WO2017199103A1 - Composés de benzamide comme modulateurs gamma ror - Google Patents

Composés de benzamide comme modulateurs gamma ror Download PDF

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WO2017199103A1
WO2017199103A1 PCT/IB2017/050368 IB2017050368W WO2017199103A1 WO 2017199103 A1 WO2017199103 A1 WO 2017199103A1 IB 2017050368 W IB2017050368 W IB 2017050368W WO 2017199103 A1 WO2017199103 A1 WO 2017199103A1
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chlorophenyl
phenyl
methyl
ethyl
ethylsulfonyl
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Sanjib Das
Laxmikant Atmaram Gharat
Rajendra Laxman HARDE
Abraham Thomas
Neelima Khairatkar-Joshi
Daisy Manish Shah
Malini Bajpai
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present patent application is directed to aryl amide compounds which may be useful as retinoid-related orphan receptor gamma t (RORyt) modulators.
  • RORs Retinoid-related orphan receptors
  • the ROR family consists of three members, ROR alpha (RORa), ROR beta (ROR ⁇ ) and ROR gamma (RORy), also known as NR1F1, NR1F2 and NR1F3 respectively (and 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, RORyl and RORyt (also known as RORy2) have been identified.
  • RORyt is a truncated form of RORy, lacking the first N-terminal 21 amino acids and is exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al., Science, 2000, 288, 2369-2372; Eberl et al., Nat Immunol., 2004, 5: 64-73) in contrast to RORy which is expressed in multiple tissues (heart, brain, kidney, lung, liver and muscle).
  • Thl7 cells are a subset of T helper cells which produce IL- 17 and other proinflammatory cytokines and 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 have also been associated in the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten et al., Nucl. Recept. Signal, 2009, 7:e003; Manel et al., Nat.
  • 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., Annu. Rev. Immunol., 2009, 27:485-517) and RORyt has been shown to play a critical role in the pathogenic responses of Thl7 cells (Ivanov et al., Cell, 2006 126: 1121-1133). RORyt deficient mice have shown no Thl7 cells and also resulted in amelioration of EAE. The genetic disruption of RORy in a mouse colitis model also prevented colitis development (Buonocore et al., Nature, 2010, 464: 1371- 1375).
  • RORyt is also shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al., J Immunol, 2010, 184: 3336-3340).
  • RORyt expression and secretion of Thl7-type of cytokines has also been reported in NK T-cells (Eberl et al., Nat. Immunol, 2004, 5: 64-73) and gamma-delta T-cells (Sutton et al, Nat. Immunol, 2009, 31: 331-341; Louten et al., J Allergy Clin. Immunol, 2009, 123: 1004-1011), suggesting an important function for RORyt in these cells.
  • the present application is directed to compounds that are modulators of the RORyt receptor.
  • the present invention relates to compound of formula (I)
  • Ring A is selected from C 6-14 aryl, 5 to 14 membered heteroaryl and C 3-6 cycloalkyl;
  • R 1 is selected from C 1-8 alkyl and haloC 1-8 alkyl
  • each occurrence of R 2 is independently selected from halogen, hydroxyl, cyano, C 1- 8 alkyl, C 1-8 alkoxy, haloC 1-8 alkyl, haloC 1-8 alkoxy, hydroxyC 1-8 alkyl and C 3-6 cycloalkyl;
  • R 3 is independently selected from hydrogen, C 1-8 alkyl, haloC 1-8 alkyl and C 3 - 6 cycloalkylC 1-8 alkyl;
  • R 4 is independently selected from C 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkyl, hydroxyC 1- ealkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-8 alkyl, 3- to 15- membered heterocyclyl and C 6-14 aryl; wherein C 3 -6cycloalkyl and C 6-14 aryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano or C 1-8 alkyl; or R 4 along with the carbon atom to which it is attached form a bicyclic ring along with ring A; wherein bicyclic ring may be carbocyclic ring or 5- to 15- heterocyclyl ring;
  • each occurrence of R 5 is independently selected from halogen, cyano, hydroxyl and C 1-
  • 'n' is 0, 1, 2 or 3;
  • 'p' is 0, 1 or 2.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (II) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein R 1 is -C2H5 (according to an embodiment defined below); R 2 is ⁇ F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl (according to another embodiment defined below); ' ⁇ ' is 0, 1 or 2 (according to yet another embodiment defined below); and 'p' is 0 or 1 (according to yet another embodiment defined below).
  • ring A is C 6-14 aryl (e.g. phenyl) or C 3-6 cycloalkyl (e.g. cyclohexyl).
  • R 1 is C 1-8 alkyl (e.g. methyl or ethyl).
  • R 2 is halogen (e.g. F, CI, Br or I), C 1-8 alkyl (e.g. methyl, ethyl, isopropyl, isobutyl or tert-butyl), haloC 1-8 alkyl (e.g. trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl) or C3- 6cycloalkyl (e.g. cyclopropyl, cyclobutyl or cyclopentyl).
  • R 2 is halogen (e.g. F, CI, Br or I), C 1-8 alkyl (e.g. methyl, ethyl, isopropyl, isobutyl or tert-butyl), haloC 1-8 alkyl (e.g. trifluoromethyl, difluoromethyl or 2,2,2-trifluoroethyl) or C3- 6cycloalkyl (e.g. cyclopropy
  • R 2 is -F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl.
