WO2018011747A1 - Composés polycycliques en tant que modulateurs de ror-gamma - Google Patents

Composés polycycliques en tant que modulateurs de ror-gamma Download PDF

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WO2018011747A1
WO2018011747A1 PCT/IB2017/054240 IB2017054240W WO2018011747A1 WO 2018011747 A1 WO2018011747 A1 WO 2018011747A1 IB 2017054240 W IB2017054240 W IB 2017054240W WO 2018011747 A1 WO2018011747 A1 WO 2018011747A1
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phenyl
cyclopropyl
ethylsulfonyl
acetamide
dichloro
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PCT/IB2017/054240
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English (en)
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Ranjit Desai
Sanjay S KUMAR
Vrajesh PANDYA
Jigar Desai
Saurin Raval
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Cadila Healthcare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel derivatives of the general formula (I) suitable as modulators of RORy, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.
  • RORy The Retinoic acid receptor-related orphan receptor ⁇ known as RORy belongs to the nuclear receptor superfamily (Hirose, T.; Smith, R. J.; Biochem. Biophys. Res. Commun. 1994, 205, 1976-1983). There are three sub-types of ROR s classified as RORa, RORP and RORy. As observed in majority of other nuclear receptors, structure of ROR s consists of four distinct regions called N-terminal A/B domain, a DNA binding domain, a hinge domain and a ligand binding domain.
  • RORyl and RORv2 which is also called as RORyt
  • RORyt Two isoforms RORyl and RORv2 (which is also called as RORyt) have been identified that differ only in N-terminal sequences (He, Y.-W.; Deftos, M. L.; Ojala, Immunity 1998, 9,797-806). Tissue distribution of this two isoforms is quite distinct, while RORyl is expressed in a variety of tissues including thymus, liver, kidney and muscle, RORyt is exclusively expressed in the cells of the immune system.
  • the isoform RORyt plays important role in the development and regulation of the immune system through its regulatory effect on T helper cells (Thl7 cell) (Ivanov, I. I.; McKenzie, B.
  • Thl7 is the IL-17 producing CD4+ Th subset and are key drivers of chronic inflammation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis (Jetten (2009) Nucl. RecepL Signal. 7: e003; Manel et al. (2008) Nat. Immunol. 9:641-649).
  • Mouse autoimmune disease models like experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) have demonstrated the role of Thl7 in autoimmune diseases.
  • RORy is central transcription factor driving Thl7 differentiation.
  • RORy The significant role of RORy in the pathogenesis of autoimmune disease forms a basis for the development of ligands which can modulate RORy activity and could lead to specific therapies for diseases mediated by RORy.
  • WO2012100732 discloses thiophene derivatives represented by following formula as RORy modulators.
  • WO2012100734 and WO201227965 disclose compounds of the following formula as RORy modulators.
  • WO2013029338 discloses biaryl modulators of RORy having following formula and their use in treatment of disease mediated by RORy.
  • WO2013171729 discloses aryl or heteroaryl carboxamides with following formula and their use as RORy modulators.
  • WO2014125426 discloses trisubstituted heterocyclic derivatives having following formula as RORy modulators.
  • WO2014179564 discloses thiazolopyrrolidine derivatives with following formula for the treatment of diseases mediated by RORy.
  • WO2015083130 and WO2015101928 disclose fused pyridine/pyrimidine derivatives and fused thiophene/thiazole derivatives respectively with following formula as RORy modulators.
  • WO2015159233 discloses aryl and heteroaryl ether compounds with following formula as RORy modulators.
  • WO2015145371 discloses following types of RORy modulators and their the treatment of disease mediated by RORy.
  • WO2015116904 discloses dihydropyrrolopyridine inhibitors of RORy with following formula.
  • WO2016193470, WO2016193468, WO2016193461, WO2016193459 and WO2016193452 disclose substituted acetamide derivatives as RORy modulators.
  • WO2017024018 and WO2017087608 disclose modulators of RORy with following formula.
