WO2012100734A1 - Compounds useful as retinoid-related orphan receptor gamma modulators - Google Patents

Compounds useful as retinoid-related orphan receptor gamma modulators Download PDF

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Publication number
WO2012100734A1
WO2012100734A1 PCT/CN2012/070678 CN2012070678W WO2012100734A1 WO 2012100734 A1 WO2012100734 A1 WO 2012100734A1 CN 2012070678 W CN2012070678 W CN 2012070678W WO 2012100734 A1 WO2012100734 A1 WO 2012100734A1
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Prior art keywords
phenyl
thiazol
added
chlorophenyl
compound
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PCT/CN2012/070678
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French (fr)
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Yonghui Wang
Ting Yang
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Glaxo Group Limited
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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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

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 (ROR0) 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 Th 17 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 ( orn 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.14: 164-174; 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.
  • 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.
  • 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.
  • 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.
  • 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 RORC gene which include ROR l 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
  • X is selected from the group consisting of:
  • Ra is H or C1-C6 alkyl
  • each Rl is independently selected from the group consisting of:
  • each R2 is independently selected from the group consisting of:
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • R3 is H or C1-C3 alkyl
  • R4 is H or Cl-C3 alkyl
  • R5 is selected from the group consisting of:
  • Rb is C1-C6 alkyl
  • the compounds of Formula I has the structure of Formula 1(A)
  • Rl, R2, R3, R4, R5, m and n are defined as in Formula I.
  • the invention relates to the compounds of Formula I, wherein X is methylamino. In one embodiment, the invention relates to the compounds of Formula I, wherein X is methyl or ethyl.
  • this invention also relates to compounds of any of the above embodiments, wherein m is 0. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein m is 1.
  • this invention also relates to compounds of any of the above embodiments, wherein Rl is CI, In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein Rl is CN. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein Rl is CF 3 .
  • this invention also relates to compounds of any of the above embodiments, wherein n is 1, In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein n is 2. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein n is 0.
  • this invention also relates to compounds of any of the above embodiments, wherein R2 is CF3. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is CI. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is methoxy. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is methyl.
  • this invention also relates to compounds of any of the above embodiments, wherein R3 is H. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R3 is CHj.
  • this invention also relates to compounds of any of the above embodiments, wherein R4 is H. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R4 is C3 ⁇ 4,
  • this invention also relates to compounds of any of the above embodiments, wherein R5 is C1-C3 alkyl. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R5 is ethyl.
  • R5 is C1-C3 alkyl. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R5 is ethyl.
  • 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.
  • 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.
  • 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).
  • 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, IR 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.
  • the compounds according to Formula I are prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction scheme. Starting materials and reagents depicted in the general reaction schemes below are commercially available or can be made from commercially available starting materials using methods known to those skilled in the art.
  • 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 where X is O or NRa.
  • Starting material substituted aryl methyl ketones 1.1 can be transformed to thiazole amines 1.2 through a one pot iodination and cyclization cascade reaction. Bromination of 1.2 provides intermediates 1.3, which are attacked by substituted phenols or substituted phenyl anilines.
  • the obtained thiazole amines 1.4 can then be coupled with an appropriate acid (commercially available or can be made from commercially avail ble starting materials using methods known to those skilled in the art) to afford the desired compounds of Formula I.
  • Mobile phase water containing 0.05% TFA / acetonitrile.
  • 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 2 C0 3 (108 g) and bromoethane (64.1 g). The reaction mixture was stirred at RT. 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 RT 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
  • Step 1 Iodine (3.33 g) was added to 1 ⁇ (4-chlorophenyl)ethanone (2.031 g) and thiourea (2 g). The reaction mixture was heated overnight at 100 °C. After cooling, the reaction mixture was triturated with diethyl ether (about 50 mL) to remove any unreacted iodine and l-(4- chlorophenyl)ethanone. The solid residue was put in cold distilled water (50 mL) and treated with ammonia solution to pH 9-10. 4-(4-Chlorophenyl)-l,3-thiazol-2-amine (2.6 g) was collected.
  • Step 2 To a mixture of 4-(4-chlorophenyl)-l,3-thiazol-2-amine (2.3 g) and copper(ll) bromide (3.94 g) was added acetonitrile (30 mL). The reaction mixture was stirred at room temperature overnight. Acetonitrile was removed under vacuum. EtOAc was added. The obtained mixture was washed with diluted ammonia 3 times.
  • Step 4 [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 31.8 mg), 4-(4-chlorophenyl)-5- [(4-methylphenyl)oxy]-l,3-thiazol-2-amine (44.1 mg), EDC (32.0 mg) and HOBt (25.6 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (4 mL) was added. The reaction mixture was stirred at RT for one and a half days. DCM was removed. The obtained crude was redissolved in THF and DMF, which was submitted to MDAP for purification under acidic conditions.
  • Step 2 [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 63.0 mg), 4-(4-chlorophenyl)-5- (phenyloxy)-l,3-thiazol-2-amine (83.5 mg), EDC (63.4 mg) and HOBt (50.7 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for three days. DCM was removed. The obtained mixture was redissolved in DMF and purified by MDAP.
  • Step 1 To a mixture of thiourea (1.147 g) and 2-bromo-l-phenylethanone (3 g) was added ethanol (100 mL). The reaction mixture was heated up to reflux (oil bath temperature: 80 °C) for 2.5 hours. The reaction was cooled down to RT. Ethanol was removed under vacuum to afford the intermediate as a white solid. Copper(II) bromide (8.42 g) and acetonitrile (40 mL) were added. The mixture was stirred at RT for 3 days. Acetonitrile was removed under vacuum. EtOAc was added. The obtained mixture was washed with diluted ammonia three times until no blue color was observed in the aqueous phase.
  • Step 3 [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 150 mg), 4-phenyl-5- (phenyloxy)-l,3-thiazol-2-amine (176 mg), EDC (151 mg) and HOBt (121 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification.
  • Step 2 [4-(Ethylsulfonyl)phenyl] acetic acid (intermediate la, 152 mg), 5-[(2- chlorophenyl)oxy]-4-phenyl-l,3-thiazol-2-amine (202.2 mg), EDC (154 mg) and HOBt (123 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification.
  • Step 2 [4-(Ethylsulfonyl)phenyl] cetic acid (intermediate la, 118 mg), 4-phenyl-5- ⁇ [2- (trifluoromethyl)phenyl]oxy ⁇ -l,3-thiazol-2-amine (174.3 mg), EDC (119 mg) and HOBt (95 mg) were added into a 10 mL vial, Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 day. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification.
  • DCM Dichloromethane
  • Step 2 [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 139 mg), 5-[(4- chlorophenyl)oxy]-4-phenyl-l,3-thiazol-2-amine (184.6 mg), EDC (140 mg) and HOBt (112 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP.
  • Step 2 [4-(Ethylsulfonyl)phenyl] acetic acid (intermediate la, 73.6 mg), 4-phenyl-5- ⁇ [4-
  • Step 2 [4-(Ethylsulfonyl)phenyl] acetic acid (intermediate la, 142 mg), 5- ⁇ [4-
  • Step 1 To a solution of l-(3-chlorophenyl)ethanone (15 g) in chloroform (100 mL) and ethyl acetate (100 mL) was added copper(II) bromide (21.67 g), and the reaction mixture was refluxed overnight. The reaction mixture was concentrated to give 2-bromo-l-(3-chlorophenyl)ethanone (18 g) as a brown oil. MS(ES + ) m/z 219 (MH ).
  • Step 2 To a solution of 2-bromo-l-(3-chlorophenyl)ethanone (28 g) in ethanol (300 mL) was added thiourea (10.04 g).
  • Step 3 To a solution of 4-(3-chlorophenyl)thiazol-2-amine (1 g) in tetrahydrofuran (20 mL) was added NBS (0.88 g). After stirring at room temperature overnight, the mixture was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic phase was washed with water (20 mL x 2), dried and concentrated to give 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.05 g) as a red liquid. MS(ES ) m/z 289 (MH ).
  • Step 4 To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g) in acetone (50 mL) was added cesium carbonate (1.42 g) and 4-chlorophenol (0.5 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The obtained solution was washed with water (40 mL x 3) and brine (30 mL x 2), dried and concentrated.
  • Step 1 To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (1.4 g) and 2-chlorophenol (0.50 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The obtained solution was washed with water (40 mL x 3) and brine (30 mL x 2), dried and concentrated.
  • Step 2 To a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 200 mg) in dichloromethane (DCM) (20mL) was added 5-(2-chlorophenoxy)-4-(3-chlorophenyl)thiazol-2-amine (300 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315 mL). After stirring at 35 °C for 2 days, the reaction mixture was washed with water (30 mL x 3), dried and concentrated.
  • DCM dichloromethane
  • Step 1 To a solution of 5-bromo-4-(3-chlorophenyl)thiazoI-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (10 mL) was added phenol (0.36 g) and cesium carbonate (1.35 g). The reaction mixture was stirred at 45 °C overnight. DCM (100 mL) was added. The obtained solution was washed with water (100 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE - 1:5 to 1: 1) to give 4-(3-chlorophenyl)-5-phenoxythiazol-2- amine (230 mg) as a red liquid. MS(ES " *) m/z 303 (MET 1 ⁇ .
  • Step 2 To a solution of 4-(3-chlorophenyl)-5-phenoxythiazol-2-amine (230 mg) in
  • DCM dichloromethane
  • Step 1 To a mixture of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (2.0 g, see step 3 for synthesis of Example 9), 2-(trifluoromethyl)phenol (1.12 g) and cesium carbonate (2.70 g) was added acetone (10 mL). The reaction mixture was stirred at 45 °C overnight. After removal of solvent, the residue was partitioned between DCM (100 mL) and water (100 mL). The organic phase was washed with water (100 mL x 2), dried and concentrated.
  • Step 1 To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (2.5 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (3.38 g) and 2,6- dichlorophenol (1.55 g). The reaction mixture was stirred at 45 °C for 2 days. DCM (50 mL) was added. The obtained solution was washed with water, dried and concentrated to give 4-(3- chlorophenyl)-5-(2,6-dichlorophenoxy)thiazol-2-amine (300 mg) as a red oil. MS(ES + ) m/z 370 (MH + ).
  • Step 1 To a solution of 3-acetylbenzonitrile (8 g) in chloroform (50 mL) and ethyl acetate (50 mL) was added copper(II) bromide (25.9 g). The reaction mixture was refluxed overnight. Solid was removed by filtration, and the filtrate was washed with sat. ammonium chloride and brine, dried, and concentrated to give 3-(2-bromoacetyl)benzonitrile (13 g) as a yellow oil. MS(ES ⁇ ) m/z 225 (MH ⁇ ).
  • Step 2 To a solution of 3-(2-bromoacetyl)benzonitrile (13 g) in ethanol (80 mL) was added thiourea (4.64 g). The reaction mixture was stirred for 5 mins. The white precipitate was collected by filtration to give 3-(2-aminothiazol-4-yl)benzonitrile (10 g). MSfES " ⁇ m/z 202 (MH 4 ).
  • Step 3 To a solution of 3-(2-aminothiazol-4-yl)benzonitrile (3 g) in tetrahydrofuran (THF) (60 mL) was added NBS (2.79 g). The reaction mixture was stirred at room temperature for 1 hour. EtOAc (80 mL) was added. The obtained solution was washed with water (50 mL x 3), dried and concentrated to give 5-bromo-4-(3-cyanophenyl)thiazol-2-amine (2.7 g) as a dark red solid. MSfES ⁇ ) m/z 279 (MH ).
  • Step 4 To a solution of 5-bromo-4-(3-cyanophenyl)thiazol-2-amine (1.0 g) in acetone (30 mL) was added cesium carbonate (1.5 g) and 4-(trifluoromethyl)phenol (0.6 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The organic phase was washed by water (30 mL x 3) and brine (25 mL x 2), dried and concentrated.
  • Step 5 To a solution of 2-(4-(ethyIsulfonyl)phenyl)acetic acid (intermediate la, 220 mg) in dichloromethane (DCM) (20 mL) was added 3-(2-amino-5-(4-(trifluoromethyl)phenolxy)thiazol-4- yl)benzonitrile (310 mg), EDC (200 mg) ⁇ HOBt (150 mg) and DIPEA (0.30 mL). After stirring at 35 °C for 2 days, the mixture was washed with water (20 mL x 3), dried and concentrated.
  • DCM dichloromethane
  • Step 1 To a solution of l-(3-(trifluoromethyl)phenyl)ethanone (5 g) in chloroform (30 mL) and ethyl acetate (30 mL) was added copper(II) bromide (7.5 g). The reaction mixture was refluxed overnight. Solvent was removed to give 3-(trifluoromethyl)benzoyl bromide (6 g) as a brown oil. MS(ES + ) m/z 253 (MH ).
  • Step 2 To a solution of 3-(trifluoromethyl)benzoyl bromide (6 g) in ethanol (100 mL) was added thiourea (5.0 g). The reaction mixture was refluxed overnight. Solvent was removed. The residue was triturated with ethyl acetate to give 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (5 g) as a white solid. MS(ES ⁇ > m/z 245 (MH 4 ).
  • Step 3 To a solution of 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (5 g) in tetrahydrofuran
  • Step 4 To a solution of 5-bromo-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (1.0 g) in acetone (25 mL) was added cesium carbonate (1.4 g) and 2-hydroxybenzonitriIe (0.6 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The organic phase was washed with water (30 mL x 3) and brine (20 mL x 2), dried and concentrate.
  • Step 2 To a solution of 3-(2-amino-5-(2-chloro-4-(trifluoromethyl)phenoxy)thiazol-4- yl)benzonitrile (300 mg) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 208 mg) in DCM (50 mL) was added EDC (436 mg), HOBt (139 mg) and DIPEA (0.79 mL). After stirring at reflux overnight, the mixture was washed with water (40 mL x 3), dried and concentrated.
  • Step 1 Lithium chloride (2.30 g) was added to a solution of l-methoxy-4-nitro-2- (trifluoromethyl)benzene (4 g) in NN-dimethylformamide (40 mL) at room temperature. The reaction mixture was stirred at 160 °C for 5 hours. After cooling to RT, the solution was diluted with EtOAc (300 mL). The mixture was washed with water (100 mL x 2) and brine (100 mL), dried and concentrated to give 4-nitro-2-(trifluoromethyl)phenol (3.5 g) as a yellow solid.
  • Step 2 Zinc (4.42 g) was added to a solution of 4-nitro-2-(trifluoromethyl)phenol (3.5 g) and ammonium formate (8.52 g) in methanol (5 mL) and water (5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered and EtOAc (80 mL) was added to the filtrate. The organic layer was washed with water (30 mL) and brine (40 mL), dried, and concentrated to afford 4-amino-2-(trifluoromethyl)phenol (2.8 g) as a yellow solid.
