253 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in trifluoroacetic acid (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-35 %) to afford [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](2- chlorophenyl)methanone (80 mg) as a yellow solid. MS(ES+) m/z 349 (MH+). Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 35 mg), EDC (38.2 mg) and HOBt (26.9 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for 10 mins. Then [2-amino-4-(2-chlorophenyl)-l,3-thiazol-5-yl](2-chlorophenyl)methanone (intermediate 21a, 53.5 mg) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure. The residue was purified by MDAP to afford N- {4-(2-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l ,3-thiazol-2-yl}- 2-[4-(ethylsulfonyl)phenyl]acetamide (12 mg) as a yellow solid. ¾-NM (400 MHz, DMSO- 6) δ ppm 1.11 (t, J= 7.2 Hz, 3H), 3.29 (q, J = 7.2 Hz, 2H), 4.02 (s, 2H), 7.13-7.17 (m, 2H), 7.20-7.29 (m, 5H), 7.31-7.33 (m, 1H), 7.63 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.14 (s, 1H); MS(ES+) m/z 559 (MH+).
Example 22
N- [5- [(2-chlorophenyl)carbonyl] -4-(3-cyanophenyl)-l,3-thiazol-2-yl]-2- [4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000042_0001
Intermediate 22a: N-[(bisi[4-(methyloxy phenyllmethyllamino carbonothioyl -3-cvanobenzamide
Figure imgf000042_0002
Step 1: see step 1 for preparing intermediate lb.
Step 2: To a solution of 3-cyanobenzoyl chloride (620 mg) in acetone (10 mL) cooled at 0 °C was added ammonium thiocyanate (570 mg). The resulting mixture was strried at this temperature for 1.5 hours. Then bis {[4-(methyloxy)phenyl]methyl} amine (1060 mg) was added to the above mixture and stirred for an addtional 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The aqueous phase was washed with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-cyanobenzamide (1.856 g) as a yellow sticky oil. MS(ES+) m/z 446 (MH+).
Intermediate 22b: 3-{2-amino-5-[(2-chlorophenyl)carbonyll-l,3-thiazol-4-yl}benzonitrile
Figure imgf000042_0003
A solution of 2-bromo-l-(2-chlorophenyl)ethanone (intermediate 4a, 173 mg) and N- [(bis { [4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-cyanobenzamide (intermediate 22a, 300 mg) in NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was stirred in TFA (4 mL) at 80 °C for about 20 hours. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-60 %) to afford 3-{2- amino-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-4-yl}benzonitrile (184 mg) as a brown solid.
MS(ES+) m/z 340 (MH+).
Preparation of the final product
A mixture of 3-{2-amino-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-4-yl}benzonitrile
(intermediate 22b, 70 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 49.4 mg), EDC (51.3 mg) and HOBt (36.2 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 1.5 days. The mixture was concentrated under reduced pressure and the residue was directly purified by MDAP to afford N-[5-[(2-chlorophenyl)carbonyl]-4-(3-cyanophenyl)-l,3-thiazol-2-yl]-2- [4-(ethylsulfonyl)phenyl]acetamide (32 mg) as a white solid. ^-NMR (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.4 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.03 (s, 2H), 7.23-7.26 (m, 2H), 7.30-7.35 (m, 1H), 7.43-7.47 (m, 2H), 7.62 (d, J= 8.3 Hz, 2H), 7.70-7.74 (m, 3H), 7.87 (d, J= 8.3 Hz, 2H), 13.20 (s, 1H); MS(ES+) m/z 550 (MH+).
Example 23
A'-[4-(3-cyanophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4-(ethylsulfonyl)phenyl]acetamide
Figure imgf000043_0001
Intermediate 23a: 3-[2-amino-5-(phenylcarbonyl)-l,3-thiazol-4-yl benzonitrile
Figure imgf000044_0001
A solution of 2-bromo-l-phenylethanone (164 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-cyanobenzamide (intermediate 22a, 350 mg) in NN-dimethylformamide (DMF) (4 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-50 %) to afford 3-[2-amino-5-(phenylcarbonyl)-l,3-thiazol-4-yl]benzonitrile (202 mg) as a yellow solid. MS(ES+) m/z 306 (MH+).
Preparation of the final product
A mixture of 3-[2-amino-5-(phenylcarbonyl)-l,3-thiazol-4-yl]benzonitrile (intermediate 23a, 70 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 54.9 mg), EDC (57.1 mg) and HOBt (40.3 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 1.5 days. The mixture was concentrated under reduced pressure and the residue was purified by MDAP to afford N-[4-(3- cyanophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4-(ethylsulfonyl)phenyl]acetamide (42 mg) as a white solid. LH-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.03 (s, 2H), 7.28 (t, J= 7.8 Hz, 2H), 7.42-7.48 (m, 2H), 7.54-7.56 (m, 2H), 7.63 (d, J= 8.3 Hz, 2H), 7.70-7.78 (m, 3H), 7.88 (d, J= 8.3 Hz, 2H), 13.13 (s, 1H); MS(ES+) m/z 516 (MH+).
Example 24
N-{5- |(2-chlorophenyl)carbonyl] -4- [3-(methyloxy)phenyl] -l,3-thiazol-2-yl}-2- [4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000044_0002
Intermediate 24a: N-[(bis{[4-(methyloxy phenyllmethyl}amino carbonothioyll-3- (methyloxy)benzamide
Figure imgf000045_0001
Step 1: see step 1 for preparing intermediate lb.
Step 2: To a solution of 3-(methyloxy)benzoyl chloride (1.1 g) in acetone (18 mL) cooled at 0 °C was added ammonium thiocyanate (0.982 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis {[4-(methyloxy)phenyl]methyl} amine (1.991 g) was added and stirred for an additional 30 mins. The mixture was concentrated under reduced pressure, and then purified directly by chromatography (EtOAc : PE = 0-15 %) to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-(methyloxy)benzamide (2.9 g) as a yellow oil. MS(ES+) m/z 451 (MH+).
Intermediate 24b: {2-amino-4-[3-(methyloxy phenyll-l,3-thiazol-5-yll(2-chlorophenvnmethanone
Figure imgf000045_0002
A solution of 2-bromo-l-(2-chlorophenyl)ethanone (intermediate 4a, 227 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-(methyloxy)benzamide (intermediate 24a, 365 mg) in N,N-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, the solvent was removed in vacuo and the residue was stirred in TFA (4 ml) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC(¾, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-25 %) to afford {2-amino-4-[3-(methyloxy)phenyl]-l,3-thiazol-5- yl}(2-chlorophenyl)methanone (220 mg) as a yellow solid. MS(ES+) m/z 345 (MH+). Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 48.7 mg), EDC (50.6 mg) and HOBt (35.7 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature under nitrogen for lO mins. Then {2-amino-4-[3-(methyloxy)phenyl]-l,3-thiazol-5-yl}(2- chlorophenyl)methanone (intermediate 24b, 70 mg) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{5-[(2-chlorophenyl)carbonyl]-4-[3- (methyloxy)phenyl]-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (30 mg) as a white solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 3.67 (s, 3H), 4.01 (s, 2H), 6.77-6.80 (m, 1H), 6.87 (t, J= 2.4 Hz, 1H), 6.93 (d, J= 7.6 Hz, 1H), 7.09 (t, J= 8.0 Hz, 1H), 7.14-7.18 (m, 1H), 7.25-7.31 (m, 2H), 7.35-7.37 (m, 1H), 7.62 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.13 (s, 1H); MS(ES+) m/z 555 (MH+). Example 25
N-{5- [(2-chlorophenyl)carbonyl] -4- [3-(trifluoromethyl)phenyl] -l,3-thiazol-2-yl}-2- [4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000046_0001
Intermediate 25a: N-[(bis{[4-(methyloxy)phenyllmethyl}amino)carbonothioyll-3-
Figure imgf000046_0002
Step 1: see step 1 for preparing intermediate lb.
Step 2: To a solution of 3-(trifluoromethyl)benzoyl chloride (1.3 g) in acetone (15 mL) cooled at 0 °C was added ammonium thiocyanate (0.949 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis {[4-(methyloxy)phenyl]methyl} amine (1.925 g) was added and the reaction mixture was stirred for an additional 30 mins. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and purified directly by chromatography (EtOAc : PE = 0-20 %) to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-(trifluoromethyl)benzamide (2.8 g) as a yellow oil. MS(ES+) m/z 489 (MH+).
Intermediate 25b: {2-amino-4-[3-(trifluoromethyl phenyll-l,3-thiazol-5-ylU2- chlorophenvDmethanone
Figure imgf000047_0001
A solution of 2-bromo-l-(2-chlorophenyl)ethanone (intermediate 4a, 234 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-(trifluoromethyl)benzamide (intermediate 25a, 408 mg) in N,N-dimethylformamide (DMF) (4 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC(¾, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-30 %) to afford {2-amino-4-[3-(trifluoromethyl)phenyl]-l,3- thiazol-5-yl}(2-chlorophenyl)methanone (230 mg) as a yellow solid. MS(ES+) m/z 383 (MH+). Preparation of the final product
A mixture of {2-amino-4-[3-(trifluoromethyl)phenyl]-l,3-thiazol-5-yl}(2- chlorophenyl)methanone (intermediate 25b, 70 mg), [4-(ethylsulfonyl)phenyl] acetic acid
(intermediate Id, 43.8 mg), HOBt (32.1 mg) and EDC (45.6 mg) in dichloromethane (DCM) (2 mL) was sealed into a vial and stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The aqueous phase was washed with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure. The residue was purified by MDAP to afford N-{5-[(2- chlorophenyl)carbonyl]-4-[3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide (32 mg) as a white solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 7.16-7.24 (m, 2H), 7.27-7.32 (m, 1H), 7.41-7.48 (m, 2H), 7.61-7.64 (m, 4H), 7.70 (d, J= 8.0 Hz, 1H), 7.87 (d, J= 8.0 Hz, 2H), 13.20 (s, 1H); 19F-NMR (376 MHz, DMSO- 6) δ ppm -61.16; MS(ES+) m/z 593 (MH+).
Example 26
A'-{4-(4-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000048_0001
Intermediate 26a: 4-chloro-N-[(di-2-propen-l-ylamino carbonothioyl benzamide
Figure imgf000048_0002
Step 1: To a solution of 4-chlorobenzoyl chloride (3.81 mL) in acetonitrile (50 mL) stirred in air at RT was added solid KSCN (4.37 g). After stirring for 45 mins, the mixture was filtered, and the filtrate was used direcly in the next step.
Step 2: The N-2-propen-l-yl-2-propen-l -amine (3.69 mL) was added into the above filtrate. The mixture was stirred at RT until the starting material was totally consumed. Solvent was removed under reduced pressure to afford the crude product, which was purified by chromatography (EtOAc : PE = 0-20 %) to afford the desired product 4-chloro-N-[(di-2-propen-l- ylamino)carbonothioyl]benzamide (4.1 g). MS(ES+) m/z 295 (MH+).
Intermediate 26b: (2-chlorophenyl)[4-(4-chlorophenyl)-2-(di-2-propen-l -ylamino)-! ,3-thiazol-5- yllmethanone
Figure imgf000048_0003
To a solution of 4-chloro-N-[(di-2-propen-l-ylamino)carbonothioyl]benzamide (intermediate 26a, 590 mg) in NN-dimethylformamide (DMF) (20 mL) stirred in air RT was added 2-bromo-l-(2- chlorophenyl)ethanone (intermediate 4a, 0.273 mL). The reaction mixture was stirred at 85 °C. After 1 hour, the mixture was poured into water, and extracted with DCM for 3 times. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by chromatography (EtOAc : PE = 0-8 %) to give the desired product (2-chlorophenyl)[4-(4- chlorophenyl)-2-(di-2-propen-l-ylamino)-l,3-thiazol-5-yl]methanone (600 mg). MS(ES+) m/z 429 (MH+).
Intermediate 26c: [2-amino-4-(4-chlorophenvn-l,3-thiazol-5-yl (2-chlorophenyl methanone
Figure imgf000049_0001
To a solution of (2-chlorophenyl)[4-(4-chlorophenyl)-2-(di-2-propen-l-ylamino)-l,3-thiazol-5- yl]methanone (intermediate 26b, 560 mg) and N,N-dimethylbarbituric acid (1222 mg) in 1,4-dioxane (30 mL) stirred under nitrogen at T was added Pd(Ph3P)4 (301 mg). The reaction mixture was stirred at reflux. After 50 hours, solvent was removed under reduced pressure to give the crude product, which was purified by chromatography (EtOAc : PE = 0-40 %). The desired product [2-amino-4-(4- chlorophenyl)-l,3-thiazol-5-yl](2-chlorophenyl)methanone (100 mg) was obtained and used directly in the next step. MS(ES+) m/z 349 (MH+). Preparation of the final product
To a solution of [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](2-chlorophenyl)methanone (intermediate 26c, 100 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 71.9 mg) and EDC (71.4 mg) in dichloromethane (DCM) (10 mL) was added HOBt (57.0 mg). The reaction mixture was stirred at RT for 1 day. Solvent was removed under reduced pressure to afford the crude product. Purification by MDAP provided N-{4-(4-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2- yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (45 mg). ¾-NMR (600 MHz, DMSO- ) δ ppm 1.10 (t, J = 7.2 Hz, 3H), 3.28 (q, J= 7.2 Hz, 2H), 4.01 (s, 2H), 7.24-7.33 (m, 4H), 7.35-7.42 (m, 4H), 7.62 (d, J= 7.8 Hz, 2H), 7.87 (d, J= 7.8 Hz, 2H), 13.17 (s, 1H); MS(ES+) m/z 559 (MH+).