  • R 2 is -F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl and 'n' is 1 or 2.
  • R 3 is hydrogen, C 1- 4alkyl (e.g. methyl or ethyl), haloC 1-8 alkyl (e.g. 2,2,2- trifluoroethyl) or C 3-6 cycloalkylC 1-8 alkyl (e.g. cyclopropylmethyl).
  • R 3 is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl.
  • R 4 is C 1- 4alkyl (e.g. methyl, ethyl, n-propyl or 1-methylethyl), haloC 1-8 alkyl (e.g.
  • hydroxyC 1-8 alkyl e.g. 1-hydroxyethyl
  • C 3-6 cycloalkyl e.g.
  • 6cycloalkyl and C 6-14 aryl are optionally substituted with one or more substituents selected from halogen (e.g. CI, F or Br) and C 1-8 alkyl (e.g. methyl).
  • halogen e.g. CI, F or Br
  • C 1-8 alkyl e.g. methyl
  • R 4 is methyl, ethyl, n-propyl, 1-methylethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,
  • ring A is phenyl or cyclohexyl
  • R 1 is ethyl
  • R 2 is -F, -CI, methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl or cyclopropyl;
  • R 3 is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl; methyl, ethyl, n-propyl, 1-methylethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,
  • R 5 is F
  • 'n' is 0, 1 or 2;
  • 'p' is 0 or 1.
  • R 1 is ethyl
  • R 3 is hydrogen methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl
  • R 4 is methyl, ethyl, n-propyl, 1-methylethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,
  • R 5 is F; is cyclohexyl, 4,4-difluorocyclohexyl, phenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4- isopropylphenyl, 4-isobutylphenyl, 4-(tert-butyl)phenyl, 3,5-dimethylphenyl, 2-chloro-4- methylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 4- (trifluoromethyl)phenyl or 4-cyclopropylphenyl; and
  • 'p' is O or l.
  • R 1 is ethyl
  • R 3 is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl
  • R 5 is F; is (1R)-l-phenylethyl, (1S)-l-phenylethyl, (1R)-l-phenylpropyl, (1S)-l-phenylpropyl, (1R)-l-(o-tolyl)ethyl, , (1S)-l-(o-tolyl)ethyl, (1R)-l-(o-tolyl)propyl, (1R)-l-(p-tolyl)ethyl, (1R)-l-(p-tolyl)propyl, (1R)-l-(4-ethylphenyl)ethyl, (1R)-l-(4- isopropylphenyl)ethyl, ( 1R)- 1 -(4-isobutylphenyl)ethyl, ( 1R)- 1 -(4-(tert-butyl)phenyl)ethyl, (1R)-l-(3,
  • 'p' is 0 or 1.
  • the compounds of formula (I) may be (R)- or (S)- enantiomer or the racemate.
  • the compound of formula (I) is the (R)-enantiomer.
  • the definition of "compounds of formula (I)” inherently includes all stereoisomers of the compound of formula (I) either as pure stereoisomer or as a mixture of two or more stereomers.
  • stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.
  • the compounds of formula (I) is a compound that may exist in the form of one or more stereoisomers, wherein one or more of those steroisomers is therapeutically active.
  • the compounds of formula (I) comprises a therapeutically active stereoisomer that is substantially free of other stereoisomers. According to yet another embodiment, compounds of formula (I) comprises a therapeutically active stereoisomer that has less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, or less than about 1% by weight of other steroisomers.
  • compounds of formula (I) with an ICso value of less than 1000 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to RORyt activity.
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • Ring A is selected from C 6-14 aryl, 5 to 14 membered heteroaryl and C 3-6 cycloalkyl;
  • R 1 is selected from C 1-8 alkyl and haloC 1-8 alkyl;
  • each occurrence of R 2 is independently selected from halogen, hydroxyl, cyano, Cl- 8alkyl, C 1-8 alkoxy, haloC 1-8 alkyl, haloC 1-8 alkoxy, hydroxylC 1-8 alkyl and C 3-6 cycloalkyl;
  • each occurrence of R 5 is independently selected from halogen, cyano, hydroxyl and C 1- 8 alkyl;
  • R 6 is independently selected from C 1-8 alkyl
  • R 7 is independently selected from haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 3-6 cycloalkyl, C3- 6cycloalkylC 1-8 alkyl, 3- to 15- membered heterocyclyl and C 6-14 aryl; wherein C 3-6 cycloalkyl and C 6-14 aryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano or C 1-8 alkyl; or R 7 along with the carbon atom to which it is attached form a bicyclic ring along with ring A; wherein bicyclic ring may be carbocyclic ring or 5- to 15- heterocyclyl ring;
  • 'n' is 0, 1, 2 or 3;
  • 'p' is 0, 1 or 2.
  • the compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (II) as defined above wherein R 1 is - ethyl (according to an embodiment defined below); R 2 is -CI or methyl (according to another embodiment defined below); and 'n' is 1 or 2 (according to yet another embodiment defined below).
  • ring A is C 6-14 aryl (e.g. phenyl).
  • R 1 is C 1-8 alkyl (e.g. methyl or ethyl).
  • R 2 is halogen (e.g. F, CI, Br or I) or C 1-8 alkyl (e.g. methyl, ethyl, isopropyl, isobutyl or f erf-butyl).
