WO2012027965A1 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

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Publication number
WO2012027965A1
WO2012027965A1 PCT/CN2011/001481 CN2011001481W WO2012027965A1 WO 2012027965 A1 WO2012027965 A1 WO 2012027965A1 CN 2011001481 W CN2011001481 W CN 2011001481W WO 2012027965 A1 WO2012027965 A1 WO 2012027965A1
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Prior art keywords
phenyl
chlorophenyl
thiazol
stirred
mixture
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PCT/CN2011/001481
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English (en)
Inventor
Yonghui Wang
Wei Cai
Qian Liu
Jia-Ning Xiang
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Glaxo Group Limited
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Publication of WO2012027965A1 publication Critical patent/WO2012027965A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

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

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Abstract

La présente invention concerne des modulateurs de récepteur orphelin associé au rétinoïde gamma (RORγ) et leur utilisation dans le traitement de maladies médiées par RORγ.
PCT/CN2011/001481 2010-09-01 2011-08-31 Nouveaux composés WO2012027965A1 (fr)

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WO2013029338A1 (fr) * 2011-09-01 2013-03-07 Glaxo Group Limited Nouveaux composés
WO2013064231A1 (fr) 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3)
WO2013079223A1 (fr) 2011-12-02 2013-06-06 Phenex Pharmaceuticals Ag Pyrrolocarboxamides en tant que modulateurs de l'activité d'un récepteur orphelin gamma (rorϒ, nr1f3) apparenté au récepteur nucléaire orphelin rar et destinés au traitement de maladies inflammatoires chroniques et auto-immunes
US9815851B2 (en) 2011-12-02 2017-11-14 Phenex Pharmaceuticals Ag Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases
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WO2013178362A1 (fr) 2012-05-31 2013-12-05 Phenex Pharmaceuticals Ag Thiazoles substitués par carboxamide ou sulfonamide et dérivés apparentés en tant que modulateurs du récepteur nucléaire orphelin ror[gamma]
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JP2015521193A (ja) * 2012-05-31 2015-07-27 フェネックス ファーマシューティカルス アーゲー オーファン核内受容体ＲＯＲγの調整剤としてのカルボキサミドまたはスルホンアミド置換されたチアゾールおよび関連する誘導体
EP3118189A1 (fr) 2012-08-09 2017-01-18 Phenex Pharmaceuticals AG Azote substitue de carboxamide ou sulfonamide contenant des heterocycles a 5 chainons en tant que modulateurs de recepteur nucleaire orphelin gamma ror
WO2014023367A1 (fr) 2012-08-09 2014-02-13 Phenex Pharmaceuticals Ag Hétérocycles à 5 chaînons contenant de l'azote substitués par carboxamide ou sulfonamide en tant que modulateurs pour le récepteur nucléaire orphelin ror gamma
US9458104B2 (en) 2012-08-09 2016-10-04 Phenex Pharmaceuticals Ag Carboxamide or sulfonamide substituted nitrogen-containing 5-membered heterocycles as modulators for the orphan nuclear receptor RORγ
US10005731B2 (en) 2012-12-06 2018-06-26 Glaxo Group Limited Modulators of the retinoid-related orphan receptor gamma (ROR-gamma) for use in the treatment of autoimmune and inflammatory diseases
WO2013171729A2 (fr) 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Composés d'aryl- et hétéroarylamide en tant que modulateur de rorγt
WO2014125426A1 (fr) * 2013-02-15 2014-08-21 Aurigene Discovery Technologies Limited Dérivés hétérocycliques trisubstitués en tant que modulateurs de ror gamma
EP3018126A4 (fr) * 2013-07-03 2016-12-07 Takeda Pharmaceuticals Co Composé hétérocyclique
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2015052675A1 (fr) * 2013-10-10 2015-04-16 Glenmark Pharmaceuticals S.A. Utilisation de composés substitués dihydro-benzimidazole comme modulateurs du ror gamma
CN105636941A (zh) * 2013-10-25 2016-06-01 葛兰素史密斯克莱有限责任公司 新的化合物
CN105980353A (zh) * 2013-12-05 2016-09-28 领先制药Cel模型知识产权公司 RORγ调节剂
US9682977B2 (en) 2013-12-10 2017-06-20 Glenmark Pharmaceuticals S.A. Bicyclic heteroaryl indole analogues useful as ROR gamma modulators
WO2015087234A1 (fr) 2013-12-10 2015-06-18 Glenmark Pharmaceuticals S.A. Analogues de l'indole héteroaryle bicyclique utiles en tant que modulateurs de gamma ror
WO2015101928A1 (fr) * 2013-12-31 2015-07-09 Aurigene Discovery Technologies Limited Dérivés de thiophène et de thiazole fusionnés utilisés en tant que modulateurs gamma ror
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2015129853A1 (fr) * 2014-02-27 2015-09-03 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci
CN104926733B (zh) * 2014-03-18 2019-05-10 北京韩美药品有限公司 作为RORγ调节剂的化合物
WO2015139619A1 (fr) * 2014-03-18 2015-09-24 北京韩美药品有限公司 Composé servant de modulateur rorγ
CN104926733A (zh) * 2014-03-18 2015-09-23 北京韩美药品有限公司 作为RORγ调节剂的化合物
WO2015159233A1 (fr) 2014-04-16 2015-10-22 Glenmark Pharmaceuticals S.A. Composés éther d'aryle et éther d'hétéroaryle en tant que modulateurs de ror gamma
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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