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WO2017010399A1 - COMPOSÉS AYANT DES EFFETS INHIBITEURS DE RORγt ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT - Google Patents

COMPOSÉS AYANT DES EFFETS INHIBITEURS DE RORγt ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT Download PDF

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WO2017010399A1
WO2017010399A1 PCT/JP2016/070151 JP2016070151W WO2017010399A1 WO 2017010399 A1 WO2017010399 A1 WO 2017010399A1 JP 2016070151 W JP2016070151 W JP 2016070151W WO 2017010399 A1 WO2017010399 A1 WO 2017010399A1
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aromatic
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compound
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Japanese (ja)
Inventor
敬 多幾山
正英 大段
義一 佐々木
士郎 木田
裕樹 立花
佳世子 畑
加藤　学
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Definitions

  • the present invention relates to a compound useful for treating a disease or condition involving ROR ⁇ t, and a pharmaceutical composition containing the compound.
  • Interleukin 17 is an inflammatory cytokine produced from Th17 cells, ⁇ T cells, and the like, and is greatly involved in the pathogenesis of autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and psoriasis. It is known that Retinoid related orphan receptor (ROR) ⁇ t expressed in Th17 cells and ⁇ T cells is known to act as a transcription factor of IL-17 and promote differentiation of T cells into Th17 cells.
  • ROR Retinoid related orphan receptor
  • ROR ⁇ t inhibitors are expected to show preventive and / or therapeutic effects on autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis and psoriasis by suppressing IL-17 production.
  • Patent Documents 1 to 29 and Non-Patent Documents 1 to 3 describe compounds that are considered useful for autoimmune diseases such as ROR ⁇ t inhibitors, ROR ⁇ t inverse agonists or P2X7 inhibitors, CCR5 agonists, etc. Are different in structure.
  • WO2013 / 0293338 WO2012 / 100734 publication WO2012 / 100732 publication WO2012 / 028100 publication WO2012 / 027965 WO2013 / 171729 WO2014 / 028669 WO2007 / 109192 publication WO2009 / 010478 WO 2006/130426 WO2014 / 179564 WO2014 / 125426 WO2014 / 086894 WO2014 / 023367 WO2013 / 178362 WO2015 / 002230 WO2013 / 169704 WO2013 / 169588 WO2013 / 169864 WO2015 / 035278 WO2014 / 009447 Publication WO2015 / 082533 WO2015 / 101928 WO2016 / 019588 WO2016 / 039408 WO2015 / 116904 Publication WO2015 / 145371 WO2015 / 082533 WO2015 / 159233
  • An object of the present invention is to provide a novel compound having a ROR ⁇ t inhibitory action. More specifically, the present invention relates to a novel compound having a preventive and / or therapeutic effect on autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis and psoriasis by having an ROR ⁇ t inhibitory action, and A pharmaceutical composition is provided.
  • the present invention relates to the following.
  • R 1A , R 1B , R 1C , R 1D , R 1E and R 1F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-ar
  • R 1 and R 2 bonded to the same carbon may together form ⁇ NR 1G
  • R 3a and R 4a , and R 3b and R 4b are each independently, together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic May form a heterocycle
  • R 3a and R 4a , and R 3b and R 4b may each independently form ⁇ NR 1H
  • R 1G and R 1H are each independently substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • m is an integer from 0 to 2
  • n is 0 or 1
  • Ring B is a 6-membered non-
  • R 3b and R 4b are a substituted or unsubstituted alkyl, or R 3b and R 4b together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbon Forming a ring or a substituted or unsubstituted non-aromatic heterocycle, or R 3b and R 4b together form ⁇ NR 1H
  • Ring B is The ring B 1 is a 5-membered non-aromatic carbocyclic ring, a 5-membered non-aromatic heterocyclic ring or a 5-membered aromatic heterocyclic ring (provided that ring B is not an indole),
  • C Ring B is benzene, n is 1, and A is substituted or unsubstituted phenyl) Or a pharmaceutically acceptable salt thereof.
  • Ring B is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, or A ring represented by B 1 ring is a 5-membered non-aromatic carbocycle, 5-membered non-aromatic heterocycle or 5-membered aromatic heterocycle,
  • the B 2 ring is a 6-membered aromatic carbocyclic ring or a 6-membered aromatic heterocyclic ring, or a pharmaceutically acceptable compound thereof according to any one of the above (1), (1 ′), (2) to (6) Salt.
  • Ring B is benzene, indazole, benzimidazole, benzothiazole, benzoxazole, dihydrobenzimidazole, dihydrobenzothiazole or dihydrobenzoxazole, p is an integer of 0 to 2, and R 5 is independently Any of the above (1), (1 ′), (2) to (6), which is halogen, hydroxy, cyano, alkyl or haloalkyl, and two R 5 together may form oxo Or a pharmaceutically acceptable salt thereof.
  • R A is the formula: Each of R A is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , Substituted or unsubstituted non-aromatic carbocyclic oxy or substituted or unsubstituted aromatic carbocyclic oxy, wherein r is an integer of 0 to 3, (1), (1 ′), (2) to (9) The compound according to any one of the above or a pharmaceutically acceptable salt thereof.
  • L is —NR 1A CO—, —CONR 1B —, —NR 1A CONR 1B —, —OC ( ⁇ O) NR 1C —, —CO—, —S—, —SO 2 —, —SO 2 NR 1D —, —NR 1E SO 2 — or —NR 1F —
  • A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • m is 0,
  • Ring B is benzene, 6-membered aromatic heterocycle, indazole, benzimidazole, benzothiazole, benzoxazole, dihydrobenzimidazole, dihydrobenzothiazole or dihydrobenzoxazole;
  • p is an integer of 0-2, each R 5 is independently halogen, hydroxy, cyano, alkyl or haloalkyl, and two R 5 together may form oxo, R
  • the ring may be formed, and R 3a and R 4a and R 3b and R 4b may each independently form ⁇ NR 1H , described in (1) or (1 ′) above Or a pharmaceutically acceptable salt thereof.
  • L is a single bond, m is 0,
  • A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • R 3b is substituted or unsubstituted alkyl
  • R 3b and R 4b together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring, or
  • R 3b and R 4b 4b together form ⁇ NR 1H
  • R 10A is unsubstituted alkyl, substituted or unsubstituted alken
  • L is a single bond
  • m is 1
  • A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group
  • Ring B is The ring B 1 is a 5-membered non-aromatic carbocyclic ring, a 5-membered non-aromatic heterocyclic ring or a 5-membered aromatic heterocyclic ring
  • R 10A is unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted aromatic carbocyclic group
  • L is a single bond
  • m is 0, A is substituted or unsubstituted phenyl, Ring B is benzene, n is 1,
  • R 10A is unsubstituted alkyl, a substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted aromatic carbocyclic group,
  • (23) (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) ) And a pharmaceutically acceptable salt thereof, or a method for treating or preventing a disease involving ROR ⁇ t, comprising administering the compound according to any one of (24)
  • (107) 1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) And a pharmaceutical composition for children or the elderly, comprising the compound according to any of (20) or a pharmaceutically acceptable salt thereof.
  • (108) (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) ) And a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a combination of an immunosuppressive agent, a steroid agent and / or a cytokine inhibitor.
  • the compound according to the present invention has ROR ⁇ inhibitory activity and is useful as a therapeutic and / or prophylactic agent for autoimmune diseases such as psoriasis.
  • Halogen includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 4 carbon atoms.
  • Alkenyl refers to a straight or branched chain having 2 to 15 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more double bonds at any position. Includes branched hydrocarbon groups.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl is a straight or branched chain having 2 to 10 carbon atoms, such as 2 to 8 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more triple bonds at any position. -Like hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included. Examples of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • “Aromatic carbocycle” means a monocyclic or two or more cyclic aromatic hydrocarbon rings. Examples thereof include benzene, naphthalene, anthracene, phenanthrene and the like. Examples of the “aromatic carbocycle” include benzene. “6-membered aromatic carbocycle” means benzene.
  • the “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. Examples of the “aromatic carbocyclic group” include phenyl.
  • Non-aromatic carbocycle means a cyclic saturated hydrocarbon or cyclic non-aromatic unsaturated hydrocarbon having one or more rings.
  • the two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
  • the “non-aromatic carbocycle” includes a ring that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocycle has, for example, 3 to 16 carbon atoms, such as 3 to 12 carbon atoms, for example 4 to 8 carbon atoms.