  • halogen e.g. F, CI, Br or I
  • C 1-8 alkyl e.g. methyl, ethyl, isopropyl, isobutyl or f erf-butyl.
  • R 5 is halogen (e.g. F or CI)
  • R 7 is haloC 1-8 alkyl (e.g. 2,2,2-trifluoroethyl), hydroxyC 1-8 alkyl (e.g. 1-
  • salkyl e.g. 3- to 15- membered heterocyclyl (e.g. or C 6-14 aryl (e.g. or
  • C 3-6 cycloalkyl and C 6-14 aryl are optionally substituted with one or more substituents selected from halogen (e.g. CI, F or Br) and C 1-8 alkyl (e.g. methyl).
  • halogen e.g. CI, F or Br
  • C 1-8 alkyl e.g. methyl
  • ring A is phenyl
  • R 1 is ethyl
  • R 2 is -CI or methyl
  • R 5 is F
  • R 6 is -CH3 or -CH 2 CH3;
  • R 7 is 2-hydroxyethyl, 2,2,2-trifluoroethyl,
  • 'n' is 1 or 2;
  • R 1 is ethyl
  • R 5 is F
  • R 6 is -CH3 or -CH 2 CH3;
  • R 7 is 2-hydroxyethyl, 2,2,2-trifluoroethyl,
  • R 1 is ethyl
  • R 3 is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl or cyclopropylmethyl
  • R 5 is F; is (1R)-(4-chlorophenyl)(4,4-difluorocyclohexyl)methyl, (1R)-l- (4-chlorophenyl)-3 ,3 ,3-trifluoropropyl, ( 1R)- 1 -(4-chlorophenyl)-2-cyclopropylethyl, ( 1R)-(2- chloro-4-methylphenyl)(phenyl)methyl, ( 1R)-(4-chlorophenyl)(phenyl)methyl, ( 1R)-(4- chlorophenyl)(p-tolyl)methyl, (1R)-(4-chlorophenyl)(cyclohexyl)methyl, (1R)-(4- chlorophenyl)(cyclopropyl)methyl, ( 1R)-(4-chlorophenyl)(cyclobutyl)methyl, ( 1R)-(4- chlorophenyl)(cyclopent
  • the compounds of formula (II) may be (R)- enantiomer.
  • the compounds of formula (II) comprises a therapeutically active R-enantiomer that is substantially free of other S-enantiomer.
  • compounds of formula (II) comprises a therapeutically active R-enantiomer that has less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, or less than about 1% by weight of other S-enantiomer.
  • the definition of "compounds of formula (II)” inherently includes all stereoisomers of the compound of formula (II) either as pure stereoisomer or as a mixture of two or more stereomers.
  • stereoisomers includes enantiomers, diasteroisomers, racemates, cis isomers, trans isomers and mixture thereof.
  • compounds of formula (II) that exhibit an IC50 value with respect to RORyt activity of less than about 1000 nM, preferably less than about 100 nM, more preferably less than about 50 nM.
  • Compounds of the present invention include the compounds in Examples 1-54.
  • the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of RORyt.
  • the present invention further provides a method of inhibiting RORyt in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
  • the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as autoimmune disease, inflammatory disease, respiratory disorders, pain and cancer comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.
  • a disease, disorder or condition modulated by RORyt such as autoimmune disease, inflammatory disease, respiratory disorders, pain and cancer
  • the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease, comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.
  • COPD chronic obstructive pulmonary disease
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C 1-8 alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • C 1- 6alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • C 1- 4alkyl refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C 1-8 alkoxy).
  • Representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloC 1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups.
  • haloC 1- 4alkyl refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC 1-8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched.
  • hydroxyC 1-8 alkyl refers to a C 1-8 alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC 1- 4alkyl).
  • hydroxyC 1- 4alkyl moieties include, but are not limited to - CH2OH and -C2H4OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-i2cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • C 3-6 cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms.
  • Examples of “C3- 6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C 3-6 cycloalkylC 1-8 alkyl).
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • carbocyclic ring refers to a ring composed exclusively of 3 to IS carbon atoms, including C 6-14 aryl or C3-i2cycloalkyl ring defined herein.
  • the carbocyclic ring may be saturated or unsaturated.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6-14 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • heteroaryl refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl).
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrirnidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl
  • heterocyclyl or “heterocyclic ring” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3- to IS- membered heterocyclyl ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazohdinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of formula (I) or (II) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I) or (II) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by the reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolysing
  • Enantiomers can also be separated by use of chiral HPLC column.
  • the chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974.
  • salt or “solvate”, and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, ro tamers, tautomers, positional isomers or racemates of the inventive compounds.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • the pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
  • compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of route of administration, such as orally or parenterally.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • the compounds of the present invention are particularly useful because they inhibit the activity of retinoid-related orphan receptor gamma, particularly retinoid -related orphan receptor gamma t (RORyt), i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit a RORyt modulating effect.
  • RORyt retinoid-related orphan receptor gamma
  • Compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of ROR gamma activity, and particularly RORyt, is required.
  • the compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt.
  • autoimmune diseases will be understood by those skilled in the art to refer to a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
  • An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ, and changes in organ function.
  • An autoimmune disorder may affect one or more organ or tissue types which include, but are not limited to, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin.