  • Step 3 Sodium nitrite (0.47 g) in 3 ⁇ 40 (3 mL) was added dropwise to a solution of 4-amino-2- (trifluoromethyl)phenol (1 g) in acetonitrile (20 mL) and hydrochloric acid (10 mL) at 0 °C . After stirring for 0.5 hour, copper(I) chloride (1.12 g) in 3 M HC1 (5 mL) was added to the mixture. Then the reaction mixture was stirred at 100 °C for 6 hours. After cooling to room temperature, the solution was diluted with EtOAc (200 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried, and concentrated.
  • Step 4 5-Bromo-4-(3-cyanophenyl)thiazol-2-amine 3-(2-Amino-5-bromothiazol-4- yl)benzonitrile (500 mg, see step 3 for synthesis of Example 15) was added to a solution of 4-chloro- 2-(trifluorometliyl)phenol (351 mg) and Cs 2 C0 3 (872 mg) in acetone (30 mL) at room temperature. The reaction mixture was stirred at 45 °C for 4 hours. The reaction mixutre was cooled to room temperature, filtered through celite and concentrated.
  • Step 5 3-(2-Amino-5-(4-chloro-2-(trifluoromethyl)phenoxy)thiazoI-4-yl)benzonitrile (170 mg) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 147 mg), HOBt (79 mg,), EDC (247 mg) and DIPEA (0.45 mL) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred at 40 °C for 12 hours. The mixture was cooled to room temperature and concentrated.
  • Step 1 Bromine (4.59 mL) was added into a solution of l,3-diphenyl-l,3-propanedione (20 g) in ethyl acetate (50 mL) dropwise at 0 °C. After the addition was complete, the resultant mixture was stirred at 0 °C until the color of bromine faded away. Solvent was removed in vacuo. The residue and thiourea (6.79 g) was dissolved into N ; N-dimethylformamide (DMF) (20 mL) and the solution was heated to 85 °C for 15 mins. The mixture was cooled down, poured into water, basified by NaHC0 3 , and extracted with EtOAc (3 times).
  • DMF N-dimethylformamide
  • Step 2 A mixture of [4-(ethylsulfonyl)phenyI]acetic acid (intermediate la, 598 mg), EDC (718 mg) and HOBt (506 mg) in dichloromethane (DCM) (10 mL) was stirred at room temperature under nitrogen for 10 mins. (2-Amino-4-phenyl-l,3-thiazol-5-yl)(phenyl)methanone (700 mg) was then added. After stirring at room temperature overnight, the reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM for 3 times.
  • DCM dichloromethane
  • Step 3 NaBH 4 (11 mg) was added into a solution of 2-[4-(ethylsulfonyl)phenyl]-N-[4-phenyl- 5-(phenylcarbonyl)-l,3-thiazol-2-yl]acetamide (100 mg) in methanol (2 mL) at room temperature in 3 portions. The reaction mixture was stirred at the same temperature for 1.5 hours. The mixture was poured into sat. NH 4 CI solution, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na 2 S0 .
  • Step 1 A mixture of 3-phenylpropanoic acid (5 g), N,C-dimethylhydroxylamine (3.9 g), HOBt (6.1 g), EDC (7.7 g) and Et 3 N (9.3 mL) in dichloromethane (DCM) (80 mL) was stirred at 25 °C overnight. The mixture was washed with 1 M HC1, sat. NaHC(1 ⁇ 4 and brine successively. The organic phase was dried over anhydrous Na 2 S0 4 .
  • DCM dichloromethane
  • Step 2 To a solution of N-methoxy-N-methyl-3-phenylpropanamide (4.5 g) in tetrahydrofuran (THF) (60 mL) stirred at 0 °C was added a solution of phenylmagnesium bromide (34 mL) (1 M in THF) dropwise. After stirring at 0 °C for 3 hours, the reaction mixture was quenched with sat. NH 4 C1 solution, and then extracted with EtOAc (80 mL). The organic phase was washed with brine, dried over anhydrous Na 2 SO,j, and concentrated in vacuo to afford 1,3-diphenylpropan-l-one (2.2 g) as a yellow solid. MS(ES + ) m/z 211 (MH ).
  • Step 3 A mixture of 1,3-diphenylpropan-l-one (2.2 g) and copper(II) bromide (3.8 g) in chloroform (20 mL) and ethyl acetate (20 mL) was stirred at reflux for 2 hours. Solvent was removed, and the residue was partitioned between water (20 mL) and EtOAc (50 mL). The organic phase was dried and concentrated to give 2-bromo- 1,3-diphenylpropan-l-one (2.6 g) as a yellow solid. MS(ES + ) m/z 289 (MH").
  • Step 4 A mixture of 2-bromo- 1,3-diphenylpropan-l-one (3.5 g) and thiourea (1.1 g) in ethanol (30 mL) was heated at reflux for 2 hours. Solvent was removed in vacuo. The residue was washed with EtOAc and water, filtered and dried to afford 4-phenyl-5-(phenylmethyl)-l,3-thiazol-2-amine (1.7 g) as a yellow soild. MS(ES + ) m/z 267 (MH").
  • [4-(Ethylsulfonyl)pbenyl]acetic acid (intermediate la, 89 mg), 4-phenyl-5-(phenylmethyl)-l,3- thiazol-2-amine (intermediate 21a, 104 mg), EDC (90 mg) and HOBt (71.7 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT over 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification.
  • Step 1 To a solution of 1,3-diphenylbutan-l-one (300 mg) in chloroform (10 mL) and ethyl acetate (10 mL) was added copper(II) bromide (657 mg). The reaction mixture was stirred at 85 °C for 3 hours. Solvent was removed, and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried and concentrated to give 2-bromo-l,3-diphenyibutan-l-one (400 mg) as a yellow solid. MS(ES ⁇ mfz 303 (MfT).
  • Step 3 A mixture of 4-phenyl-5-(l-phenylethyl)thiazol-2-amine (70 mg), 2-(4- (ethylsulfonyl)phenyl)acetic acid (intermediate la, 68.4 mg), HOBt (42.1 mg) and EDC (52.6 mg) in dichloromethane (DCM) (15 mL) was stirred at RT overnight The mixture was washed with water (60 mL x 3) and brine (60 mL). The organic phase was dried over anhydrous Na 2 S0 4 , and concentrated.
  • DCM dichloromethane
  • Step 1 Borane-tetrahydrofuran complex (17.67 mL) was added dropwise to a solution of 3-(2- chlorophenyl)propanoic acid (1.3 g) in THF (50 mL) cooled at 0 °C over 30 mins. The reaction mixture was warmed to room temperature and stirred overnight, The mixture was then cooled to 0 °C and quenched with brine. The organic layer was separated, and the aqueous layer was extracted with etiryl acetate (100 mL x 2). The combined organic phases were dried over sodium sulfate and concentrated to afford 3-(2-chlorophenyl)propan-l-ol (1.7 g) as a yellow oil. MSfES ⁇ m/z 153 ((MH- H 2 0) + ).
  • DCM dichloromethane
  • DCM dichloromethane
  • Step 5 A mixture of 3-(2-chlorophenyl)-l -(3-chlorophenyl)propan-l-one (0.68 g) and copper(II) bromide (1.09 g) in chloroform (10 mL) and ethyl acetate (10 mL) was stirred at 85 °C for 3 hours. Solvent was removed, and the residue was partitioned between water (30mL) and ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2).
  • Step 6 A mixture of 2-bromo-3-(2-chlorophenyl)-l-(3-chlorophenyl)propan-l-one (800 mg) and thiourea (340 mg) in ethanol (20 mL) was stirred at 85 °C overnight. Solvent was removed. The residue was suspended in CH 2 C1 2 (30 mL), and the mixture was filtered to remove insoluble solid.
  • Step 1 To a mixture of thiourea (3.42 g) and 2-bromo-l-(4-chlorophenyl)ethanone (10.5 g) was added ethanol (100 mL). The reaction mixture was heated up to reflux (oil bath temperature: 85 °C) overnight. The reaction mixture was cooled to RT. Solid was filtered off and washed with diethyl ether to afford 4-(4-chlorophenyl)-l,3-thiazol-2-amine as a white solid. MSfES ) m/z 211 (Nfflf).
  • Step 2 To a mixture of 4-(4-chIorophenyl)-l,3-thiazol-2-amine (3.8 g) and copper(II) bromide (12.48 g) was added acetonitrile (30 mL). The reaction mixture was stirred at room temperature overnight. Acetonitrile was removed in vacuo. EtOAc was added. The obtained mixture was washed with diluted ammonia 3 times. The organic phase was then washed with brine and dried over Na2SC>4.
  • Step 3 To a solution of N-methylaniline (49.6 mg, 0.463 mmol) in NN-dimethylformamide (DMF) (0.5 mL) was added sodium hydride (23.13 mg). The vial was sealed and stirred at RT for 40 mins. A solution of 5-bromo-4-(4-chIorophenyl)-l ,3-thiazol-2-amine (67 mg) in NN- dimethylformamide (DMF) (0.5 mL) was carefully added at 0 °C. The reaction mixture was stirred at this temperature for 10 mins, and then quenched with water. The obtained mixture was extracted with EtOAc for 3 times. The combined organics were washed with brine, dried over Na 2 SC> .
  • Step 4 [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 44 mg), 4-(4-chlorophenyl)-N 5 - methyl-A ⁇ -phenylthiazole ⁇ -diamine (60.9 mg), EDC (44.3 mg) and HOBt (35.4 mg) were added into a 10 mL vial.
  • Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give N- ⁇ 4-(4-chlorophenyl)-5-
  • Step 1 A mixture of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (2 g, see step 3 for synthesis of Example 9), 2-chloro-N-methylbenzenamine (1.08 g) and cesium carbonate (2.70 g) in acetone (5 mL) was stirred at 55 °C overnight. Solvent was removed, and the residue was partitioned between DCM (10 mL) and water (10 mL). The organic phase was washed with water (10 mL x 3), dried and concentrated to give A ⁇ -(2-chlorophenyl)-4-(3-chlorophenyl)-N 5 -methylthiazole-2,5-diamine (400 mg) as a red solid. MStES*) m z 351 (MET 1 ).
  • Step 2 A mixture of 2-(4-(ethylsuIfonyI)phenyl)acetic acid (intermediate 1 a, 313 mg), ⁇ -(2- chloropheny ⁇ S-chlorophenyli-A ⁇ -methyltliiazole ⁇ .S-diamine (400 mg), EDC (657 mg), HOBt (210 mg) and DIPEA (1.20 mL) in dichloromethane (DCM) (20 mL) was stirred at 45 °C overnight. DCM (50 mL) and water (50 mL) were added. The organic phase was washed with water (30 mL x 3), dried and concentrated.
  • DCM dichloromethane
  • Step 1 To a solution of 5-bromo-4-(3-chlorophenyl)thiazoI-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (1.4 g) and 2- isopropylphenol (0.51 g). The reaction mixture was stirred at 45 °C overnight. After removal of solvent, ethyl acetate was added. The organic solution was washed with water (30 mL x 3) and brine (25 mL x 2), dried and concentrated.
  • Step 2 To a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate l , 200 mg) in dichloromethane (DCM) (25 mL) was added 4-(3-chlorophenyl)-5-(2-isopropylphenoxy)thiazol-2- amine (300 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315 mL). After stirring at 35 °C for 2 days, the mixture was washed with water (40 mL x 3), dried and concentrated.
  • DCM dichloromethane
  • Step 1 To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (1.4 g) and 4- methoxyphenol (0.48 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The obtained solution was washed with water (40 mL x 3) and brine (30 mL x 2), dried and concentrated.
  • Step 2 To a solution of 2-(4-(ethyIsulfonyl)phenyl)acetic acid (intermediate la, 200 mg) in dichloromethane (DCM) (20 mL) was added 4-(3-chlorophenyl)-5-(4-methoxyphenoxy)thiazol-2- amine (280 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315 mL). After stirring at 35 °C for 2 days, the reaction mixture was washed with water (25 mL x 3), dried and concentrated.
  • DCM dichloromethane
  • Step 2 A mixture of l-(3-(bromomethyl)phenyl)ethanone (2.4 g), dimethylamine
  • Step 3 Bromine (568 mg) in acetic acid (30 mL) was added dropwise to a solution of l-(3- ((dimethylamino)methyl)phenyl)ethanone (700 mg) in acetic acid (20 mL) at 10 °C. The reaction mixture was stirred overnight. Solvent was removed to give 2-bromo-l -(3- ((dimethylamino)methyl)phenyl)ethanone (1.0 g) as an oil. MSfES ) m/z 256 (MET).
  • Step 4 A mixture of 2-bromo-l -(3-((dimethylamino)methyl)phenyl)ethanone (1.0 g) and thiourea (0.535 g) in ethanol (10 mL) was stirred at 80 °C overnight. Solvent was removed to give 4- (3-((dimethylamino)methyl)phenyl)thiazol-2-amine (800 mg). MS(ES + ) m/z 234 (MH ⁇ ).
  • Step 5 NBS (336 mg) was added to a solution of 4-(3-((dimethylamino)methyl)phenyl)thiazoI- 2-amine (800 mg) in THF (10 mL). The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed to give 5-bromo-4-(3-((dimethylamino)methyl)phenyl)thiazol-2-amine (800 mg). MSCES ) m z 312 (MH ⁇ .
  • Step 6 To a solution of 5-bromo-4-(3-((dimethylamino)methyl)phenyl)thiazol-2-amine (800 mg) in acetone (50 mL) was added 2-(trifluoromethyl)phenol (571 mg) and cesium carbonate (1.25 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The organic phase was washed with water (50 mL x 3), dried and concentrated.
  • Step 7 To a solution of 4-(3-((dimethylamino)methyl)phenyl)-5-(2- (trifluoromethyl)phenoxy)thiazol-2-amine (100 mg) in DCM (15 mL) was added 2-(4- (ethylsulfonyl)phenyl)acetic acid (intermediate la, 87 mg), HOBt (46.7 mg), EDC (146 mg) and DIPEA (0.266 mL). After stirring at reflux overnight, the mixture was washed with water and brine, dried and concentrated.
  • 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.
  • 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 SRC 1(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 (M HHHHHHLVPRGS) 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.
  • lysis buffer 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 SRC1(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'- CTCGAGT AGAGCAGG AC AGGGAGGAA-3 1 (Xhol site is underlined) and reverse primer, 5'- AAGCTTGGATGGATGAGTTTGTGCCT-3 1 (Hindlll site is underlined).
  • forward primer 5'- CTCGAGT AGAGCAGG AC AGGGAGGAA-3 1 (Xhol site is underlined)
  • reverse primer 5'- AAGCTTGGATGGATGAGTTTGTGCCT-3 1 (Hindlll site is underlined).
  • the 1.1 kb DNA bands were excised, purified, and inserted into pMD19-T Simple Vector (Takara).
  • 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-hic reporter construct.
  • PCR was used to amplify human IL17 promoter region from genomic DNA using primers as follows: forward 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.
  • Mouse CD4+ cells were purified 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. Un-coated wells were used as controls. CD4+ Cells were resuspended in RPMI complete medium and were added to the 96-well plates at 3E5 cells/well, with the total volume being 90 ul. Cytokine cocktail and 20ul of each compound were then added to the wells (DMSO final volume 0.1%).