  • cyclopropane cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
  • the two or more non-aromatic carbocyclic groups include indane, indene, acenaphthene, tetrahydronaphthalene, fluorene and the like.
  • Examples of the “5-membered or 6-membered non-aromatic carbocycle” include “5-membered non-aromatic carbocycle” such as cyclopentane, cyclopentene and cyclopentadiene, and “6-membered non-aromatic carbon such as cyclohexane, cyclohexene and cyclohexadiene”. Ring ". In the non-aromatic carbocyclic group having two or more rings, the bond may be present in any ring.
  • cycloalkane examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane and the like.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the non-aromatic carbocyclic group having 2 or more rings also includes those in which the ring in the above “aromatic carbocyclic group” is condensed with a monocyclic or 2 or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group has, for example, 3 to 16 carbon atoms, for example, 3 to 12 carbon atoms, for example 4 to 8 carbon atoms.
  • Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • “Aromatic heterocycle” means a single ring or two or more aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
  • Two or more aromatic heterocycles include those obtained by condensing the above “aromatic carbocycle” to a single ring or two or more aromatic heterocycles.
  • the monocyclic aromatic heterocycle is, for example, 5 to 8 members, for example, 5 or 6 members.
  • the heterocyclic ring illustrated by said "monocyclic aromatic heterocyclic group” is mentioned.
  • Specific examples of the bicyclic aromatic heterocycle and the tricyclic or higher aromatic heterocycle include the “bicyclic aromatic heterocyclic group” and “tricyclic aromatic heterocyclic group” described above. Heterocyclic rings.
  • the “5-membered or 6-membered aromatic heterocycle” means a 5-membered or 6-membered aromatic ring in the above “aromatic heterocycle”.
  • “5-membered aromatic heterocycle” such as pyrrole, imidazole, pyrazole, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, and pyridine, pyridazine, pyrimidine, “6-membered aromatic heterocycle” such as pyrazine.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is, for example, a 5- to 8-membered cyclic group, for example, 5-membered or 6-membered.
  • pyrrolyl imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
  • the bicyclic aromatic heterocyclic group is, for example, a cyclic group in which two 5- to 8-membered rings are condensed, for example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria
  • examples include zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyri
  • the aromatic heterocyclic group having three or more rings is, for example, a cyclic group in which three 5- to 8-membered rings are condensed, such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, And dibenzofuryl.
  • a bond may be present in any ring.
  • Non-aromatic heterocycle means a single or two or more non-aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
  • the non-aromatic heterocyclic ring having two or more rings is the above-mentioned “aromatic carbocycle”, “non-aromatic carbocycle”, and / or “aromatic heterocycle” in addition to a single ring or two or more non-aromatic heterocyclic rings. Also included are those in which each ring is condensed.
  • the “non-aromatic heterocycle” includes a ring that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic ring is, for example, 3 to 8 members, for example, 5 or 6 members. Specific examples include the heterocyclic rings exemplified above for the “monocyclic non-aromatic heterocyclic group”. Examples of the non-aromatic heterocyclic group having two or more rings include the heterocyclic rings exemplified in the above “two or more non-aromatic heterocyclic groups”.
  • the “5-membered or 6-membered non-aromatic heterocycle” means a 5-membered or 6-membered non-aromatic ring in the above “non-aromatic heterocycle”.
  • “5-membered non-aromatic heterocycles” such as oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydrofuran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dioxolane, dioxole and thiolane and dioxane, thiane
  • “6-membered non-aromatic heterocycles” such as piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydropyran, dihydrooxazine, tetrahydropyridazine, hexahydropyrimidine, dioxazine, thiazine and thiopyran.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring Means.
  • Two or more non-aromatic heterocyclic groups are (i) a ring in which the above “aromatic carbocycle”, “non-aromatic carbocycle”, and / or “aromatic heterocycle” are condensed to the above-mentioned “non-aromatic heterocycle” of one or more rings Group, and (ii) includes a cyclic group in which a “non-aromatic carbocycle” is fused to the above “aromatic heterocycle”.
  • non-aromatic heterocyclic group includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is, for example, 3 to 8 members, for example, 5 or 6 members.
  • non-aromatic heterocyclic group having two or more rings examples include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl, dihydrobenzoxazolyl, dihydrobenzofuryl, dihydrobenzothiazolyl. , Dihydrobenzimidazolyl, tetrahydroquinolyl, dihydropyrrolopyridyl and the like.
  • the bond may be present in any ring.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. Examples thereof include hydroxymethyl and hydroxyethyl.
  • “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom.
  • Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Examples include methoxy, ethoxy, n-propyloxy, isopropyloxy or tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Examples include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned. “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. “Alkylcarbonyl” includes, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • Haloalkylcarbonyl means a group in which the above “haloalkyl” is bonded to a carbonyl group.
  • monofluoromethylcarbonyl monofluoroethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, trifluoroethylcarbonyl, trichloroethylcarbonyl and the like can be mentioned.
  • examples thereof include trifluoromethylcarbonyl and trichloromethylcarbonyl.
  • “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned. Examples of “monoalkylamino” include methylamino and ethylamino. “Dialkylamino” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different.
  • Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
  • dimethylamino and diethylamino are mentioned.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • methylsulfonyl and ethylsulfonyl are mentioned.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • Haloalkylsulfonyl means a group in which the “haloalkyl” is bonded to a sulfonyl group.
  • monofluoromethylsulfonyl, monofluoroethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, trifluoroethylsulfonyl, trichloroethylsulfonyl and the like can be mentioned. Examples thereof include trifluoromethylsulfonyl and trichloromethylsulfonyl.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned. Examples thereof include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Two alkylcarbonyl groups may be the same or different.
  • dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Examples thereof include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, and the like. Examples include methylsulfonylamino and ethylsulfonylamino. It is done.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Two alkylsulfonyl groups may be the same or different.
  • dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned. Examples thereof include dimethylsulfonylamino and diethylsulfonylamino.
  • alkylimino means a group in which the “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkylimino means a group in which the “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • alkynylimino means a group in which the “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like. Examples of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy. “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl may be mentioned.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • the “haloalkylsulfanyl” means a group in which the “haloalkyl” is bonded to a sulfanyl group.
  • Examples thereof include monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like. Examples thereof include trifluoromethylsulfanyl and trichloromethylsulfanyl.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl. “Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned. “Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylsulfamoyl and diethylsulfamoyl.
  • Trialkylsilyl means a group in which three of the above “alkyl” are bonded to a silicon atom.
  • the three alkyls may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc. Examples include benzyl, phenethyl, and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • Non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • non-aromatic heterocyclic alkyloxy means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”.
  • non-aromatic heterocyclic alkyloxyalkyl substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylcarbamoyl” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples include benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl, benzhydrylcarbamoyl, tritylcarbamoyl, naphthylmethylcarbamoyl, dibenzylcarbamoyl and the like.
  • non-aromatic carbocyclic alkylcarbamoyl means a group in which the “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples thereof include cyclopropylmethylcarbamoyl, cyclobutylmethylcarbamoyl, cyclopentylmethylcarbamoyl, cyclohexylmethylcarbamoyl and the like.
  • aromatic heterocyclic alkylcarbamoyl means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl.
  • pyridylmethylcarbamoyl furanylmethylcarbamoyl, imidazolylmethylcarbamoyl, indolylmethylcarbamoyl, benzothiophenylmethylcarbamoyl, oxazolylmethylcarbamoyl, isoxazolylmethylcarbamoyl, thiazolylmethylcarbamoyl, isothiazolylmethylcarbamoyl , Pyrazolylmethylcarbamoyl, isopyrazolylmethylcarbamoyl, pyrrolidinylmethylcarbamoyl, benzoxazolylmethylcarbamoyl and the like.
  • Non-aromatic heterocyclic alkylcarbamoyl means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples thereof include tetrahydropyranylmethylcarbamoyl, morpholinylethylcarbamoyl, piperidinylmethylcarbamoyl, piperazinylmethylcarbamoyl and the like.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like. “Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkylamino means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • pyridylmethylamino furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • the “aromatic carbocyclic” moiety is the same as the above “aromatic carbocyclic group”.
  • “Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
  • “Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic carbamoyl” means a group in which the above “aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. For example, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocycle carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
  • the “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • non-aromatic carbocyclic carbamoyl means a group in which the above “non-aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples include cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • Aromatic heterocyclic oxy means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
  • “Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle carbamoyl” means a group in which the above “aromatic heterocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl.