  • autoimmune (or autoimmune-related) disorders include multiple sclerosis, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic obstructive pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease, allergy, osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease - spru
  • inflammation will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white.
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other farms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this present patent application, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may be used for treatment of arthritis, including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
  • arthritis including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
  • the compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • bronchospasm bronchospasm
  • cough cough
  • respiratory disorders include, but are not limited to, bronchitis, bronchiolitis, bronchiectasis, acute nasoparyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory
  • the compounds of the present invention may also be used for treatment of pain conditions.
  • the pain can be acute or chronic pain.
  • the compounds of the present invention may be used for treatment of e.g., inflammatory pain, arthritic pain, neuropathic pain, postoperative pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns; migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, viral, parasitic or bacterial infection, posttraumatic injury, or pain associated with irritable bowel syndrome.
  • the compounds of the present invention may further be used for treatment of gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
  • gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
  • the compounds of the present invention may be useful in the treatment of cancer, and pain associated with cancer.
  • cancers include, e.g., multiple myeloma and bone disease associated with multiple myeloma, melanoma, medulloblastoma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, hepatocellular carcinoma, gastric cancer, bladder carcinoma and colon cancer.
  • the compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease.
  • COPD chronic obstructive pulmonary disease
  • Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula I, (la) or (lb), or a pharmaceutically-acceptable salt thereof, to a subject (particularly a human) in need thereof.
  • the present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by RORyt.
  • the compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.
  • the daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg.
  • a suitable coupling agent such as EDCI and optional presence of HOBt, DCC, T3P or HATU
  • the reaction may be optionally carried out in the presence of suitable base selected from Et3N, DIPEA, pyridine or DMAP.
  • suitable solvent for the reaction may be selected from CH2CI2, CHCI3, DMF or mixture thereof.
  • the reaction may be carried out in a suitable solvent selected from CH 2 CI 2 , CHCI 3 , DMF and THF or combination thereof.
  • the N-alkylation of compound of formula (6) with an alkylating agent of formula (7) (wherein X is halogen) using a base such as sodium hydride in a solvent, like THF, DMF, etc. affords the nitro benzamide derivative of formula (8).
  • the reduction of nitro group of compound of formula (8) using iron powder in the presence of aqueous acetic acid or ammonium chloride furnishes the corresponding amine compound of formula (la).
  • the reduction reaction may be carried out in suitable solvent selected from ethanol, water or combination thereof.
  • a suitable dehydrating agent eg. titanium (VI) isopropoxide or titanium (VI) ethoxide
  • a suitably substituted imine compound of formula (R or S)-(H') can be prepared by condensation of appropriately substituted aryl aldehyde (9') with (R or S)-2-methylpropane-2-sulfinamide (10) in the presence of a suitable base such as cesium carbonate in a solvent such as dichloromethane, which on futher reaction with Grignard reagent of formula R 4 MgX gives substantially pure (R,R) or (S,S)-(12) diastereomer after chromatographic purification (WO 2012177893, 2012).
  • R 1 , R 2 , R 3 , R 5 , n and p are as defined with respect to a compound of formula (I) and R 8 is C 1- 8 alkyl) is depicted in the Synthetic Scheme 4.
  • Acid catalyzed removal of chiral auxiliary gives amino compound of formula (24) with two chiral centers, as a salt of the corresponding acid (e.g. HQ).
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent.
  • the purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • Step 1 intermediate 100 mg, 0.64 mmol
  • THF 6.0 mL
  • 4-nitrobenzoyl chloride 132 mg, 0.70 mmol
  • the reaction mixture was stirred for 2 h at room temperature.
  • the reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated ammonium chloride solution (20 mL).
  • the organic layer was washed with water (30 mL) and dried over anhydrous sodium sulfate.
  • the residue thus obtained was purified by silica gel column chromatography to yield 152 mg of titled compound.
  • *H NMR 300 MHz, DMSO-rfe
  • Step 2 intermediate 300 mg, 0.98 mmol
  • ammonium chloride 527 mg, 9.84 mmol
  • Iron powder 165 mg, 2.95 mmol
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2).
  • the combined organic layers were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated to obtain 255 mg of the titled product.
  • Step 1 intermediate (1.02 g, 5.68 mmol) in 1,4-dioxane (10 mL) was added 60% aqueous sulfuric acid (10 mL) at RT and the mixture was stirred overnight at 120 °C. The mixture was cooled to RT and quenched with ice cold water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with water (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography to afford 651 mg of the titled compound.
  • *H NMR 300 MHz, CDCb) ⁇ 1.59 (s, 7H), 7.24-7.28 (m, 3H), 7.38 (s, 1H); APCI-MS (m/z) 202 (M+H) + .
  • Step 2 intermediate To a stirred solution of Step 2 intermediate (403 mg, 2.02 mmol) in dichloromethane (5 mL) were added diphenylphosphoryl azide (837 mg, 3.04 mmol) and triethylamine (910 mg, 4.05 mmol) at RT. The mixture was stirred for 3 h at RT. The reaction was quenched with ice cold water (50 mL), acidified with HC1 till pH 2 and extracted with dichloromethane (100 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated to give the acyl azide.
  • the acyl azide obtained was dissolved in tert-butanol (10 mL) and refluxed overnight under stirring. The mixture was cooled to RT and concentrated under reduced pressure to yield 562 mg of the titled product. The crude product obtained was used as such for next step.