  • RORy modulators Although several compounds have been reported in the literature as RORy modulators, none of these compounds have reached the market and looking at the significant unmet medical need for such compounds based on their potential beneficial effects as discussed above, there is a need for identifying further compounds which can act as RORy modulators.
  • novel compounds useful as RORy modulators which may have beneficial effects in the treatment of autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis and the like which are mediated by RORy and methods for their preparation.
  • the present invention discloses novel compounds as defined by the general formula (I) that modulates the activity of RORy and provides treatment option for autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis which are mediated by RORy.
  • the compounds of the present invention are useful in the treatment of the human or animal body, by regulation of RORy receptor gene expression.
  • the compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of number of autoimmune or inflammatory diseases mentioned above.
  • the main objective of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis.
  • autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis.
  • compositions containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture are provided.
  • novel compounds of the present invention for the treatment of autoimmune diseases, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.
  • a method of treatment of diseases which can be treated or whose symptoms can be reversed by administering a therapeutically effective & non-toxic amount of the compound of formula (I) or their pharmaceutically acceptable compositions to the mammals.
  • the present invention relates to compounds of the general formula
  • A represents monocyclic or bicyclic heterocyclic ring system
  • Ri and R 2 are each independently selected from halogen, (Ci-C3)alkyl, alkoxy, CF 3 ;
  • Y and Z independently represents -CH- or N atom
  • R 3 at each occurrence is independently selected from hydrogen, halogen, (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, (C 6 -Ci 0 )aryl, (C 6 -Ci 0 )heteroaryl, (C 3 -C 6 )cycloalkyl, (C 4 -C 6 ) heterocyclyl or -NR7R8;
  • R4 is selected from hydrogen, halogen, (Ci-C 3 )alkyl
  • R5 is selected from (Ci-C 3 )alkyl
  • R 6 is selected from (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, cycloalkanylalkyl, (C 4 -C 6 )
  • heterocyclyl heterocyclylalkyl
  • R 4 and R 6 together with the N atom can cyclize to form five membered heterocyclic ring with 0-1 double bond and may further contain from 1-2 N atoms;
  • Substituents on R 3 may be selected from the group comprising of hydrogen, hydroxy, cyano, halogen, COOH, oxo, halo(Ci-C 6 )alkyl, optionally substituted (Ci-C 6 )alkyl, - 0(Ci-C 6 alkyl), -OCF 3 , (C 3 -C 6 )cycloalkyl or -NR7R8 wherein each of R 7 and Rg at each occurrence is independently selected form hydrogen or (Ci-C 6 )alkyl;
  • the alkyl group as used herein before may further substituted with hydrogen, hydroxy, -COOH, cyano, halo, oxo, imino, haloalkyl, (Ci-C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl;
  • n represents integers from 1-2;
  • Preferred Ri and R 2 may be selected from halogen and (Ci-C 3 )alkyl
  • Preferred A is selected from oxadiazole and benzoxazole
  • R 3 is selected from (Ci-C 6 )alkyl, (C 6 -Cio)aryl, (C 3 -C 6 )cycloalkyl, (C 4 -C 6 ) heterocyclyl;
  • Preferred substituents on R 3 is selected from hydrogen, hydroxy, cyano, halogen, halo(Ci-C 6 )alkyl, optionally substituted (Ci-C 6 )alkyl, -0(Ci-C 6 alkyl), -OCF 3 ;
  • Preferred heterocyclic rings formed when R 4 and R 6 together with the N atom to form a ring are indole and indazole.
  • the groups, radicals described above may be selected from:
  • alkyl used either alone or in combination with other radicals, denotes a linear or branched radical containing one to eight carbons, selected from methyl, ethyl, n-propyl, zso-propyl, n-butyl, sec-butyl, tert-buty ⁇ , amyl, i-amyl, n-pentyl, n- hexyl, and the like;
  • the "alkenyl” group used either alone or in combination with other radicals is selected from a radical containing from two to eight carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl and the like;
  • the "alkenyl” group includes dienes and trienes of straight and branched chains;
  • alkynyl used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to eight carbon atoms, more preferably thienyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and the like.