  • pyridylcarbamoyl, oxazolylcarbamoyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • non-aromatic heterocyclic oxycarbonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • non-aromatic heterocyclic carbamoyl means a group in which the above “non-aromatic heterocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl.
  • non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents (a) and (b).
  • Halogen hydroxy, carboxy, amino, carbamoyl, sulfamoyl, cyano, nitro, trialkylsilyl, Alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyloxy, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, haloalkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, Alkynyloxycarbonyl, alkylsulfanyl, haloalkylsulfanyl, monoalkylcarbamoyl and dialkylcarbamoyl.
  • the atom at any position on the ring may be bonded to one or more groups selected from the following substituent (c) and substituent (d).
  • Halogen hydroxy, carboxy, amino, carbamoyl, sulfamoyl, cyano, nitro, trialkylsilyl, Alkyl, haloalkyl, hydroxyalkyl, alkyloxyalkyl, Alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyloxy, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, haloalkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, Examples include alkynyloxycarbonyl, alkylsulfanyl, haloalkylsulfanyl, monoalkylcarbamoyl, dialkylcarbamoyl, pentafluoride
  • aromatic carbocyclic ring, non-aromatic carbocyclic ring, aromatic heterocyclic ring and non-aromatic heterocyclic ring in the substituent (d) may be further substituted with one or more groups selected from the substituent (c). Good).
  • the “aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • R 1 and R 2 bonded to the same carbon together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle
  • R 3a and R 4a and R 3b and R 4b are each independently, together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic R 6 and R 7 together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • R 1 and R 2 bonded to the same carbon together form ⁇ NR 1G includes, for example, the following cases.
  • A represents, for example, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted aromatic heterocyclic group.
  • A represents, for example, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic It is a heterocyclic group.
  • A is, for example, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A1).
  • A is, for example, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl or substituted or unsubstituted pyrazinyl.
  • A is a “substituted or unsubstituted non-aromatic carbocyclic group”, “substituted or unsubstituted aromatic carbocyclic group”, “substituted or unsubstituted non-aromatic heterocyclic group” or “substituted or non-substituted In the case of ⁇ substituted aromatic heterocyclic group '', examples of the substituent include: Halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, pentafluorosulfanyl, Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non
  • the substituent is, for example, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, pentafluorosulfanyl, aromatic carbocyclic group, One or more groups selected from a non-aromatic heterocyclic group, a non-aromatic carbocyclic oxy, an aromatic carbocyclic oxy and oxo which may be substituted with a halogen.
  • the substituent is, for example, one or more groups selected from halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy (hereinafter referred to as A2).
  • the substituent is, for example, one or more groups selected from halogen and cyano.
  • the substituent is, for example, one or more groups selected from fluoro and chloro.
  • A is, for example, the formula: (In the formula, s is an integer from 0 to 4, for example, u is an integer from 0 to 3, v is an integer from 0 to 2, w is 0 or 1, R A is, for example, each independently Halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, pentafluorosulfanyl, A non-aromatic carbocyclic group optionally substituted with one or more groups selected from the substituent (b), an aromatic optionally substituted with one or more groups selected from the substituent (b) Carbocyclic group, non-aromatic carbocyclic oxy optionally substituted with one or more groups selected from substituent (b), substituted with one or more groups selected from substituent (b) Or
  • w is 0 or 1
  • s, u and v are each independently an integer of 0 to 3, for example, an integer of 1 to 3, for example 1 or 2, for example 1, for example 2.
  • R A is, for example, each independently a halogen , Cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, pentafluorosulfanyl, aromatic carbocyclic group, non-aromatic optionally substituted with halogen It may be a heterocyclic group, non-aromatic carbocyclic oxy or aromatic carbocyclic oxy, or two R A together may form oxo.
  • w is 0 or 1
  • s, u and v are each independently an integer of, for example, 0 to 2, for example 1 or 2
  • R A is, for example, each independently Halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.
  • w is 0 or 1
  • s, u and v are each independently an integer of, for example, 0 to 2, for example 1 or 2
  • R A is, for example, each independently And halogen or cyano (hereinafter referred to as A4).
  • w is 0 or 1
  • s, u and v are each independently an integer of, for example, 0 to 2, for example 1 or 2
  • R A is, for example, each independently Fluoro or chloro.
  • R A is, for example, the formula: R A is substituted with, for example, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, pentafluorosulfanyl, aromatic carbocyclic group, halogen Or a non-aromatic heterocyclic group, non-aromatic carbocyclic oxy, aromatic carbocyclic oxy or oxo, and s is an integer from 0 to 2, for example 1 or 2.
  • A is, for example, the formula: And each R A is independently halogen or cyano (hereinafter referred to as A5).
  • A is, for example, the formula: And each R A is independently halogen.
  • A is, for example, the formula: And R A is halogen.
  • A is, for example, the formula: And each R A is independently halogen.
  • A is, for example, the formula: And each R A is independently halogen.
  • L is a single bond, —NR 1A CO—, —CONR 1B —, —SO 2 —, —SO 2 NR 1D — or —NR 1E SO 2 —, and m and n are each independently 0 or 1 and R 1 and R 2 are both hydrogen;
  • R 3a , R 4a , R 3b and R 4b are each independently Hydrogen, halogen, or substituted or unsubstituted alkyl, R 3a and R 4a may each independently be hydroxy, R 3a and R 4a and R 3b and R 4b are each independently Together with the carbon atoms to which they are attached, they may form a substituted or unsubstituted non-aromatic carbocycle, wherein R 3a and R 4a and R 3b and R 4b are each independently taken together.
  • L1H NR 1H may be formed (hereinafter referred to as L1).
  • L is, for example, a single bond.
  • L is, for example, —NR 1A CO—.
  • L is, for example, —CONR 1B .
  • L is, for example, —SO 2 —.
  • m is 0 and n is 0.
  • R 3a , R 4a , R 3b and R 4b are each independently, for example, Are hydrogen or substituted or unsubstituted alkyl, or R 3a and R 4a and R 3b and R 4b are each independently, together with the carbon atom to which they are attached, substituted or unsubstituted non-aromatic A carbocycle may be formed.
  • R 3a , R 4a , R 3b and R 4b are each independently, for example, It may be hydrogen or alkyl, or R 3a and R 4a and R 3b and R 4b may each independently combine with the carbon atom to which they are attached to form a cycloalkane.
  • R 3a , R 4a , R 3b and R 4b are both hydrogen, for example.
  • R 3a and R 4a are hydrogen, and R 3b and R 4b are each independently alkyl.
  • R 3a and R 4a are hydrogen, and R 3b and R 4b are both methyl.
  • R 3a and R 4a are hydrogen, and R 3b and R 4b together with the carbon atom to which they are attached form cyclopropane.
  • each symbol has the same meaning as the above item (1)).
  • L1-2 R 3b and R 4b are each independently hydrogen or substituted or unsubstituted alkyl, or R 3b and R 4b are taken together with the carbon atom to which they are attached.
  • a substituted or unsubstituted non-aromatic carbocyclic ring may be formed (hereinafter referred to as L2).
  • L2 for example, R 3b and R 4b are each independently hydrogen or alkyl, or R 3b and R 4b together with the carbon atom to which they are attached form a cycloalkane. (Hereinafter referred to as L3).
  • R 3b and R 4b are each independently alkyl (hereinafter referred to as L4).
  • L4 alkyl
  • iPr isopropyl
  • iBu is isobutyl
  • tBu is tert-butyl
  • cPr is cyclopropyl
  • cHex is cyclohexyl
  • Bn is benzyl
  • Ring B is, for example, a 6-membered aromatic carbocycle, a 6-membered non-aromatic heterocycle or a 6-membered aromatic heterocycle, or The bond a is bonded to —NHC ( ⁇ O) CR 6 R 7 —, the bond b is bonded to —CR 3b Rb 4 —, B 1 ring is a 6-membered aromatic carbocyclic ring, a 5-membered or 6-membered non-aromatic heterocyclic ring or a 5-membered or 6-membered aromatic heterocyclic ring, B 2 ring is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle, p is, for example, an integer from 0 to 3, R 5 is each independently, for example, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group Two R
  • the ring B is, for example, a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, or
  • B 1 ring is a 5-membered or 6-membered non-aromatic heterocyclic ring or a 5-membered or 6-membered aromatic heterocyclic ring
  • B 2 ring is 6-membered aromatic carbocyclic ring (hereinafter referred to as B2).
  • ring B is, for example, benzene, pyridine, benzimidazole, indazole, dihydrobenzthiazole.