  • Step 4 2-(3-Chlorophenyl)propan-2-amine trifluoroacetic acid To a stirred solution of Step 3 intermediate (562 mg, 2.08 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (3.0 mL) at 0 °C. The resulting mixture was stirred at RT for 3 h. The solvent was evaporated under reduced pressure to obtain 310 mg of the titled compound. The crude product obtained was used as such for next step.
  • Step 4 intermediate 310 mg, 1.07 mmol
  • dichloromethane 10 mL
  • emylamine 819 mg, 8.10 mmol
  • DMAP 20 mg, 0.16 mmol
  • 4- nitrobenzoyl chloride 301 mg, 1.62 mmol
  • the mixture was stirred overnight at room temperature.
  • the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated ammonium chloride solution (20 mL).
  • the organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step S intermediate (249 mg, 0.78 mmol) in dry DMF (3.0 mL) was added sodium hydride (60% w/w, 40 mg, 1.01 mmol) at 0 °C followed by methyl iodide (165 mL, 1.17 mmol) and stirring continued for 15 min.
  • the resultant suspension was stirred at RT for 2h.
  • the mixture was quenched with cold water (5 mL), the precipitate obtained was filtered and dried under vacuum to afford 213 mg of the titled compound.
  • Step 7 4-Ammo-N-[2-(3-chlorophenyl)propan-2-yl]-N-methylbenzamide
  • Step 6 intermediate 204 mg, 0.61 mmol
  • ammonium chloride 324 mg, 6.13 mmol
  • a mixture of ethanol and water 3:1, 10 mL
  • iron powder 102 mg, 1.83 mmol
  • the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (50 mL x 2).
  • the combined organic layers were washed with water (40 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step 1 l-(3-Chloro phenyl)ethanamine
  • the titled compound was prepared by the reaction of Step 1 intermediate (201 mg, 1.29 mmol) with 4-nitrobenzoyl chloride (287 mg, 1.54 mmol) in the presence of triethylamine (390 mg, 3.87 mmol) and DMAP (16 mg, 0.29 mmol) in dichloromethane (10 mL) at 0 °C as per the procedure described in step 5 of Intermediate 2 to yield 208 mg of the product.
  • Step 3 N- [ 1 -(3 -Chlorophenyl)ethyl] -N-methyl-4-nitrobenzamide
  • the titled compound was prepared by the reaction of Step 2 intermediate (203 mg, 0.67 mmol) with methyl iodide (63 mL, 1.00 mmol) using sodium hydride (60% w/w, 34 mg, 0.86 mmol) in dry DMF (5.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 208 mg of the desired product.
  • Step 4 4-Ammo-N-[l-(3-chlorophenyl)ethyl]-N-methylbenzamide
  • the titled compound was prepared by the nitro reduction of Step 3 intermediate (202 mg, 0.63 mmol) using iron powder (106 mg, 1.90 mmol) and ammonium chloride (339 mg, 6.33 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C as per the procedure described in step 7 of Intermediate 2 to yield 132 mg of the product.
  • Step 1 N-((R)- l-(3-Chloro phenyl)emyl)-2-methylpropane-2-sulfinamide
  • Step 2 (R)- 1 -(3 -Chloro phenyl)emanarnine hydrochloride
  • Step 1 intermediate To an ice cold solution of Step 1 intermediate (311 mg, 1.14 mmol) in diethyl ether (10 mL) was added 4 M HC1 in dioxane (2.85 mL, 11.43 mmol) at RT. The resulting mixture was stirred at 0 °C for lh. The solvent was evaporated under reduced pressure and the residue thus obtained was dried under vacuum to obtain 231 mg of the titled compound.
  • the titled compound was prepared by the reaction of Step 2 intermediate (503 mg, 3.23 mmol) with 4-nitrobenzoyl chloride (719 mg, 3.87 mmol) in the presence of triethylamine (1.36 g, 9.77 mmol) and DMAP (39 mg, 0.32 mmol) in dichloromethane (10 mL) at 0 °C as per the procedure described in step 5 of Intermediate 2 to yield 712 mg of the product.
  • Step 4 N-[(1R)-l-(3-Chloro phenyl)ethyl]-N-methyl-4-nitrobenzamide
  • the titled compound was prepared by the reaction of Step 3 intermediate (256 mg, 0.84 mmol) with methyl iodide (178 mg, 1.26 mmol) using sodium hydride (60% w/w, 44 mg, 1.09 mmol) in dry DMF (4 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 203 mg of the desired product.
  • Step 5 4-Ammo-N-[(1R)-l-(3-Chlorophenyl)emyl]-N-methylbenzamide
  • the titled compound was prepared by the nitro reduction of Step 4 intermediate (198 mg, 0.62 mmol) using iron powder (104 mg, 1.86 mmol) and ammonium chloride (332 mg, 6.21 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C as per the procedure described in step 7 of Intermediate 2 to yield 127 mg of the product.
  • Step 1 intermediate (1.71 g, 8.80 mmol) and the resultant mixture was stirred at RT for 2 h.
  • the reaction mixture was quenched with saturated aqueous solution of ammonium chloride, diluted with ethyl acetate and filtered through celite bed. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 1.65 g of titled product.