  • 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 culture was incubated in 37°C for 3 days and supematants were collected for ELISA.
  • the IL-17 ELISAs were performed according to manufacturer's instructions (R&D Systems).
  • Thl7 differentiation culture described above was maintained for 5 days and cells were analyzed by IL-17 and IFN- ⁇ intracellular staining according to manufacturer's instructions (BD Biosciences).
  • 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.
  • EAE Experimental Autoimmune Encephalomyelitis
  • Collagen-induced arthritis is an animal model of rheumatoid arthritis.
  • CIA can be 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 are 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 is given to the mice at lOOmg/kg twice a day starting from day 20 after the first immunization. Mice are examined for onset and severity of disease in a blinded manner.
  • Arthritis symptoms can be 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 is graded, giving a maximum possible score of 16 per mouse. Clinical score data can be expressed as means ⁇ s.e.m. Foot volume of the mice can be determined using a YLS-7B foot volume measuring instrument (Shandong Academy of Medical Science).
  • 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, asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' 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 he 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 artis n 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.
  • the invention relates to the compounds of the invention for use in the treatment of diseases mediated by RORy.
  • 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, asthma, type I diabetes,
  • 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.
  • 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.
  • 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 nig-
  • 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. 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.

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Abstract

Disclosed are retinoid-related orphan receptor gamma (RORγ) modulators of Formula (I) and their use in the treatment of diseases mediated by RORγ, wherein the radicals have the meanings as defined in the invention.

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 (ROR0) 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 Th 17 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 ( orn 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.14: 164-174; 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 X, Rl, R2, R3, R4, R5, m and n 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.
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.
"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 RORC gene which include ROR l 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 imgf000005_0001
Formula I
wherein:
X is selected from the group consisting of:
- O;
- NRa wherein Ra is H or C1-C6 alkyl; and
- C1-C3 alkyl optionally substituted with OH; each Rl is independently selected from the group consisting of:
- halo;
- CN;
- OH;
- C1-C3 alkoxy optionally substituted with one to three F; and
- C1-C3 alkyl optionally substituted with one to three F or N(CH3)(CH3);
each R2 is independently selected from the group consisting of:
- halo;
- CN;
- OH;
- C1-C3 alkoxy optionally substituted with one to three F; and
- C1-C3 alkyl optionally substituted with one to three F;
m is 0, 1 or 2;
n is 0, 1 or 2;
R3 is H or C1-C3 alkyl;
R4 is H or Cl-C3 alkyl;
R5 is selected from the group consisting of:
- C1-C6 alkyl optionally substituted with one to three F, OH or C1-C3 alkoxy; and
- NHRb wherein Rb is C1-C6 alkyl.
In one embodiment, the compounds of Formula I has the structure of Formula 1(A)
Figure imgf000006_0001
Formula 1(A) or a pharmaceutically acceptable salt thereof,
wherein Rl, R2, R3, R4, R5, m and n are defined as in Formula I. In one embodiment, the invention relates to the compounds of Formula I, wherein X is methylamino. In one embodiment, the invention relates to the compounds of Formula I, wherein X is methyl or ethyl.
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein m is 0. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein m is 1.
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein Rl is CI, In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein Rl is CN. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein Rl is CF3.
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein n is 1, In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein n is 2. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein n is 0.
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is CF3. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is CI. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is methoxy. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R2 is methyl.
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R3 is H. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R3 is CHj.
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R4 is H. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R4 is C¾,
In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R5 is C1-C3 alkyl. In one embodiment, this invention also relates to compounds of any of the above embodiments, wherein R5 is ethyl. 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, IR 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. Starting materials and reagents depicted in the general reaction schemes below are commercially available or can be made from commercially available starting materials using methods known to those skilled in the art.
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
[Conditions: a) iodine, thiourea, 100 °C; b) CuBr2, acetonitrile; or NBS, THF; c) substituted phenol or substituted phenyl anilines, Cs2C03, acetone, 55 °C; d) EDC, HOBt, DCM]
Scheme 1 represents a general reaction scheme for preparing compounds of Formula I where X is O or NRa. Starting material substituted aryl methyl ketones 1.1 can be transformed to thiazole amines 1.2 through a one pot iodination and cyclization cascade reaction. Bromination of 1.2 provides intermediates 1.3, which are attacked by substituted phenols or substituted phenyl anilines. The obtained thiazole amines 1.4 can then be coupled with an appropriate acid (commercially available or can be made from commercially avail ble starting materials using methods known to those skilled in the art) to afford the desired 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
DCE 1,2-dichloroethane
DCM dichloromethane
DIPEA diisopropylethylamine
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide
EA ethyl acetate
EDC N-(3-dimemylaminopropyl)-N-ethylcarbodiimide hydrochloride ES electrospray
HOBt hydroxybenzotriazole
LCMS liquid chromatography mass spectrometry
MDAP mass directed automated preparative liquid chromatography.
MS mass spectrometry
NBS N-bromosuccinimide
NMP N-methyI-2-pyrrolidone
PCC pyridinium chlorochromate
PE petroleum ether
R.T room temperature
sat. saturated
TFA trifluoroacetic acid
THF tetrahydrofuran
Chromatography
Unless stated otherwise, all chromatography was carried out using silica columns. LCMS
1) Acidic condition:
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 condition:
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
1) acidic condition 1:
Instrument: Waters instrument
Column: Sunfire Prep CI 8 column (5 um, 19 x 50 mm)
Mobile phase: water containing 0.05% TFA / acetonitrile.
2) acidic condition 2:
Instrument: Gilson GX-281
Column: Sunfire prep CI 8 OBD; 5 um, 100 mm * 30 mm;
Mobile phase: A: 0.05% TFA/H20; B: MeCN;
3) basic condition 1:
Instrumnet: Waters instrument
Column: Xbridge Prep CI 8 column (5 um, 19 x 50 mm)
Mobile phase: water containing 0.04% ammonia/ acetonitrile. 4) basic condition 2:
Instrumnet: Gilson 281(PHG-005);
Column: Shimadzu PRC-ODS 20 *250 mm, 15um two connected in series;
Mobile phase: A: 10 mM NH4HC03 B:MeCN;
5) basic condition 3:
Instrumnet: Gilson GX-281;
Column: Agela Durashell RP 21.5*250 mm 10 μτη;
Mobile phase: A: 0.04% N¾ H20/water; B: CH3CN;
Example 1
iV-{4-(4-chlorophenyl)-5-[(4-methylphenyl)oxy]-l,3-thiazol-2-yl}-2-[4- (ethylsulfonyl)phenyl] acetamide
Figure imgf000013_0001
Intermediate la: r4-(ethylsulfonypphenyl]acetic acid
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 (4- {[(ethyloxy)carbonothioyl]thio}phenyl)acetic acid (90 g) as a dark red Kquid. MSfES ) m/z 257 (MH1).
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 (4-mercaptophenyl)acetic acid (33 g)as a yellow solid. 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 2C03 (108 g) and bromoethane (64.1 g). The reaction mixture was stirred at RT. 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 ethyl [4-(ethylthio)phenyl]acetate (34 g) as a pale yellow solid. MS(ES+) m/z 225 (MIT).
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 RT 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 ethyl [4- (ethylsulfonyl)phenyl]acetate (25 g) as a yellow liquid. MSiES4) m/z 257 (MH4).
Step 5: To a solution of ethyl [4-(emylsulfonyl)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 [4-(ethylsulfonyI)phenyl]acetic acid (20 g) as a yellow solid. Ή-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, 7= 11.2 Hz, 2H), 12.53 (s, 1H); MS(ES ) m/z 229 (MH ).
Preparation of the final product
Step 1: Iodine (3.33 g) was added to 1 ~(4-chlorophenyl)ethanone (2.031 g) and thiourea (2 g). The reaction mixture was heated overnight at 100 °C. After cooling, the reaction mixture was triturated with diethyl ether (about 50 mL) to remove any unreacted iodine and l-(4- chlorophenyl)ethanone. The solid residue was put in cold distilled water (50 mL) and treated with ammonia solution to pH 9-10. 4-(4-Chlorophenyl)-l,3-thiazol-2-amine (2.6 g) was collected. Ή- NMR (400 MHz, DMSO-rf6) δ ppm 7.06 (s, 1H), 7.39 (d, J= 8.5 Hz, 2H), 7.72 (d, J= 8.5 Hz, 2H); MS(ES+) in/z 211 (MH+). Step 2: To a mixture of 4-(4-chlorophenyl)-l,3-thiazol-2-amine (2.3 g) and copper(ll) bromide (3.94 g) was added acetonitrile (30 mL). The reaction mixture was stirred at room temperature overnight. Acetonitrile was removed under vacuum. EtOAc was added. The obtained mixture was washed with diluted ammonia 3 times. The organic phase was then washed with brine and dried over Na2S0 . Filtration and concentration afforded 5-bromo-4-(4-chlorophenyl)-l,3-thiazol-2-amine (2.7 g). MS(ES+) m/z 289 (MH ).
Step 3: To a mixture of 5-bromo-4-(4-chlorophenyl)-l,3-thiazol-2-amine (90 mg), 4- methylphenol (37.0 mg) and cesium carbonate (122 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred overnight. Solvent was removed. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :4) to afford 4-(4-chlorophenyl)-5-[(4- memylphenyl)oxy]-l,3-thiazol-2-amine (44.1 mg). MSiES*) m/z 317 (MET).
Step 4: [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 31.8 mg), 4-(4-chlorophenyl)-5- [(4-methylphenyl)oxy]-l,3-thiazol-2-amine (44.1 mg), EDC (32.0 mg) and HOBt (25.6 mg) were added into a 10 mL vial. Dichloromethane (DCM) (4 mL) was added. The reaction mixture was stirred at RT for one and a half days. DCM was removed. The obtained crude was redissolved in THF and DMF, which was submitted to MDAP for purification under acidic conditions. Solvent was evaporated in vacuo to give the required product N-{4-(4-chlorophenyl)-5-[(4-methylphenyl)oxy]- l ,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (29 mg) as a white solid. 'H-NMR (400 MHz, DMSO-ί/ΰ) δ ppm 1.02 (t, J = 7.4 Hz, 3H), 2.19 (s, 3H), 3.21 (q, J= 7.3 Hz, 2H), 3.86 (s, 2H), 6.97 (d, J= 8.6 Hz, 2H), 7.1 1 (d, J= 8.3 Hz, 2H), 7.42 (d, J= 8.7 Hz, 2H), 7.53 (d, J= 8.4 Hz, 2H), 7.79 (td, J= 2.6 Hz, 4.6 Hz, 4H), 12.56 (s, 1H); MS(ES+) m/z 527 (MH+).
Example 2
V-[4-(4-chIorophenyl)-5-(phenyloxy)-l,3-thiazol-2-yl]-2-[4-(ethyIsulfonyl)phenyi]acetamide
Figure imgf000015_0001
Step 1: To a mixture of 5-bromo-4-(4-chlorophenyl)-l,3-thiazol-2-amine (153.1 mg, see step 2 for synthesis of Example 1), phenol (54.7 mg) and cesium carbonate (207 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred for 5 hours. Solvent was removed. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :4) to afford 4-(4-chlorophenyl)- 5-(phenyloxy)-l ,3-thiazol-2-amine (83.5 mg). MSfES4 m/z 303 (MH+). Step 2: [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 63.0 mg), 4-(4-chlorophenyl)-5- (phenyloxy)-l,3-thiazol-2-amine (83.5 mg), EDC (63.4 mg) and HOBt (50.7 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for three days. DCM was removed. The obtained mixture was redissolved in DMF and purified by MDAP. Solvent was freeze-dried to give N-[4-(4-chlorophenyl)-5-(phenyloxy)-l,3-thiazol-2-yl]-2-[4- (ethylsulfonyl)phenyl]acetamide (40 mg) as a white solid. Ή-NMR (400 MHz, OMSO-d6) δ ppm 1.02 (t, J= 7.3 Hz, 3H), 3.21 (q, J= 7.3 Hz, 2H), 3.87 (s, 2Η), 7.09 (t, J= 8.2 Hz, 3Η), 7.32 (t, J= 8.0 Hz, 2H), 7.42 (d, J= 8.7 Hz, 2H), 7.54 (d, J= 8.3 Hz, 2H), 7.75-7.83 (m, 4H), 12.59 (s, 1H); MS(ES^) m/z 513 (MR*). Example 3
2-[4-(ethylsuIfonyl)phenyl]-iV- 4-phenyl-5-(phenyloxy)-l,3-thiazol-2-yl]acetamide
Figure imgf000016_0001
Step 1: To a mixture of thiourea (1.147 g) and 2-bromo-l-phenylethanone (3 g) was added ethanol (100 mL). The reaction mixture was heated up to reflux (oil bath temperature: 80 °C) for 2.5 hours. The reaction was cooled down to RT. Ethanol was removed under vacuum to afford the intermediate as a white solid. Copper(II) bromide (8.42 g) and acetonitrile (40 mL) were added. The mixture was stirred at RT for 3 days. Acetonitrile was removed under vacuum. EtOAc was added. The obtained mixture was washed with diluted ammonia three times until no blue color was observed in the aqueous phase. The organic phase was then washed with brine and dried over NajSC . After filtration and concentration, the crude product was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :0) to afford 5-bromo-4-phenyl-l ,3-thiazol-2-amine (2 g). MSfES^ m/z 255 (MH^).
Step 2: To a mixture of 5-bromo-4-phenyl-l,3-thiazol-2-amine (213.3 mg), phenol (102 mg) and cesium carbonate (409 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred for 7 hours. Solvent was removed. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1:4) to afford 4-phenyl-5-(phenyloxy)-l ,3-thiazol-2-amine (172.4 mg), MS(ES+) m/z 269 (MH*).
Step 3: [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 150 mg), 4-phenyl-5- (phenyloxy)-l,3-thiazol-2-amine (176 mg), EDC (151 mg) and HOBt (121 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give 2-[4-(ethylsulfonyl)phenyl]-N-[4-phenyl-5- (phenyloxy)-l,3-thiazol-2-yl]acetamide (40.9 mg) as a white solid. 'H-NMR (400 MHz, DMSO-i 6) δ ppm 1.03 (t, J= 7.4 Hz, 3Η), 3.21 (q, J= 7.4 Hz, 2Η), 3.87 (s, 2H), 7.03-7.12 (m, 3H), 7.23 (t, J= 7.4 Hz, IH), 7.35-7.37 (m, 4H), 7.54 (d, J= 8.3 Hz, 2H), 7.79 (d, J= 8.3 Hz, 4H), 12.57 (s, IH); MSfES ) m/z 479 (MH^.