  • p is, for example, an integer of 0 to 2
  • R 5 is each independently, for example, halogen, cyano, alkyl, haloalkyl or a substituted or unsubstituted aromatic carbocyclic group, R 5 together may form oxo.
  • p is an integer of, for example, 0 to 2
  • R 5 is each independently, for example, halogen, cyano, alkyl, haloalkyl, or phenyl optionally substituted with halogen or haloalkyl, 2 R 5 together may form oxo.
  • p is an integer of, for example, 0 to 2
  • R 5 is, for example, each independently, halogen, cyano, or haloalkyl, and two R 5 together form oxo. (Hereinafter referred to as B3).
  • p is, for example, an integer from 0 to 2
  • R 5 is independently, for example, halogen.
  • p is, for example, 0, for example, 1, for example, 2.
  • R 5 may be substituted on any ring.
  • R 5 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group, R 5 together may form an oxo, p is an integer from 0 to 2 and t is an integer from 0 to 2) (Hereinafter referred to as B5).
  • R 5 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted aromatic carbocyclic group
  • R 5 is, for example, each independently a halogen, cyano, alkyl, haloalkyl or a substituted or unsubstituted aromatic carbocyclic group.
  • R 5 is, for example, halogen, cyano, haloalkyl, or an aromatic carbocyclic group optionally substituted with halogen or haloalkyl (hereinafter referred to as B6).
  • the formula: R 5 is, for example, halogen or haloalkyl (hereinafter referred to as B7).
  • the formula: And R 5 is, for example, halogen or haloalkyl.
  • R 6 is, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-substituted An aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, and R 7 is, for example, hydrogen, halogen, hydroxy, or substituted or unsubstituted alkyl (hereinafter referred to as R671).
  • R 6 is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted non-aromatic heterocyclic group.
  • R 6 is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl (wherein the substituents are cyano, hydroxy; carboxy; alkyloxy; haloalkyloxy; carbamoyl; alkyloxycarbonyl; monoalkylcarbamoyl; non-substituted)
  • a non-aromatic carbocyclic group and one or more groups selected from an aromatic heterocyclic group optional
  • R 6 is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl (wherein the substituents are cyano, hydroxy, carboxy; one or more groups selected from and carbamoyl) (hereinafter, R672 And).
  • R671 above R 6 and R 7 are each independently, for example, hydrogen, hydroxy, or unsubstituted alkyl. In the R671, R 6 and R 7 are both hydrogen (hereinafter referred to as R673).
  • R 6 and R 7 for example, together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as R674). To do).
  • the substituent for example, the substituent is one or more groups selected from hydroxy, alkyl, haloalkyl and hydroxyalkyl.
  • q is an integer from 0 to 2
  • R 8 is halogen or substituted or unsubstituted alkyl
  • R 9 is hydrogen
  • halogen or substituted or unsubstituted E is SO 2 R 10A
  • R 10A is substituted or unsubstituted alkyl (hereinafter referred to as X1).
  • q is 0 or 1
  • R 8 is halogen
  • X is ⁇ CR 9 — or ⁇ N—
  • R 9 is hydrogen or halogen
  • E is SO 2 R 10A
  • R 10A Is substituted or unsubstituted alkyl (hereinafter referred to as X2).
  • X CH- (hereinafter referred to as X3).
  • X N- (hereinafter referred to as X4).
  • R 10A is unsubstituted alkyl or haloalkyl.
  • R 10A is unsubstituted alkyl.
  • R 10A is alkyl having 1 to 3 carbon atoms.
  • R 10A is ethyl.
  • the compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • a suitable catalyst such as Pd / C
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fum
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph.
  • a solvate for example, hydrate etc.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • Co-crystal means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
  • Second Step Compound a3 can be obtained by reacting compound a2 with an oxidizing agent such as metachloroperbenzoic acid at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours in a solvent such as dichloromethane.
  • Step 3 Compound a1 synthesized by a commercially available or known method in a solvent such as methanol, ethanol, THF or the like is substituted with a substituted sodium sulfinate synthesized by a commercially available or known method at 0 to 50 ° C. for 1 hour.
  • the compound a3 can be obtained by reacting for ⁇ 48 hours, preferably 1 hour to 24 hours.
  • compound a3 is converted to 0 with alkyl halide, alkyl tosylate, alkyl mesylate, etc. in the presence of a base such as sodium hydride, potassium tert-butoxy, sodium hydroxide aqueous solution or the like.
  • a base such as sodium hydride, potassium tert-butoxy, sodium hydroxide aqueous solution or the like.
  • Compound a4 can be obtained by reacting at -80 ° C for 1 hour to 48 hours, preferably 1 hour to 24 hours.
  • Step 5 Compound a4 can be reacted in a mixed solvent of methanol, ethanol, etc. with water in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. a5 can be obtained.
  • Compound a4 is reacted in a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a5.
  • a solvent such as methanol or ethanol
  • palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a5.
  • Step 6 In a solvent such as THF, NMP, DMSO, DMF, etc., compound a5 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. ⁇ 1 can be obtained.
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • compound A-1 is also obtained by sequentially adding the acylating reagents of -20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C., and reacting for 0.1 to 6 hours, preferably 1 to 3 hours. be able to.
  • the target compound can be obtained by subjecting to the same reaction as in step 6.
  • Step 1 Compound a6 synthesized by a commercially available or known method in a mixed solvent of methanol, ethanol, and the like and water in the presence of iron and ammonium chloride at 80 to 100 ° C. for 1 to 48 hours, preferably 1 hour By reacting for ⁇ 24 hours, compound a7 can be obtained.
  • Compound a6 is reacted in a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a7.
  • compound a7 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine,
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • a base such as triethylamine
  • a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. -2 can be obtained.
  • compound A-2 is also obtained by sequentially adding the acylating reagents of -20 ° C to 50 ° C, preferably 0 ° C to 20 ° C, and reacting for 0.1 to 6 hours, preferably 1 to 3 hours. be able to.
  • Compound a9 is reacted in a solvent such as methanol or ethanol in the presence of palladium on carbon or palladium hydroxide on carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a10.
  • compound a10 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine,
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • a base such as triethylamine
  • a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. Can be obtained.
  • compound a11 can also be obtained by sequentially adding the acylating reagent and reacting at ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. it can.
  • Step 4 Compound a12 can be obtained by reacting compound a11 with a basic aqueous solution.
  • the reaction temperature is 0 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
  • the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF and the like, and these can be used alone or in combination.
  • compound a12 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine,
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • Compound A is prepared by adding a commercially available or publicly known amine compound in the presence of a base such as triethylamine and reacting at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours.
  • a halide can be obtained by reacting compound a12 with a halogenating agent.
  • halogenating agent examples include thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like, and 1 to 5 molar equivalents can be used with respect to compound a12.
  • the reaction temperature is ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • As the reaction solvent acetonitrile, THF, toluene, dichloromethane and the like can be used.
  • Compound A-3 can also be obtained by reacting the resulting halide with an amine compound synthesized by a commercially available or known method in the presence of a base.
  • a base include triethylamine, DIEA, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • the reaction solvent include acetonitrile, THF, toluene, dichloromethane and the like.
  • the target compound can be obtained by subjecting it to the same reaction as in Step 5 to Step 5.
  • the compound a13 may be subjected to the following second step without being subjected to this step.
  • Second Step In a mixed solvent of methanol, ethanol, etc. and water, compound a14 is reacted in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours, to give compound a15.
  • a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a15.
  • compound a15 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine,
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • a base such as triethylamine
  • a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours, to thereby obtain compound a16.
  • compound a16 in a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, or the like is added to compound a15 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method
  • the compound a16 can also be obtained by sequentially adding the acylating reagent and reacting at ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. it can.
  • Fourth Step Compound a17 can be obtained by reacting compound a16 with an acid or a Lewis acid.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), and the like, and 1 to 10 molar equivalents can be used with respect to the compound a16.
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • reaction solvent examples include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
  • a solvent such as THF, NMP, DMSO, and DMF
  • compound a17 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • a base such as triethylamine
  • a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C.
  • -4 can be obtained.
  • a solvent such as dichloromethane, dichloroethane or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or the like is added as a base to compound a17, and acid chloride or acid anhydride synthesized by a commercially available or known method, etc.
  • the compound A-4 can also be obtained by sequentially adding the acylating reagent and reacting at ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. be able to.
  • Second Step In a solvent such as THF, NMP, DMF and the like, compound a20 is converted to 0 with alkyl halide, alkyl tosylate, alkyl mesylate, etc. in the presence of a base such as sodium hydride, potassium tert-butoxy, sodium hydroxide aqueous solution or the like.