  • Step 2 intermediate 1.4 g, 8.42 mmol
  • dichloromethane 100 mL
  • Dess-Martin periodinane 3.57 g, 8.42 mmol
  • the mixture was stirred at RT for 2 h.
  • the reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution, water and brine.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to obtain 682 mg of titled product.
  • Step 4 (5)-N-((S)-2-(Benzyloxy)propyMene)-2-methylpropane-2-sulfinamide
  • the titled compound was prepared by the reaction of Step 3 intermediate (680 mg, 4.14 mmol) with (S)-(-)-2-methyl-2-propanesulfmamide (553 mg, 4.56 mmol) using titanium (VI) isopropoxide (1.84 g, 6.58 mmol) in THF (30 mL) as per the procedure described in the Step 1 of Intermediate 4 to yield 798 mg of the product.
  • Step 5 (5)-N-((1S,2S)-2-(Benzyloxy)- l-(p-tolyl)propyl)-2-methylpropane-2-sulfmarnide
  • Step 4 intermediate 510 mg, 1.91 mmol
  • anhydrous toluene (20 mL) at -78 °C was added /j-tolylmagnesium bromide (lAf, 3.8 mL, 3.81 mmol) and the reaction was stirred for 3h at -78 °C.
  • the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 x 50 mL).
  • the combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated.
  • the residue was purified by silica gel column chromatography to yield 402 mg of the titled compound.
  • Step 5 intermediate 400 mg, 1.11 mmol
  • methanol 15 mL
  • 4Af HC1 in 1,4-dioxane 1.4 mL, 5.56 mmol
  • the solvents were evaporated under reduced pressure and the residue obtained was triturated twice with n-pentane (5 mL). The solid was filtered and dried under vacuum to yield 257 mg of the desired product.
  • Step 7 N-((1S,2S)-2-(benzyloxy)-l-(p-tolyl)rffopyl)-4-nitrobenzamide
  • the titled compound was prepared by the reaction of Step 6 intermediate (245 mg, 0.84 mmol) with 4-nitrobenzoyl chloride (187 mg, 1.00 mmol) in the presence of triethylamine (425 mg, 4.19 mmol) in dichloromethane (20 mL) at RT as per the procedure described in step 5 of Intermediate 2 to yield 308 mg of the product.
  • Step 8 N-((1S,2S)-2-(Benzyloxy)-l-(p-tolyl ⁇
  • the titled compound was prepared by the reaction of Step 7 intermediate (300 mg, 0.74 mmol) with methyl iodide (126 mg, 0.89 mmol) using sodium hydride (60% w/w, 44 mg, 1.11 mmol) in DMF (5.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 208 mg of the product.
  • the titled compound was prepared by the nitro reduction of Step 8 intermediate (100 mg, 0.23 mmol) using iron powder (67 mg, 1.19 mmol) and ammonium chloride (128 mg, 2.39 mmol) in a mixture of ethanol and water (5:1, 18 mL) at 90 °C as per the procedure described in step 7 of Intermediate 2 to yield 83 mg of the product.
  • the crude product obtained was used as such for next step.
  • ESI-MS (m z) 389 (M+H) + The structure, chemical name and analytical data of the intermediates prepared by following the procedure described in Intermediate 13 are given in Table 2.
  • Step 1 (R)-N-(2-chloro -4-methylbenzylidene)-2-methylpropane-2-sulfinamide
  • Step 2 (R)-N-((R)-(2-Chloro -4-methylphenyl)(phenyl)methyl)-2-methylpropane-2- sulfinamide
  • phenylmagnesium bromide (1.57 mL, 4.72 mmol) and the reaction was stirred at 0 °C for lh.
  • the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 2).
  • Step 3 (R)- 1 -(2-Chloro-4-methylphenyl)- 1 -phenylmethanamine hydrochloride
  • Step 2 intermediate To an ice cooled solution of Step 2 intermediate (391 mg, 1.16 mmol) in diethyl ether (5 mL) was added 4Af HC1 in dioxane (3 mL, 11.67 mmol) at RT and the resulting mixture was stirred for lh. The solvents were evaporated under reduced pressure and the residue obtained was triturated with diethyl ether (5 mL). The solid was filtered and dried under vacuum to yield 331 mg of the desired product.
  • Step 4 (R)-N-((2-Chloro -4-methylphenyl)(phenyl)methyl)-4-nitrobenzamide
  • the titled compound was prepared by the reaction of Step 3 intermediate (320 mg, 1.19 mmol) with 4-nitrobenzoyl chloride (264 mg, 1.43 mmol) in the presence of triethylamine (326 mg, 3.57 mmol) in dichloromethane (10 mL) as per the procedure described in step 5 of Intermediate 2 to yield 254 mg of the product.
  • Step 5 (R)-N-((2-Chloro -4-methylphenyl)(phenyl)methyl)-N-methyl-4-nitrobenzamide
  • the titled compound was prepared by the reaction of Step 4 intermediate (240 mg, 0.63 mmol) with methyl iodide (139 mg, 0.94 mmol) using sodium hydride (60% w/w, 32 mg, 0.81 mmol) in dry DMF (3.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 231 mg of the product.