Example 4
N- {5- [(2-chlorophenyl)oxy] nyI)phenyl] acetamide
Figure imgf000017_0001
Step 1: To a mixture of 2-chlorophenol (124 mg), 5-bromo-4-phenyl-l,3-thiazol-2-amine (245.3 mg, see step 1 for synthesis of Example 3) and cesium carbonate (470 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred overnight Solvent was removed. The obtained crude was purified by flash chromatography (DCM : MeOH = 1 :0 to 9: 1) to afford 5-[(2- chlorophenyl)oxy]-4-phenyl-l,3-thiazol-2-amine (202.2 mg). MS(ES+) m/z 303 (MIT*).
Step 2: [4-(Ethylsulfonyl)phenyl] acetic acid (intermediate la, 152 mg), 5-[(2- chlorophenyl)oxy]-4-phenyl-l,3-thiazol-2-amine (202.2 mg), EDC (154 mg) and HOBt (123 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give N-{5-[(2- chlorophenyl)oxy]-4-phenyl-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (11.3 mg) as a yellowish solid. 1 H-NMR (400 MHz, OM$>Q-d6) δ ppm 1.03 (t, J= 7.4 Hz, 3H), 3.24 (q, J= 7.4 Hz, 2H), 3.88 (s, 2H), 7.05-7.09 (m, IH), 7.12 (td, J= 7.7 Hz, 1.5 Hz, IH), 7.24 (td, J= 7.9 Hz, 1.8 Hz, 2H), 7.35 (t, J= 7.8 Hz, 2H), 7.50 - 7.58 (m, 3H), 7.73-7.83 (m, 4H), 12.53 (s, IH); MSQsS m/z 513 (MH+).
Example 5
2-[4-(ethylsulfonyl)phenyl]-/V-(4-phenyl-5-{[2-(trifluoromethyl)phenyl]oxy}-l,3-thiazol-2- yl) acetamide
Figure imgf000018_0001
Step 1: To a mixture of 5-bromo-4-phenyl-l,3-thiazol-2-amine (279.9 mg, see step 1 for synthesis of Example 3), 2-(trifluoromethyl)phenol (178 mg) and cesium carbonate (536 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred overnight. Solvent was removed. The obtained crude was purified by flash chromatography (DCM : MeOH = 1 :0 to 9: 1) to afford 4-phenyl-5-{[2-(trifluoromethyl)phenyl]oxy}-l)3-thiazol-2-amine (174.3 mg). MS(ES+) m/z 337 (MH^.
Step 2: [4-(Ethylsulfonyl)phenyl] cetic acid (intermediate la, 118 mg), 4-phenyl-5-{[2- (trifluoromethyl)phenyl]oxy}-l,3-thiazol-2-amine (174.3 mg), EDC (119 mg) and HOBt (95 mg) were added into a 10 mL vial, Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 day. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give 2-[4- (ethylsulfonyl)phenyl]-N-(4-phenyl-5-{[2-(trifluoromemyl)phenyl]oxy}-l ,3-thiazol-2-yl)acetamide (38.7 mg) as a white solid. ]H-NMR (400 MHz, DMSO-i¾ δ ppm 0.96 (t, J= 7.3 Hz, 3H), 3.15 (q, J = 7.3 Hz, 2H), 3.82 (s, 2H), 7.06 (d, J= 8.5 Hz, 1H), 7.19 (d, J= 5.8 Hz, 1H), 7.20 (s, 1H), 7.23-7.31 (m, 2H), 7.43-7.52 (m, 3H), 7.65-7.75 (m, 5H), 12.61 (s, 1H); 19F-NMR (376 MHz, DMSO-i/6) δ ppm -60.27; MS(ES+) m/z 547 (MH").
Example 6
A'-{5-[(4-chIorophenyl)ox ]-4-phenyl-l,3-t iazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide
Figure imgf000018_0002
Step 1: To a mixture of 5-bromo-4-phenyl-l,3-thiazoI-2-amine (260.4 mg, see step 1 for synthesis of Example 3), 4-chlorophenol (131 mg) and cesium carbonate (499 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred overnight. Solvent was removed. The obtained crude was purified by flash chromatography (DCM : MeOH = 1 :0 to 9: 1) to afford 5-[(4- chlorophenyl)oxy]-4-phenyl-l,3-thiazoI-2-amine (184.6 mg). MSfES") m/z 303 (MH+). Step 2: [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 139 mg), 5-[(4- chlorophenyl)oxy]-4-phenyl-l,3-thiazol-2-amine (184.6 mg), EDC (140 mg) and HOBt (112 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP. Solvent was evaporated in vacuo to give N-{5-[(4-chlorophenyl)oxy]-4-phenyl- l,3-thiazol-2-yI}-2-[4-(ethylsulfonyl)phenyl]acetamide (47,4 mg) as a yellowish solid. Ή-ΝΜΚ. (400 MHz, DMSCWi) δ ppm 1.03 (t, J= 7.4 Hz, 3H), 3.21 (q, J= 7.3 Hz, 2H), 3.88 (s, 2H), 7.06-7.12 (m, 2H), 7.20-7.27 (m, 1H), 7.30-7.39 (m, 4H), 7.55 (d, J= 8.3 Hz, 2H), 7.75 (dd, = 8.3 Hz, 1.3 Hz, 2H)} 7.79 (d, J= 8.3 Hz, 2H), 12.61 (s, 1H); MS(ES ) m/z 513 (MH*). Example 7
2-[4-(ethylsuIfonyl)phenylJ-Ar-(4-phenyl-S-{[4-(trifluoromethyl)phenyl]oxy}-l,3-thiazol-2- yl)acctamide
Figure imgf000019_0001
Step 1: To a mixture of 5-bromo-4-phenyl-1 ,3-thiazol-2-amine (262.8 mg, see step 1 for synthesis of Example 3), 4-(trifiuoromethyl)phenoI (167 mg) and cesium carbonate (503 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred overnight. Solvent was removed. The obtained crude was purified by flash chromatography (DCM : MeOH = 1 :0 to 9: 1) to afford 4-phenyl-5-{[4-(trifluoromethyl)phenyl]oxy}-l,3-thiazol-2-amine (108.5 mg). MS(ES+) m/z 337 (MH ).
Step 2: [4-(Ethylsulfonyl)phenyl] acetic acid (intermediate la, 73.6 mg), 4-phenyl-5-{[4-
(trifluoromethyl)phenyl]oxy}-l,3-thiazol-2-amine (108.5 mg), EDC (74.2 mg) and HOBt (59.3 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT over 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give 2-[4- (ethylsulfonyl)phenyl]-N-(4-phenyl-5-{[4-(trifluoromethyl)phenyl]oxy}-lJ3-thiazol-2-yl)acetamide (9.6 mg) as a white solid. Ή-NMR (400 MHz, DMSO-i/6) δ ppm 1.03 (t, J= 7.4 Hz, 3H), 3.22 (q, J= 7.3 Hz, 2H), 3.89 (s, 2H), 7.19-7.29 (m, 3H), 7.34 (t, 8.3 Hz, 2H), 7.56 (d, J= 8.5 Hz, 2H), 7.67 (d, J= 9.0 Hz, 2H), 7.74 (d, J= 8.3 Hz, 2H), 7.80 (d, J= 8.3 Hz, 2H), 12.66 (s, 1H); 19F-NMR (376 MHz, DMSO-d4) δ ppm -60.33; MSfES4) /z 547 (MH*). Example 8 2-[4-(ethylsulfonyl)phenyl]-iV-(5-{[4-(methyIoxy)phenyl]oxy}-4-phenyl-l,3-thiazol-2- yl)acetamide
Figure imgf000020_0001
Step 1: To a mixture of 5-bromo-4-phenyl-l,3-thiazol-2-amine (285.5 mg, see step 1 for synthesis of Example 3), 4-(methyloxy)phenol (139 mg) and cesium carbonate (547 mg) was added acetone (3 mL). The reaction mixture was heated to 55 °C and stirred overnight. Solvent was removed. The obtained crude was purified by flash chromatography (DCM : MeOH = 1 :0 to 9: 1) to afford 5-{[4-(methyloxy)phenyl]oxy}-4-phenyl-l,3-thiazol-2-amine (185.8 mg). MSfES*) m/z 299 (MH+).
Step 2: [4-(Ethylsulfonyl)phenyl] acetic acid (intermediate la, 142 mg), 5-{[4-
(methyloxy)phenyl]oxy}-4-phenyi-l,3-thiazol-2-amine (185.8 mg), EDC (143 mg) and HOBt (114 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give 2-[4- (ethylsulfonyI)phenyl]-N-(5- {[4-(methyloxy)phenyl]oxy}-4-phenyl-l,3-thiazol-2-yl)acetamide (38.1 mg) as a white solid. Ή-NMR (400 MHz, DMSO-rf6) δ ppm 1.08 (t, J= 7.3 Hz, 3H), 3.27 (q, J= 7.3 Hz, 2H), 3.71 (s, 3H), 3.91 (s, 2H), 6.92 (d, J= 9.0 Hz, 2H), 7.09 (d, J= 9.0 Hz, 2H), 7.24-7.34 (m, IH), 7.38-7.43 (m, 2H), 7.59 (d, J= 8.3 Hz, 2H), 7.81-7.89 (m, 4H), 12.55 (s, IH); MSfES" m/z 509 (MH . Example 9
Ar-(5-(4-chIorophenoxy)-4- -chlorophenyl)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide
Figure imgf000020_0002
Step 1: To a solution of l-(3-chlorophenyl)ethanone (15 g) in chloroform (100 mL) and ethyl acetate (100 mL) was added copper(II) bromide (21.67 g), and the reaction mixture was refluxed overnight. The reaction mixture was concentrated to give 2-bromo-l-(3-chlorophenyl)ethanone (18 g) as a brown oil. MS(ES+) m/z 219 (MH ). Step 2: To a solution of 2-bromo-l-(3-chlorophenyl)ethanone (28 g) in ethanol (300 mL) was added thiourea (10.04 g). The reaction mixture was refluxed overnight. Solvent was removed, and the residue was triturated with diethyl ether to give 4-(3-chlorophenyl)thiazol-2-amine (23 g) as a white solid. MSfES4") m/z 211 (MH"t).
Step 3: To a solution of 4-(3-chlorophenyl)thiazol-2-amine (1 g) in tetrahydrofuran (20 mL) was added NBS (0.88 g). After stirring at room temperature overnight, the mixture was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic phase was washed with water (20 mL x 2), dried and concentrated to give 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.05 g) as a red liquid. MS(ES ) m/z 289 (MH ).
Step 4: To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g) in acetone (50 mL) was added cesium carbonate (1.42 g) and 4-chlorophenol (0.5 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The obtained solution was washed with water (40 mL x 3) and brine (30 mL x 2), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1:6) to afford 5-(4-chlorophenoxy)-4-(3- chlorophenyl)thiazol-2-amine (600 mg) as a white solid. MSfES4) m/z 337 (MH ).
Step 5: 2-(4-(Ethylsulfonyl)phenyl)acetic acid (intermediate la, 220 mg), 5-(4-chlorophenoxy)- 4-(3-chlorophenyl)thiazol-2-amine (300 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315mL) was added in a 100 mL round bottom flask. Dichloromethane (20 mL) was added, and the reaction mixture was stirred at 35 °C for 2 days. The mixture was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :3) to afford the crude product. Further purification by preparative HPLC afforded N-(5-(4-chlorophenoxy)-4-(3- chlorophenyl)thiazoL2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (78 mg) as a white solid. 'H-NMR (400 MHz, CDC13) S ppm 1.33 (t} J= 7.2 Hz, 3H), 3.17 (qs J= 7.2 Hz, 2H), 3.82 (s, 2H), 7.05 (d, /= 9.2 Hz, 2H), 7.26-7.32 (m, 4H), 7.49 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 7.2 Hz, 1H), 7.89 (s, 1H), 7.93 (d, J= 8.0 Hz, 2H), 9.45 (s, 1H); MS(ES ) m/z 547 (MH+).
Example 10
Ar-(5-(2-chIorophenoxy)-4-(3-chlorophenyl)thiazol-2-yl)-2-(4-(ethyIsaIfonyl)phenyl)acetamide
Figure imgf000021_0001
Step 1: To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (1.4 g) and 2-chlorophenol (0.50 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The obtained solution was washed with water (40 mL x 3) and brine (30 mL x 2), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0:1 to 1 :6) to give 5-(2-chlorophenoxy)-4-(3-chlorophenyl)thiazol-2-amine (600 mg) as a white solid. MSfES"1) m/z 337 (MH*).
Step 2: To a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 200 mg) in dichloromethane (DCM) (20mL) was added 5-(2-chlorophenoxy)-4-(3-chlorophenyl)thiazol-2-amine (300 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315 mL). After stirring at 35 °C for 2 days, the reaction mixture was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0:1 to 1:3) to give the crude product, which was further purified by preparative HPLC to afford N-(5-(2-chlorophenoxy)-4-(3-chlorophenyl)thiazol-2- yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (53 mg) as a white solid. ¾-NMR (400 MHz, CDC13) δ ppm 1.33 (t, J= 7.2 Hz, 3H), 3.17 (q, J= 7.2 Hz, 2H), 3.82 (s, 2H), 7.07-7.13 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.35 (m, 2H), 7,47-7.49 (m, 3H), 7.84 (d, J= 7.6 Hz, 1H), 7.92 (d, J= 8.0 Hz, 2H), 7.96 (s, 1H), 9.87 (s, 1H); MSfES*) m/z 547 (MET*).
Example 11
N-(4-(3-chlorophenyI)-5-phenoxythiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetarnide
Figure imgf000022_0001
Step 1: To a solution of 5-bromo-4-(3-chlorophenyl)thiazoI-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (10 mL) was added phenol (0.36 g) and cesium carbonate (1.35 g). The reaction mixture was stirred at 45 °C overnight. DCM (100 mL) was added. The obtained solution was washed with water (100 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE - 1:5 to 1: 1) to give 4-(3-chlorophenyl)-5-phenoxythiazol-2- amine (230 mg) as a red liquid. MS(ES"*) m/z 303 (MET1}.
Step 2: To a solution of 4-(3-chlorophenyl)-5-phenoxythiazol-2-amine (230 mg) in
dichloromethane (DCM) (20 mL) was added 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 831 mg), EDC (728 mg), HOBt (140 mg) and DIPEA (589 mg). After stirring at 35 °C for 2 days, the reaction mixture was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :3) to give the crude product. Further purification by preparative HPLC afforded N-(4-(3-chlorophenyl)-5-phenoxythiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide (18 mg) as a white solid. Ή-NMR (400 MHz, CD<¾) δ ppm 1.30 (t, J= 7.2 Hz, 3H), 3.13 (q, J= 7.2 Hz, 2H), 3.76 (s, 2H), 7.10-7.16 (m, 3H), 7.24-7.35 (m, 5H), 7.45 (d, J= 8.0 Hz, 2H), 7.77 (d, J= 8.0 Hz, IH), 7.89 (d, J= 8.0 Hz, IH), 9.71 (s, IH); MS(ES*) m/z 513 (MH+).