  • a base such as sodium hydride, potassium tert-butoxy, sodium hydroxide aqueous solution or the like.
  • Compound a21 can be obtained by reacting at -80 ° C for 1 hour to 48 hours, preferably 1 hour to 24 hours.
  • R 3b and R 4b together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, a dihalogenated alkyl, What is necessary is just to make it react similarly using ditosylation alkyl, dimesylation alkyl, etc.
  • compound a21 is reacted in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours to give compound a22.
  • a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a22.
  • compound a22 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine,
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine
  • a base such as triethylamine
  • a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. Can be obtained.
  • compound a22 in a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or the like is added to compound a22 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method
  • the compound a23 can also be obtained by sequentially adding the acylating reagent and reacting at ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. it can.
  • the deprotection reaction can be carried out by selecting various conditions depending on the protecting group.
  • a benzyl group or a benzyloxycarbonyl group can be deprotected by catalytic reduction or the like.
  • the tert-butyloxycarbonyl group can be deprotected by an ordinary method using an acid.
  • R 1E of the target compound is a group other than hydrogen
  • the compound obtained by deprotection is reacted with a halogenated alkyl, tosylated alkyl in the presence of a base in a solvent such as methanol, ethanol, THF, DMF
  • the target compound A-6 can be obtained by reacting with a mesylated alkyl or the like.
  • the base examples include triethylamine, N-methylmorpholine, N, N-diisopropylethylamine and the like.
  • the reaction temperature is 0 to 80 ° C., and the reaction time is 1 to 48 hours, preferably 1 to 24 hours.
  • the target compound can be obtained by subjecting to the same reaction as in the fifth step.
  • First Step Compound a28 can be obtained by reacting compound a11 obtained by the above production method (3) with a reducing agent.
  • the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound a11.
  • the reaction temperature is 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature.
  • the reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane, water and the like, and these can be used alone or in combination.
  • Second Step After reacting dimethyl sulfoxide with oxalyl chloride or trifluoroacetic anhydride, reacting with compound a28 and treating with amine, compound a29 can be obtained.
  • the reaction temperature is -78 ° C to -15 ° C, preferably -78 ° C to -40 ° C.
  • the reaction time is 0.1 to 4 hours, preferably 0.5 to 2 hours.
  • amine examples include trimethylamine, triethylamine, tripropylamine, and tributylamine.
  • reaction solvent include dichloromethane, THF, dioxane, benzene and the like.
  • compound a29 can be obtained using Dess-Martin reagent as the oxidizing agent.
  • Compound a30 can be obtained by reacting compound a29 with a nucleophile.
  • nucleophilic agents examples include lithium reagents such as methyl lithium and ethyl lithium, Grignard reagents such as methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, ethyl magnesium bromide, ethyl magnesium chloride, and ethyl magnesium iodide, and metal salts thereof. And can be used in an amount of 1 to 5 molar equivalents relative to compound a29.
  • the reaction temperature is -78 ° C to the reflux temperature of the solvent, preferably -45 ° C to 0 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 6 hours.
  • reaction solvent examples include tetrahydrofuran, hexane, diethyl ether, methyl tert-butyl ether, toluene, dichloromethane and the like, and these can be used alone or in combination.
  • Fourth Step After reacting dimethyl sulfoxide with oxalyl chloride or trifluoroacetic anhydride, reacting with compound a30 and treating with amine, compound A-9 can be obtained.
  • the reaction temperature is -78 ° C to -15 ° C, preferably -78 ° C to -40 ° C.
  • the reaction time is 0.1 to 4 hours, preferably 0.5 to 2 hours.
  • Examples of the amine include trimethylamine, triethylamine, tripropylamine, and tributylamine.
  • Examples of the reaction solvent include dichloromethane, THF, dioxane, benzene and the like.
  • Compound A-9 can also be obtained using Dess-Martin reagent as the oxidizing agent.
  • the compound according to the present invention has ROR ⁇ t inhibitory action, it is useful as a therapeutic and / or prophylactic agent for immune-related diseases such as autoimmune diseases and allergic diseases. Preferably, it is useful as a therapeutic agent and / or preventive agent for autoimmune diseases.
  • an ROR ⁇ t inhibitor having an IC50 of 10 ⁇ M or less in the human ROR ⁇ t reporter assay described below is desirable.
  • autoimmune diseases include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome, systemic lupus erythematosus, scleroderma, thrombocytopenia, myasthenia gravis, ulcerative colitis, Crohn's disease , Graves' disease, polymyositis, type 1 diabetes, asthma, uveitis and the like.
  • the compound of the present invention has not only an ROR ⁇ t inhibitory action but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
  • d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • a pharmaceutical composition containing the compound of the present invention When a pharmaceutical composition containing the compound of the present invention is administered, it can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, Syrups, limonades, spirits, fragrances, extracts, decoctions, tinctures, etc.
  • the tablet may be a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet, and the powder and granules are dry syrup.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • injections, drops, external preparations eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, mouthwashes, enemas, Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered.
  • the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type and the like.
  • отноеские can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by appropriately changing the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention, so that You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years.
  • the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the compound of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, route of administration, etc., but usually 0.05 to 100 mg / kg / day when administered orally. Preferably, it is within the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the compound of the present invention may be used in combination with an immunosuppressant, a steroid agent, a cytokine inhibitor, etc.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the immunosuppressive agent include tacrolimus, cyclosporine, cyclophosphamide, methotrexate and the like.
  • Specific examples of the steroid include dexamethasone, betamethasone, prednisolone, hydrocortisone and the like.
  • Cytokine inhibitors include anti-cytokine antibodies, cytokine receptor antagonists, soluble cytokine receptors, MAP kinase inhibitors, cytokine production inhibitors, TASE inhibitors, ICE inhibitors, cytokine gene transcription factor decoys, siRNA, antisense, etc. Specific examples thereof include etanalcept, infliximab, adalimumab, anakinra, tocilizumab, ustekimab and the like.
  • RT represents a retention time in LC / MS: liquid chromatography / mass spectrometry, and was measured under the following conditions.
  • Measurement conditions 1 Column: Shim-pack XR-ODS (2.2 ⁇ m, id 50 ⁇ 3.0 mm) (Shimadzu) Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
  • Mobile phase [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution.
  • Measurement condition 3 Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 ⁇ m id 2.1 ⁇ 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
  • Measurement condition 4 Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 ⁇ m id 2.1 ⁇ 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
  • Example 1 Synthesis of Compound 3 First Step Synthesis of Compound (2) 4-Fluorobenzenethiol (compound (1), 5 mL, 46.9 mmol) is dissolved in NMP (50 mL), sodium hydride (w / w 60%, 1.9 g, 47.5 mmol) is added, and the mixture is stirred at room temperature for 10 minutes. 1- (Bromomethyl) -4-nitrobenzene (10 g, 46.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours and then allowed to stand overnight at room temperature.
  • Step 2 Synthesis of Compound (3)
  • Compound (2) (10 g, 38 mmol) was dissolved in dichloromethane (100 mL), metachloroperbenzoic acid (22.9 g, 95 mmol) was slowly added under ice-cooling, and the mixture was warmed to room temperature and stirred for 3 hours. Ice-cooled, dimethyl sulfoxide (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (500 mL), 2M aqueous sodium hydroxide solution (300 mL) were added, and the organic layer was 2M aqueous hydrochloric acid (300 mL), saturated brine.
  • Step 3 Synthesis of Compound (4)
  • Compound (3) (9 g, 31 mmol), tetrabutylammonium bromide (0.5 g, 0.05 mmol), 1,2-dibromoethane (3.2 mL, 37 mmol) were dissolved in dichloromethane (100 mL), and 50% water An aqueous sodium oxide solution (100 mL) was added and the mixture was stirred at 35 ° C. for 6 hours. 1,2-Dibromoethane (3.2 mL, 37 mmol) was added, and the mixture was stirred at 30 ° C. overnight.
  • N, N-diisopropylethylamine (2.3 mL, 13 mmol) was added. Stir at room temperature for 1 hour and let stand overnight. Ethyl acetate (200 mL) and water (200 mL) were added, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to obtain compound 3 (730 mg, yield 33.2%). Obtained.