Example 27
V-{4-(4-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000050_0001
Intermediate 27a: (4-chlorophenvn[4-(4-chlorophenyl -2-(di-2^roperi-l-ylamino -l,3-thiazol-5- yllmethanone
Figure imgf000050_0002
To a solution of 4-chloro-N-[(di-2-propen-l-ylamino)carbonothioyl]benzamide (intermediate 26a, 590 mg) in DMF (10 ml) was added 2-bromo-l-(4-chlorophenyl)ethanone (560 mg). The reaction mixture was heated to 85 °C. After stirring for 1 hour, the mixture was cooled to room temperature and poured into water. The resulting solution was extracted with DCM for 3 times. The combined organic phases were washed with saturated sodium bicarbonate and brine, and then dried over Na2SC>4. The crude product was obtained after filtration and evaporation, which was purified by chromatography (EtOAc : PE = 0-15 %) to afford (4-chlorophenyl)[4-(4-chlorophenyl)-2-(di-2- propen-l-ylamino)-l,3-thiazol-5-yl]methanone (600 mg). MS(ES+) m/z 429 (MH+).
Intermediate 27b: [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl (4-chlorophenyl)methanone
Figure imgf000050_0003
To a solution of (4-chlorophenyl)[4-(4-chlorophenyl)-2-(di-2-propen-l-ylamino)-l,3-thiazol-5- yl]methanone (intermediate 27a, 320 mg) and NN-dimethylbarbituric acid (465 mg) in 1,4-dioxane (25 mL) stirred under nitrogen at T was added Pd(Ph3P)4 (129 mg). The reaction mixture was stirred at reflux. After 50 hours, the mixture was concentrated under reduced pressure to give the crude product, which was purified by chromatography (EtOAc : PE = 0-40 %). [2-Amino-4-(4- chlorophenyl)-l,3-thiazol-5-yl](4-chlorophenyl)methanone (100 mg) was obtained and used directly in the next step. MS(ES+) m/z 349 (MH+).
Preparation of the final product
To a solution of [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](4-chlorophenyl)methanone (intermediate 27b, 90 mg), EDC (64.2 mg) and HOBt (51.3 mg) in dichloromethane (DCM) (10 mL) was added [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 64.7 mg). The reaction mixture was stirred at T for 1 day. Solvent was removed under reduced pressure to afford the crude product. Purification by MDAP provided N-{4-(4-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2- yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (15 mg). ¾-NMR (600 MHz, DMSO- ) δ ppm 1.10 (t, J = 7.8 Hz, 3H), 3.29 (q, J= 7.8 Hz, 2H), 4.02 (s, 2H), 7.29 (d, J= 7.8 Hz, 2H), 7.36 (d, J= 7.8 Hz, 2H), 7.40 (d, J= 6.0 Hz, 2H), 7.56 (d, J= 7.8 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 7.8 Hz, 2H), 13.13 (s, 1H); MS(ES+) m/z 559 (MH+).
Example 28
A'-[4-(4-chlorophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000051_0001
Intermediate 28a: (2-chlorophenvn[4-(4-chlorophenyl -2-(di-2-propen-l-ylamino -l,3-thiazol-5-
Figure imgf000051_0002
To a solution of 4-chloro-N-[(di-2-propen-l-ylamino)carbonothioyl]benzamide (intermediate 26a, 590 mg) in NN-dimethylformamide (DMF) (10 mL) stirred in air at RT was added 2-bromo-l- phenylethanone (372 mg). The reaction mixture was stirred at 85 °C. After 1 hour, the mixture was poured into water, and extracted with DCM for 3 times. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by chromatography (EtOAc : PE = 0-8 %) to give (2-chlorophenyl)[4-(4-chlorophenyl)-2-(di-2-propen-l-ylamino)-l,3-thiazol-5- yl]methanone (510 mg). MS(ES+) m/z 395 (MH+).
Intermediate 28b: [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yll(phenyl)methanone
Figure imgf000051_0003
To a solution of [4-(4-chlorophenyl)-2-(di-2-propen-l-ylamino)-l,3-thiazol-5- yl](phenyl)methanone (intermediate 28a, 510 mg) and NN-dimethylbarbituric acid (1089 mg) in 1,4- dioxane (30 mL) stirred under nitrogen at T was added Pd(Ph3P)4 (269 mg). The reaction mixture was stirred at reflux. After 50 hours, solvent was removed under reduced pressure to give the crude product, which was purified by chromatography (EtOAc : PE = 0-40 %). The desired product (120 mg) was obtained and used directly in the next step. MS(ES+) m/z 349 (MH+).
Preparation of the final product
To a solution of [2-amino-4-(4-chlorophenyl)-l,3-thiazol-5-yl](phenyl)methanone
(intermediate 28b, 78 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 62.2 mg) and EDC (61.8 mg) in dichloromethane (DCM) (10 mL) was added HOBt (49.3 mg). The reaction mixture was stirred at RT for 1 day. Solvent was removed under reduced pressure to afford the crude product.
Purification by MDAP provided N-[4-(4-chlorophenyl)-5-(phenylcarbonyl)-l,3-thiazol-2-yl]-2-[4-
(ethylsulfonyl)phenyl]acetamide (30 mg). ¾-NMR (600 MHz, DMSO- 6) δ ppm 1.10 (t, J = 7.2 Hz,
3H), 3.28 (q, J= 7.2 Hz, 2H), 4.01 (s, 2H), 7.26-7.31 (m, 4H), 7.41 (d, J= 8.4 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.57 (d, J= 7.2 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.87 (d, J= 8.4 Hz, 2H), 13.10 (s, 1H);
MS(ES+) m/z 525 (MH+).
Example 29
A'-{4-(3-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (methylsulfonyl)phenyl]acetamide
Figure imgf000052_0001
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](3-chlorophenyl)methanone (intermediate 13a, 60 mg), [4-(methylsulfonyl)phenyl]acetic acid (38.6 mg), EDC (42.8 mg) and HOBt (30.2 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature under nitrogen for 2 days. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4-(3-chlorophenyl)-5-[(3-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-
(methylsulfonyl)phenyl]acetamide (14 mg) as a white solid. ¾-NMR (400 MHz, DMSO- 6) δ ppm 3.22 (s, 3H), 4.02 (s, 2H), 7.21-7.33 (m, 4H), 7.40 (t, J= 1.7 Hz, 1H), 7.45-7.49 (m, 3H), 7.63 (d, J = 8.3 Hz, 2H), 7.92 (d, J= 8.3 Hz, 2H), 13.15 (s, 1H); MS(ES+) m/z 545 (MH+). Example 30
A'-{4-(3-chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (methylsulfonyl)phenyl]acetamide
Figure imgf000053_0001
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](2-chlorophenyl)methanone
(intermediate 9a, 60 mg), [4-(methylsulfonyl)phenyl]acetic acid (38.6 mg), EDC (42.8 mg) and HOBt (30.2 mg) in dichloromethane (DCM) (3 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4-(3- chlorophenyl)-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (methylsulfonyl)phenyl]acetamide (42 mg) as a white solid. ¾-NM (400 MHz, DMSO- 6) δ ppm 3.22 (s, 3H), 4.01 (s, 2H), 7.19-7.42 (m, 7H), 7.41 (dd, J= 1.4 Hz, J= 7.5 Hz, 1H), 7.62 (d, J= 8.3 Hz, 2H), 7.90-7.92 (m, 2H), 13.16 (s, 1H); MS(ES+) m/z 545 (MH+).
Example 31
A'-{4-(3-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (methylsulfonyl)phenyl]acetamide
Figure imgf000053_0002
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](4-chlorophenyl)methanone (intermediate 42b, 55 mg), [4-(methylsulfonyl)phenyl]acetic acid (35.4 mg), EDC (39.2 mg) and HOBt (27.7 mg) in dichloromethane (DCM) (3 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue was purified by MDAP to afford N-{4- (3-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-
(methylsulfonyl)phenyl]acetamide (20 mg) as a white solid. ¾-NMR (400 MHz, DMSO- ) δ ppm 3.22 (s, 3H), 4.02 (s, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.32-7.36 (m, 4H), 7.40 (t, J = 1.8 Hz, 1H), 7.53- 7.57 (m, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.91-7.93 (m, 2H), 13.13 (s, 1H); MS(ES+) m/z 545 (MH+).
Example 32
A'-[5-[(2-chlorophenyl)carbonyl]-4-(3-cyanophenyl)-l,3-thiazol-2-yl]-2-{4-[(2,2,2- trifluoroethyl)sulfonyl]phenyl}acetamide
Figure imgf000054_0001
Step 1 to 2: see steps 1&2 for preparing intermediate Id.
Step 3: A mixture of 2-(4-mercaptophenyl)acetic acid (300 mg) and H2S04 (0.01 mL) in methanol (10 mL) was heated to 70 °C with stirring for 45 mins. The reaction mixture was cooled to 0 °C in an ice bath. The solution was neutralized with NaHC(¾ to pH = 7, and then concentrated to 5 mL. DCM (15 mL) and water (10 mL) was added. The aqueous was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated to give the crude product (300 mg). MS(ES+) m/z 183 (MH+).
Step 4: A mixture of methyl 2-(4-mercaptophenyl)acetate (1.2 g), l,l,l-trifluoro-2-iodoethane (1.4 g) and K2CO3 (2.4 g) in NN-dimethylformamide (DMF) (30 mL) was stirred at room
temperature for 3 hours. Water (50 mL) and DCM (50mL) was added. The aqueous was extracted with DCM (30 mL x 4). The combined organic phases were washed with brine (30 mL x 3), dried over Na2S04, filtered, and concentrated to give the crude product (1.2 g). MS(ES+) m/z 265 (MH+).
Step 5: A mixture of methyl 2-(4-mercaptophenyl)acetate (1.2 g) and mCPBA (1.9 g) in dichloromethane (DCM) (50 mL) was stirred at room temperature overnight. Solvent was evaporated under reduced pressure. DCM (30 mL) was added and the mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel; PE : EA = 100:0 to 100:3) to afford methyl 2-(4-(2,2,2-trifluoroethylthio)phenyl)acetate (1.2 g) as an oil. MS(ES+) m/z 297 (MH+).
Step 6: A mixture of methyl 2-(4-(2,2,2-trifluoroethylsulfonyl)phenyl)acetate (1.1 g) and cone. HC1 (30 mL) in acetic acid (30 mL) was stirred at 105 °C for 1.5 hours. Solvent was removed under reduce pressure. Water (30 mL) and DCM (30 mL) was added. The aqueous was washed with DCM (15 mL x 3). The combined organic phases were dried over Na2S04, filtered, and concentrated to give the title product 2-(4-(2,2,2-trifluoroethylsulfonyl)phenyl)acetic acid (700 mg) as a white solid. LH- NM (400 MHz, DMSO- ) δ ppm 3.77 (s, 2H), 4.94 (q, J= 10.0 Hz, 2H), 7.59 (d, J= 8.0 Hz, 2H), 7.91 (d, J= 8.0 Hz, 2H), 12.57 (s, 1H); MS(ES+) m/z 283 (MH+).
Preparation of the final product
A mixture of 3-{2-amino-5-[(2-chlorophenyl)carbonyl]-l,3-thiazol-4-yl}benzonitrile
(intermediate 22b, 60 mg), {4-[(2,2,2-trifluoroethyl)sulfonyl]phenyl}acetic acid (intermediate 32a, 52.3 mg), EDC (44.0 mg) and HOBt (31.0 mg) was stirred at room temperature overnight. Then more {4-[(2,2,2-trifluoroethyl)sulfonyl]phenyl}acetic acid (52.3 mg), EDC (44.0 mg) and HOBt (31.0 mg) were added and the reaction was stirred for another two days. The mixture was concentrated under reduced pressure. The residue was diluted with DMF and further purified by MDAP to afford N-[5- [(2-chlorophenyl)carbonyl]-4-(3-cyanophenyl)-l,3-thiazol-2-yl]-2-{4-[(2,2,2- trifluoroethyl)sulfonyl]phenyl}acetamide (20 mg) as a white solid. ¾-NMR (400 MHz, DMSO- ) δ ppm 4.05 (s, 2H), 4.96 (q, J= 9.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 2H), 7.30-7.35 (m, 1H), 7.43-7.47 (m, 2H), 7.65-7.74 (m, 5H), 7.95 (d, J= 8.4 Hz, 2H), 13.21 (s, 1H); 19F-NMR (376 MHz, DMSO- ) δ ppm -59.79; MS(ES+) m/z 604 (MH+). Example 33
2-[4-(ethylsulfonyl)phenyl]- V-[4-[3-(4-morpholinyl)phenyl]-5-(phenylcarbonyl)-l,3-thiazol-2- yl]acetamide trifluoroacetate
Figure imgf000056_0001
Intermediate 33a: (2-amino-4-(3-moφholinophenyl)thiazol-5-yl)(phenyl)methanone
Figure imgf000056_0002
Step 1: To a solution of 3-bromobenzoyl chloride (2.5 g) in acetone (25 mL) cooled at 0 °C was added ammonium thiocyanate (1.734 g). The resulting mixture was strried at this temperature for 1.5 hours. Then bis {[4-(methyloxy)phenyl]methyl} amine (3.22 g, synthesis of this starting material, see step 1 for preparing intermediate lb) was added to the above mixture and stirred for an addtional 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the resulting residue was dissovled in EtOAc and washed with water and brine, dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-bromobenzamide (6.018 g) as a light yellow sticky oil. MS(ES+) m/z 499 (MH+).