Example 12
Ar-(4-(3-chlorophenyl)-5-(o-tolyloxy)thiazol-2-yl)-2-(4-(ethyIsulfonyl)phenyI)acetamide
Figure imgf000023_0001
Step 1: To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (30 mL) was added o-cresol (0.411 g) and cesium carbonate (1.35 g). The reaction mixture was stirred at 45 °C overnight. DCM (100 mL) was added. The obtained solution was washed with water (100 mL x 3), dried and concentrated. Purification by flash chromatography (EtOAc : PE = 3: 1) afforded 4-(3-chlorophenyl)-5-(o~tolyloxy)thiazol-2-amine (110 mg) as an oil. MS(ES" m/z 316 (MET).
Step 2: To a solution of 4-(3-chlorophenyl)-5-(o-tolyloxy)thiazol-2-amine (127 mg) in dichloromethane (DCM) (30 mL) was added 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 110 mg), EDC (385 mg), HOBt (74 mg) and DIPEA (311 mg). After stirring at 45 °C for 4 days, the reaction mixture was washed with water (50 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0:1 to 1 :3) to give the crude product. Further purification by preparative HPLC afforded N-(4-(3-chlorophenyl)-5-(o-tolyloxy)thiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide (36 mg) as a white solid. Ή-NMR (400 MHz, CDC13) δ ppm 1.29 (t, J= 7.2 Hz, 3H), 2.37 (s, 3H), 3.13 (q, J= 7.2 Hz, 2H), 3.73 (s, 2H), 6.99 (d, J= 8.0 Hz, IH), 7.07- 7.12 (m, 2H), 7.23-7.32 (m, 3H), 7.42 (d, J= 8.0 Hz, 2H), 7.82 (d, J= 8.0 Hz, IH), 7.88 (d, J= 8.8 Hz, 2H), 7.94 (s, IH), 9.60 (s, IH); MSfES^) m/z 527 (MET).
Example 13 A^~(4-(3-chlorophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-2-(4- (ethyIsulfonyl)phenyl)acetamide
Figure imgf000024_0001
Step 1: To a mixture of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (2.0 g, see step 3 for synthesis of Example 9), 2-(trifluoromethyl)phenol (1.12 g) and cesium carbonate (2.70 g) was added acetone (10 mL). The reaction mixture was stirred at 45 °C overnight. After removal of solvent, the residue was partitioned between DCM (100 mL) and water (100 mL). The organic phase was washed with water (100 mL x 2), dried and concentrated. Purification by flash chromatography (EtOAc : PE = 3: 1) afforded 4-(3-chlorophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-amine (900 mg) as a red liquid. MSiES4) m/z 370 (MET),
Step 2: To a solution of 4-(3-chlorophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-amine (900 mg) in dichloromethane (DCM) (20 mL) was added 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate l , 831 mg), EDC (1.40 g), HOBt (446 mg) and DIPEA (1.696 mL). After stirring at 35 °C for 4 days, the mixture was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :3) to give the crude product. Further purification by preparative HPLC afforded N-(4-(3-chlorophenyl)-5-(2-
(trifluoromethyl)phenoxy)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (49 mg) as a white solid. lH-NMR (400 MHz, CDC13) δ ppm 1.30 (t, J= 7.2 Hz, 3H), 3.15 (q, J= 7.2 Hz, 2H), 3.80 (s, 2H), 7.05 (d, J= 8.0 Hz, 1H), 7.20-7.32 (m, 3H), 7.42-7.50 (m, 3H), 7.69 (d, J= 7.2 Hz, 1H), 7.77 (d, J= 7.2 Hz, 1H), 7.89-7.91 (m, 3H), 9.54 (s, 1H); MS(ES-) m/z 581 (MH+).
Example 14
Ai-{4-(3-chlorophenyl)-5-(2,6-dichIorophenoxy)thiazol-2-yl)-2-(4- (ethyIsulfonyl)phenyl)acetamide
Figure imgf000024_0002
Step 1: To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (2.5 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (3.38 g) and 2,6- dichlorophenol (1.55 g). The reaction mixture was stirred at 45 °C for 2 days. DCM (50 mL) was added. The obtained solution was washed with water, dried and concentrated to give 4-(3- chlorophenyl)-5-(2,6-dichlorophenoxy)thiazol-2-amine (300 mg) as a red oil. MS(ES+) m/z 370 (MH+).
Step 2: To a solution of 2-(4-(ethylsulfony])phenyl)acetic acid (intermediate la, 442 mg) in DCM (20 mL) was added 4-(3-chlorophenyl)-5-(2,6-dichlorophenoxy)thiazol-2-amine (300 mg), HOBt (148 mg), EDC (626 mg) and DIPEA (464 mg). After stirring at 45 °C overnight, the reaction mixture was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1:3) to give the crude product. Further purification by preparative HPLC gave N-(4-(3-chlorophenyl)-5-(2,6-dichlorophenoxy)thiazol-2-yI)-2-(4- (ethylsulfonyl)phenyl)acetamide (40 mg) as a white solid. 'H-NMR (400 MHz, CDC13) δ ppm 1.29 (t, J= 7.2 Hz, 3H), 3.10 (qt J= 7.2 Hz, 2H), 3.73 (s, 2H), 7.19 (t, J= 8.0 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 7.38-7.46 (m, 5H), 7.90 (d, J= 8.0 Hz, 2H), 7.97 (d, /= 8.0 Hz, 1H), 8.03 (s, 1H), 9.75 (s, 1H); MS(ES+) m/z 580 (MH+).
Example 15
Ar-(4-(3-cyanophenyl)-5-(4-(trifluoromethy])phenoxy)thiazol-2-y])-2-(4- (ethylsulfonyl)phenyI)acetamide
Figure imgf000025_0001
Step 1: To a solution of 3-acetylbenzonitrile (8 g) in chloroform (50 mL) and ethyl acetate (50 mL) was added copper(II) bromide (25.9 g). The reaction mixture was refluxed overnight. Solid was removed by filtration, and the filtrate was washed with sat. ammonium chloride and brine, dried, and concentrated to give 3-(2-bromoacetyl)benzonitrile (13 g) as a yellow oil. MS(ES÷) m/z 225 (MH÷).
Step 2: To a solution of 3-(2-bromoacetyl)benzonitrile (13 g) in ethanol (80 mL) was added thiourea (4.64 g). The reaction mixture was stirred for 5 mins. The white precipitate was collected by filtration to give 3-(2-aminothiazol-4-yl)benzonitrile (10 g). MSfES"^ m/z 202 (MH4).
Step 3: To a solution of 3-(2-aminothiazol-4-yl)benzonitrile (3 g) in tetrahydrofuran (THF) (60 mL) was added NBS (2.79 g). The reaction mixture was stirred at room temperature for 1 hour. EtOAc (80 mL) was added. The obtained solution was washed with water (50 mL x 3), dried and concentrated to give 5-bromo-4-(3-cyanophenyl)thiazol-2-amine (2.7 g) as a dark red solid. MSfES^) m/z 279 (MH ).
Step 4: To a solution of 5-bromo-4-(3-cyanophenyl)thiazol-2-amine (1.0 g) in acetone (30 mL) was added cesium carbonate (1.5 g) and 4-(trifluoromethyl)phenol (0.6 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The organic phase was washed by water (30 mL x 3) and brine (25 mL x 2), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 1 : 1 to 1:3) to give 3-(2-amino-5-(4- (trifluoromethyl)phenolxy)thiazoI-4-yl)benzonitrile (500 mg) as a white solid. MSfES^) m/z 362 (MH+).
Step 5: To a solution of 2-(4-(ethyIsulfonyl)phenyl)acetic acid (intermediate la, 220 mg) in dichloromethane (DCM) (20 mL) was added 3-(2-amino-5-(4-(trifluoromethyl)phenolxy)thiazol-4- yl)benzonitrile (310 mg), EDC (200 mg)} HOBt (150 mg) and DIPEA (0.30 mL). After stirring at 35 °C for 2 days, the mixture was washed with water (20 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :4) to give the crude product, which was further purified by preparative HPLC to afford N-(4-(3-cyanophenyI)-5-(4-
(trifIuorometliyl)phenoxy)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (69 mg) as a white solid. 'H-NMR (400 MHz, CDC13) δ ppm 1.33 (t, J= 7.2 Hz, 3H), 3.17 (q, J= 7.2 Hz, 2H), 3.82 (s, 2H), 7.19 (d, J= 7.2 Hz, 2H), 7.46 (t, J= 6.4 Hz, 1H), 7.56-7.63 (m, 5H)} 7.96 (d, J= 6.8 Hz, 2H), 8.09 (d, J= 6.4 Hz, 1H), 8.20 (s, 1H), 9.29 (s, 1H); MS(ES*) m/z 572 (MH*).
Example 16
N-(4-(3-cyanophenyl)-5-(2-(trifluoromethyl)phenoxy)thiazoI-2-yl)-2-(4- (ethylsulf onyl)phenyl) acetamide
Figure imgf000026_0001
Step 1: To a solution of 5-bromo-4-(3-cyanophenyl)thiazol-2-amine (700 mg, see step 3 for synthesis of Example 15) in acetone (50 mL) was added cesium carbonate (977 mg) and 2- (trifluoromethyl)phenol (446 mg). The reaction mixture was stirred at 45 °C overnight. Solvent was removed. The residue was purified by flash chromatography (EtOAc : PE = 1:3) to give 3-(2-amino- 5-(2-(trifluorornetliyl)phenoxy)thiazol-4-yl)benzonitrile (300 mg) as a yellow oil. MSfES4) m/z 362 (MH+).
Step 2: To a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 168 mg) in DCM (20 mL) was added 3-(2-amino-5-(2-(trifluoromethyl)phenoxy)thiazol-4-yl)benzonitrile (222 mg), HOBt (113 mg), EDC (353 mg) and DIPEA (476 mg). After stirring at 45 °C overnight, the reaction mixture was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0:1 to 1 :3) to give the crude. Further purification by preparative HPLC afforded N-(4-(3-cyanophenyl)-5-(2-(trifluoromethyI)phenoxy)thiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide (29 mg). Ή-NMR (400 MHz, CDC13) δ ppm 1.30 (t, J= 7.2 Hz, 3H), 3.15 (q, J= 7.2 Hz, 2H), 3.92 (s, 2H), 7.07 (d, J= 8.0 Hz, 1H), 7.25 (t, J= 8.0 Hz, 1H), 7.44-7.48 (m, 2H), 7.55-7.58 (m, 3H), 7.70 (d, J- 8.0 Hz, 1H), 7.93 (d, J= 8.0 Hz, 2H), 8.14 (d, J= 8.0 Hz, 1H), 8.22 (s, 1H), 9.54 (s, 1H); MS(ES ) m/z 570 (MH ).
Example 17
iV-(5-(2-cyanophenoxy)-4-(3-(trifluoromethyl)phenyl)thiazol-2~yI)-2-(4- (ethylsulfonyl)phenyl)acetamide
Figure imgf000027_0001
Step 1: To a solution of l-(3-(trifluoromethyl)phenyl)ethanone (5 g) in chloroform (30 mL) and ethyl acetate (30 mL) was added copper(II) bromide (7.5 g). The reaction mixture was refluxed overnight. Solvent was removed to give 3-(trifluoromethyl)benzoyl bromide (6 g) as a brown oil. MS(ES+) m/z 253 (MH ).
Step 2: To a solution of 3-(trifluoromethyl)benzoyl bromide (6 g) in ethanol (100 mL) was added thiourea (5.0 g). The reaction mixture was refluxed overnight. Solvent was removed. The residue was triturated with ethyl acetate to give 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (5 g) as a white solid. MS(ES^> m/z 245 (MH4).
Step 3: To a solution of 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (5 g) in tetrahydrofuran
(THF) (50 mL) was added NBS (4.5 g), and the reaction mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added. The organic phase was washed with water (30 mL x 3), dried, and concentrated to give 5-brorno-4-(3-(trifluoromethyI)phenyl)thiazol-2-amine (5.0 g) as a red liquid. MS(ES ) m/z 323 (MPT1).
Step 4: To a solution of 5-bromo-4-(3-(trifluoromethyl)phenyl)thiazol-2-amine (1.0 g) in acetone (25 mL) was added cesium carbonate (1.4 g) and 2-hydroxybenzonitriIe (0.6 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The organic phase was washed with water (30 mL x 3) and brine (20 mL x 2), dried and concentrate. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :3) to give 2-(2-amino-4-(3- (trifluoromethyl phenyl)thiazol-5-yloxy)benzonitrile (500 mg) as a white solid. MS(ES+) m/z 362 (MH+). Step 5: To a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 200 mg) in dichlorometliane (DCM) (20 mL) was added 2-(2-amino-4-(3-(trifluoromethylphenyl)thiazol-5- yloxy)benzonitrile (315 mg), EDC (200 mg), HOBt (150 mg) and DIPEA (0.30 mL). After stirring at 35 °C for 2 days, the mixture was washed with water (30 mL x 3), dried and concentrate. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1:3) to give the crude product. Further purification by preparative HPLC afforded N-(5-(2-cyanophenoxy)-4-(3-
(trifluoromethyl)phenyl)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (25 mg) as a white solid. Ή-NMR (400 MHz, CDCh) δ ppm 1.34 (t, J= 7.2 Hz, 3H), 3.17 (q, J= 7.2 Hz, 2H), 3.94 (s, 2H), 7.04 (d, J= 8.4 Hz, 1H), 7.22 (t, J= 7.2 Hz, 1H), 7.49-7.59 (m, 5H), 7.71 (d, J= 3.6 Hz, 1H), 7.97 (d, J= 8.4 Hz, 2H), 8.06 (d, J= 3.6 Hz, 1H), 8.15 (s, IH), 9.10 (s, 1H); 19F-NMR (376 MHz, CDC13) δ ppm -62.84; MSfES ) m/z 572 (MH+).
Example 18
iV-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-(3-cyanophenyl)thiazol-2-yI)-2-(4- (ethylsuIfonyl)phenyI)acetamide
Figure imgf000028_0001
Step 1: To a solution of 5-brorao-4-(3-cyanophenyl)thiazol-2-amine (1 g, see step 3 for synthesis of Example 15) in acetone (50 mL) was added 2-chloro-4-(trifluoromethyl)phenol (300 and cesium carbonate (1.40 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and the residue was purified by flash chromatography (EtOAc : PE = 1:3) to give 3-(2- amino-5-(2-chloro-4-(trifluoromethyl)phenoxy)m^ (300 mg) as a yellow oil.
MS(ES*) m/z 397 (MH+).
Step 2: To a solution of 3-(2-amino-5-(2-chloro-4-(trifluoromethyl)phenoxy)thiazol-4- yl)benzonitrile (300 mg) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 208 mg) in DCM (50 mL) was added EDC (436 mg), HOBt (139 mg) and DIPEA (0.79 mL). After stirring at reflux overnight, the mixture was washed with water (40 mL x 3), dried and concentrated.