  • alkynyl includes di- and tri-ynes
  • cycloalkyl or "alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
  • alkoxy group used either alone or in combination with other radicals is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, i-butoxy, zso-butoxy, pentyloxy, hexyloxy, and the like;
  • haloalkyl group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
  • the "aryl” or “aromatic” group used either alone or in combination with other radicals is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl and the like;
  • heterocyclyl or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2- oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothi
  • heteroaryl or “heteroaromatic” group used either alone or in combination with other radicals is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl,
  • heterocyclylalkyl used either alone or in combination with other radicals, is selected from groups containing an heterocyclyl radical, as defined above, attached directly to an alkyl radical, as define above;
  • cycloalkanylalkyl used either alone or in combination with other radicals, is selected from groups containing a cycloalkyl radical, as defined above, attached directly to an alkyl radical, as define above;
  • heteroaryl radical as defined above, attached directly to an alkyl radical, as define above;
  • Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.
  • the compounds of formula (I) may optionally be converted to their suitable pharmaceutically acceptable salts by processes as are known in the art.
  • the novel compounds of the present invention can further be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • Preferred compounds according to the present invention include but are not limited to:
  • novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms.
  • Such stereoisomers and/or diastereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be within the scope of the present invention.
  • the compound (II) can be obtained using general techniques described in literature for carbocyclic/heterocyclic ring generation (for e.g. in WO2005034837, WO2015140130).
  • the compound (III) can be obtained by reduction of nitro group by using general nitro group reduction techniques described in the literature. Preferred methods involve reduction using stannous chloride and catalytic hydrogenation in solvents like methanol, tetrahydrofuran, etc.
  • the compounds of general formula (IV) can be obtained by several methods described in the literature for the synthesis of N- substituted glycine derivatives.
  • the compounds of the general formula (I) can be obtained by coupling of (III) and (IV) using various amide bond formation techniques as described in for e.g. Tetrahedron 2005, 61, 10827.
  • the compounds of the general formula (VI) can be obtained by coupling of (III) and (V) using various amide bond formation techniques as described in for e.g. Tetrahedron 2005, 61, 10827.
  • the compounds of the general formula (I) are then obtained by oxidation of (VI) using various sulfur oxidation techniques available in literature. Preferred method involves oxidation with oxone in aq. acetone.
  • cheme 3 Synthesis of compounds of general formula (I)
  • PG protecting group such as BOC (tert-butyloxycarbonyl), Cbz (Benzyloxy carbonyl) etc.
  • L leaving group such as CI, Br, etc.
  • the compounds of the general formula (VIII) can be obtained by coupling of (III) and (VII) using various amide bond formation techniques as described in for e.g. Tetrahedron 2005, 61, 10827, followed by removal of PG using various deprotection methods reported in literature. For e.g. BOC group can be removed by acid treatment and Cbz group can be removed by catalytic hydrogenation. The compounds of general formula (VIII) are then reacted with (IX) using various nucleophilic displacement techniques reported in literature to obtained compounds (I).