  • Step 6 (R)-4-Ammo-N-((2-chloro-4-methylphenyl)(phenyl)methyl)-N-methylbenzamide
  • the titled compound was prepared by the nitro reduction of Step 5 intermediate (210 mg, 0.53 mmol) using iron powder (89 mg, 1.59 mmol) and ammonium chloride (284 mg, 5.31 mmol) in a mixture of ethanol and water (3: 1, 10 mL) at 100 °C as per the procedure described in step 7 of Intermediate 2 to yield 145 mg of the titled compound.
  • Step 2 N- [( 1R)- 1 -(4-Chlorophenyl)ethyl] -2-fluoro-N-methyl-4-nitrobenzamide
  • the titled compound was prepared by the reaction of Step 1 intermediate (506 mg, 1.56 mmol) with methyl iodide (339 mg, 2.35 mmol) using sodium hydride (60% w/w, 81 mg, 2.03 mmol) in dry DMF (5.0 mL) at 0 °C as per the procedure described in step 6 of Intermediate 2 to yield 451 mg of the product.
  • Step 3 4- Amino-iV- [( 1R)- 1 -(4-chlorophenyl)ethyl] -2-fluoro-iV-methylbenzamide
  • the titled compound was prepared by the nitro reduction of Step 2 intermediate (431 mg, 1.27 mmol) using iron powder (214 mg, 3.83 mmol) and ammonium chloride (684 mg, 12.79 mmol) in a mixture of ethanol and water (3:1, 10 mL) at 70 °C as described in step 7 of Intermediate 2 to obtain 318 mg of the product.
  • Step 2 N-[(R)-(4-Chloro phenyl)(phenyl)methyl]emanamine
  • Step 1 intermediate To a stirred solution of Step 1 intermediate (361 mg, 1.38 mmol) in THF (10 mL) at 0 °C was added borane-DMS complex (303 ⁇ , 3.19 mmol). The resulting mixture was warmed to RT and refluxed for 2 h. The mixture was cooled to 0 °C and quenched with methanol (2 mL) and stirred for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (20 mL) and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 243 mg of the product.
  • the titled compound was prepared by the reaction of Step 2 intermediate (231 mg, 0.94 mmol) with 4-nitrobenzoylchloride (209 mg, 1.12 mmol) in the presence of DMAP (12 mg, 0.09 mmol) and triethylamine (392 ⁇ L, 2.82 mmol) in dichloromethane (5.0 mL) at room temperature as per the procedure described in step 5 of Intermediate 2 to yield 351 mg of desired product.
  • Step 4 4- Amino-iV- [(R)-(4-chlorophenyl)(phenyl)methyl] -N-ethylbenzamide
  • the titled compound was prepared by the nitro reduction of Step 3 intermediate (332 mg, 0.84 mmol) using iron powder (141 mg, 2.52 mmol) and ammonium chloride (450 mg, 8.40 mmol) in a mixture of ethanol and water (1:1, 10 mL) at 100 °C as per the procedure described in step 7 of Intermediate 2 to obtain 231 mg of the product.
  • Step 1 ( 1R)- 1 -(4-Chlorophenyl)-iV-(cyclopropylmethyl)
  • Step 2 N- [( 1R)- 1 -(4-Chlorophenyl)ethyl] -N-(cyclopropylmethyl)-4-mtrobenzamide
  • the titled compound was prepared by the reaction of Step 1 intermediate (491 mg, 2.39 mmol) with 4-nitrobenzoyl chloride (522.8 mg, 2.81 mmol) in the presence of triethylamine (712 mg, 7.04 mmol) and DMAP (28 mg, 0.23 mmol) in dichloromethane (10 mL) at 0 °C as per the procedure described in step 5 of Intermediate 2 to yield 278 mg of the product.
  • Step 3 4- Amino-N- [( 1R)- 1 -(4-chlorophenyl)ethyl] -N-(cyclopropylmethyl)benzamide
  • the titled compound was prepared by the nitro reduction of Step 2 intermediate (268 mg, 0.74 mmol) using iron powder (125 mg, 2.24 mmol) and ammonium chloride (399 mg, 7.46 mmol) in a mixture of ethanol and water (3: 1, 10 mL) at 100 °C as per the procedure described in step 7 of Intermediate 2 to yield 161 mg of the product.
  • Step 1 N-((15,25)-2-(Benzyloxy)-l-(p-tolyl)propyl)-4-(2-(4-)
  • the titled compound was prepared by the reaction of Intermediate 13 (80 mg, 0.20 mmol) with [4-(ethylsulfonyl)phenyl] acetic acid (56 mg, 0.24 mmol) in the presence of EDCI.HC1 (59 mg, 0.30 mmol), HOBt (42 mg, 0.30 mmol) and N,N'-diisopropylethylamine (53 mg, 0.41 mmol) in DMF (7.0 mL) as per the procedure described in Example 1 to yield 128 mg of the desired product as a solid.
  • Step 2 4-(2-(4-(Emylsulfonyl)phenyl)acetamido)-N-((15,25)-2-hydroxy-l-(p-tolyl)propyl)- N-methylbenzamide
  • methanol 10 mL
  • catalytic amount of palladium on carbon 10%, 50% wet
  • methanol 10 mL
  • the reaction was diluted with methanol (S mL) and filtered through celite bed. The filtrate was concentrated and purified by silica gel column chromatography to yield 32 mg of the titled product.