Step 2: A solution of 2-bromo-l-phenylethanone (0.502 g) and N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-bromobenzamide (1.2 g) in NN- dimethylformamide (DMF) (6 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to affrod [2-(bis{[4-
(methyloxy)phenyl] methyl} amino)-4-(3-bromophenyl)-l ,3-thiazol-5-yl](phenyl)methanone (1.486 g) as a yellow sticky solid. MS(ES+) m/z 599 (MH+).
Step 3: A mixture of [2-(bis{[4-(methyloxy)phenyl]methyl}amino)-4-(3-bromophenyl)-l,3- thiazol-5-yl](phenyl)methanone (350 mg), morpholine (203 mg), palladium(II) acetate (26.2 mg), BINAP (72.7 mg) and CS2CO3 (951 mg) in toluene (3.5 mL) was bubbled with N2, and then stirred at 90 °C for 3 hours. After cooling to room temperature, the mixture was filtered through silica gel and celite. The solid was washed with DCM and EtOAc. The filtrate was collected and concentrated under reduced pressure. The residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHC(¾, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford {2-amino-4-[3-(4- morpholinyl)phenyl]-l,3-thiazol-5-yl}(phenyl)methanone (236 mg) as a light brown solid. MS(ES ) m/z 366 (MH+).
Preparation of the final product
A mixture of {2-amino-4-[3-(4-morpholinyl)phenyl]-l,3-thiazol-5-yl}(phenyl)methanone (intermediate 33a, 120 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 54.0 mg), EDC (52.9 mg) and HOBt (37.3 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure and the residue was purified by MDAP under acidic condition to afford 2-[4-(ethylsulfonyl)phenyl]-N-[4-[3-(4-morpholinyl)phenyl]- 5-(phenylcarbonyl)-l,3-thiazol-2-yl]acetamide trifluoroacetate (40 mg) as a yellow solid. ¾-NM (400 MHz, DMSO-d6) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 2.86-2.88 (m, 4H), 3.29 (q, J= 7.3 Hz, 2H), 3.65-3.67 (m, 4H), 4.01 (s, 2H), 6.80-6.82 (m, 2H), 6.88 (d, J= 7.6 Hz, 1H), 7.08 (t, J= 7.8 Hz, 1H), 7.23 (t, J= 7.7 Hz, 2H), 7.43 (t, J= 7.4 Hz, 1H), 7.51-7.53 (m, 2H), 7.64 (d, J= 8.3 Hz, 2H), 7.88 (d, J= 8.3 Hz, 2H), 13.05 (s, 1H); MS(ES+) m/z 576 (MH+).
Example 34
2-[4-(ethylsulfonyl)phenyl]- V-(5-{[4-(2-hydroxyethyl)phenyl]carbonyl}-4-phenyl-l,3-thiazol-2- yl)acetamide
Figure imgf000058_0001
Intermediate 34a: 2-(4-{[2-({[4-(ethylsulfonvnphenyllace1^l}amino -4-phenyl-l,3-thiazol-5-
Figure imgf000058_0002
Step 1: To a solution of 2-phenylethyl acetate (5 g) in dichloromethane (DCM) (200 mL) was added aluminium chloride (4.06 g) and the mixture was cooled to 0 °C. Then acetyl chloride (2.382 mL) was added dropwise, followed by addition of more aluminium chloride (4.06 g). The resulting mixture was stirred at 0 °C for 1.5 hours. The mixture was poured into ice/water and 5 mL of cone. HC1 was added. The organic layer was separated, washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure and the residue was purified by chromatography (EtOAc : PE = 0-8 %) to afford 2-(4-acetylphenyl)ethyl acetate (262 mg) as a pale sticky oil. Ή-ΝΜΡ (400 MHz, CDC13) δ ppm 2.03 (s, 3H), 2.59 (s, 3H), 3.00 (t, J= 6.8 Hz, 2H), 4.30 (t, J= 6.8 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2H), 7.90 (d, J= 8.0 Hz, 2H); MS(ES+) m/z 207 (MH+).
Step 2: To a solution of 2-(4-acetylphenyl)ethyl acetate (260 mg) in diethyl ether (5 mL) cooled at 0 °C was added bromine (0.068 mL) dropwise. The resulting mixture was stirred at room temperature for 1.5 hours. Solvent was removed in vacuo to afford 2-[4-(2-bromoacetyl)phenyl]ethyl acetate (362 mg) as a yellow oil. MS(ES+) m/z 285 (MH+).
Step 3: A solution of 2-[4-(2-bromoacetyl)phenyl]ethyl acetate (362 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 320 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-40 %) to afford 2-{4-[(2-amino-4-phenyl- l,3-thiazol-5-yl)carbonyl]phenyl}ethyl acetate (312 mg) as a brown sticky solid. MS(ES+) m/z 367 (MH+).
Step 4: A mixture of 2-{4-[(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl}ethyl acetate
(106 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 50 mg), EDC (46.9 mg) and HOBt (33.0 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature overnight. Solvent was removed under pressure. The residue was purified by chromatography (EtOAc : PE = 0-50 %) to afford 2-(4- { [2-( { [4-(ethylsulfonyl)phenyl]acetyl} amino)-4-phenyl- 1 ,3-thiazol-5- yl]carbonyl}phenyl)ethyl acetate (147 mg) as a brown sticky solid. MS(ES+) m/z 577 (MH+).
Preparation of the final product
To a solution of 2-(4-{[2-({[4-(ethylsulfonyl)phenyl]acetyl}amino)-4-phenyl-l,3-thiazol-5- yl]carbonyl}phenyl)ethyl acetate (intermediate 34a, 80 mg) in tetrahydrofuran (THF) (1.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (13.97 mg). The resulting mixture was stirred at room temperature for 4 hours. The mixture was neutralized with 2 M HCl, diluted with DMF and further purified by MDAP to afford 2-[4-(ethylsulfonyl)phenyl]-N-(5-{[4-(2- hydroxyethyl)phenyl]carbonyl}-4-phenyl-l,3-thiazol-2-yl)acetamide (18 mg) as a white solid. ¾- NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 2.68 (t, J= 6.9 Hz, 2H), 3.29 (q, J= 7.3 Hz, 2H), 3.52 (t, J= 7.0 Hz, 2H), 4.01 (s, 2H), 7.13 (d, J= 8.2 Hz, 2H), 7.20-7.26 (m, 3H), 7.40 (dd, J = 1.7 Hz, J = 7.7 Hz, 2H), 7.51 (d, J= 8.2 Hz, 2H), 7.63 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.05 (s, 1H); MS(ES+) m/z 535 (MH+).
Example 35
2-[4-(ethylsulfonyl)phenyl]- V-(5-{[4-(3-hydroxypropyl)phenyl]carbonyl}-4-phenyl-l,3-thiazol-2- yl)acetamide
Figure imgf000059_0001
Intermediate 35a: 3-(4-{[2-({[4-(ethylsulfonyl)phenyllacetyl}amino)-4-phenyl-l,3-thiazol-5- yl"|carbonyllphenyl)propyl acetate
Figure imgf000060_0001
Figure imgf000060_0002
Step 1: Acetyl chloride (13.66 g) was added into a solution of 3 -phenyl- 1-propanol (15.8 g), Et3N (32.3 mL) and DMAP (1.417 g) in dichloromethane (DCM) (250 mL) at 0 °C dropwise. The resultant mixture was stirred at the same temperature. After 1 hour, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with 1 M HC1 and brine. The organic phase was then dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated in vacuo to afford 3-phenylpropyl acetate (11.8 g) as a yellow oil. Ή-ΝΜΡ (400 MHz, CDC13) δ ppm 1.93-2.01 (m, 2H), 2.06 (s, 3H), 2.69 (t, J= 7.2 Hz, 2H), 4.09 (t, J= 6.4 Hz, 2H), 7.18-7.22 (m, 3H), 7.26-7.31 (m, 2H); MS(ES+) m/z 179 (MH+).
Step 2: Acetyl chloride (2.64 g) was added into a mixture of aluminium chloride (3.74 g) and
3-phenylpropyl acetate (5 g) in dichloromethane (DCM) (50 mL) at 0 °C dropwise under N2. Then more aluminium chloride (3.74 g) was added. The resultant mixture was stirred at 0 °C for 8 hours. The reaction mixture was poured into cold 2 M HC1 slowly, and then diluted with water. The obtained mixture was extracted with DCM for 3 times. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (EtOAc : PE = 0-15 %) to afford 3-(4- acetylphenyl)propyl acetate (5.7 g) as a yellow oil. LH-NMR (400 MHz, CDC13) δ ppm 1.95-2.05 (m, 2H), 2.06 (s, 3H), 2.59 (s, 3H), 2.76 (t, J= 8.0 Hz, 2H), 4.09 (t, J= 6.4 Hz, 2H), 7.28 (d, J= 8.4 Hz, 2H), 7.90 (d, J= 8.0 Hz, 2H); MS(ES+) m/z 221 (MH+).
Step 3: Bromine (0.234 mL) was added into a solution of 3-(4-acetylphenyl)propyl acetate (1 g) in diethyl ether (5 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to afford 3-[4-(2- bromoacetyl)phenyl]propyl acetate (1.1 g) as a yellow oil. MS(ES+) m/z 299 (MH+).
Step 4: A mixture of 3-[4-(2-bromoacetyl)phenyl]propyl acetate (224 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 300 mg) in NN- dimethylformamide (DMF) (5 mL) was heated to 85 °C for 45 mins under N2. Solvent was removed under reduced pressure. The residue was dissolved into TFA (4 mL) and the resultant solution was heated to 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was basified with sat. NaHCC>3 solution, and then extracted with EtOAc for 3 times. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (EtOAc : PE = 0-50 %) to afford 3-{4-[(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl}propyl acetate (130 mg) as a yellow solid. MS(ES+) m/z 381 (MH+).
Step 5: A mixture of 3-{4-[(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl}propyl acetate (100 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 66.0 mg), HOBt (53.3 mg) and EDC (76 mg) in dichloromethane (DCM) (5 mL) was stirred at room temperature overnight under N2. The reaction mixture was washed with 2 M HCl, sat. NaHCC>3 solution and brine successively. The organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated in vacuo to afford 3-(4-{[2-({[4-(ethylsulfonyl)phenyl]acetyl}amino)-4-phenyl-l,3-thiazol-5- yl]carbonyl}phenyl)propyl acetate (150 mg) as a yellow solid. MS(ES+) m/z 591 (MH+).
Preparation of the final product
A mixture of 3-(4-{[2-({[4-(ethylsulfonyl)phenyl]acetyl}amino)-4-phenyl-l,3-thiazol-5- yl]carbonyl}phenyl)propyl acetate (intermediate 35a, 150 mg) and lithium hydroxide hydrate (42.6 mg) in tetrahydrofuran (THF) (6 mL) and water (1.5 mL) was stirred at room temperature overnight. The mixture was acidified by cone. HCl, diluted with water, and then extracted with EtOAc for 3 times. The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduce pressure, and the residue was purified by MDAP to afford 2-[4- (ethylsulfonyl)phenyl]-N-(5-{[4-(3-hydroxypropyl)phenyl]carbonyl}-4-phenyl-l,3-thiazol-2- yl)acetamide (55 mg) as a white solid. ^-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J = 7.2 Hz, 3H), 1.58-1.65 (m, 2H), 2.56 (t, J= 7.6 Hz, 1H), 3.26-3.32 (m, 6H), 4.01 (s, 2H), 7.08 (d, J= 8.4 Hz, 2H), 7.18-7.26 (m, 3H), 7.36-7.38 (m, 2H), 7.48 (d, J= 8.4 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 13.05 (s, 1H); MS(ES+) m/z 549 (MH+).
Example 36
A'-(4-(3-cyanophenyl)-5-{[4-(2-hydroxyethyl)phenyl]carbonyl}-l,3-thiazol-2-yl)-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000062_0001
A solution of 2-[4-(2-bromoacetyl)phenyl]ethyl acetate (211 mg, synthesis of this starting material, see steps 1&2 for preparing intermediate 34a) and N-[(bis{[4-
(methyloxy)phenyl]methyl}amino)carbonothioyl]-3-cyanobenzamide (intermediate 22a, 300 mg) in NN-dimethylformamide (DMF) (4 mL) was stirred at 85°C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-60 %) to afford 2-(4-{[2- amino-4-(3-cyanophenyl)-l,3-thiazol-5-yl]carbonyl}phenyl)ethyl acetate (202 mg) as a brown sticky oil. MS(ES+) m/z 392 (MH+).