Purification by flash chromatography (EtOAc : PE = 1:3) gave the crude product. Further purification by reverse-phase chromatography afforded N-(5-(2-chloro-4-(trifluoromethyl)phenoxy)-4-(3- cyanophenyl)thiazol-2-yI)-2-(4-(ethylsulfonyl)phenyl)acetamide (78 mg) as a white solid. Ή-NMR (400 MHz, DMSO-fiftf) δ ppm 1.10 (t, J= 7.2 Hz, 3H), 3.29 (q, J= 7.2 Hz, 2H), 3.98 (s, 2H), 7.38 (d, J= 8.8 Hz, 1H), 7.60-7.70 (m, 4H), 7.81 (d, 7= 8.0 Hz, 1H), 7.87 (d, J= 8.0 Hz, 2H), 8.07-8.13 (m, 2H), 8.16 (s, 1H), 12.84 (s, 1H); MSfES*) m/z 606 (MH4).
Example 19
Ar-(5-(4-chloro-2-(trifluoromethyl)phenoxy)-4-(3-cyanophenyl)thiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide
Figure imgf000029_0001
Step 1: Lithium chloride (2.30 g) was added to a solution of l-methoxy-4-nitro-2- (trifluoromethyl)benzene (4 g) in NN-dimethylformamide (40 mL) at room temperature. The reaction mixture was stirred at 160 °C for 5 hours. After cooling to RT, the solution was diluted with EtOAc (300 mL). The mixture was washed with water (100 mL x 2) and brine (100 mL), dried and concentrated to give 4-nitro-2-(trifluoromethyl)phenol (3.5 g) as a yellow solid.
Step 2: Zinc (4.42 g) was added to a solution of 4-nitro-2-(trifluoromethyl)phenol (3.5 g) and ammonium formate (8.52 g) in methanol (5 mL) and water (5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the mixture was filtered and EtOAc (80 mL) was added to the filtrate. The organic layer was washed with water (30 mL) and brine (40 mL), dried, and concentrated to afford 4-amino-2-(trifluoromethyl)phenol (2.8 g) as a yellow solid.
Step 3: Sodium nitrite (0.47 g) in ¾0 (3 mL) was added dropwise to a solution of 4-amino-2- (trifluoromethyl)phenol (1 g) in acetonitrile (20 mL) and hydrochloric acid (10 mL) at 0 °C . After stirring for 0.5 hour, copper(I) chloride (1.12 g) in 3 M HC1 (5 mL) was added to the mixture. Then the reaction mixture was stirred at 100 °C for 6 hours. After cooling to room temperature, the solution was diluted with EtOAc (200 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried, and concentrated. The residue was purified by flash chromatography (DCM : PE = 1: 1) to afford 4-chloro-2-(trifluoromethyl)phenoI (700 mg) as a brown oil. MS(ES+) m/z 195 (MH ).
Step 4: 5-Bromo-4-(3-cyanophenyl)thiazol-2-amine 3-(2-Amino-5-bromothiazol-4- yl)benzonitrile (500 mg, see step 3 for synthesis of Example 15) was added to a solution of 4-chloro- 2-(trifluorometliyl)phenol (351 mg) and Cs2C03 (872 mg) in acetone (30 mL) at room temperature. The reaction mixture was stirred at 45 °C for 4 hours. The reaction mixutre was cooled to room temperature, filtered through celite and concentrated. The crude product was purified by flash chromatography (EtOAc : PE = 1:4) to afford 3-(2-amino-5-(4-chloro-2- (trifluoromethyl)phenoxy)thiazol-4-yl)benzonitrile (170 mg) as a yellow solid. MSfES4) m/z 396
(MH4 .
Step 5: 3-(2-Amino-5-(4-chloro-2-(trifluoromethyl)phenoxy)thiazoI-4-yl)benzonitrile (170 mg) was added to a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate la, 147 mg), HOBt (79 mg,), EDC (247 mg) and DIPEA (0.45 mL) in dichloromethane (15 mL) at room temperature. The reaction mixture was stirred at 40 °C for 12 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 1 :4 to 1 : 1) to afford the crude product (100 mg) as a yellow oil. Further purification by preparative HPLC to afford N-(5-(4-chloro-2-(rrifluoromethyl)phenoxy)-4-(3-cyanophenyl)thiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide (28 mg) as a white solid. Ή-NMR (400 MHz, CDC13) δ ppm 1.31 (t, J= 7.2 Hz, 3H), 3.15 (q, J= 7.2 Hz, 2H), 3.93 (s, 2H), 6.99 (d, J= 9.2 Hz, 1H), 7.39-7.48 (m, 2H), 7.56-7.58 (m, 3H), 7.67 (d, J= 2.4 Hz, 1H), 7.93-7.95 (m, 2H), 8.09 (m, lH), 8.20 (m, 1H), 9.30 (s, 1H); l9FNMR (376 MHz, CDC13): δ ppm -61.95.
Example 20
2-[4-(ethylsulfonyl)phenyl]-iV-{5-[hydroxy(phenyl)methyl]-4-phenyl-l,3-thiazol-2-yl}acetamide
Figure imgf000030_0001
Step 1: Bromine (4.59 mL) was added into a solution of l,3-diphenyl-l,3-propanedione (20 g) in ethyl acetate (50 mL) dropwise at 0 °C. After the addition was complete, the resultant mixture was stirred at 0 °C until the color of bromine faded away. Solvent was removed in vacuo. The residue and thiourea (6.79 g) was dissolved into N;N-dimethylformamide (DMF) (20 mL) and the solution was heated to 85 °C for 15 mins. The mixture was cooled down, poured into water, basified by NaHC03, and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated in vacuo. The solid formed was collected by filtration and washed with cold EtOAc, MeOH successively. The crude product was dried in vacuo to afford (2-amino-4-phenylthiazol-5-yl)(phenyl)methanone (14 g) as a yellow solid. The mother liquid was purified by chromatography on silica gel (EtOAc ; PE = 0: 1 to 1 : 1) to afford (2-amino-4-phenyl-l,3- thiazol-5-yl)(phenyl)methanone (4 g) as a yellow solid. MS(ES+) m/z 281 (MH+).
Step 2: A mixture of [4-(ethylsulfonyl)phenyI]acetic acid (intermediate la, 598 mg), EDC (718 mg) and HOBt (506 mg) in dichloromethane (DCM) (10 mL) was stirred at room temperature under nitrogen for 10 mins. (2-Amino-4-phenyl-l,3-thiazol-5-yl)(phenyl)methanone (700 mg) was then added. After stirring at room temperature overnight, the reaction mixture was partitioned between DCM and water. The aqueous phase was extracted with DCM for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04- After filtration, solvent was removed under in vacuo to afford 2-[4-(ethylsulfonyl)phenyl]-N-[4-phenyl-5-(phenylcarbonyl)-l,3- thiazol-2-yl]acetamide (1.121 g) as a yellow solid. MS(ES+) m/z 491 (MH+).
Step 3: NaBH4 (11 mg) was added into a solution of 2-[4-(ethylsulfonyl)phenyl]-N-[4-phenyl- 5-(phenylcarbonyl)-l,3-thiazol-2-yl]acetamide (100 mg) in methanol (2 mL) at room temperature in 3 portions. The reaction mixture was stirred at the same temperature for 1.5 hours. The mixture was poured into sat. NH4CI solution, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S0 . After filtration, solvent was removed under reduced pressure and the residue was purified by MDAP to afford 2-[4- (emylsuIfonyl)phenyl]-N-{5-[hydroxy(phenyl)methyl]-4-phenyl-l,3 hiazol-2-yl}acetamide (40 mg) as a white solid. Ή-NMR (400 MHz, DMSO-f¾) δ ppm 1.08 (t, J= 7.2 Hz, 3H), 3.27 (q, J= 7.2 Hz, 2H)S 3.90 (s, 2H), 5.99 (s, 1H), 6.37 (br s, 1H), 7.22-7.27 (m, 1H), 7.31 (d, 7= 4.4 Hz, 4H), 7.39 (t, J = 7.6 Hz, 1H), 7.47 (t, J= 7.6 Hz, 2H), 7.58 (d, J~ 8.0 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 7.84 (d, J= 8.4 Hz, 2H), 12.51 (s, 1H); MS(ES ) m/z 493 (MH+).
Example 21
2-[4-(ethylsulfonyl)phenyl]-Ar-[4-pheny)-5-(phenylmethyl)-l,3-thiazol-2-yl]acetamide
Figure imgf000031_0001
Intermediate 21a: 4-phenyl-5-('piienylmetriylV1.3-tliiazol-2-amine
Step 1: A mixture of 3-phenylpropanoic acid (5 g), N,C-dimethylhydroxylamine (3.9 g), HOBt (6.1 g), EDC (7.7 g) and Et3N (9.3 mL) in dichloromethane (DCM) (80 mL) was stirred at 25 °C overnight. The mixture was washed with 1 M HC1, sat. NaHC(¼ and brine successively. The organic phase was dried over anhydrous Na2S04. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (EtOAc : PE = 3: 1) to afford N-methoxy-N-methyl- 3-phenylpropanamide (4.8 g) as a yellow solid. MSiES4) m/z 1 4 (MH+).
Step 2: To a solution of N-methoxy-N-methyl-3-phenylpropanamide (4.5 g) in tetrahydrofuran (THF) (60 mL) stirred at 0 °C was added a solution of phenylmagnesium bromide (34 mL) (1 M in THF) dropwise. After stirring at 0 °C for 3 hours, the reaction mixture was quenched with sat. NH4C1 solution, and then extracted with EtOAc (80 mL). The organic phase was washed with brine, dried over anhydrous Na2SO,j, and concentrated in vacuo to afford 1,3-diphenylpropan-l-one (2.2 g) as a yellow solid. MS(ES+) m/z 211 (MH ).
Step 3: A mixture of 1,3-diphenylpropan-l-one (2.2 g) and copper(II) bromide (3.8 g) in chloroform (20 mL) and ethyl acetate (20 mL) was stirred at reflux for 2 hours. Solvent was removed, and the residue was partitioned between water (20 mL) and EtOAc (50 mL). The organic phase was dried and concentrated to give 2-bromo- 1,3-diphenylpropan-l-one (2.6 g) as a yellow solid. MS(ES+) m/z 289 (MH").
Step 4: A mixture of 2-bromo- 1,3-diphenylpropan-l-one (3.5 g) and thiourea (1.1 g) in ethanol (30 mL) was heated at reflux for 2 hours. Solvent was removed in vacuo. The residue was washed with EtOAc and water, filtered and dried to afford 4-phenyl-5-(phenylmethyl)-l,3-thiazol-2-amine (1.7 g) as a yellow soild. MS(ES+) m/z 267 (MH").
Preparation of the final product
[4-(Ethylsulfonyl)pbenyl]acetic acid (intermediate la, 89 mg), 4-phenyl-5-(phenylmethyl)-l,3- thiazol-2-amine (intermediate 21a, 104 mg), EDC (90 mg) and HOBt (71.7 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT over 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give 2-[4-(ethylsulfonyl)phenyl]-N-[4-phenyl-5- (phenylmethyl)-l,3-thiazol-2-yl]acetamide (119 mg) as a white solid. ]H-NMR (400 MHz, DMSO-rfe) δ ppm 1.02 (t, J= 7.4 Hz, 3H), 3.20 (q, J= 7.4 Hz, 2H), 3.83 (s, 2H), 4.16 (s, 2H), 7.09-7.19 (m, 3H), 7.24 (t, J= 7.3 Hz, 2H), 7.25-7.31 (m, 1H), 7.39 (t, J= 7.5 Hz, 2H), 7.48-7.58 (m, 4H), 7.77 (d, J= 8.3 Hz, 2H), 12.44 (s, 1H); MSfES ) m/z 477 (MH4).
Example 22 2-(4-(ethy]sulfonyl)phenyl)-7V-(4-phenyl-5-(l-pheny]ethyl)thiazol-2-yl)acetamide
Figure imgf000033_0001
Step 1: To a solution of 1,3-diphenylbutan-l-one (300 mg) in chloroform (10 mL) and ethyl acetate (10 mL) was added copper(II) bromide (657 mg). The reaction mixture was stirred at 85 °C for 3 hours. Solvent was removed, and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried and concentrated to give 2-bromo-l,3-diphenyibutan-l-one (400 mg) as a yellow solid. MS(ES^} mfz 303 (MfT).
Step 2: A mixture of 2-bromo- 1,3-diphenylbutan-l-one (400 mg) and thiourea (201 mg) in ethanol (20 mL) was stirred at 85 °C overnight. Solvent was removed. The residue was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried and concentrated. Purification by flash chromatography (EtOAc : PE = 1:5) gave 4-phenyl-5-(l-phenylethyl)thiazol-2-amine (70 mg) as a light yellow oil. MSiES m/z 281 (MR*).
Step 3: A mixture of 4-phenyl-5-(l-phenylethyl)thiazol-2-amine (70 mg), 2-(4- (ethylsulfonyl)phenyl)acetic acid (intermediate la, 68.4 mg), HOBt (42.1 mg) and EDC (52.6 mg) in dichloromethane (DCM) (15 mL) was stirred at RT overnight The mixture was washed with water (60 mL x 3) and brine (60 mL). The organic phase was dried over anhydrous Na2S04, and concentrated. The residue was purified by prep-HPLC to give 2-(4-(ethylsulfonyl)phenyl)-N-(4- phenyl-5-(l-phenylethyl)thiazol-2-yl)acetamide (50 mg) as a brown solid. 'H-NMR (400 MHz, DMSO-rfe) δ ppm 1.10 (t, J= 6.4 Hz, 3H), 1.61 (d, J= 6.4 Hz, 3H). 3.28 (q, J= 6.4 Hz, 2H), 3.91 (s, 2H), 4.56 (q, J= 6.4 Hz, 1H), 7.21-7.39 (m, 6H), 7.42-7.46 (m, 2H), 7.51-7.63 (m, 2H), 7.60 (d, J= 7.6 Hz, 2H), 7.85 (d, J= 7.6 Hz, 2H); MS(ES+) mJz 491 (MH* . Example 23
JV-{4-(3-chlorophenyl)-5-i(2-chlorophenyl)met yl]-l,3-thiazol-2-yI}-2-[4- (ethylsuIfonyl)phenyl]acetamide
Figure imgf000034_0001
Intermediate 23a: 5-(2-cMorobenzyl)-4-(3-chlorophenyl)thiazol-2-amine
Step 1: Borane-tetrahydrofuran complex (17.67 mL) was added dropwise to a solution of 3-(2- chlorophenyl)propanoic acid (1.3 g) in THF (50 mL) cooled at 0 °C over 30 mins. The reaction mixture was warmed to room temperature and stirred overnight, The mixture was then cooled to 0 °C and quenched with brine. The organic layer was separated, and the aqueous layer was extracted with etiryl acetate (100 mL x 2). The combined organic phases were dried over sodium sulfate and concentrated to afford 3-(2-chlorophenyl)propan-l-ol (1.7 g) as a yellow oil. MSfES^ m/z 153 ((MH- H20)+).