  • Example 3 Synthesis of Compound 2 Sodium hydride (60 w / w%, 100 mg, 0.2 mmol) was added to methanol (500 ⁇ l), stirred for 10 minutes, and compound 5 (100 mg, 0.2 mmol) dissolved in 0.5 mL of DMF was added. The mixture was stirred at room temperature for 3 hours, dichloromethane and water were added, the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to give compound 2 (33 mg, yield 32.0%). .
  • Step 3 Synthesis of Compound 9
  • the above residue (30 mg), 2- (4- (ethylsulfonyl) phenyl) acetic acid (21 mg, 0.09 mmol) and HATU (41 mg, 0.11 mmol) were added to DMF (0.5 mL) and stirred, and N, N- Diisopropylethylamine (0.05 mL, 0.27 mmol) was added. Stir at room temperature for 1 hour. Dichloromethane and water were added, and the organic layer was concentrated and purified by silica gel chromatography to obtain Compound 9 (3 mg, yield of the second to third steps: 2.3%).
  • Example 6 Synthesis of Compound 1 First Step Synthesis of Compound (10) Sodium hydride (w / w 60%, 15 mg, 0.37 mmol) was added to dimethylformamide (0.2 mL) and stirred, and 4-chlorophenylthiol (45 mg, 0.31 mmol) was added and stirred for 10 minutes. To this solution was added a DMF (0.5 mL) solution of compound (6) (100 mg, 0.31 mmol), and the mixture was stirred at room temperature for 1 hour, further heated up and stirred at 40 ° C. for 2 hours. The mixture was cooled to room temperature and washed with ethyl acetate and water. The obtained organic layer was concentrated to dryness to obtain a concentrated residue containing compound (10).
  • Step 2 Synthesis of Compound (11) Ethanol (1 mL) was added to the residue and stirred to make a suspension, and half of the residue was transferred to a microwave tube. Ammonium chloride (50 mg) aqueous solution (0.5 mL) and iron (50 mg, 0.9 mmol) were added and sealed, followed by stirring at 80 ° C. for 1 hour. After cooling to room temperature, dichloromethane and water were added, and the organic layer was concentrated to dryness. The crude product was purified by silica gel chromatography to obtain a crude product (11) (6 mg, yield of the first and second steps 7.0%). Used in the next reaction without further purification.
  • Step 4 Synthesis of Compound 1
  • Dichloromethane (1 mL) was added to the above concentrated residue, metachloroperbenzoic acid (20 mg, 0.12 mmol) was added under ice-cooling, the mixture was returned to room temperature, stirred for 1 hour, and allowed to stand overnight at room temperature.
  • DMSO 0.1 mL was added, and the mixture was stirred at room temperature for 30 minutes, and washed with dichloromethane and water. Purification by silica gel chromatography gave Compound 1 (6 mg, 32.4th step yield 52.4%).
  • Example 7 Synthesis Step 1 of Compound 11 Synthesis of Compound (13) 1- (Bromomethyl) -4-nitrobenzene (compound (1), 500 mg, 2.3 mmol) is dissolved in ethanol (5 mL), sodium ethanesulfinate (269 mg, 2.3 mmol) is added, and the mixture is sealed and room temperature is 100 ° C. For 2 hours and then cooled to room temperature. After concentration, the precipitated white solid was collected by filtration using ethyl acetate and hexane to obtain Compound (13) (374 mg, yield 70.9%).
  • Step 2 Synthesis of Compound (17)
  • Compound (16) (418 mg, 1.04 mmol) is dissolved in a mixture of THF (2 mL) and methanol (1 mL), 2M aqueous sodium hydroxide solution (0.62 mL, 1.24 mmol) is added, and the mixture is stirred at room temperature for 21 hours. The mixture was further stirred at 50 ° C. for 2 hours. The mixture was neutralized with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (17) (317 mg, yield 78.6%).
  • Step 3 Synthesis of Compound 28 Compound (17) (20 mg, 0.051 mmol), 4-fluoroaniline (11.4 mg, 0.103 mmol) and HATU (29.3 mg, 0.077 mmol) were added to DMF (200 ⁇ L) and stirred, and triethylamine (14.2 ⁇ L, 0.103 mmol). ) was added. The mixture was stirred at room temperature for 1 hour, treated with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to give compound 28 (25 mg).
  • Example 9 Synthesis of Compound 78
  • Compound (18) 500 mg, 2.07 mmol
  • ethyl acetate 15 mL
  • 10% palladium / carbon 466 mg
  • the reaction vessel was purged with hydrogen and stirred at room temperature for 30 minutes.
  • the palladium was filtered through Celite, and the filtrate was concentrated to dryness to obtain a concentrated residue containing the compound (19). From the residue, Compound 78 was obtained in the same manner as in First Step, Second Step and Third Step of Example 8.
  • Example 10 Synthesis Step 1 of Compound 113 Synthesis of Compound (21) Sodium hydride (917 mg, 22.9 mmol) was added to DMF (10 mL), and diethyl methylmalonate (3.0 mL, 22.9 mmol) dissolved in DMF (10 mL) was added to the suspension. After stirring at 0 ° C. for 30 minutes, a DMF solution of compound (20) (2.0 g, 10.4 mmol) was added and stirred at 70 ° C. for 2 hours. The mixture was treated with saturated aqueous ammonia chloride and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated.
  • Step 2 Synthesis of Compound (22)
  • Compound (21) (1.65 g, 5.00 mmol) was dissolved in acetic acid (17 mL), concentrated sulfuric acid (4 mL, 75 mmol) diluted with water (6.3 mL) was added, and the mixture was stirred at 100 ° C. for 5 hr. After treating with water, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to obtain compound (22) (1.1 g, yield 95.7%). .
  • Step 3 Synthesis of Compound (29) 1-tert-butyl 3-ethyl malonate (151 ⁇ L, 0.80 mmol) and tert-butoxypotassium (108 mg, 0.96 mmol) were added to dioxane (1 mL), and the mixture was stirred at room temperature for 3 minutes. Subsequently, compound (28) (100 mg, 0.40 mmol) and [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (5.85 mg, 0.008 mmol) were added.
  • Step 4 Synthesis of Compound (30)
  • the concentrated residue containing the compound (29) was dissolved in methylene chloride (1.5 mL), trifluoroacetic acid (1.6 mL, 20.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated to dryness and purified by silica gel chromatography to obtain compound (30).
  • 1 H-NMR (CDCl 3 ) ⁇ : 9.04 (d, 1H), 8.16 (dd, 1H), 7.54 (d, 1H), 4.21 (q, 2H), 3.97 (s, 2H), 3.16 (q, 2H ), 1.33 (t, 3H), 1.28 (t, 3H).
  • Step 5 Synthesis of compound (31) Compound (30) (22.1 mg, 0.086 mmol) is dissolved in a mixture of THF (0.1 mL) and methanol (0.1 mL), 4M aqueous lithium hydroxide solution (24.8 ⁇ L, 0.10 mmol) is added, and the mixture is stirred at room temperature for 3 hours. did. The reaction solution was concentrated to dryness to obtain a concentrated residue containing compound (31).
  • Step 6 Synthesis of Compound 395 The concentrated residue containing Compound (31) and the concentrated residue containing Compound (27), HATU (37.7 mg, 0.099 mmol) were added to DMF (1 mL) and stirred, and triethylamine (18.3 ⁇ L, 0.132 mmol) was added.
  • Example 12 Synthesis of Compound 466 First Step Synthesis of Compound (32) Diethylmalonate (34.3 mL, 226 mmol) was gradually added to a DMF (300 mL) suspension of sodium hydride (9 g, 226 mmol) in a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 1 hour. Subsequently, compound (31) (20 g, 113 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. A 2M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate.
  • tert-butoxypotassium (5.3 g, 47.5 mmol) was further added and stirred at 0 ° C. for 1 hour, and then tert-butoxypotassium (5.3 g, 47.5 mmol) was further added and stirred at 0 ° C. for 1 hour. did.
  • a 2M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (35) (7.8 g, yield 69.6%).
  • Example 14 Synthesis Step 1 of Compound 420 Synthesis of Compound (39)
  • Compound (38) (10.4 mg, 0.024 mmol) was dissolved in a mixture of THF (0.1 mL) and methanol (0.1 mL), and 4M aqueous lithium hydroxide solution (18.0 ⁇ L, 0.072 mmol) was added. , And stirred at 70 ° C. for 2 hours. A saturated aqueous ammonium acetate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated.