Figure imgf000062_0002
A mixture of 2-(4-{[2-amino-4-(3-cyanophenyl)-l,3-thiazol-5-yl]carbonyl}phenyl)ethyl acetate (intermediate 36a, 70 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 42.9 mg), EDC (44.6 mg) and HOBt (31.4 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 3 days. The mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM for 3 times. The combined organic layers were washed with diluted HCl, sat. NaHCC>3 and brine. Then the solution was dried over anhydrous Na2SC>4. After filtration, solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (THF) (2.5 mL) and water (0.8 mL), to which lithium hydroxide monohydrate (30.0 mg) was added and resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified with 2 M HCl, and then diluted with DMF. The solution was purified by MDAP to afford N-(4-(3-cyanophenyl)-5-{[4-(2- hydroxyethyl)phenyl]carbonyl}-l,3-thiazol-2-yl)-2-[4-(ethylsulfonyl)phenyl]acetamide (12 mg) as a white solid. ^-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 2.70 (t, J= 7.0 Hz, 2H), 3.29 (q, J= 7.4 Hz, 2H), 3.54 (dd, J= 6.9 Hz, J= 9.0 Hz, 2H), 4.02 (s, 2H), 4.68 (t, J= 5.1 Hz, 1H), 7.14 (d, J= 8.1 Hz, 2H), 7.44-7.50 (m, 3H), 7.63 (d, J= 8.3 Hz, 2H), 7.71-7.77 (m, 3H), 7.87 (d, J = 8.3 Hz, 2H), 13.10 (br s, 1H); MS(ES+) m/z 560 (MH+). Example 37
3-(4-{[2-({[4-(ethylsulfonyl)phenyl]acetyl}amino)-4-phenyl-l,3-thiazol-5- yl] carbonyl}phenyl)propanoic acid
Figure imgf000063_0001
Intermediate 37a: methyl 3-{4-[(2-amino-4- henyl-l,3-thiazol-5-yl)carbonyllphenyl}propanoate
Figure imgf000063_0002
Step 1: To a solution of 3-phenylpropanoic acid (10 g) in methanol (100 mL) was added thionyl chloride (0.05 mL) dropwise. The resulting mixture was stirred at room temperature overnight. Solvent was removed in vacuo to afford methyl 3-phenylpropanoate (10.896 g) as a light yellow liquid. MS(ES+) m/z 165 (MH+).
Step 2: To a solution of methyl 3-phenylpropanoate (5 g) in dichloromethane (DCM) (200 mL) was added aluminium chloride (4.06 g) and the mixture was cooled to 0 °C. Then acetyl chloride (2.60 mL) was added dropwise and more aluminium chloride (4.06 g) was added, the resulting mixture was stirred at 0 °C for 6.5 hours. Then the mixture was poured into ice/water and 5 mL of cone. HCl was added. The organic layer was separated, washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure and the residue was purified by chromatography (EtOAc : PE = 0-15 %) to afford methyl 3-(4-acetylphenyl)propanoate (3.372 g) as a colorless liquid. Ή-ΝΜΡ (400 MHz, CDC13) δ ppm 2.58 (s, 3H), 2.66 (t, J= 7.7 Hz, 2H), 3.01 (t, J = 7.7 Hz, 2H), 3.67 (s, 3H), 7.29 (d, J= 8.3 Hz, 2H), 7.89 (d, J= 8.3 Hz, 2H).
Step 3: To a solution of methyl 3-(4-acetylphenyl)propanoate (1.5 g) in diethyl ether (35 mL) stirred at 0 °C was added bromine (0.393 mL) dropwise. The resulting mixture was warmed to room temperature and stirred for 1 hour. The mixture was concentrated in vacuo to afford methyl 3-[4- (bromoacetyl)phenyl]propanoate (2.019 g) as a brown solid. MS(ES+) m/z 285 (MH+).
Step 4: A solution of methyl 3-[4-(bromoacetyl)phenyl]propanoate (224 mg) and N-[(bis{[4-
(methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 300 mg) in NN- dimethylformamide (DMF) (4 mL) was stirred at 85°C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-60 %) to afford methyl 3-{4- [(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl}propanoate (217 mg) as a yellow solid.
MS(ES+) m/z 367 (MH+).
Preparation of the final product
A mixture of methyl 3-{4-[(2-amino-4-phenyl-l,3-thiazol-5-yl)carbonyl]phenyl}propanoate (intermediate 37a, 70 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 45.8 mg), EDC (47.6 mg) and HOBt (33.6 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 3 days. The mixture was partitioned between DCM and water. The aqueous layer was extracted with DCM for 3 times. The combined organic layers were washed with diluted HCl, sat. NaHC(¾ and brine, and then dried over anhydrous Na2SC>4. After filtration, solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (THF) (2.5 mL) and water (0.8 mL), to which lithium hydroxide monohydrate (32.1 mg) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was acidified with 2 M HCl, diluted with DMF and further purified by MDAP to afford 3-(4-{[2-({[4-(ethylsulfonyl)phenyl]acetyl}amino)-4-phenyl-l,3-thiazol- 5-yl]carbonyl}phenyl)propanoic acid (47 mg) as a white solid. LH-NM (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 2.46 (t, J= 7.6 Hz, 2H), 2.77 (t, J= 7.5 Hz, 2H), 3.29 (q, J= 7.3 Hz, 2H), 4.01 (s, 2H), 7.13 (d, J= 8.2 Hz, 2H), 7.18-7.27 (m, 3H), 7.37-7.39 (m, 2H), 7.49 (d, J= 8.2 Hz, 2H), 7.63 (d, J= 8.3 Hz, 2H), 7.87 (d, 7= 8.3 Hz, 2H), 12.16 (br s, 1H), 13.06 (s, 1H); MS(ES+) m/z 563 (MH+).
Example 38
3- [2-({ [4-(ethylsulfonyl)phenyl] acetyl} amino)-5-(phenylcarbonyl)-l,3-thiazol-4-yl] benzoic acid
Figure imgf000065_0001
Intermediate 38a: methyl 3-[2-amino-5-(phenylcarbonyl -l,3-thiazol-4-yllbenzoate
Figure imgf000065_0002
Step 1: SOCl2 (8.10 mL) was added to a solution of 3-[(methyloxy)carbonyl]benzoic acid (1 g) in dichloromethane (DCM) (15 mL) and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in dry DCM. Solvent was evapourated again to afford the acyl chloride as a light yellow solid. This acyl chloride was dissolved in acetone (15 mL) and cooled to 0 °C, to which ammonium thiocyanate (0.845 g) was added. The mixture was then stirred at this temperature for 1.5 hours. Then bis{[4- (methyloxy)phenyl]methyl} amine (1.571 g, synthesis of this intermediate, see step 1 for preparing intermediate lb) was added at the same temperature and stirred for an additional 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (EtOAc : PE = 0-30 %) to afford methyl 3-({[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]amino}carbonyl)benzoate (1.307 g) as a brown sticky solid. MS(ES+) m/z 479 (MH+).
Step 2: A solution of 2-bromo-l-phenylethanone (175 mg) and methyl 3-({[(bis{[4-
(methyloxy)phenyl]methyl}amino)carbonothioyl]amino}carbonyl)benzoate (400 mg) in NJV- dimethylformamide (DMF) (4 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was stirred in TFA (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-80 %) to afford methyl 3-[2- amino-5-(phenylcarbonyl)-l,3-thiazol-4-yl]benzoate (196 mg) as a yellow sticky solid. MS(ES+) m/z 339 (MH+).
Preparation of the final product
A mixture of methyl 3-[2-amino-5-(phenylcarbonyl)-l,3-thiazol-4-yl]benzoate (intermediate 38a, 80 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 56.7 mg), EDC (58.9 mg) and HOBt (41.5 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature overnight. As some starting material still remained and the mixture turned to be turbid, NN-dimethylformamide (DMF) (1 mL) was added to make the mixture clearer and stirred for an additional day. The mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM for 3 times. The combined organic layers were washed with 2 M HCl, sat. NaHCOs, and then brine. The solution was dried over Na2S04. After removal of solvent, the residue was redissolved in tetrahydrofuran (THF) (2.5 mL) and water (0.8 mL), to which lithium hydroxide monohydrate (79 mg) was added and the mixture was stirred at room temperature overnight. The mixture was acidified with 2 M HCl, and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc for 3 times. The combined organic layers were washed with brine and concentrated under reduced pressure. The resulting residue was purified by MDAP to afford 3-[2-({[4-(ethylsulfonyl)phenyl]acetyl}amino)-5- (phenylcarbonyl)-l,3-thiazol-4-yl]benzoic acid (31 mg) as a white solid. LH-NM (400 MHz,
DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J = 7.3 Hz, 2H), 4.02 (s, 2H), 7.24-7.32 (m, 3H), 7.44 (t, J = 7.4 Hz, 1H), 7.55-7.60 (m, 3H), 7.64 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 8.02 (t, J = 1.5 Hz, 1H), 13.01 (br s, 1H), 13.13 (s, 1H); MS(ES+) m/z 535 (MH+).
Example 39
TV- [5- |(2-chlorophenyl)carbonyl] -4-(3-hydroxyphenyl)-l,3-thiazol-2-yl] -2- [4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000066_0001
To a solution of N-{5-[(2-chlorophenyl)carbonyl]-4-[3-(methyloxy)phenyl]-l,3-thiazol-2-yl}- 2-[4-(ethylsulfonyl)phenyl]acetamide (example 24, 181 mg) in dichloromethane (DCM) (5 mL) cooled at -40 °C was added BBr3 (1 M in DCM, 1.3 mL) dropwise. The resulting mixture was stirred at this temperature for 3 hours and stirred at room temperature overnight. The mixture was quenched with water and extracted with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to afford the crude product (157 mg) as a yellow solid. 70 mg of this crude product was redissolved in N,N- dimethylformamide (DMF) (6 mL) and purified by MDAP to afford N-[5-[(2- chlorophenyl)carbonyl]-4-(3-hydroxyphenyl)-l,3-thiazol-2-yl]-2-[4-(ethylsulfonyl)phenyl]acetamide (28 mg) as a white solid. ¾-NMR (400 MHz, DMSO- ) δ ppm 1.10 (t, J= 7.3 Hz, 3H), 3.29 (q, J= 7.3 Hz, 2H), 4.01 (s, 2H), 6.61 (dd, J= 1.8 Hz, J= 8.1 Hz, 1H), 6.73 (d, J= 7.7 Hz, 1H), 6.81 (t, J = 1.8 Hz, 1H), 6.92 (t, J= 7.9 Hz, 1H), 7.16-7.20 (m, 1H), 7.28-7.35 (m, 3H), 7.62 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 9.42 (br s, 1H), 13.10 (s, 1H); MS(ES+) m/z 541 (MH+).
Figure imgf000067_0001
Example 40
A'-{5-[(2-cyanophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide
Figure imgf000067_0002
Step 1: Bromine (0.518 mL) was added into a solution of l-(2-bromophenyl)ethanone (2 g) in diethyl ether (20 mL) at 0 °C dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to afford 2-bromo-l-(2- bromophenyl)ethanone (2.9 g) as a yellow oil. MS(ES+) m/z 276 (MH+).
Step 2: A mixture of 2-bromo-l-(2-bromophenyl)ethanone (1 g) and N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 1.664 g) in NN- dimethylformamide (DMF) (10 mL) was heated to 85 °C for 45 mins. After cooling to RT, the mixture was poured into brine, and extracted with EtOAc for 3 times. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was redissolved into TFA (4 mL), and the resultant solution was heated to 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was basified by sat. NaHCC>3 solution, and then extracted with EtOAc for 3 times. The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on solica gel (EtOAc : PE = 0-30 %) to afford (2- amino-4-phenyl-l,3-thiazol-5-yl)(2-bromophenyl)methanone (1.1 g) as a yellow solid. MS(ES ) m/z 359 (MH+).
Step 3: A mixture of (2-amino-4-phenyl-l,3-thiazol-5-yl)(2-bromophenyl)methanone (200 mg), [4-(ethylsulfonyl)phenyl] acetic acid (intermediate Id, 140 mg), HOBt (113 mg) and EDC (160 mg) in dichloromethane (DCM) (5 mL) was stirred at room temperature under N2 overnight. The mixture was washed with 1 M HCl, sat. NaHCC>3 and brine successively. The organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated in vacuo to afford N-{5-[(2- bromophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (330 mg) as a yellow solid. MS(ES+) m/z 569 (MH+).
Step 4: A mixture of N-{5-[(2-bromophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl]acetamide (100 mg), iodocopper (3.34 mg) and cyanocopper (31.5 mg) in N- methyl-2-pyrrolidone (NMP) (4 mL) was heated to 120 °C for 1 hour. The mixture was poured into water, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by MDAP to afford N-{5-[(2-cyanophenyl)carbonyl]-4-phenyl- l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (9.2 mg). Ή-ΝΜΡ (400 MHz, DMSO- ) δ ppm 1.11 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.04 (s, 2H), 7.14-7.23 (m, 3H), 7.29-7.31 (m, 2H), 7.44-7.51 (m, 2H), 7.54-7.57 (m, 1H), 7.64 (d, J= 8.4 Hz, 2H), 7.67-7.70 (m, 1H), 7.88 (d, J= 8.0 Hz, 2H), 13.21 (s, 1H); MS(ES+) m/z 516 (MH+).
Figure imgf000068_0001
Example 41
A'-{5-[(4-chlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000069_0001
Intermediate 41a: (2-amino-4-phenyl-l,3-thiazol-5-yl (4-chlorophenvnmethanone
Figure imgf000069_0002
A solution of 2-bromo-l-(4-chlorophenyl)ethanone (146 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 250 mg) in NN- dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins to finish the first step ring closure reaction. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in trifluoroacetic acid (4 mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-45 %) to afford (2-amino-4-phenyl-l,3- thiazol-5-yl)(4-chlorophenyl)methanone (127 mg) as a yellow solid. MS(ES+) m/z 315 (MH+).
Preparation of the final product
A mixture of [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 53.3 mg), EDC (55.4 mg) and HOBt (39.1 mg) in dichloromethane (DCM) (2 mL) was stirred at room temperature for 15 mins. Then (2-amino-4-phenyl-l,3-thiazol-5-yl)(4-chlorophenyl)methanone (intermediate 41a, 70 mg) was added, and the mixture was stirred at room temperature overnight. The obtained solution was partitioned between DCM and water. The aqueous layer was washed with DCM for 3 times. The combined organics were washed with brine and dried over anhydrous Na2S04. After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford N- {5-[(4- chlorophenyl)carbonyl]-4-phenyl-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (50 mg) as a white solid. LH-NM (400 MHz, DMSO- 6) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 7.18-7.30 (m, 5H), 7.34-7.37 (m, 2H), 7.54-7.51 (m, 2H), 7.64 (d, J
7.88 (d, J= 8.4 Hz, 2H), 13.10 (s, 1H); MS(ES+) m/z 525 (MH+).