Step 2: To a solution of 3-(2-chlorophenyl)propan-l-ol (1.7 g) in dichloromethane (DCM) (20 mL) was added PCC (2.58 g). The reaction mixture was stirred at RT overnight. Solvent was removed, and the residue was purified by flash chromatography (EtOAc : PE = 1 : 100 to 1 :50) to give 3-(2- chlorophenyl)propanaI (0.6 g) as a yellow oil.
Step 3: To a solution of 3-(2-chlorophenyl)propanal (500 mg) in tetrahydrofuran (THF) (25 mL) was added (3-chJorophenyl)magnesium bromide (768 mg) at 0 °C. The reaction mixture was stirred at RT for 3 hours. The mixture was washed with water (30 mL). The organic phase was dried over anhydrous Na2S04, filtered and concentrated. Purification by flash chromatography (EtOAc : PE = 1: 10) gave 3-(2-chIorophenyl)-l -(3-chlorophenyl)propan-l-ol (700 mg) as a light yellow oil.
Step 4: To a solution of 3-(2-chlorophenyl)-l-(3-chlorophenyl)propan-l-ol (0.7 g) in dichloromethane (DCM) (20 mL) was added PCC (0.644 g). The reaction mixture was stirred at RT overnight. Solvent was removed, and the residue was purified by flash chromatography (EtOAc : PE = 1: 10) to give 3-(2-chlorophenyl)-l-(3-chlorophenyl)propan-l-one (0.68 g) as a white solid.
Step 5: A mixture of 3-(2-chlorophenyl)-l -(3-chlorophenyl)propan-l-one (0.68 g) and copper(II) bromide (1.09 g) in chloroform (10 mL) and ethyl acetate (10 mL) was stirred at 85 °C for 3 hours. Solvent was removed, and the residue was partitioned between water (30mL) and ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous Na2S0 and concentrated in vacuo to afford 2-bromo-3-(2- chlorophenyl)-l -(3-chlorophenyl)propan-l-one (800 mg) as a white solid. Step 6: A mixture of 2-bromo-3-(2-chlorophenyl)-l-(3-chlorophenyl)propan-l-one (800 mg) and thiourea (340 mg) in ethanol (20 mL) was stirred at 85 °C overnight. Solvent was removed. The residue was suspended in CH2C12 (30 mL), and the mixture was filtered to remove insoluble solid. The filtrate was concentrated in vacuo, and the residue was triturated with petroleum ether to give 5- (2-chlorobenzyl)-4-(3-chlorophenyl)thiazol-2-amine (450 mg) as a yellow solid. MS^ES^ m/z 335 (MH+).
Preparation of the final product
5-(2-Chlorobenzyl)-4-(3-chlorophenyl)thiazol-2-amine (intermediate 23a, 220 mg), [4- (ethylsulfonyl)phenyl]acetic acid (intermediate la, 150 mg), EDC (151 mg) and HOBt (121 mg) were added into a 10 mL vial. Dichloromethane (DCM) (10 mL) was added. The reaction mixture was stirred at RT over 2 days. Solvent was removed. The crude product was redissolved in DMF and submitted to MADP for further purification to afford N-{4-(3-chlorophenyl)-5-[(2- chlorophenyl)methyl]-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (102.8 mg) as a white solid.Ή-NMR (400 MHz, DMSO-^) 5 ppm 1.02 (t, J= 7.3 Hz, 3H), 3.20 (d, J= 7.5 Hz, 2H), 3.83 (s, 2H), 4.27 (s, 2H), 7.20-7.27 (m, 3H), 7.35-7.46 (m, 3H), 7.46-7.54 (m, 3H), 7.56-7.60 (m, 1H), 7.77 (d, J= 8.3 Hz, 2H), 12.47 (s, 1H); MS(ES+) m/z 545 (MH*).
Example 24
N- {4-(4-chlorophenyI)-5- [methyl(phenyl) amino]-l,3-thiazoI-2-yl}-2- [4- (ethylsulf onyI)phenyl] acetamide
Figure imgf000035_0001
Step 1: To a mixture of thiourea (3.42 g) and 2-bromo-l-(4-chlorophenyl)ethanone (10.5 g) was added ethanol (100 mL). The reaction mixture was heated up to reflux (oil bath temperature: 85 °C) overnight. The reaction mixture was cooled to RT. Solid was filtered off and washed with diethyl ether to afford 4-(4-chlorophenyl)-l,3-thiazol-2-amine as a white solid. MSfES ) m/z 211 (Nfflf).
Step 2: To a mixture of 4-(4-chIorophenyl)-l,3-thiazol-2-amine (3.8 g) and copper(II) bromide (12.48 g) was added acetonitrile (30 mL). The reaction mixture was stirred at room temperature overnight. Acetonitrile was removed in vacuo. EtOAc was added. The obtained mixture was washed with diluted ammonia 3 times. The organic phase was then washed with brine and dried over Na2SC>4. After filtration and concentration, the crude product was purified by flash chromatography (EtOAc : PE = 0: 1 to 1: 1) to afford 5-bromo-4-(4-chlorophenyl)-l,3-thiazol-2-amine (3.1 g). MSiES ) m/z 289 (MH .
Step 3: To a solution of N-methylaniline (49.6 mg, 0.463 mmol) in NN-dimethylformamide (DMF) (0.5 mL) was added sodium hydride (23.13 mg). The vial was sealed and stirred at RT for 40 mins. A solution of 5-bromo-4-(4-chIorophenyl)-l ,3-thiazol-2-amine (67 mg) in NN- dimethylformamide (DMF) (0.5 mL) was carefully added at 0 °C. The reaction mixture was stirred at this temperature for 10 mins, and then quenched with water. The obtained mixture was extracted with EtOAc for 3 times. The combined organics were washed with brine, dried over Na2SC> . After filtration and concentration, 4-(4-chlorophenyl)-N5-methyl-Ns-phenylthiazole-2,5-diamine (61 mg) was achieved. MSiES'1) m/z 316 (MFT).
Step 4: [4-(Ethylsulfonyl)phenyl]acetic acid (intermediate la, 44 mg), 4-(4-chlorophenyl)-N5- methyl-A^-phenylthiazole^^-diamine (60.9 mg), EDC (44.3 mg) and HOBt (35.4 mg) were added into a 10 mL vial. Dichloromethane (DCM) (5 mL) was added. The reaction mixture was stirred at RT for 3 days. DCM was removed. The obtained crude was redissolved in DMF and submitted to MDAP for purification. Solvent was evaporated in vacuo to give N-{4-(4-chlorophenyl)-5-
[methyl(phenyl)amino]-l,3-thiazol-2-yl}-2-[4-(ethylsulfonyl)phenyl]acetamide (36.2 mg) as an off- white solid. Ή-NMR (400 MHz, DMSO-i/6) δ ppm 1.16 (t, J= 7.3 Hz, 3H), 3.23 (s, 3H), 3.34 (q, J= 7.3 Hz, 2H), 4.00 (s, 2H), 6.78-6.88 (m, 3H), 7.27 (dd, J= 7.5 Hz, 8.5 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 7.68 (d, J= 8.3 Hz, 2H), 7.86 (d, J= 8.7 Hz, 2H), 7.92 (d, J= 8.3 Hz, 2H), 12.68 (s, 1H);
MS(ES+) m/z 526 (MH+).
Example 25
Ar-(4-(3-chlorophenyl)-5-((2-chlorophenyl)(methyl)amino)thiaz:oI-:
(ethylsulfonyl)phenyl)acetamide
Figure imgf000036_0001
Step 1: A mixture of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (2 g, see step 3 for synthesis of Example 9), 2-chloro-N-methylbenzenamine (1.08 g) and cesium carbonate (2.70 g) in acetone (5 mL) was stirred at 55 °C overnight. Solvent was removed, and the residue was partitioned between DCM (10 mL) and water (10 mL). The organic phase was washed with water (10 mL x 3), dried and concentrated to give A^-(2-chlorophenyl)-4-(3-chlorophenyl)-N5-methylthiazole-2,5-diamine (400 mg) as a red solid. MStES*) m z 351 (MET1).
Step 2: A mixture of 2-(4-(ethylsuIfonyI)phenyl)acetic acid (intermediate 1 a, 313 mg), ^-(2- chloropheny ^^S-chlorophenyli-A^-methyltliiazole^.S-diamine (400 mg), EDC (657 mg), HOBt (210 mg) and DIPEA (1.20 mL) in dichloromethane (DCM) (20 mL) was stirred at 45 °C overnight. DCM (50 mL) and water (50 mL) were added. The organic phase was washed with water (30 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :3) to give the crude product. Further purification by prep-HPLC afforded N-(4-(3-chlorophenyl)-5-((2- chlorophenyl)(methyl)amino)thiazol-2-yl)-2-(4-(emylsulfonyl)phenyl)acetarnide (50 mg) as a white solid. Ή-ΝΜΡ (400 MHz, CDC13) 5 ppm 1.28 (t, J= 7.2 Hz, 3H), 3.11 (q, J= 7.2 Hz, 2H), 3.19 (s, 3H), 3,58 (s, 2H), 7.01 (t, J= 7.8 Hz, 1H), 7.13-7.39 (m, 7H), 7.85(d, J= 8.0 Hz, 2H), 7.89 (d, J= 8.0 Hz, 1H), 7.95 (s, 1H), 10.66 (s, 1H); MSfES") m/z 561 (MH+).
Example 26
AL(4-(3-chlorophenyl)-5-(2-iso ropylphenoxy)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide
Figure imgf000037_0001
Step 1: To a solution of 5-bromo-4-(3-chlorophenyl)thiazoI-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (1.4 g) and 2- isopropylphenol (0.51 g). The reaction mixture was stirred at 45 °C overnight. After removal of solvent, ethyl acetate was added. The organic solution was washed with water (30 mL x 3) and brine (25 mL x 2), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :6) to give 4-(3-chlorophenyl)-5-(2-isopropylphenoxy)thiazol-2-amine (500 mg) as a white solid. MS(ES+) m/z 346 (MH+).
Step 2: To a solution of 2-(4-(ethylsulfonyl)phenyl)acetic acid (intermediate l , 200 mg) in dichloromethane (DCM) (25 mL) was added 4-(3-chlorophenyl)-5-(2-isopropylphenoxy)thiazol-2- amine (300 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315 mL). After stirring at 35 °C for 2 days, the mixture was washed with water (40 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1:4) to give the crude product, which was further purified by preparative HPLC to afford N-(4-(3-chlorophenyl)-5-(2-isopropyIphenoxy)thiazol- 2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (32 mg) as a white solid. Ή-NMR (400 MHz, CDC13) δ ppm 1.26-1.30 (m, 9H), 3.17 (q, J= 12 Hz, 2H), 3.38-3.47 (m, 1H), 3.78 (s, 2H), 6.70-6.98 (m, 2H), 7.15-7.17 (m, 2H), 7.28-7.37 (m, 3H), 7.47 (d, J= 8.0 Hz, 2H), 7.89 (d, J= 8.0 Hz, 2H), 7.93 (s, 1H), 11.53 (s, 1H); MSfES^ m/z 555 (MH+). Example 27
N-(4-(3-chlorophenyl)-5-(4-methoxyphenoxy)tluazol-2-yl)-2-(4-(ethyIsulfonyl)phenyl)acetamide
Figure imgf000038_0001
Step 1: To a solution of 5-bromo-4-(3-chlorophenyl)thiazol-2-amine (1.0 g, see step 3 for synthesis of Example 9) in acetone (50 mL) was added cesium carbonate (1.4 g) and 4- methoxyphenol (0.48 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The obtained solution was washed with water (40 mL x 3) and brine (30 mL x 2), dried and concentrated. The residue was purified by flash chromatography (PE : EtOAc = 1 :0 to 5: 1) to give 4-(3-chlorophenyl)-5-(4-methoxyph enoxy)thiazol-2-amine (500 mg) as a white solid. MS(ES+) m/z 333 (MH4).
Step 2: To a solution of 2-(4-(ethyIsulfonyl)phenyl)acetic acid (intermediate la, 200 mg) in dichloromethane (DCM) (20 mL) was added 4-(3-chlorophenyl)-5-(4-methoxyphenoxy)thiazol-2- amine (280 mg), EDC (207 mg), HOBt (166 mg) and DIPEA (0.315 mL). After stirring at 35 °C for 2 days, the reaction mixture was washed with water (25 mL x 3), dried and concentrated. The residue was purified by flash chromatography (EtOAc : PE = 0: 1 to 1 :2) to give the crude product, which was further purified by preparative HPLC to afford N-(4-(3-chlorophenyl)-5-(4-methoxyphenoxy)thiazol- 2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide (11 mg) as a white solid. 'H- MR (400 MHz, CDC¾) δ ppm 1.31 (t, J= 7.2 Hz, 3H), 3.14 (q, J= 7.2 Hz, 2H), 3.81 (s, 3H), 3.90 (s, 2H), 6.88 (d, J= 8.8 Hz, 2H), 7.08 (d, J= 8.8 Hz, 2H), 7.30-7.38 (m, 2H), 7.54 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 7.6 Hz, 1H), 7.92 (d, J= 8.4 Hz, 3H); MS(ES") m/z 543 (MH*). Example 28
N-(4-(3-((dimethylamino)methyl)phenyl)-5-(2-(trifluoromethyl)phenoxy)thiazol-2-yl)-2-(4- (ethylsulfonyl)phenyl)acetamide trifluoroacetate
Figure imgf000039_0001
Step 1: A solution of l-m-tolylethanone (5.0 g), NBS (6.63 g) and benzoic peroxyanhydride (1.81 g) in acetonitrile (10 mL) was stirred at 85 °C under nitrogen for 20 hours. Solvent was removed, and the residue was purified by flash chromategraphy (EtOAc : PE = 0: 1 to 1:20) to give 1- (3-(bromomethyl)phenyl)ethanone (2.4 g) as an oil. MS(ES+) m/z 213 (MH4).
Step 2: A mixture of l-(3-(bromomethyl)phenyl)ethanone (2.4 g), dimethylamine
hydrochloride (0.735 g) and potassium carbonate (1.37 g) in DCM (30 mL) was stirred at room temperature overnight. Solid was removed by filtration, and the filtrate was washed with water (10 mL x 2) and brine (10 mL x 2), The organic phase was dried and concentrated to give l-(3- ((dimethylamino)methyI)phenyl)ethanone (700 mg). MS(ES+) m/z 178 (MH+).
Step 3: Bromine (568 mg) in acetic acid (30 mL) was added dropwise to a solution of l-(3- ((dimethylamino)methyl)phenyl)ethanone (700 mg) in acetic acid (20 mL) at 10 °C. The reaction mixture was stirred overnight. Solvent was removed to give 2-bromo-l -(3- ((dimethylamino)methyl)phenyl)ethanone (1.0 g) as an oil. MSfES ) m/z 256 (MET).