  • Example 15 Synthesis of Compound 469 Copper trifluoromethanesulfonate (41.9 mg, 0.116 mmol) and sodium ethylsulfinate (26.9 mg, 0.232 mmol) were dissolved in DMSO (0.3 mL), and N, N′-dimethylethane-1,2, -Diamine (26.1 ⁇ L, 0.243 mmol) was added and stirred at room temperature for 5 minutes. Subsequently, a solution of compound (40) (30 mg, 0.116 mmol) in DMSO (0.15 mL) was added, and the mixture was stirred at 120 ° C. for 3 hours.
  • Example 16 Synthesis Step 1 of Compound 494 Synthesis of Compound (42)
  • Compound (42) (500 mg, 2.06 mmol) was dissolved in DMF (5 mL), sodium hydride (purity 60%, 99 mg, 2.48 mmol) and 2-bromoacetic acid t-butyl ester (366 ⁇ L, 2.476 mmol). And stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (43) (543 mg, yield 73.8%).
  • Step 2 Synthesis of Compound (44)
  • Compound (44) was obtained from compound (43) in the same manner as in Step 5 and Step 6 of Example 11.
  • Step 3 Synthesis of Compound 494
  • Compound (44) (85 mg, 0.131 mmol) was dissolved in methylene chloride (1.5 mL), TFA (1.5 mL, 19.5 mmol) was added, and the mixture was stirred at room temperature for 30 min. After adding saturated brine, the mixture was extracted with ethyl acetate, and the organic layer was washed again with saturated brine, dried over sodium sulfate, and concentrated.
  • Example 17 Synthesis of Compound 470 From compound (30), compound 470 was obtained in the same manner as in the first, second and third steps of Example 17.
  • Example 18 Synthesis Step 1 of Compound 493 Synthesis of Compound (46)
  • Compound (45) (1.0 g, 6.06 mmol) was dissolved in dichloromethane (12 mL), trimethylcyanide (1.06 mL, 7.87 mmol) and 1M titanium chloride toluene solution (1.30 mL, 1.30 mmol). The mixture was stirred at room temperature for 12 hours and concentrated. The concentrated residue was dissolved in dioxane (15 mL), 12M hydrochloric acid solution (7.5 mL, 90 mmol) was added, and the mixture was heated to reflux for 6 hours.
  • Step 2 Synthesis of Compound (47) Compound (46) (200 mg, 0.951 mmol) was dissolved in dioxane (10 mL), 12M hydrochloric acid solution (5 mL, 60 mmol) was added, sealed, and heated to reflux for 6 hours. Extraction was performed with chloroform, and the organic layer was washed with saturated brine.
  • Test Example 1 Human ROR ⁇ t Reporter Assay A gene fused with human binding binding domain of human ROR ⁇ t and DNA binding domain of GAL4 was introduced into Luc2P luciferase-expressing HEK293 cells to produce a stable expression cell line.
  • a stable expression cell line in which a DMSO solution of the present invention is dispensed at 40-120 nL per well into a 384-well plate and suspended in a medium (DMEM containing bovine serum and antibiotics mixed solution) was seeded at a rate of 20000-24000 per well and cultured at 37 ° C. under 5% carbon dioxide for 20 hours.
  • the reagent of the luciferase quantification system One Glo Luciferase Assay System (Promega) was added at 20 ⁇ L per well and allowed to stand at room temperature for 10 minutes, and then the luminescence of each well was measured with ViewLux (Perkin Elmer). Inhibition of the compound of the present invention was calculated by calculating the concentration (IC 50 ) at which the inhibition rate was 50%, with the value of luminescence intensity without the compound of the present invention being 0% inhibition and 100% inhibition when no cells were added. Activity was evaluated. IC 50 was calculated using Spotfire (manufactured by TIBCO Software).
  • test results of the compounds of the present invention are shown in the following table.
  • the following compounds had an IC 50 of 5 ⁇ M or less.
  • Test Example 2 Human ROR ⁇ t binding test A DMSO solution of the compound of the present invention is dispensed into a 96-well plate in a certain amount (22.5 nL, 45 nL, or 205 nL) per well with an automatic dispensing device, and a measurement buffer (50 mM Hepes- Add 200 nM [3H] -Dixoxin diluted with NaOH (pH 7.4), 150 mM NaCl, 5 mM MgCl 2 , 1 mM DTT, 0.1% BSA) and 20 ⁇ L per well of GST-ROR ⁇ t Ligand Binding Domain. Start and let stand at room temperature for 1-4 hours.
  • a measurement buffer 50 mM Hepes- Add 200 nM [3H] -Dixoxin diluted with NaOH (pH 7.4), 150 mM NaCl, 5 mM MgCl 2 , 1 mM DTT, 0.1% BSA
  • the measured value when the compound of the present invention is not contained is 0% inhibition, 1 to 2 ⁇ M, N- ⁇ 4- (3-chlorophenyl) -5-[(2-chlorophenyl) carbonyl] -1,3-
  • thiazol-2-yl ⁇ -2- [4- (ethylsulfonyl) phenyl] acetamide was added as 100% inhibition, the concentration (IC 50 ) at which the inhibition rate was 50% was calculated, and the inhibitory activity of the compound of the present invention Evaluated.
  • GST-RORgt Ligand Binding Domain was added in such an amount that the measured value in the 0% inhibition condition of this test was about 2000 to 4000 CPM.
  • IC 50 was calculated using Spotfire (manufactured by TIBCO Software). The following compounds had an IC 50 of 0.5 ⁇ M or less.
  • Test Example 3 TPA induction K14. Action in Stat3C Tg mouse psoriasis model A transgenic mouse (K14. Stat3C Tg mouse) in which an active Stat3 (Signal Transducer and Activator of Transcription 3) is constantly expressed in the epidermis under the human Keratin 14 (K14) promoter. use. K14. After shaving of Stat3C Tg mice (6 weeks old, female), 100 ⁇ L of 2 nmol of TPA (12-O-tetradecanoylphorbol-13-acetate, Sigma) acetone solution is shaved once every two days for 10 days. Applying to the eyes causes psoriasis-like dermatitis.
  • TPA (12-O-tetradecanoylphorbol-13-acetate
  • the compound of the present invention is dissolved in acetone (concentration 1 or 5%), and 100 ⁇ L of the solution is applied twice a day every day from the first day to the tenth day. A group to which acetone was similarly applied is taken as a control group.
  • the degree of dermatitis was evaluated for three items: erythema, scale, and skin hardness (classified as score 0 to 6, 0: considered, 1: mild, 3: moderate, 6: severe), and the total was total Calculated as dermatitis score.
  • the skin tissue is removed 3 hours after the final TPA application, and a part thereof is immersed and fixed in a 10% neutral buffered formalin solution for use in histopathological evaluation.
  • Formalin-fixed tissue is stained with hematoxylin and eosin after embedding and slicing, and epidermal thickening is measured by image analysis using Image-Pro Plus.
  • image analysis using Image-Pro Plus.
  • three skin tissues with a diameter of 8 mm were collected and subjected to T-PER (Tissue Protein Extraction Reagent, Thermo Science) including Protease Inhibitor Cocktail (Thermo Scientific). After centrifugation, the amounts of IL-17 and IL-22 contained in the supernatant are measured with an ELISA kit (R & D).
  • Test Example 4 Effect on chick Th17 differentiation Blood was collected from a healthy person, and after adjusting peripheral blood mononuclear cells (PBMC) using Ficoll-Paque PLUS solution (GE Healthcare Japan), naive CD4 T cells were naive. Isolate with CD4 T cell isolation kit II (Miltenyi Biotec) and suspend in XVIVO-20 medium (Lonza). In a 96-well BD biocoat T cell activation plate (anti-human CD3) to which 50 ⁇ L of the compound of the present invention diluted in a medium was added, add 50000 isolated naive CD4 T cells per well. After seeding with 100 ⁇ L, add 50 ⁇ L of Th17 differentiation medium.
  • PBMC peripheral blood mononuclear cells
  • Ficoll-Paque PLUS solution GE Healthcare Japan
  • Th17 differentiation medium 1 ⁇ g / mL anti-CD28 antibody, 2 ⁇ g / mL anti-IL-4 antibody, 2 ⁇ g / mL Anti-IFN- ⁇ antibody, 25 ng / mL IL-23, 25 ng / mL IL-6, 25 ng / mL IL-1 ⁇ , 10 ng / mL TGF- ⁇ . After culturing the cells at 37 ° C.
  • Th17 differentiation medium containing the same concentration of the compound of the present invention
  • IL-2 Immunense, Shionogi & Co.
  • IL-2 is added to a final concentration of 20 U / mL.