Example 42
A'-{4-(3-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000070_0001
Step 1: see step 1 for preparing intermediate lb.
Step 2: To a solution of 3-chlorobenzoyl chloride (2 g) in acetone (30 mL) cooled at 0 °C was added ammonium thiocyanate (1.74 g) and the resulting mixture was stirred at this temperature for 1 hour. Then bis {[4-(methyloxy)phenyl]methyl} amine (3.53 g) was added at this temperature and stirred for an additional 30 mins. The mixture was concentrated under reduced pressure, and then purified directly by chromatography (EtOAc : PE = 0-15 %) to afford N-[(bis{[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (5.32 g) as a yellow sticky oil. MS(ES+) m/z 455 (MH+).
Intermediate 42b: [2-amino-4-(3-chlorophenyl -l,3-thiazol-5-yl (4-chlorophenvnmethanone
Figure imgf000070_0002
A solution of 2-bromo-l-(4-chlorophenyl)ethanone (136 mg) and N- [(bis {[4- (methyloxy)phenyl]methyl}amino)carbonothioyl]-3-chlorobenzamide (intermediate 42a, 250 NN-dimethylformamide (DMF) (3 mL) was stirred at 85 °C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (4mL) at 80 °C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-30 %) to afford [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](4- chlorophenyl)methanone (188 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).
Preparation of the final product
A mixture of [2-amino-4-(3-chlorophenyl)-l,3-thiazol-5-yl](4-chlorophenyl)methanone (intermediate 42b, 80 mg), [4-(ethylsulfonyl)phenyl]acetic acid (intermediate Id, 54.9 mg), EDC (57.1 mg) and HOBt (40.2 mg) in dichloromethane (DCM) (3.5 mL) was stirred at room temperature for 3 days. Solvent was removed under reduced pressure and the residue was purified directly by MDAP to afford N-{4-(3-chlorophenyl)-5-[(4-chlorophenyl)carbonyl]-l,3-thiazol-2-yl}-2-[4-
(ethylsulfonyl)phenyl]acetamide (54 mg) as a white solid. ¾-NM (400 MHz, DMSO- ) δ ppm 1.09 (t, J= 7.3 Hz, 3H), 3.28 (q, J= 7.3 Hz, 2H), 4.01 (s, 2H), 7.24 (t, J= 7.8 Hz, 1H), 7.31-7.35 (m, 4H), 7.40 (t, J= 1.8 Hz, 1H), 7.53-7.56 (m, 2H), 7.62 (d, J= 8.3 Hz, 2H), 7.87 (d, J= 8.3 Hz, 2H), 13.12 (s, 1H); MS(ES+) m/z 559 (MH+). Example 43
A'-(5-benzoyl-4-(3-((dimethylamino)methyl)phenyl)thiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide
Figure imgf000071_0001
Step 1: To a mixture of methyl 3-formylbenzoate (950 mg) and dimethylamine hydrochloride (613 mg) in dichloromethane (DCM) (40 mL) at 0 °C was added NaBH(OAc)3 (1.859 g) portionwise. The mixture was warmed to room temperature and stirred at room temperature for 18 hours. The mixture was washed with sat, NaHCOs solution (20mL x 2) and then brine (40 mL). The organic phase was dried over Na2SC>4, filtered and concentrated to yield the crude methyl 3- ((dimethylamino)methyl)benzoate (1.23 g) as a yellow solid. MS(ES+) m/z 194 (MH+).
Step 2: To a mixture of methyl 3-((dimethylamino)methyl)benzoate (1.2 g) in methanol (10 mL) was added a solution of LiOH (0.294 g) in water (5 mL). The mixture was stirred at 30 °C overnight. After removal of methanol in vacuo, the pH of the mixture was adjusted to 2.0 with 2 M HC1 solution. The mixture was extracted with butan-l-ol (20mL x 3). The combined organic phase was concentrated to yield 3-((dimethylamino)methyl)benzoic acid (900 mg) as a white solid. MS(ES ) m/z 180 (MH+).
Step 3: A mixture of 3-((dimethylamino)methyl)benzoic acid (900 mg) and oxalyl dichloride (574 mg) in dichloromethane (DCM) (20 mL) was stirred at 45 °C for 3 hours. The mixture was concentrated in vacuo, and then dry DCM (30 mL) was added. The mixture was concentrated again to afford 3-((dimethylamino)methyl)benzoyl chloride (1 g) as a light yellow solid.
Step 4: 3-((Dimethylamino)methyl)benzoyl chloride (1 g) was dissolved in acetone (30 mL) and cooled to 0 °C, to which ammonium thiocyanate (1.48 g) was added. The mixture was then stirred at this temperature for 2 hours. To the above mixture bis(4-methoxybenzyl)amine (1.224 g) was added at the same temperature and stirred for an additional 2 hours. The mixture was
concentrated under reduced pressure and then purified by column chromatography (PE : EA = 4:1 and then DCM : MeOH = 20:1) to afford N-(bis(4-methoxybenzyl)carbamothioyl)-3- ((dimethylamino)methyl)benzamide (630 mg) as a yellow solid. MS(ES+) m/z 478 (MH+).
Step 5: A solution of N-(bis(4-methoxybenzyl)carbamothioyl)-3-
((dimethylamino)methyl)benzamide (630 mg) and 2-bromo-l-phenylethanone (118 mg) in N,N- dimethylformamide (DMF) (20 mL) was stirred at 85 °C under nitrogen for 2 hours. After removal of DMF in vacuo, the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to yield the crude product, which was then purified by column chromatography (silica-gel, DCM : MeOH = 15: 1) to afford (2-(bis(4-methoxybenzyl)amino)-4-(3- ((dimethylamino)methyl) phenyl) thiazol-5-yl)(phenyl)methanone (550 mg) as a yellow solid.
MS(ES+) m/z 578 (MH+).
Step 6: A mixture of (2-(bis(4-methoxybenzyl)amino)-4-(3-((dimethylamino)methyl) phenyl) thiazol-5-yl)(phenyl)methanone (520 mg) in 2,2,2-trifluoroacetic acid (6686 μΐ) was stirred at 85 °C for 18 hours. Most of TFA was evaporated in vacuo. The residue was dissolved in DCM (30 mL) and then washed with sat. NaHCC>3 solution (20mL x 2) and brine (40 mL). The organic phase was dried over Na2SC>4, filtered and concentrated to yield (2-amino-4-(3-
((dimethylamino)methyl)phenyl)thiazol-5-yl)(phenyl)methanone (260 mg) as a yellow oil. MS(ES+) m/z 338 (MH+).
Step 7: A mixture of (2-amino-4-(3-((dimethylamino)methyl)phenyl)thiazol-5- yl)(phenyl)methanone (260 mg), 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 460 mg), BOP (579 mg) and Et3N (0.281 mL) in dichloromethane (DCM) (10 mL) was stirred at 40 °C for 18 hours. As the reaction was not finished, more 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 460 mg) was added and the mixture was stirred at room temperature for another 18 hours until almost full conversion. DCM (30 mL) was added to the mixture and then washed with sat. NaHCC>3 solution (30 mL x 2) and brine (30 mL). The organic phase was dried over Na2SC>4, filtered and concentrated to give the crude product, which was purified by column chromatography (silica-gel, PE : EA : DCM = 3: 1 :1) and preparative HPLC (A: Water (0.1%NH3H2O); B: CAN (0.1%NH3H2O) ret. time : 8.0 mins) to afford the pure product (70 mg) as a yellow solid. LH-NMR (400 MHz, CDC13) δ ppm 1.27 (t , J= 7.2 Hz, 3H), 2.20 (s, 6H), 3.13 (q, J= 7.2 Hz, 2H), 3.35 (s, 2H), 3.61 (s, 2H), 7.13-7.21 (m, 4 H), 7.28-7.44 (m, 4H), 7.45 (s, 1H), 7.63 (d, J= 8.4 Hz, 2H), 7.82 (d, J= 8.4 Hz, 2H); MS(ES+) m/z 548 (MH+).
Example 44
2-(4-(ethylsulfonyl)phenyl)- V-(5-(3-fluorobenzoyl)-4-(3-(trifluoromethyl)phenyl)thiazol-2- yl)acetamide
Figure imgf000073_0001
Step 1: To a solution of methyl 3-(trifluoromethyl)benzoate (2.8 g) in methanol (10 mL) was added NaOH (17.14 mL). The mixture was stirred at RT overnight. After removal of methanol in vacuo, HC1 (2 M) was added to adjust the above mixture to pH 2. The resulting white solid was filtered, washed with water and dried in vacuo to afford 3-(trifluoromethyl)benzoic acid (2.8 g) as a white solid. MS(ES+) m/z 191 (MH+).
Step 2: To a mixture of 3-(trifluoromethyl)benzoic acid (1.6 g) in dichloromethane (DCM) (20 mL) was added sulfurous di chloride (3.00 g) dropwise. The mixture was then stirred at 40 °C for 2 hours. The mixture was evaporated in vacuo, and then dry DCM (20 mL) was added. The mixture was concentrated again to give 3-(trifluoromethyl)benzoyl chloride (1.38 g) as a light yellow oil.
Step 3: The above 3-(trifluoromethyl)benzoyl chloride (1.38 g) was dissolved in acetone (30 mL) and cooled to 0 °C, to which ammonium thiocyanate (993 mg) was added. The mixture was then stirred at this temperature for 2 hours. To the mixture bis(4-methoxybenzyl)amine (4.26 g) was added at the same temperature and stirred for an additional 1 hour. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (EA : PE = 0:1 to 1 :3) to afford N-(bis(4-methoxybenzyl) carbamothioyl)-3-(trifluoromethyl)benzamide (3.1 g) as a light yellow solid. MS(ES+) m/z 489 (MH+).
Step 4: A solution of N-(bis(4-methoxybenzyl) carbamothioyl)-3-(trifluoromethyl) benzamide
(3.1 g) and 2-bromo-l-(3-fluorophenyl)ethanone (400 mg) in N,N-dimethylformamide (DMF) (15 mL) was stirred at 85 °C under nitrogen for 1.5 hours. After removal of DMF in vacuo, the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo to yield the crude product, which was then purified by column chromatography (silica-gel, PE : EtOAc : DCM = 8:1 :1) to afford (2-(bis(4-methoxybenzyl)amino)-4-(3-(trifluoromethyl)phenyl)thiazol-5-yl)(3- fluorophenyl)methanone (1.5 g) as a yellow solid. MS(ES+) m/z 607 (MH+).
Step 5: A mixture of (2-(bis(4-methoxybenzyl)amino)-4-(3-(trifluoromethyl)phenyl)thiazol-5- yl)(3-fluorophenyl)methanone (1.5 g) in TFA (9.53 mL) was stirred at 80 °C overnight. MeOH (10 mL) was added to the reaction and the mixture was left at T overnight. The resulting solid was collected by filtration and dried in vacuo to afford (2-amino-4-(3-(trifluoromethyl)phenyl)thiazol-5- yl)(3 -fluorophenyl) methanone (570 mg) as a yellow solid.
Step 6: A mixture of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 187 mg), (2- amino-4-(3-(trifluoromethyl)phenyl)thiazol-5-yl)(3-fluorophenyl) methanone (200 mg), HOBt (167 mg), EDC (209 mg) and DIPEA (0.286 mL) in dichloromethane (DCM) (30 mL) was stirred at 40 °C for 18 hours. LCMS showed 40% of amine left, so more 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate Id, 187 mg) was added to the mixture and stirred for another 18 hours. LCMS showed most of SM was consumed. The mixture was washed with sat. NaHCC>3 solution (20 mL x 2) and brine (30 mL). The organic phase was dried over Na2SC>4, filtered and concentrated to yield the crude, which was purified by column chromatography (silica-gel, PE : EtOAc : DCM = 4: 1 : 1) to get the product as white solid (91% purity), which was washed with PE / EtOAc (4:1, 20 mL) to afford the pure 2-(4-(ethylsulfonyl)phenyl)-N-(5-(3-fluorobenzoyl)-4-(3-(trifluoromethyl)phenyl)thiazol-2- yl)acetamide (120 mg) as a white solid. ¾-NMR (400 MHz, CDC13) δ ppm 1.32 (t , J= 7.6 Hz, 3H), 3.17 (q, J= 7.6 Hz, 2H), 3.91 (s, 2H), 7.09-7.12 (m, 1H), 7.19-7.21 (m, 1H), 7.28-7.37 (m, 3H), 7.50- 7.53 (m, 3H), 7.60 (d, J= 8.0 Hz, 1H), 7.65 (s, 1H), 7.93 (d, J= 7.6 Hz, 2H), 9.65 (br, 1H); 19F-NMR (376 MHz, CDC13) δ ppm -57, -108; MS(ES+) m/z 577 (MH+). Biological Data
As stated above, the compounds according to Formula I are RORy modulators, and are useful in the treatment of diseases mediated by RORy. The biological activities of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a RORy modulator, as well as tissue and in vivo models. Dual Fluorescence Energy Transfer (FRET) Assay
This assay is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand dependent manner. RORy is a typical nuclear receptor in that it has an AF2 domain in the ligand binding domain (LBD) which interacts with co-activators. The sites of interaction have been mapped to the LXXLL motifs in the co-activator SRC1(2) sequences. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length co-activator.