Step 4: A mixture of 2-bromo-l -(3-((dimethylamino)methyl)phenyl)ethanone (1.0 g) and thiourea (0.535 g) in ethanol (10 mL) was stirred at 80 °C overnight. Solvent was removed to give 4- (3-((dimethylamino)methyl)phenyl)thiazol-2-amine (800 mg). MS(ES+) m/z 234 (MH^).
Step 5: NBS (336 mg) was added to a solution of 4-(3-((dimethylamino)methyl)phenyl)thiazoI- 2-amine (800 mg) in THF (10 mL). The reaction mixture was stirred at room temperature for 30 mins. Solvent was removed to give 5-bromo-4-(3-((dimethylamino)methyl)phenyl)thiazol-2-amine (800 mg). MSCES ) m z 312 (MH^.
Step 6: To a solution of 5-bromo-4-(3-((dimethylamino)methyl)phenyl)thiazol-2-amine (800 mg) in acetone (50 mL) was added 2-(trifluoromethyl)phenol (571 mg) and cesium carbonate (1.25 g). The reaction mixture was stirred at 45 °C overnight. Solvent was removed, and ethyl acetate was added. The organic phase was washed with water (50 mL x 3), dried and concentrated. Purification by flash chromatography (EtOAc : PE = 1:3) afforded 4-(3-((dimemylamino)methyl)phenyl)-5-(2- (trifluoromethyl)phenoxy)thiazol-2-amine (120 mg) as a yellow oil. MSfES*) m/z 37S (MH1 .
Step 7: To a solution of 4-(3-((dimethylamino)methyl)phenyl)-5-(2- (trifluoromethyl)phenoxy)thiazol-2-amine (100 mg) in DCM (15 mL) was added 2-(4- (ethylsulfonyl)phenyl)acetic acid (intermediate la, 87 mg), HOBt (46.7 mg), EDC (146 mg) and DIPEA (0.266 mL). After stirring at reflux overnight, the mixture was washed with water and brine, dried and concentrated. Purification by reverse phase flash chromatography using TFA contained elution gave N-(4-(3-((dimethylamino)methyl)phenyI)-5-(2-(trifJuoromethy])phenoxy)thiazol-2-y])-2- (4-(ethylsulfonyl)phenyl)acetamide trifluoroacetate (12 mg) as a white solid. Ή-NMR (400 MHz, DMSO-<¾) δ ppm 1.28 (t, J= 7.6 Hz, 3H), 2.80 (s, 6H), 3.12 (q, J= 7.6 Hz, 2H), 3.93 (s, 2H), 4.16 (s, 2H), 7.06 (d, J= 8.0 Hz, 1H), 7.15-7.25 (m, 2H), 7.36 (t, J= 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.60-7.70 (m, 3H), 7.85-7.95 (m, 3H), 8.31 (s, 1H), 12.27 (s, 1H); 19F-NMR (376 MHz, DMSO-t¾) 5 ppm: -61.55, -75.45; MSiES*) m/z 604 (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 f RET) 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 SRC 1(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 ofROR -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 (M HHHHHHLVPRGS) 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
(CPS SH S S LTERH ILHRLLQEG SPS) 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 SRC1(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'- CTCGAGT AGAGCAGG AC AGGGAGGAA-31 (Xhol site is underlined) and reverse primer, 5'- AAGCTTGGATGGATGAGTTTGTGCCT-31 (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-hic 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 Stainin2 Studies
ELISA
Mouse CD4+ cells were purified 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. Un-coated wells were used as controls. CD4+ Cells were resuspended in RPMI complete medium and were added to the 96-well plates at 3E5 cells/well, with the total volume being 90 ul. Cytokine cocktail and 20ul of each compound were then added to the wells (DMSO final volume 0.1%). 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 culture was incubated in 37°C for 3 days and supematants were collected for ELISA. The IL-17 ELISAs were performed according to manufacturer's instructions (R&D Systems).
Intracellular staining
The Thl7 differentiation culture described above was maintained for 5 days and cells were analyzed by IL-17 and IFN-γ intracellular staining according to manufacturer's instructions (BD Biosciences).
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.
As shown in the Table below, all exemplified compounds except Examples 27 and 28 were tested in the dual FRET assay described above. All tested compounds were found to have a pIC50 between 6 and 9.
As shown in the Table below, all exemplified compounds (Examples 1-28) were tested in the Jurkat cell luciferase assay described above and were found to have a pIC50 between 5 and 8.
As shown in the Table below, all exemplified compounds except Examples 9, 11, 14, 17, 20, 22 and 26-28 were tested in the Thl7 ELISA assay described above. All tested compounds except Examples 3, 8, 21 and 24 were found to have a pIC50 above 5. Examples 3, 8, 21 and 24 were each tested once and found to have a pIC50 below 5, the detection limit of the assay.
Example ROR Dual FRET Assay Jurkat Cell Luciferase Assay Thl7 Assay No (pIC50) (pIC50) (pICSO)
1 7.4 6.3 5.3
2 7.4 6.2 5.4
3 7.2 6.4 <5.0
4 7.9 6.6 5.8
5 7.8 6.9 6.0
6 8.1 6.1 5.8
7 7.7 6.4 6.2
8 7.7 6.2 <5.0
9 7.7 6.4
10 8.1 6.7 5.5
11 7.9 6.2
12 7.6 6.4 5.5
13 7.5 6.7 5.7
14 7.3 6.3
15 7.9 6.6 6.3
16 7.9 7.1 6.5
17 7.9 6.9
18 7.8 7.2 6.4
19 7.7 7.5 6.8
20 6.4 5.6
21 6.7 5.9 <5.0
22 6.7 5.7
23 7.9 6.7 5.4
24 7.2 6.0 <5.0
25 7.6 7.0 6.4
26 7.5 6.3
27 6.7
28 6.3
EAE Studies
Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis. The ability of a test compound to ameliorate EAE was measured in the EAE studies. Wild- type mice of the C57BL/6 (B6) strain can be obtained from Shanghai Laboratory Animal Resource Center. EAE can be 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. 5s peptide (300 μ¾ π™ΐ3β) 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 is given orally on day 0 at 100 mg/kg twice a day. Mice can be 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 can be expressed as means ± s.e.m.
CIA Studies
Collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis. CIA can be 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 are 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 is given to the mice at lOOmg/kg twice a day starting from day 20 after the first immunization. Mice are examined for onset and severity of disease in a blinded manner. Arthritis symptoms can be 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 is graded, giving a maximum possible score of 16 per mouse. Clinical score data can be expressed as means ± s.e.m. Foot volume of the mice can be determined using a YLS-7B foot volume measuring instrument (Shandong Academy of Medical Science).
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, asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' 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 he 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 artis n 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, asthma, type I diabetes,
neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Gaves' 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 nig-
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

WHAT IS CLAIMED IS:
1. A compound of Fonnula I or a pharmaceutically acceptable salt thereof
Figure imgf000052_0001
Formula I
wherein:
X is selected from the group consisting of:
- O;
- NRa wherein Ra is H or C1-C6 alkyl; and
- C1-C3 alkyl optionally substituted with OH;
each Rl is independently selected from the group consisting of:
- halo;
- CN;
- OH;
- C1-C3 alkoxy optionally substituted with one to three F; and
- C1-C3 alkyl optionally substituted with one to three F or N(CH3)(CH3);
each R2 is independently selected from the group consisting of:
- halo;
- CN;
- OH;
- C1-C3 alkoxy optionally substituted with one to three F; and
- C1-C3 alkyl optionally substituted with one to three F;
m is 0, 1 or 2
n is 0, 1 or 2;
R3 is H or C1-C3 alkyl;
R4 is H or Cl-C3 alkyI;
R5 is selected from the group consisting of:
- C1-C6 alkyl optionally substituted with one to three F, OH or C1-C3 alkoxy; and
- NHRb wherein Rb is C1-C6 alkyl.
2. A compound of Formula 1(A) or a pharmaceutically acceptable salt thereof
Figure imgf000053_0001
wherein:
each Rl is independently selected from the group consisting of:
- halo;
- CN;
- OH;
- C1-C3 alkoxy optionally substituted with one to three F; and
- C1-C3 alkyl optionally substituted with one to three F or N(CH3)(CH3);
each R2 is independently selected from the group consisting of:
- halo;
- CN;
- OH;
- C1-C3 alkoxy optionally substituted with one to three F; and
- C1-C3 alkyl optionally substituted with one to three F;
m is 0, 1 or 2
n is 0, 1 or 2;
R3 is H OT CI -C3 alkyl;
R4 is H or Cl -C3 alkyl;
R5 is selected from the group consisting of:
- C1-C6 alkyl optionally substituted with one to three F, OH or C1-C3 alkoxy; and
- NHRb wherein Rb is C1-C6 alkyl.
3. A compound or salt according to claim 1, wherein X is methylamino.
4. A compound or salt according to any of claims 1 to 3, wherein m is 0.
5. A compound or salt according to any of claims 1 to 3, wherein R I is CI or CN and m is 1.
6. A compound or salt according to any of claims 1 to 5, wherein n is 1 or 2.
7. A compound or salt according to claim 6, wherein each R2 is CI or CF3.
8. A compound or salt according to any of claims 1 to 7, wherein R3 is H.
9. A compound or salt according to any of claims 1 to 8, wherein R4 is H.
10. A compound or salt according to any of claims 1 to 9, wherein R5 is ethyl.
11. A pharmaceutical composition which comprises a compound according to any of claims 1 to 10 and a pharmaceutically acceptable carrier or excipient.
12. A pharmaceutical composition for use in the treatment of multiple sclerosis which comprises a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition for use in the treatment of rheumatoid arthritis which comprises a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
14. A method for treating multiple sclerosis which comprises administering to a host in need thereof a safe and effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.
15. A method for treating rheumatoid arthritis which comprises administering to a host in need thereof a safe and effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.
PCT/CN2012/070678 2011-01-24 2012-01-20 Compounds useful as retinoid-related orphan receptor gamma modulators WO2012100734A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2013019626A1 (en) * 2011-07-29 2013-02-07 Tempero Pharmaceuticals, Inc. Compounds and methods
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
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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
WO2014062938A1 (en) * 2012-10-19 2014-04-24 Bristol-Myers Squibb Company Rory modulators
WO2014179564A1 (en) * 2013-05-01 2014-11-06 Vitae Pharmaceuticals, Inc. Thiazalopyrrolidine inhibitors of ror-gamma
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
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
WO2016145298A1 (en) 2015-03-12 2016-09-15 The Regents Of The University Of California METHODS FOR TREATING CANCER WITH RORgamma INHIBITORS
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
EP3101008A1 (en) * 2015-06-05 2016-12-07 Lead Pharma Cel Models IP B.V. Ror gamma (rory) modulators
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
EP2975031A4 (en) * 2013-03-14 2017-04-19 Takeda Pharmaceutical Company Limited Heterocyclic compound
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
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
US9902735B2 (en) 2014-05-28 2018-02-27 Glaxosmithkline Intellectual Property Development Limited Heteroaryl substituted compounds as RORγ inhibitors
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
WO2018123918A1 (en) * 2016-12-26 2018-07-05 科研製薬株式会社 Pyrazole derivative and drug containing same
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN108610301A (en) * 2016-12-12 2018-10-02 中山大学 A kind of chiral fragrant miscellaneous amine derivant and its synthetic method and application
WO2018185675A1 (en) 2017-04-04 2018-10-11 Glenmark Pharmaceuticals S.A. Substituted oxoazetidine analogues as ror gamma modulators
CN109081794A (en) * 2018-09-28 2018-12-25 吉首大学 N- virtue acetyl-amino thiocarbamide type urease inhibitor and its preparation method and purposes
US10189775B2 (en) 2015-08-28 2019-01-29 Glenmark Pharmaceuticals S.A. Carbocyclic compounds as ROR gamma modulators
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10472376B2 (en) 2013-07-03 2019-11-12 Takeda Pharmaceutical Company Limited Amide compound
RU2727698C2 (en) * 2015-06-05 2020-07-23 Лид Фарма Холдинг Б.В. ROR GAMMA (RORγ) MODULATORS
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
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
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
US11229636B2 (en) 2015-05-15 2022-01-25 Aurigene Discovery Technologies Limited Substituted tetrahydroquinolinone compounds as ROR gamma modulators
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WO2023144559A1 (en) 2022-01-28 2023-08-03 AdoRx Therapeutics Limited Antagonist of adenosine receptors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092146A2 (en) * 2003-04-14 2004-10-28 The Institutes For Pharmaceutical Discovery, Llc N- (((((1,3-thiazol-2-yl) amino) carbonyl) phenyl) sulfonyl) phenylalanine derivatives and related compounds for the treatment of diabetes
WO2008057862A2 (en) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-&kappav;B ACTIVITY AND USE THEREOF

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092146A2 (en) * 2003-04-14 2004-10-28 The Institutes For Pharmaceutical Discovery, Llc N- (((((1,3-thiazol-2-yl) amino) carbonyl) phenyl) sulfonyl) phenylalanine derivatives and related compounds for the treatment of diabetes
WO2008057862A2 (en) * 2006-11-01 2008-05-15 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-&kappav;B ACTIVITY AND USE THEREOF

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WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
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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
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KR101732973B1 (en) 2012-08-09 2017-05-08 페넥스 파마슈티컬스 아게 Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor ror[gamma]
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WO2014062938A1 (en) * 2012-10-19 2014-04-24 Bristol-Myers Squibb Company Rory modulators
US10035790B2 (en) 2012-10-19 2018-07-31 Exelixis, Inc. RORγ modulators
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WO2013171729A2 (en) 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as rorgamat modulator
WO2013171729A3 (en) * 2013-01-08 2014-02-06 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as ror gamma t modulator
US9834520B2 (en) 2013-03-14 2017-12-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
EP2975031A4 (en) * 2013-03-14 2017-04-19 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2014179564A1 (en) * 2013-05-01 2014-11-06 Vitae Pharmaceuticals, Inc. Thiazalopyrrolidine inhibitors of ror-gamma
US9868748B2 (en) 2013-05-01 2018-01-16 Vitae Pharmaceuticals, Inc. Thiazolopyrrolidine inhibitors of ROR- γ
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US11053262B2 (en) 2013-07-03 2021-07-06 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having RORyT inhibitory action
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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
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US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
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US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
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WO2015139619A1 (en) * 2014-03-18 2015-09-24 北京韩美药品有限公司 Compound serving as rorγ modulator
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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
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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
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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
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EP3101008A1 (en) * 2015-06-05 2016-12-07 Lead Pharma Cel Models IP B.V. Ror gamma (rory) modulators
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WO2016193470A1 (en) * 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Ror gamma (rory) modulators
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US10344024B2 (en) 2015-08-03 2019-07-09 Glenmark Pharmaceuticals S.A. Compounds as ROR gamma modulators
WO2017021879A1 (en) 2015-08-03 2017-02-09 Glenmark Pharmaceuticals S.A. Novel compounds as ror gamma modulators
US9975887B2 (en) 2015-08-03 2018-05-22 Glenmark Pharmaceuticals S.A. Compounds as ROR gamma modulators
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