  • BINAP 2,2'-Bis(diphenylphosphino)-l, r-binaphthyl
  • CDCI 3 Deuterated chloroform
  • CDI ⁇ , ⁇ -Carbonyldiimidazole
  • DIPEA Disopropyl ethyl amine
  • DIBAL-H Diisobutylaluminium hydride
  • LiOH:H 2 0 Lithium hydroxide monohydrate
  • Step 1 ethyl 2-cyano-2-(2,6-dich tate
  • Step 4 l -(2,6-dichloro-4-nitrophen -N'-hydroxycyclopropane- l-carboximidamide
  • Step 5 3-( l -(2,6-dichloro-4-nitrophenyl)cyclopropyl)-5-(4-fluorophenyl)- 1 ,2,4- oxadiazole
  • Step 6 3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)aniline
  • Step 1 1 -(2,6-dichloro-4-nitrophenyl)cyclopropane- 1 -carbaldehyde
  • Step 3 1 -(2,6-dichloro-4-nitrophenyl)-N-(4-fluoro-2-hydroxyphenyl)cyclopropane- 1 - carboxamide
  • Step 4 2-( 1 -(2,6-dichloro-4-nitrophenyl)cyclopropyl)-6-fluorobenzo[d]oxazole
  • Step 2 5-chloro-3-( 1 -(2,6-dichloro-4-nitrophenyl)cyclopropyl)- 1 ,2,4-oxadiazole
  • Step 3 3-(l-(2,6-dichloro-4-nitrophenyl)cyclopropyl)-N,N-dimethyl-l,2,4-oxadiazol-5- amine
  • Step 4 3-(l-(4-amino-2,6-dichlorophenyl)cyclopropyl)-N,N-dimethyl-l,2,4-oxadiazol-5- amine
  • Step 2 N-(4-(ethylsulfonyl)phenyl -2,2,2-trifluoroacetamide
  • Step 3 4-(ethylsulfonyl)-N-(2,2,2-trifluoroethyl)aniline
  • Step 4 ethyl N-(4-(ethylsulfonyl)phenyl)-N-(2,2,2-trifluoroethyl)glycinate
  • Step 5 N-(4-(ethylsulfonyl)phenyl)- -(2,2,2-trifluoroethyl)glycine
  • Step 1 ethyl (4-(ethylsulfonyl)phenyl)glycinate
  • Step 2 ethyl N-(4-(ethylsulfonyl)phenyl)-N-methylglycinate
  • Step 3 N-(4-(ethylsulfonyl)pheny -N-methylglycine
  • Step 1 N-(4-(ethylthio)phenyl)acetamide
  • 4-(ethylthio)aniline 1.0 g, 6.53 mmol
  • DIPEA 1.368 ml, 7.83 mmol
  • acetic anhydride 0.616 ml, 6.53 mmol
  • the reaction mixture was stirred at RT for 1.5 h.
  • the reaction mixture was diluted with EtOAc, washed with water and evaporated under reduced pressure to get 1.10 g of title product as liquid.
  • ESI-MS m/z: 196.05 (M+H) + .
  • Step 3 ethyl N-ethyl-N-(4-(ethylthio)phenyl)glycinate Prepared using product of step 2 and similar procedure as described for the synthesis of ethyl (4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-2.
  • ESI-MS m/z: 268.10 (M+H) + .
  • Step 4 ethyl N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycinate
  • Step 1 N-(cyclopropylmethyl)-4-(ethylthio)aniline
  • Step-2 ethyl N-(cyclopropylmethyl)-N-(4-(ethylthio)phenyl)glycinate
  • Step-3 ethyl N-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)phenyl)glycinate
  • Step-4 N-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)phenyl)glycine
  • Step 2 ethyl N-(4-(ethylthio)phenyl)-N-(oxetan-3-yl)glycinate
  • Step 3 ethyl N-(4-(ethylsulfonyl)phenyl)-N-(oxetan-3-yl)glycinate
  • Step 1 N-(6-(ethylthio)pyridin-3-y -2,2,2-trifluoroacetamide
  • Step 3 ethyl N-(6-(ethylthio)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycinate
  • Step 4 ethyl N-(6-(ethylsulfonyl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycinate
  • Step 5 N-(6-(ethylsulfonyl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycine
  • Step 1 l-(indolin-l-yl)ethan-l-one
  • Step 2 l-acetylindoline-5-sulfonyl chloride
  • Step 4 l-(5-(ethylsulfonyl)indolin-l-yl)ethan-l-one
  • Step 6 ethyl 2-(5-(ethylsulfonyl)indolin-l-yl)acetate
  • Step 7 2-(5-(ethylsulfonyl)indoli -l-yl)acetic acid
  • Step-3 2-(5-(methylsulfonyl)-lH-indol-l-yl)acetic acid
  • Step 1 5-(ethylthio)-lH-indazole
  • 5-bromo-lH-indazole (0.500 g, 2.54 mmol) and copper (I) iodide (0.967 g, 5.08 mmol) in N-Methyl-2-pyrrolidinone (17.0 ml)
  • sodium ethanefhiolate 0.27 g, 5.08 mmol
  • reaction mixture was stirred at 150°C for 1 h. After complete conversion of starting material, reaction mixture was cooled to 25 °C and diluted with 50 ml of EtOAc.