The assay measures ligand-mediated interaction of the co-activator peptide with the purified bacterial-expressed RORy ligand binding domain (RORy-LBD) to indirectly assess ligand binding. RORy has a basal level of interaction with the co-activator SRC 1(2) in the absence of ligand, thus it is possible to find ligands that inhibit or enhance the RORy/SRCl(2) interaction.
Materials
Generation of RORy-LBD bacterial expression plasmid
Human RORy Ligand Binding Domain (RORy-LBD) was expressed in E.coli strain
BL21(DE3) as an amino-terminal polyhistidine tagged fusion protein. DNA encoding this recombinant protein was sub-cloned into a modified pET21a expression vector (Novagen). A modified polyhistidine tag (MKKHHHHHHLVPRGS) was fused in frame to residues 263-518 of the human RORy sequence.
Protein Purification
Approximately 50 g E.coli cell pellet was resuspended in 300 ml of lysis buffer (30 mM imidazole pH 7.0 and 150 mM NaCl). Cells were lysed by sonication and cell debris was removed by centrifugation for 30 minutes at 20,000g at 4°C. The cleared supernatant was filtered through a 0.45 uM cellulose acetate membrane filter. The clarified lysate was loaded onto a column (XK-26) packed with ProBond Nickel Chelating resin (InVitrogen), pre-equilibrated with 30 mM imidazole pH 7.0 and 150 mM NaCl. After washing to baseline absorbance with the equilibration buffer, the column was developed with a gradient from 30 to 500 mM imidazole pH 7.0. Column fractions containing the RORy-LBD protein were pooled and concentrated to a volume of 5 mis. The concentrated protein was loaded onto a Superdex 200 column pre-equilibrated with 20 mM Tris-Cl pH 7.2 and 200 mM NaCl. The fractions containing the desired RORy-LBD protein were pooled together.
Protein Biotinylation
Purified RORy-LBD was buffer exchanged by exhaustive dialysis [3 changes of at least 20 volumes (>8000x)] against PBS [lOOmM NaPhosphate, pH 8 and 150mM NaCl]. The concentration of RORy-LBD was approximately 30uM in PBS. Five-fold molar excess of NHS-LC-Biotin (Pierce) was added in a minimal volume of PBS. This solution was incubated with occasional gentle mixing for 60 minutes at ambient room temperature. The modified RORy-LBD was dialyzed against 2 buffer changes - TBS pH 8.0 containing 5mM DTT, 2mM EDTA and 2% sucrose - each at least 20 times of the volume. The modified protein was distributed into aliquots, frozen on dry ice and stored at -80°C. The biotinylated RORy-LBD was subjected to mass spectrometric analysis to reveal the extent of modification by the biotinylation reagent. In general, approximately 95% of the protein had at least a single site of biotinylation and the overall extent of biotinylation followed a normal distribution of multiple sites ranged from one to five.
A biotinylated peptide corresponding to amino acid 676 to 700
(CPSSHSSLTERHKILHRLLQEGSPS) of the co-activator steroid receptor coactivator SRC1(2) was generated using similar method.
Assay
Preparation of Europium labeled SRC 1(2) peptide: biotinylated SRC 1(2) solution was prepared by adding an appropriate amount of biotinylated SRC 1(2) from the lOOuM stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of Europium labeled Streptavidin was then added to the biotinylated SRC 1(2) solution in a tube to give a final concentration of 10 nM. The tube was inverted gently and incubated for 15 minutes at room temperature. Twenty-fold excess biotin from the 10 mM stock solution was added and the tube was inverted gently and incubated for 10 minutes at room temperature.
Preparation of APC labeled RORy-LBD: biotinylated RORy-LBD solution was prepared by adding an appropriate amount of biotinylated RORy-LBD from the stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of APC labeled Streptavidin was then added to the biotinylated RORy-LBD solution in a tube to give a final concentration of 20 nM. The tube was inverted gently and incubated for 15 minutes at room temperature. Twenty- fold excess biotin from the 10 mM stock solution was then added and the tube was inverted gently and incubated for 10 minutes at room temperature.
Equal volumes of the above-described Europium labeled SRC 1(2) peptide and the APC labeled RORy-LBD were gently mixed together to give 20nM RORy-LBD, ΙΟηΜ APC-Strepavidin, 20nM SRC 1(2) and 5nM Europium- Streptavidin. The reaction mixtures were incubated for 5 minutes. Using a Thermo Combi Multidrop 384 stacker unit, 25 ul of the reaction mixtures per well was added to the 384-well assay plates containing lul of test compound per well in 100% DMSO. The plates were incubated for lhour and then read on ViewLux in Lance mode for EU/APC.
Jurkat Cell Luciferase Assay
RORy is known to bind to a CNS (conserved non-coding sequences) enhancer element in the IL17 promoter. In this assay, RORy activity is indirectly assessed using a luciferase reporter construct which contains the human IL17 promoter having the RORy-specific CNS enhancer element.
Inhibition of RORy activity by a compound will result in a decrease in luciferase activity of Jurkat cells transfected with the reporter construct.
Materials
Jurkat cell line
For the luciferase reporter plasmid, the 3 Kb human IL17 promoter containing the RORy- specific CNS enhancer element was PCR amplified from human genomic DNA and cloned into a pGL4-Luc2/hygro reporter plasmid sequencially as Xhol-Hindlll (1.1 Kb) and Kpnl-Xhol (1.9 Kb) fragments. For the 1.1 Kb fragment, PCR was used to amplify human IL17 proximal promoter region from genomic DNA of 293T cells using primers as follows: forward primer, 5'- CTCGAGTAGAGCAGGACAGGGAGGAA-3' (Xhol site is underlined) and reverse primer, 5'- AAGCTTGGATGGATGAGTTTGTGCCT-3 ' (Hindlll site is underlined). The 1.1 kb DNA bands were excised, purified, and inserted into pMD19-T Simple Vector (Takara). After DNA sequencing confirmation, the 1.1 kb DNA was digested with Xhol and Hindlll and inserted into Xhol/Hindlll sites of pGL4.31 [luc2P/GAL4UAS/Hygro] (Promega) to generate the pIL17-lkb-luc reporter construct. For the 1.9 Kb fragment, PCR was used to amplify human IL17 promoter region from genomic DNA using primers as follows: forward primer,5'- GGTACCTGCCCTGCTCTATCCTGAGT-3' (Kpnl site is underlined) and reverse primer, 5'-
CTCGAGTGGTGAGTGCTGAGAGATGG-3' (Xhol site is underlined). The resulting 1.9 kb DNA bands were excised, gel purified, and cloned into a pMD19-T Simple Vector (Takara). DNA sequencing analysis revealed that there were three point mutations but none of which affected RORy binding. The 1.9 kb DNA fragment was released by double digestion with Kpnl and Xhol and inserted into pIL17-lkb-luc to generate the luciferase reporter plasmid "pIL17-3kb-CNS-luc." To overexpress RORyt, the full-length cDNA of human RORyt identical to the published sequence NM_001001523 was cloned into pcDNA3.1 at the Kpnl-Notl cloning sites to generate the RORyt overexpression plasmid "CDNA3.1DhRORy49-8".
The luciferase reporter plasmid and the RORyt overexpression plasmid were transfected into Jurkat cell line and a stable clone was identified. The stable clone was grown in 10% dialyzed FBS in RPMI (1640) with 800ug/ml geneticin and 400ug/ml hygromecin.
Assay
Compounds were dissolved in DMSO at three concentrations, lOmM, 400uM and 16uM, and were dispensed into 384-wells assay plate at 40nl, 12.5nl, 5nl respectively. The volume was adjusted with pure DMSO to a give a final uniform volume of 40 nl Jurkat cells described above were counted and centrifuged. The growth medium was discarded and the cells were resuspended with assay medium (phenol red free RPMI) at lE-6/ml. Cells were added to each of the compounds in the assay plates. Cells were either untreated or treated with CD3 microbeads (Miltenyi Biotec) at 1 ul beads per 500,000 cells. Cells were culture overnight and luciferase assay (Promega) was performed. Data were collected by ViewLux (using luciferase greiner 384 setting).
Thl7 ELISA/Intracellular Staining Assays
ELISA CD4+ cells were isolated from splenocytes of C57BL/6 (B6) mice (Shanghai Laboratory
Animal Resource Center) using the CD4+ T Cell Isolation II Kit according to manufacturer's instructions (Miltenyi Biotec). 96 well plates were pre-coated with anti-CD3 antibody. CD4+ cells were resuspended in RPMI complete medium and were added to the 96-well plates at 3xl05 cells/well, with the total volume of each well being 90 ul. A cytokine cocktail (90 ul) was then added to stimulate Thl7 differentiation. Each compound diluted to various concentrations in DMSO (DMSO final volume 0.1 %) was then added. The final concentrations of antibodies (R&D Systems) and cytokines (R&D Systems) were: anti-mCD3, 5ug/ml; anti-mCD28, 2ug/ml; anti-mlFNy, lOug/ml; anti-mIL4, lOug/ml; mIL-6, 20ng/ml; mIL-23, lOng/ml; mIL-Ιβ, lOng/ml; TGF-β, lOng/ml. The cell culture was incubated at 37°C for 3 days. Supernatants were collected and IL-17 concentration was determined by ELISA, performed according to manufacturer's instructions (R&D Systems). The optical density (OD) at 405 nm were measured with a microplate reader (BioRad) and the IL-17 quantity were extrapolated from the standard curve. The percentage of IL-17 inhibition was calculated by referring to the positive control (100%) and the pIC50 were determined by GraphPad. Intracellular staining
The Thl7 differentiation cell culture described above was maintained for 5 days instead of 3 days. The effect of compounds on the production of IL-17 and IFN-γ in the cells was determined by intracellular staining according to manufacturer's instructions (BD Biosciences).
As shown by ELISA and intracellular staining, the RORy modulator of Example 9 significantly reduced IL-17 production in Thl7 cells (Figure 1).
Assay Data
The data described below represents a mean pIC50 value of multiple test results if the test was performed more than once. It is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the testing.
All exemplified compounds except Example 27 were tested in the dual FRET assay described above. All tested compounds except Examples 5, 14, 18, 31, 41 and 42 were found to have a pIC50 between 6 and 9. Example 31 was tested three times and had a pIC50 below 6 in each test. Examples 5, 14, 18, 41 and 42 were tested multiple times and each compound had at least one result indicating it enhanced the RORy/SRCl(2) interaction in the assay; however, all of them were found to inhibit RORy activity in the Jurkat cell luciferase assay and the Thl7 ELISA assay described above.
All exemplified compounds (Examples 1-44) were tested in the Jurkat cell luciferase assay described above. All tested compounds except Examples 37 and 38 were found to have a pIC50 between 6 and 9. Example 37 was tested twice and Example 38 was tested once, and all showed a pIC50 below 5, the detection limit of the assay.
All exemplified compounds except Examples 35, 37, 38, 40 and 43 were tested in the Thl7 ELISA assay described above. All tested compounds were found to have a pIC50 between 5 and 8.
The assay data for the compounds of Examples 2, 3, 9, 10, 13, 25, 29, 30, 32 and 44 are shown in the Table below.
Example ROR Dual FRET Assay Jurkat Cell Luciferase Assay Thl7 Assay
No (pIC50) (pIC50) (pIC50)
2 8.2 7.7 7.2
3 8.0 7.4 6.2
9 8.0 8.0 6.8
10 7.8 7.5 6.8
13 8.0 6.9 6.9
25 7.9 7.4 6.6
29 8.0 6.9 6.4
30 7.9 7.1 6.7
32 7.7 7.9 5.3
44 7.6 7.2 6.8
EAE Studies
Wild-type mice of the C57BL/6 (B6) strain were obtained from Shanghai Laboratory Animal Resource Center. EAE was induced by intravenous injections of 100 ng of pertussis toxin (List Biological Laboratories) and then subcutaneous immunization with 200 μΐ of an emulsion composed of MOG35.55 peptide (300 μg/mouse) in PBS and an equal volume of complete Freund's adjuvant containing 5 mg/ml heat-killed Mycobacterium tuberculosis H37Ra (Difco Laboratories) on day 0, followed by another intravenous injections of 100 ng of pertussis toxin on day 2 as described previously (Wang et al. (2006) J. Clin. Invest. 116: 2434-2441). Each compound was given orally on day 0 at 100 mg/kg twice a day. Mice were scored for disease severity daily using a EAE scoring system (Wang et al. (2006) J. Clin. Invest. 116: 2434-2441): 0, no overt signs of disease; 1, limp tail or hind limb weakness but not both; 2, limptail and paraparesis (weakness, incomplete paralysis of one or two hind limbs); 3, paraplegia (complete paralysis of two hind limbs); 4, paraplegia with forelimb weakness or paralysis; and 5, moribund state or death. Clinical score data were expressed as means ± s.e.m.
As shown in Figure 2, the RORy modulator of Example 9 delayed EAE onset.