  • Step. 1 N-(( 1S,2S)-2-(Benzyloxy)- 1 -(4-chlorophenyl)propyl)-4-(2-(4-(ethyl- sulfonyl)phenyl)acetamido)-N-methylbenzamide
  • the titled compound was prepared by the reaction of Intermediate 33 (190 mg, 0.46 mmol) with [4-(ethylsulfonyl)phenyl] acetic acid (127 mg, 0.55 mmol) in the presence of EDCI.HC1 (134 mg, 0.69 mmol), HOBt (94 mg, 0.69 mmol) and N.N'-diisopropylemylamine (180 mg, 1.39 mmol) in DMF (5.0 mL) as per the procedure described in Example 1 to yield 247 mg of the desired product as a solid.
  • the crude product was used as such for next step.
  • ESI-MS m/z 619 (M+H) + .
  • Step 2 N-((15.25)-l-(4-Chlorophenyl)-2-hvdroxvpropvl)-4-(2-(4-(ethvlsulfonvl)- phenyl)acetarnido)-N-methylbenzarnide
  • Step 1 intermediate 100 mg, 0.16 mmol
  • dichloromethane 15 mL
  • anhydrous ferric chloride 104 mg, 0.64 mmol
  • the resulting suspension was stirred at RT for 16 h.
  • the reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (SO mL) followed by water (SO mL).
  • SO mL saturated aqueous sodium bicarbonate solution
  • the organic layer was dried over anhydrous sodium sulfate and concentrated.
  • the residue thus obtained was purified by silica gel column chromatography to yield 12 mg of titled compound as a solid.
  • TR-FRET assay for ROR gamma
  • the assay is based on the principle that binding of the agonist to the ROR gamma causes a conformational change around helix 12 in the ligand binding domain, resulting in higher affinity for the co-activator peptide.
  • ROR gamma being constitutively active, the Fluorescein- D22 co-activator peptide used in the assay is recruited in the absence of a ligand. Binding of the co-activator peptide, causes an increase in the TR-FRET signal while binding of an antagonist decreases the recruitment of the co-activator peptide, causing a decrease in the TR- FRET signal compared to control with no compound.
  • the assay was performed using a two- step procedure, pre-incubation step with the compound followed by the detection step on addition of the anti-GST tagged terbium (Tb) and fluorescein tagged fluorophores as the acceptor.
  • Test compounds or reference compounds such as T0901317 were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration.
  • DMSO dimethylsulfoxide
  • the final concentration of DMSO in the reaction was 4% (v/v).
  • the assay mixture was prepared by mixing lOnM of the GST-tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaCl, 5mM DTT and 0.01% BSA with or without the desired concentration of the compound. The reaction was incubated at 22°C for 1 hour.
  • the pre-incubation step was terminated by addition of the detection mixture containing 300nM Fluorescein-D22 co-activator peptide and lOnM lantha screen Tb-anti GST antibody into the reaction mixture. After shaking for S minutes the reaction was further incubated for 1 hour at room temperature and read at 4°C on an Infinite F500 reader as per the kit instructions (Invitrogen). The inhibition of test compound was calculated based on the TR-FRET ratio of 520/495. The activity was calculated as a per cent of control reaction. ICso values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.
  • the compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 ⁇ and 10.0 ⁇ are given in the table along with ICso (nM) details for selected examples. The compounds were found to have ICso less than lOOOnM, preferably less than lOOnM, more preferably less than 50nM.
  • ICso (nM) values are set forth in Table 7 wherein "A” refers to an IC50 value of less than 50 nM, “B” refers to IC50 value in range of 50.01 to 100.0 nM and “C” refers to IC50 values more than 100 nM.

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Abstract

La présente invention concerne des composés de formule (I) et leurs sels pharmaceutiquement acceptables, le noyau A, R1, R2, R3, R4, R5, n et p étant tels que définis dans la description, qui sont actifs comme modulateurs du récepteur orphelin lié au rétinoïde gamma t (RORγt). Ces composés empêchent, inhibent ou suppriment l'action du RORγt et sont donc utiles pour traiter des maladies, des troubles, des syndromes ou des pathologies médiés par le RORγt tels que, par exemple, la douleur, l'inflammation, la BPCO, l'asthme, la polyarthrite rhumatoïde, la colite, la sclérose en plaques, le psoriasis, les maladies neurodégénératives et le cancer.
PCT/IB2017/050368 2016-05-18 2017-01-25 Composés de benzamide comme modulateurs gamma ror Ceased WO2017199103A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012027965A1 (fr) * 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
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
WO2016193459A1 (fr) * 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012027965A1 (fr) * 2010-09-01 2012-03-08 Glaxo Group Limited Nouveaux composés
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
WO2016193459A1 (fr) * 2015-06-05 2016-12-08 Lead Pharma Cel Models Ip B.V. Modulateurs de ror gamma (rory)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DING ET AL.: "Inhibition of RORt activity and Th17 differentiation by a set of novel compounds", BMC IMMUNOLOGY, vol. 16, no. 1, 2015, pages 32, XP021222491 *
WEI ZHANG ET AL.: "Increasing Human Th17 Differentiation through Activation of Orphan Nuclear Receptor Retinoid Acid-Related Orphan Receptor (ROR) by a Class of Aryl Amide Compounds", MOLECULAR PHARMACOLOGY, vol. 82, no. 4, 2012, pages 583 - 590, XP055220056 *

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