  • Step 2 ethyl 2-(5-(ethylthio)-lH-indazol-l-yl)acetate
  • Step 1 tert-butyl (2-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)amino)- -oxoethyl)(methyl)carbamate
  • Step 2 N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl) phenyl)-2-(methylamino)acetamide hydrochloride
  • Step 3 N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide
  • Step 1 N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-(5-(ethylthio)-lH-indazol-l-yl)acetamide
  • Step 2 N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-(5 -(ethylsulf onyl)- 1 H-indazol- 1 -yl)acetamide
  • RORyt (zRORyt) inhibitors were screened in RORE (RORyt Response Element) based Luciferase assay by transient transfection of 5X RORE (5 tandem repeats of RORyt Response Element) and full length human RORyt together in COS-7 cells.COS-7 cells were maintained as monolayer in complete DMEM (High Glucose) medium in presence of 2mM Glutamin and IX Sodium Pyruvate. Day before transfection, 15000 cells were seeded in 96 well cell culture plate in ⁇ antibiotic free medium and incubated at 37°C in 5% C0 2 containing humidified chamber O/N.
  • Transfection complex for the required numbers of wells were prepared from pGL2- promoter-5XRORE-Luc plasmid, pcDNA3.1 (+)- zRORyt expression plasmid, ⁇ -GAL plasmid (transfection control), and Lipofectamine 3000 (Invitrogen). 50 ⁇ 1 of transfection complex were added in ⁇ of complete medium to respective wells, mixed gently and plate was incubated for 5-6 h at 37°C in 5% C0 2 containing humidified chamber.
  • novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of formula (I) or pharmaceutical compositions containing them are useful as RORy modulators suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with autoimmune diseases.
  • composition is provided by employing conventional techniques.
  • composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.
  • the quantity of active component that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • the present invention of formula (I) can be coadministered in combination with one or more suitable pharmaceutically active agents.
  • the pharmaceutical compositions of the invention can be coadministered with or can include one or more other therapeutic compounds or adjuvants, such as but not limited to other (1) TNF-a Inhibitors; (2) non-selective COX-l/COX-2 inhibitors; (3) COX-2 inhibitors (4) other agents for inflammatory and autoimmune disease including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquin, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostate-B, BAFF/

Abstract

La présente invention concerne des composés qui sont des modulateurs de RORγ et leur utilisation pour le traitement de maladies ou d'affections médiées par RORγ. La présente invention concerne en outre des procédés de préparation de ces composés, leurs formes tautomères, de nouveaux intermédiaires impliqués dans leur synthèse, leurs sels pharmaceutiquement acceptables, des procédés d'utilisation de ces composés et des compositions pharmaceutiques les contenant.