  • the cells are washed with a medium, transferred to a 96-well round bottom plate, and cultured for 5 hours in the presence of Leukocyte Activation Cocktail, with BD GolgiPlug (BD Bioscience).
  • IL-17 positive cells were stained with Fixable Viability Dye (eBioscience), subjected to membrane permeabilization with Fixation and Permeabilization Solution (BD Bioscience), stained with fluorescently labeled anti-CD4 antibody and anti-IL-17 antibody (eBioscience), and in CD4-positive living cells The ratio of IL-17 positive cells is analyzed with a BD FACSCanto II flow cytometer.
  • the proportion of IL-17-producing cells is 0% inhibition, and when Th17 differentiation is not induced (anti-CD28 antibody, anti-IL-4 antibody, anti-IFN- ⁇ antibody instead of Th17 differentiation medium)
  • the ratio of IL-17-producing cells (when cultured with the addition of a medium containing only NO) is defined as 100% inhibition, and the concentration (IC 50 ) at which the inhibition rate is 50% is calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the IC 50 is calculated using Spotfire (registered trademark, manufactured by TIBCO Software).
  • Test Example 5 Effect on IL-17 production from chick PBMC Blood was collected from a healthy person, and PBMC was prepared using Ficoll-Paque PLUS solution (GE Healthcare Japan), followed by 10% bovine serum (FBS, Equitech- Bio Inc) -containing RPMI 1640 medium (Life Technologies). After seeding 100 ⁇ L of the prepared PBMC in a 96-well BD biocoat T cell activation plate (anti-human CD3) to which 50 ⁇ L of the compound of the present invention diluted in a medium is added per well, so that there are 100,000 PBMCs per well. Add 50 ⁇ L of medium containing anti-CD28 antibody to a final concentration of 2 ⁇ g / mL. After culturing the cells at 37 ° C.
  • IL-17 is measured by an ELISA kit (R & D). Inhibition of the compound of the present invention was calculated by calculating the concentration (IC 50 ) at which the inhibition rate was 50%, with the amount of IL-17 in the absence of the compound of the present invention being 0% inhibition and the case of not adding cells being 100% inhibition. Assess activity.
  • the IC 50 is calculated using Spotfire (registered trademark, manufactured by TIBCO Software).
  • Test Example 6 Effect on IL-23 Induced Intradermal IL-17 Production 5 ⁇ g / mL with phosphate buffered saline on the dorsal skin after shaving of C57BL / 6 mice (Charles River, 8-9 weeks old, female) Recombinant mouse IL-23 (Wako) diluted 50 ⁇ L is administered intradermally.
  • a solvent Polysorbate 80 / Polyethylene Glycol 400 / 0.5% Carboxymethylethylcellulose and 20
  • Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • resorufin CYP1A2 metabolite
  • a fluorescent multilabel counter or LC / MS / MS
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxylated The body CYP2C19 metabolite
  • dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. Calculated.
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • the bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group.
  • systemic clearance (CLtot) was calculated by dividing the intravenous dose by AUC after intravenous administration.
  • Compound 457 BA 56.2%
  • Test Example 9 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention were reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. .
  • buffer 50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride
  • the reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction).
  • the compound of the present invention in the supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was defined as 100% at 0 minutes. Calculated.
  • the residual ratio of the following compounds was 90% or more.
  • CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction with respect to CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes were used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when the compound of the present invention was added at each concentration was calculated.
  • IC was calculated by inverse estimation using a logistic model. Preincubation 0 min IC / Preincubation 30 min IC was defined as the Shifted IC value, and when the Shifted IC was 1.5 or more, Positive, and when the Shifted IC was 1.0 or less, it was defined as Negative.
  • CYP3A4 Fluorescence MBI Test is a test for examining the enhancement of CYP3A4 inhibition of the compound of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction exists).
  • start the reaction with the part as the indicator.
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system.
  • Is used to calculate IC 50 by inverse estimation using a logistic model. The case where the difference in IC 50 value is 5 ⁇ mol / L or more is (+), and the case where it is 3 ⁇ mol / L or less is ( ⁇ ).
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate:
  • the cells are suspended in 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL) To the MicroF buffer).
  • TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • hERG Test Example 12 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels are used, The action of the compounds of the present invention on the delayed rectifier K + current (I Kr ) playing a role was investigated.
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, and further records the I Kr induced repolarization stimulation of -50mV when given 2 seconds.
  • Test Example 13 Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. A 10 mmol / L compound solution is prepared in DMSO. 2 ⁇ L of the compound solution of the present invention is added to 198 ⁇ L of JP-1 solution and JP-2 solution, respectively, or 6 ⁇ L of the compound solution of the present invention is added to JP-1 solution and JP-2 solution 594 ⁇ L, respectively. After standing at 25 ° C. for 16 hours (condition 1) or shaking at room temperature for 1 hour (condition 2), the mixed solution is filtered with suction.
  • the composition of JP-1 solution is as follows. Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
  • the composition of JP-2 solution is one of the following.
  • Composition 1 About 200 mL of 0.2 mol / L sodium hydroxide test solution is added to 200 mL of 0.2 mol / L potassium dihydrogen phosphate test solution to adjust the pH to 6.8, and then 600 mL of water is added.
  • Composition 2 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate are dissolved in water to make 1000 mL.
  • Composition 3 1.40 g of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.
  • Test Example 14 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution ( Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL, add 1 volume of water to 1 volume), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (Add JP-2 solution to 1.08 g of TCA to make 100 mL) 200 ⁇ L each. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added.
  • JP-1 solution 2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL
  • JP-2 solution Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous diso
  • the mixture is filtered, and 100 ⁇ L of methanol is added to 100 ⁇ L of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsules The compound of the present invention, lactose and calcium stearate are mixed and mixed uniformly to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are mixed, mixed well, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally Disintegrating Tablets The compound of the present invention and crystalline cellulose are mixed and compressed after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry Syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to prepare an injection.
  • Formulation Example 7 Instillation Compound of the present invention and phosphate buffer are mixed to prepare an injection.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to obtain an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A base such as the compound of the present invention and an adhesive plaster is mixed to obtain a patch.
  • the compound represented by the formula (I) has ROR ⁇ t inhibitory action and is considered useful for diseases involving ROR ⁇ t, for example, autoimmune diseases.

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Abstract

Cette invention concerne des composés ayant des effets inhibiteurs de RORγt représentés par la formule (I). Composés représentés par la formule (I) (où L représente -NR1ACO-, -SO2- ou autres, A représente un groupe carbocyclique aromatique substitué ou non, ou autre, R1, R2, R3a, R4a, R3b et R4b représentent un atome d'hydrogène ou un alkyle substitué ou non, ou autre, m vaut de 0 à 2, n est 0 ou 1, le cycle B représente un cycle carbocyclique aromatique, un cycle hétérocyclique aromatique, etc., R1A représente un atome d'hydrogène, etc., E représente SO2R10A, etc., R10A représente un alkyle substitué ou non, etc., X représente =CR9- ou =N-, R5 et R8 représentent un atome d'halogène, un hydroxy, etc., R9 représente un atome d'hydrogène, un atome d'halogène, un hydroxy, etc., R6 et R7 représentent un atome d'hydrogène, un atome d'halogène, un alkyle substitué ou non, etc., p vaut de 0 à 4 et q, de 0 à 3) ou sels pharmaceutiquement acceptables de ceux-ci.
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WO2018138356A1 (fr) * 2017-01-27 2018-08-02 Genfit Modulateurs de rorgamma et leurs utilisations
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WO2019088057A1 (fr) * 2017-10-31 2019-05-09 東レ株式会社 Dérivé d'anilide et son utilisation médicale
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US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
CN113072521A (zh) * 2020-01-06 2021-07-06 广东东阳光药业有限公司 RORγt抑制剂及其在药物中的应用
CN113072542A (zh) * 2020-01-06 2021-07-06 广东东阳光药业有限公司 RORγt抑制剂及其制备方法和用途
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US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
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WO2025054431A1 (fr) * 2023-09-07 2025-03-13 Xenon Pharmaceuticals Inc. Composés hétérocycliques à cycles benzéniques fusionnés et leurs utilisations
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WO2021228215A1 (fr) * 2020-05-15 2021-11-18 上海辉启生物医药科技有限公司 COMPOSÉ BIARYLE CAPABLE DE SERVIR DE RÉGULATEUR DE RORγ
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WO2023232870A1 (fr) 2022-05-31 2023-12-07 Immunic Ag Modulateurs de rorg/rorgt pour le traitement d'infections virales de type covid-19
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