CIA Studies
Collagen-induced arthritis (CIA) was induced in 8-week old male DBA/1 mice via an initial intradermal (i.d.) injection of an emulsion consisting of bovine type II collagen in CFA. Mice were intraperitoneally (i.p.) injected with bovine type II collagen 21 days later to boost the immune system, resulting in chronic inflammation in both the hind and the front paws. Each compound was given to the mice at lOOmg/kg twice a day starting from day 20 after the first immunization. Mice were examined for onset and severity of disease in a blinded manner. Arthritis symptoms were graded by the following scoring system: grade 0, normal appearance; grade 1, slight erythema/ edema (1-3 digits); grade 2, erythema/ edema in more than 3 digits or mild swelling in ankle/wrist joint; grade 3, erythema/ edema in entire paw; grade 4, massive erythema/ edema of entire paw extending into proximal joints, ankylosis, loss of function. Each limb was graded, giving a maximum possible score of 16 per mouse. Clinical score data were expressed as means ± s.e.m. Foot volume of the mice was determined using a YLS-7B foot volume measuring instrument (Shandong Academy of Medical Science).
As shown in Figure 3, the RORy modulator of Example 9 reduced disease severity in CIA mice.
Methods of Use
The compounds of the invention are modulators of RORy and can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases. The Inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, asthma, chronic obstructive pulmonary disease and allergy. Accordingly, in another aspect the invention is directed to methods of treating such diseases.
The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
As used herein, "treat" in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
As used herein, "patient" refers to a human or other animal.
The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.1 mg to 1000 mg.
Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
In one embodiment, the invention relates to the use of the compounds of the invention in the preparation of a medicament for the treatment of diseases mediated by RORy. In another embodiment, the invention relates to the compounds of the invention for use in the treatment of diseases mediated by RORy. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease and type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gaves' disease, asthma, chronic obstructive pulmonary disease and allergy. Compositions
The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 0.1 mg to 1000 mg.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically- acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

Claims

1. A compound of Formula I or a harmaceutically acceptable salt thereof
Figure imgf000086_0001
Formula 1
wherein:
Rl is phenyl optionally substituted with one to three substituents selected from the group consisting of:
- halo;
- CN;
- (CH2)nOH;
- C1-C3 alkoxy;
- (CH2)nCOOH;
- C1-C4 alkyl optionally substituted with one to three F;
- heterocycloalkyl; and
- NRaRa wherein Ra is H or C1-C3 alkyl;
R2 is
- 1,3-benzodioxol or
- phenyl optionally substituted with one to three substituents selected from the group consisting of:
- halo;
- CN;
- (CH2)nOH;
- C1-C3 alkoxy;
- C1-C4 alkyl optionally substituted with one to three F; and
- (CH2)nCOOH;
R3 is H or Cl-C6 alkyl;
R4 is H or Cl-C6 alkyl;
C1-C6 alkyl optionally substituted with one to three F; n is 0, 1, 2, 3, 4, 5 or 6; and
wherein when said R2 is other than 1,3-benzodioxol, then at least one of Rl and R2 is phenyl having at least one substituent.
2. A compound or salt according to claim 1, wherein Rl is phenyl substituted with CI or F.
3. A compound or salt according to claim 2, wherein Rl is 3-chlorophenyl or 3 -fluorophenyl.
4. A compound or salt according to claim 1, wherein Rl is 3-cyanophenyl.
5. A compound or salt according to claim 1, wherein Rl is 3-(trifluoromethyl)phenyl.
6. A compound or salt according to any of claims 1 to 5, wherein R2 is phenyl substituted with CI or F.
7. A compound or salt according to claim 6, wherein R2 is 2-chlorophenyl or 3-chlorophenyl.
8. A compound or salt according to claim 6, wherein R2 is 2-fluorophenyl or 3-fluorophenyl.
9. A compound or salt according to any of claims 1 to 5, wherein R2 is 2-methoxyphenyl.
10. A compound or salt according to any of claims 1 to 5, wherein R2 is 2-methylphenyl.
11. A compound or salt according to any of claims 1 to 10, wherein R3 is H.
12. A compound or salt according to any of claims 1 to 11 , wherein R4 is H.
13. A compound or salt according to any of claims 1 to 12, wherein R5 is ethyl or methyl.
14. A pharmaceutical composition which comprises a compound according to any of claims 1 to 13 and a pharmaceutically acceptable carrier or excipient.
15. A compound according to any of claims 1 to 13 for use in the treatment of multiple sclerosis.
16. A compound according to any of claims 1 to 13 for use in the treatment of rheumatoid arthritis.
17. A pharmaceutical composition for use in the treatment of multiple sclerosis which comprises a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition for use in the treatment of rheumatoid arthritis which comprises a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.
19. A method of treatment of multiple sclerosis which comprises administering to a host in need thereof an effective amount of a compound according to any of claims 1 to 13 or a
pharmaceutically acceptable salt thereof.
20. A method of treatment of rheumatoid arthritis which comprises administering to a host in need thereof an effective amount of a compound according to any of claims 1 to 13 or a
pharmaceutically acceptable salt thereof.
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Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012139775A1 (en) 2011-04-14 2012-10-18 Phenex Pharmaceuticals Ag Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor rar-related orphan receptor-gamma (rorgamma, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
WO2013064231A1 (en) 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3)
WO2013079223A1 (en) 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases
WO2013171729A2 (en) 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as rorgamat modulator
WO2013178362A1 (en) 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma]
WO2014023367A1 (en) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma
WO2014125426A1 (en) * 2013-02-15 2014-08-21 Aurigene Discovery Technologies Limited Trisubstituted heterocyclic derivatives as ror gamma modulators
WO2015052675A1 (en) * 2013-10-10 2015-04-16 Glenmark Pharmaceuticals S.A. Substituted dihydro-benzimidazole compounds as ror gamma modulators
WO2015087234A1 (en) 2013-12-10 2015-06-18 Glenmark Pharmaceuticals S.A. Bicyclic heteroaryl indole analogues useful as ror gamma modulators
WO2015101928A1 (en) * 2013-12-31 2015-07-09 Aurigene Discovery Technologies Limited Fused thiophene and thiazole derivatives as ror gamma modulators
WO2015129853A1 (en) * 2014-02-27 2015-09-03 東レ株式会社 Cyclic amine derivative and pharmaceutical use thereof
CN104926733A (en) * 2014-03-18 2015-09-23 北京韩美药品有限公司 Compound used as RORgamma conditioning agent
WO2015159233A1 (en) 2014-04-16 2015-10-22 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl ether compounds as ror gamma modulators
WO2015198232A1 (en) 2014-06-25 2015-12-30 Piramal Enterprises Limited Fused triterpene compounds and uses thereof
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2016069976A1 (en) * 2014-10-30 2016-05-06 Janssen Pharmaceutica Nv THIAZOLES AS MODULATORS OF RORyt
CN105636941A (en) * 2013-10-25 2016-06-01 葛兰素史密斯克莱有限责任公司 Novel compounds
WO2016110821A1 (en) 2015-01-08 2016-07-14 Advinus Therapeutics Limited Bicyclic compounds, compositions and medicinal applications thereof
WO2016128908A1 (en) 2015-02-12 2016-08-18 Advinus Therapeutics Limited Bicyclic compounds, compositions and medicinal applications thereof
CN105980353A (en) * 2013-12-05 2016-09-28 领先制药Cel模型知识产权公司 RORγ modulator
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2016185342A1 (en) * 2015-05-15 2016-11-24 Aurigene Discovery Technologies Limited Substituted tetrahydroquinolinone compounds as ror gamma modulators
EP3018126A4 (en) * 2013-07-03 2016-12-07 Takeda Pharmaceuticals Co HETEROCYCLIC COMPOUND
WO2016193894A1 (en) 2015-05-29 2016-12-08 Glenmark Pharmaceuticals S.A. Treatment of respiratory disorders using ror- gamma inhibitors
WO2017021879A1 (en) 2015-08-03 2017-02-09 Glenmark Pharmaceuticals S.A. Novel compounds as ror gamma modulators
CN106536489A (en) * 2014-05-28 2017-03-22 葛兰素史密斯克莱知识产权发展有限公司 Novel compounds
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017131156A1 (en) 2016-01-29 2017-08-03 東レ株式会社 Cyclic amine derivative and pharmaceutical use thereof
CN107108602A (en) * 2015-01-09 2017-08-29 协和发酵麒麟株式会社 The preparation method of thiazole
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017199103A1 (en) * 2016-05-18 2017-11-23 Glenmark Pharmaceuticals S.A. Benzamide compounds as ror gamma modulators
US9845319B2 (en) 2014-10-30 2017-12-19 Janssen Pharmaceutiuca NV Amide substituted thiazoles as modulators of RORyt
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9850236B2 (en) 2014-10-30 2017-12-26 Janssen Pharmaceutica Nv Trifluoromethyl alcohols as modulators of RORγt
US9868724B2 (en) 2014-05-28 2018-01-16 Glaxosmithkline Intellectual Property Development Limited Compounds
WO2018011747A1 (en) 2016-07-14 2018-01-18 Cadila Healthcare Limited Polycyclic compounds as ror-gamma modulators
WO2018011746A1 (en) 2016-07-14 2018-01-18 Cadila Healthcare Limited Cyclopropyl derivatives as ror-gamma modulators
US9902715B2 (en) 2014-05-28 2018-02-27 Glaxosmithkline Intellectual Property Development Limited Compounds
WO2018042342A1 (en) 2016-08-30 2018-03-08 Glenmark Pharmaceuticals S.A. 1,2,3-benzotriazole derivatives as ror gamma t modulators
US10005731B2 (en) 2012-12-06 2018-06-26 Glaxo Group Limited Modulators of the retinoid-related orphan receptor gamma (ROR-gamma) for use in the treatment of autoimmune and inflammatory diseases
WO2018116285A1 (en) 2016-12-23 2018-06-28 Glenmark Pharmaceuticals S.A. Substituted morpholine derivatives as ror gamma modulators
US10011566B2 (en) 2015-12-15 2018-07-03 Astrazeneca Ab Compounds
WO2018185675A1 (en) 2017-04-04 2018-10-11 Glenmark Pharmaceuticals S.A. Substituted oxoazetidine analogues as ror gamma modulators
US10189775B2 (en) 2015-08-28 2019-01-29 Glenmark Pharmaceuticals S.A. Carbocyclic compounds as ROR gamma modulators
WO2019022235A1 (en) 2017-07-27 2019-01-31 東レ株式会社 Therapeutic agent or prophylactic agent for alopecia areata
WO2019044940A1 (en) * 2017-08-31 2019-03-07 東レ株式会社 Cyclic amine derivative and use thereof for medical purposes
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
WO2019213470A1 (en) 2018-05-03 2019-11-07 Eternity Bioscience Inc. Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorϒ) and pharmaceutical uses thereof
WO2020108538A1 (en) * 2018-11-27 2020-06-04 正大天晴药业集团股份有限公司 RORγ INHIBITOR HAVING SULFONYL STRUCTURE
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US10975037B2 (en) 2018-06-18 2021-04-13 Janssen Pharmaceutica Nv Phenyl substituted pyrazoles as modulators of RORγt
US10975068B2 (en) 2016-04-27 2021-04-13 Janssen Pharmaceutica Nv 6-aminopyridin-3-yl thiazoles as modulators of RORγT
US10975057B2 (en) 2018-06-18 2021-04-13 Janssen Pharmaceutica Nv 6-aminopyridin-3-yl pyrazoles as modulators of RORgT
WO2021083311A1 (en) 2019-10-31 2021-05-06 江苏恒瑞医药股份有限公司 ACID ADDITION SALT OF RORγ REGULATOR
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
US11034658B2 (en) 2018-06-18 2021-06-15 Janssen Pharmaceutica Nv Pyridinyl pyrazoles as modulators of RORγT
WO2021092242A3 (en) * 2019-11-05 2021-07-22 Dermira, Inc. Ror gamma t inhibitors and topical uses thereof
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
US11345666B2 (en) 2018-06-18 2022-05-31 Janssen Pharmaceutica Nv Phenyl and pyridinyl substituted imidazoles as modulators of RORγT

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063743A1 (en) * 2003-12-26 2005-07-14 Kyowa Hakko Kogyo Co., Ltd. Thiazole derivative
WO2010010908A1 (en) * 2008-07-23 2010-01-28 協和発酵キリン株式会社 Therapeutic agent for migraine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005063743A1 (en) * 2003-12-26 2005-07-14 Kyowa Hakko Kogyo Co., Ltd. Thiazole derivative
WO2010010908A1 (en) * 2008-07-23 2010-01-28 協和発酵キリン株式会社 Therapeutic agent for migraine