PCT/IB2017/054240 2016-07-14 2017-07-13 Composés polycycliques en tant que modulateurs de ror-gamma WO2018011747A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113527172A (zh) * 2020-04-21 2021-10-22 上海交通大学医学院附属仁济医院 M2乙酰胆碱受体拮抗剂及其用途
US11208407B2 (en) * 2017-08-02 2021-12-28 Merck Sharp & Dohme Corp. Substituted phenyl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors

Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005034837A2 (fr) 2003-10-08 2005-04-21 Cardiome Pharma Corporation Composés à structure imidazo et leurs utilisations
WO2012027965A1 (fr) 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012100734A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Composés utiles en tant que modulateurs du récepteur apparenté au récepteur des rétinoïdes gamma
WO2012100732A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Modulateurs des récepteurs orphelins gamma apparentés au récepteur des rétinoïdes, composition les contenant et utilisations associées
WO2013029338A1 (fr) 2011-09-01 2013-03-07 Glaxo Group Limited Nouveaux composés
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
WO2014179564A1 (fr) 2013-05-01 2014-11-06 Vitae Pharmaceuticals, Inc. Inhibiteurs du ror-gamma à base de thiazalopyrrolidine
WO2015083130A1 (fr) 2013-12-06 2015-06-11 Aurigene Discovery Technologies Limited Pyridine et dérivés de pyrimidine à l'état fondu à titre de modulateurs ror gamma
WO2015082533A1 (fr) * 2013-12-05 2015-06-11 Lead Pharma Cel Models Ip B.V. Modulateurs du ror gamma (rory)
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
WO2015116904A1 (fr) 2014-02-03 2015-08-06 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror-gamma à base de dihydropyrrolopyridine
WO2015140130A1 (fr) 2014-03-17 2015-09-24 Remynd Nv Composés d'oxadiazole
WO2015145371A1 (fr) 2014-03-27 2015-10-01 Piramal Enterprises Limited Modulateurs de ror-gamma et leurs utilisations
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
WO2016193461A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rorγ)
WO2016193470A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)
WO2016193459A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)
WO2016193452A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rorγ)
WO2016193468A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)
WO2017024018A1 (fr) 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
WO2017087608A1 (fr) 2015-11-20 2017-05-26 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005034837A2 (fr) 2003-10-08 2005-04-21 Cardiome Pharma Corporation Composés à structure imidazo et leurs utilisations
WO2012027965A1 (fr) 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
WO2012100734A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Composés utiles en tant que modulateurs du récepteur apparenté au récepteur des rétinoïdes gamma
WO2012100732A1 (fr) 2011-01-24 2012-08-02 Glaxo Group Limited Modulateurs des récepteurs orphelins gamma apparentés au récepteur des rétinoïdes, composition les contenant et utilisations associées
WO2013029338A1 (fr) 2011-09-01 2013-03-07 Glaxo Group Limited Nouveaux composés
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
WO2014179564A1 (fr) 2013-05-01 2014-11-06 Vitae Pharmaceuticals, Inc. Inhibiteurs du ror-gamma à base de thiazalopyrrolidine
WO2015082533A1 (fr) * 2013-12-05 2015-06-11 Lead Pharma Cel Models Ip B.V. Modulateurs du ror gamma (rory)
WO2015083130A1 (fr) 2013-12-06 2015-06-11 Aurigene Discovery Technologies Limited Pyridine et dérivés de pyrimidine à l'état fondu à titre de modulateurs ror gamma
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
WO2015116904A1 (fr) 2014-02-03 2015-08-06 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror-gamma à base de dihydropyrrolopyridine
WO2015140130A1 (fr) 2014-03-17 2015-09-24 Remynd Nv Composés d'oxadiazole
WO2015145371A1 (fr) 2014-03-27 2015-10-01 Piramal Enterprises Limited Modulateurs de ror-gamma et leurs utilisations
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
WO2016193461A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rorγ)
WO2016193470A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)
WO2016193459A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)
WO2016193452A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rorγ)
WO2016193468A1 (fr) 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)
WO2017024018A1 (fr) 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
WO2017087608A1 (fr) 2015-11-20 2017-05-26 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
HE, Y.-W.; DEFTOS, M. L., OJALA, IMMUNITY, vol. 9, 1998, pages 797 - 806
HIROSE, T.; SMITH, R. J., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 205, 1994, pages 1976 - 1983
IVANOV, I. I.; MCKENZIE, B. S.; ZHOU, L., CELL, vol. 126, 2006, pages 1121 - 1133
JETTEN, NUCL. RECEPL SIGNAL, vol. 7, 2009, pages e003
MANEL ET AL., NAT. IMMUNOL., vol. 9, 2008, pages 641 - 649
TETRAHEDRON, vol. 61, 2005, pages 10827

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11208407B2 (en) * 2017-08-02 2021-12-28 Merck Sharp & Dohme Corp. Substituted phenyl compounds as indoleamine 2,3-dioxygenase (IDO) inhibitors
CN113527172A (zh) * 2020-04-21 2021-10-22 上海交通大学医学院附属仁济医院 M2乙酰胆碱受体拮抗剂及其用途

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