Cited By (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8946446B2 (en) 2011-04-14 2015-02-03 Phenex Pharmaceuticals Ag Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-γ (ROR-γ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases
WO2012139775A1 (en) 2011-04-14 2012-10-18 Phenex Pharmaceuticals Ag Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor rar-related orphan receptor-gamma (rorgamma, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
WO2013064231A1 (en) 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag SEVEN-MEMBERED SULFONAMIDES AS MODULATORS OF RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORγ, NR1F3)
WO2013079223A1 (en) 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases
US9815851B2 (en) 2011-12-02 2017-11-14 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases
US10301272B2 (en) 2012-05-31 2019-05-28 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ROR[γ]
JP2015521193A (en) * 2012-05-31 2015-07-27 フェネックス ファーマシューティカルス アーゲー Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators of the orphan nuclear receptor RORγ
TWI511960B (en) * 2012-05-31 2015-12-11 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor rorγ
KR101742954B1 (en) 2012-05-31 2017-06-02 페넥스 파마슈티컬스 아게 Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma]
WO2013178362A1 (en) 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted thiazoles and related derivatives as modulators for the orphan nuclear receptor ror[gamma]
EA028330B1 (en) * 2012-05-31 2017-11-30 Фенекс Фармасьютикалз Аг CARBOXAMIDE OR SULFONAMIDE SUBSTITUTED THIAZOLES AND RELATED DERIVATIVES AS MODULATORS FOR THE ORPHAN NUCLEAR RECEPTOR RORγ
EP3118189A1 (en) 2012-08-09 2017-01-18 Phenex Pharmaceuticals AG Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma
US9458104B2 (en) 2012-08-09 2016-10-04 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor RORγ
WO2014023367A1 (en) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror gamma
US10005731B2 (en) 2012-12-06 2018-06-26 Glaxo Group Limited Modulators of the retinoid-related orphan receptor gamma (ROR-gamma) for use in the treatment of autoimmune and inflammatory diseases
WO2013171729A2 (en) 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as rorgamat modulator
WO2014125426A1 (en) * 2013-02-15 2014-08-21 Aurigene Discovery Technologies Limited Trisubstituted heterocyclic derivatives as ror gamma modulators
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
EP3018126A4 (en) * 2013-07-03 2016-12-07 Takeda Pharmaceuticals Co HETEROCYCLIC COMPOUND
WO2015052675A1 (en) * 2013-10-10 2015-04-16 Glenmark Pharmaceuticals S.A. Substituted dihydro-benzimidazole compounds as ror gamma modulators
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CN105980353B (en) * 2013-12-05 2019-06-14 领先制药控股公司 RORγ modulators
CN105980353A (en) * 2013-12-05 2016-09-28 领先制药Cel模型知识产权公司 RORγ modulator
WO2015087234A1 (en) 2013-12-10 2015-06-18 Glenmark Pharmaceuticals S.A. Bicyclic heteroaryl indole analogues useful as ror gamma modulators
US9682977B2 (en) 2013-12-10 2017-06-20 Glenmark Pharmaceuticals S.A. Bicyclic heteroaryl indole analogues useful as ROR gamma modulators
WO2015101928A1 (en) * 2013-12-31 2015-07-09 Aurigene Discovery Technologies Limited Fused thiophene and thiazole derivatives as ror gamma modulators
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2015129853A1 (en) * 2014-02-27 2015-09-03 東レ株式会社 Cyclic amine derivative and pharmaceutical use thereof
CN104926733A (en) * 2014-03-18 2015-09-23 北京韩美药品有限公司 Compound used as RORgamma conditioning agent
WO2015139619A1 (en) * 2014-03-18 2015-09-24 北京韩美药品有限公司 Compound serving as rorγ modulator
CN104926733B (en) * 2014-03-18 2019-05-10 北京韩美药品有限公司 Compound as ROR gamma modulators
WO2015159233A1 (en) 2014-04-16 2015-10-22 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl ether compounds as ror gamma modulators
US9718817B2 (en) 2014-04-16 2017-08-01 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl ether compounds as ROR gamma modulators
CN106536489A (en) * 2014-05-28 2017-03-22 葛兰素史密斯克莱知识产权发展有限公司 Novel compounds
CN106536489B (en) * 2014-05-28 2020-02-07 葛兰素史密斯克莱知识产权发展有限公司 Retinoid-related orphan receptor gamma modulators and uses thereof
US9902715B2 (en) 2014-05-28 2018-02-27 Glaxosmithkline Intellectual Property Development Limited Compounds
US9902735B2 (en) 2014-05-28 2018-02-27 Glaxosmithkline Intellectual Property Development Limited Heteroaryl substituted compounds as RORγ inhibitors
US9868724B2 (en) 2014-05-28 2018-01-16 Glaxosmithkline Intellectual Property Development Limited Compounds
WO2015198232A1 (en) 2014-06-25 2015-12-30 Piramal Enterprises Limited Fused triterpene compounds and uses thereof
US10105373B2 (en) 2014-06-25 2018-10-23 Piramal Enterprises Limited Fused triterpene compounds and uses thereof
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10080744B2 (en) 2014-10-30 2018-09-25 Janssen Pharmaceutica Nv Thiazoles as modulators of RORγt
WO2016069976A1 (en) * 2014-10-30 2016-05-06 Janssen Pharmaceutica Nv THIAZOLES AS MODULATORS OF RORyt
US9850236B2 (en) 2014-10-30 2017-12-26 Janssen Pharmaceutica Nv Trifluoromethyl alcohols as modulators of RORγt
US10150762B2 (en) 2014-10-30 2018-12-11 Janssen Pharmaceutica, Nv Trifluoromethyl alcohols as modulators of RORγt
US9861618B2 (en) 2014-10-30 2018-01-09 Janssen Pharmaceutica Nv Thiazoles as modulators of RORγt
JP2017534626A (en) * 2014-10-30 2017-11-24 ヤンセン ファーマシューティカ エヌ．ベー． Thiazole as a modulator of RORγt
US9845319B2 (en) 2014-10-30 2017-12-19 Janssen Pharmaceutiuca NV Amide substituted thiazoles as modulators of RORyt
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2016110821A1 (en) 2015-01-08 2016-07-14 Advinus Therapeutics Limited Bicyclic compounds, compositions and medicinal applications thereof
US10894790B2 (en) 2015-01-09 2021-01-19 Kyowa Kirin Co., Ltd Production method of thiazole derivative
CN107108602A (en) * 2015-01-09 2017-08-29 协和发酵麒麟株式会社 The preparation method of thiazole
US10214523B2 (en) 2015-01-09 2019-02-26 Kyowa Hakko Kirin Co., Ltd. Production method of thiazole derivative
EP3242877A4 (en) * 2015-01-09 2018-10-17 Kyowa Hakko Kirin Co., Ltd. Production method of thiazole derivative
US10618894B2 (en) 2015-01-09 2020-04-14 Kyowa Kirin Co., Ltd. Production method of thiazole derivative
WO2016128908A1 (en) 2015-02-12 2016-08-18 Advinus Therapeutics Limited Bicyclic compounds, compositions and medicinal applications thereof
US11229636B2 (en) 2015-05-15 2022-01-25 Aurigene Discovery Technologies Limited Substituted tetrahydroquinolinone compounds as ROR gamma modulators
KR20180029971A (en) * 2015-05-15 2018-03-21 오리진 디스커버리 테크놀로지스 리미티드 Substituted tetrahydroquinolinone compounds as ROR gamma modulators
WO2016185342A1 (en) * 2015-05-15 2016-11-24 Aurigene Discovery Technologies Limited Substituted tetrahydroquinolinone compounds as ror gamma modulators
CN113121497A (en) * 2015-05-15 2021-07-16 奥瑞基尼探索技术有限公司 Substituted tetrahydroquinolinone compounds as ROR gamma modulators
US12377088B2 (en) 2015-05-15 2025-08-05 Aurigene Oncology Limited Substituted tetrahydroquinolinone compounds as ROR gamma modulators
KR102702236B1 (en) 2015-05-15 2024-09-04 오리진 온콜로지 리미티드 Substituted tetrahydroquinolinone compounds as ROR gamma modulators
JP2020117514A (en) * 2015-05-15 2020-08-06 オーリジーン ディスカバリー テクノロジーズ リミテッドＡｕｒｉｇｅｎｅ Ｄｉｓｃｏｖｅｒｙ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｌｉｍｉｔｅｄ Substituted tetrahydroquinolinone compounds as ror gamma modulators
JP2018515531A (en) * 2015-05-15 2018-06-14 オーリジーン ディスカバリー テクノロジーズ リミテッドＡｕｒｉｇｅｎｅ Ｄｉｓｃｏｖｅｒｙ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｌｉｍｉｔｅｄ Substituted tetrahydroquinoline compounds as ROR gamma modulators
EA036679B1 (en) * 2015-05-15 2020-12-08 Ауриген Дискавери Текнолоджиз Лимитед Substituted tetrahydroquinolinone compounds as retinoid-related orphan receptor gamma (ror) modulators
WO2016193894A1 (en) 2015-05-29 2016-12-08 Glenmark Pharmaceuticals S.A. Treatment of respiratory disorders using ror- gamma inhibitors
US9855229B2 (en) 2015-05-29 2018-01-02 Glenmark Pharmaceuticals S.A. Treatment of respiratory disorders using ROR-gamma inhibitors
EP3686187A1 (en) 2015-08-03 2020-07-29 Glenmark Pharmaceuticals S.A. Process for the preparation of ror gamma modulators
WO2017021879A1 (en) 2015-08-03 2017-02-09 Glenmark Pharmaceuticals S.A. Novel compounds as ror gamma modulators
US10988467B2 (en) 2015-08-03 2021-04-27 Glenmark Pharmaceuticals S.A. Compounds as ROR gamma modulators
US10344024B2 (en) 2015-08-03 2019-07-09 Glenmark Pharmaceuticals S.A. Compounds as ROR gamma modulators
US9975887B2 (en) 2015-08-03 2018-05-22 Glenmark Pharmaceuticals S.A. Compounds as ROR gamma modulators
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10336688B2 (en) 2015-08-28 2019-07-02 Glenmark Pharmaceuticals S.A. Carbocyclic compounds as ROR gamma modulators
US10189775B2 (en) 2015-08-28 2019-01-29 Glenmark Pharmaceuticals S.A. Carbocyclic compounds as ROR gamma modulators
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10011566B2 (en) 2015-12-15 2018-07-03 Astrazeneca Ab Compounds
US10526286B2 (en) 2015-12-15 2020-01-07 Astrazeneca Ab Compounds
US11453644B1 (en) 2015-12-15 2022-09-27 Astrazeneca, Ab Compounds
US10988445B2 (en) 2015-12-15 2021-04-27 Astrazeneca Ab Compounds
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
KR20180100573A (en) 2016-01-29 2018-09-11 도레이 카부시키가이샤 Cyclic amine derivatives and uses thereof
AU2017210685B2 (en) * 2016-01-29 2020-09-24 Toray Industries, Inc. Cyclic amine derivative and medical use thereof
WO2017131156A1 (en) 2016-01-29 2017-08-03 東レ株式会社 Cyclic amine derivative and pharmaceutical use thereof
US10364222B2 (en) 2016-01-29 2019-07-30 Toray Industries, Inc. Cyclic amine derivative and medical use thereof
EP3409660A4 (en) * 2016-01-29 2019-06-26 Toray Industries, Inc. CYCLIC AMINE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
US10975068B2 (en) 2016-04-27 2021-04-13 Janssen Pharmaceutica Nv 6-aminopyridin-3-yl thiazoles as modulators of RORγT
WO2017199103A1 (en) * 2016-05-18 2017-11-23 Glenmark Pharmaceuticals S.A. Benzamide compounds as ror gamma modulators
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2018011747A1 (en) 2016-07-14 2018-01-18 Cadila Healthcare Limited Polycyclic compounds as ror-gamma modulators
WO2018011746A1 (en) 2016-07-14 2018-01-18 Cadila Healthcare Limited Cyclopropyl derivatives as ror-gamma modulators
WO2018042342A1 (en) 2016-08-30 2018-03-08 Glenmark Pharmaceuticals S.A. 1,2,3-benzotriazole derivatives as ror gamma t modulators
WO2018116285A1 (en) 2016-12-23 2018-06-28 Glenmark Pharmaceuticals S.A. Substituted morpholine derivatives as ror gamma modulators
WO2018185675A1 (en) 2017-04-04 2018-10-11 Glenmark Pharmaceuticals S.A. Substituted oxoazetidine analogues as ror gamma modulators
US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
KR20200033224A (en) 2017-07-27 2020-03-27 도레이 카부시키가이샤 Treatment or prevention of alopecia areata
US10881649B2 (en) 2017-07-27 2021-01-05 Toray Industries, Inc. Therapeutic agent or preventive agent for alopecia areata
WO2019022235A1 (en) 2017-07-27 2019-01-31 東レ株式会社 Therapeutic agent or prophylactic agent for alopecia areata
WO2019044940A1 (en) * 2017-08-31 2019-03-07 東レ株式会社 Cyclic amine derivative and use thereof for medical purposes
WO2019213470A1 (en) 2018-05-03 2019-11-07 Eternity Bioscience Inc. Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorϒ) and pharmaceutical uses thereof
US12187684B2 (en) 2018-05-03 2025-01-07 Jiangsu Hengrui Medicine Co., Ltd. Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (RORγ) and pharmaceutical use thereof
US11034658B2 (en) 2018-06-18 2021-06-15 Janssen Pharmaceutica Nv Pyridinyl pyrazoles as modulators of RORγT
US10975037B2 (en) 2018-06-18 2021-04-13 Janssen Pharmaceutica Nv Phenyl substituted pyrazoles as modulators of RORγt
US11345666B2 (en) 2018-06-18 2022-05-31 Janssen Pharmaceutica Nv Phenyl and pyridinyl substituted imidazoles as modulators of RORγT
US10975057B2 (en) 2018-06-18 2021-04-13 Janssen Pharmaceutica Nv 6-aminopyridin-3-yl pyrazoles as modulators of RORgT
WO2020108538A1 (en) * 2018-11-27 2020-06-04 正大天晴药业集团股份有限公司 RORγ INHIBITOR HAVING SULFONYL STRUCTURE
CN113166061B (en) * 2018-11-27 2023-11-21 正大天晴药业集团股份有限公司 RORγ inhibitors containing sulfonyl structures
CN113166061A (en) * 2018-11-27 2021-07-23 正大天晴药业集团股份有限公司 ROR gamma inhibitors containing sulfonyl structures
WO2021083311A1 (en) 2019-10-31 2021-05-06 江苏恒瑞医药股份有限公司 ACID ADDITION SALT OF RORγ REGULATOR
WO2021092242A3 (en) * 2019-11-05 2021-07-22 Dermira, Inc. Ror gamma t inhibitors and topical uses thereof

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