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WO2018116285A1 - Dérivés de morpholine substitués en tant que modulateurs de ror gamma - Google Patents

Dérivés de morpholine substitués en tant que modulateurs de ror gamma Download PDF

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Publication number
WO2018116285A1
WO2018116285A1 PCT/IB2017/058391 IB2017058391W WO2018116285A1 WO 2018116285 A1 WO2018116285 A1 WO 2018116285A1 IB 2017058391 W IB2017058391 W IB 2017058391W WO 2018116285 A1 WO2018116285 A1 WO 2018116285A1
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ethylsulfonyl
benzyl
disease
morpholino
fluoro
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V. S. Prasada Rao Lingam
Laxmikant Atmaram Gharat
Neelima Khairatkar-Joshi
Daisy Manish Shah
Malini Bajpai
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • WO2012/100732, WO2012/100734, WO2012/064744, WO2013/171729 and WO 2015/008234 discloses heterocyclic compounds which are modulators of retinoid-related orphan receptor gamma (RORy) receptor activity.
  • RORy retinoid-related orphan receptor gamma
  • X 1 is O
  • the invention also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
  • the present invention relates to a method of treating a disease, disorder or condition modulated by RORyt, such as chronic obstructive pulmonary disease (COPD), asthma, cough, pain, inflammatory pain, chronic pain, acute pain, arthritis, osteoarthritis, multiple sclerosis, rheumatoid arthritis, colitis, ulcerative colitis and inflammatory bowel disease, comprising administering to a subject in need thereof a compound according to any of the embodiments described herein.
  • COPD chronic obstructive pulmonary disease
  • hydroxyCi-salkyl refers to an Ci-salkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi-4alkyl).
  • hydroxyCi-4alkyl moieties include, but are not limited to - CH2OH and -C2H4OH.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, iso
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • compositions described herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the compounds of the present invention are particularly useful because they inhibit the activity of retinoid-related orphan receptor gamma, particularly retinoid-related orphan receptor gamma t (RORyt), i.e., they prevent, inhibit, or suppress the action of RORyt, and/or may elicit a RORyt modulating effect.
  • RORyt retinoid-related orphan receptor gamma
  • Compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of ROR gamma activity, and particularly RORyt, is required.
  • the compounds of the present patent application are modulators of RORyt and can be useful in the treatment of diseases/disorder mediated by RORyt. Accordingly, the compounds and the pharmaceutical compositions of this invention may be useful in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORyt.
  • autoimmune diseases will be understood by those skilled in the art to refer to a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
  • An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ, and changes in organ function.
  • An autoimmune disorder may affect one or more organ or tissue types which include, but are not limited to, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, joints, muscles, red blood cells, and skin.
  • autoimmune (or autoimmune-related) disorders include multiple sclerosis, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, gastrointestinal disorder, inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, Sjorgen's syndrome, atopic dermatitis, optic neuritis, respiratory disorder, chronic obstructive pulmonary disease (COPD), asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain- Barre syndrome, psoriatic arthritis, Gaves' disease, allergy, osteoarthritis, Kawasaki disease, mucosal leishmaniasis, Hashimoto's thyroiditis, Pernicious anemia, Addison's disease, Systemic lupus erythematosus, Dermatomyositis, Sjogren syndrome, Lupus erythematosus, Myasthenia gravis, Reactive arthritis, Celiac disease - spru
  • inflammation will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white.
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this present patent application, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may be used for treatment of arthritis, including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
  • arthritis including, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, collagen-induced arthritis (CIA) and other arthritic conditions.
  • the compounds of the present invention may be used for treatment of respiratory disorders including, but are not limited to, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and cough.
  • COPD chronic obstructive pulmonary disease
  • asthma asthma
  • bronchospasm bronchospasm
  • cough cough
  • the compounds of the present invention may further be used for treatment of gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
  • gastrointestinal disorder such as, but not limited to, irritable bowel syndrome, inflammatory bowel disease, colitis, ulcerative colitis, biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with gastrointestinal distension.
  • the compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of Atopic dermatitis and psoriasis.
  • the compounds of the present invention may be useful in a treatment of disease, disorder, syndrome or condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma and cough.
  • COPD chronic obstructive pulmonary disease
  • Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula (I) or (II) or a pharmaceutically-acceptable salt thereof, to a subject (particularly a human) in need thereof.
  • the present inventions further relates to the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by RORyt.
  • the compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered may vary with the compound employed, the mode of administration, the treatment desired and the disorder.
  • the daily dosage of the compound of the invention administered may be in the range from about 0.05 mg/kg to about 100 mg/kg.
  • the starting materials used herein are commercially available or were prepared by methods known in the art to those of ordinary skill or by methods disclosed herein.
  • the intermediates and compounds of the present invention can be prepared through the reaction schemes as follows.
  • the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and cleavage of protecting groups etc., by following procedures known in the art of organic synthesis.
  • the acid-amine coupling of acid compound of formula (1) with amine compound of formula (2) in the presence of a suitable coupling agent(s) and suitable base gives compound of formula (I).
  • the suitable coupling agent(s) may be l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) in the presence of HOBt, NN'-dicyclohexylcarbodiimide (DCC), propyl phosphonic anhydride
  • T3P or (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-&]pyridinium-3-oxid hexafluorophosphate) (HATU).
  • the suitable base used in the reaction may be Et 3 N, DIPEA, pyridine or DMAP.
  • the acid amine coupling reaction may be carried out in a suitable solvent such as dichlorome thane, CHCb, DMF and THF or mixture thereof.
  • a general approach for the preparation of compounds of formula (la) (wherein R 1 , R 2 , 'm', and 'n' are as defined with respect to a compound of formula (I)) is depicted in synthetic scheme 2.
  • substitution reaction of appropriate isomer (R or S) of substituted 2-amino-2-phenylethanol compound of formula (3)* with chloroacetyl chloride of formula (4) in the presence of a suitable base and solvent yields the chloro acetamide derivative of formula (5).
  • the suitable base for the reaction may be triethylamine, DIPEA, or pyridine and the solvent can be selected from dichloromethane, THF, chloroform or dichloroethane * [Substituted 2-amino-2-phenylethanol compound of formula (3) can be synthesized following the procedure described in Tetrahedron- Asymmetry. 2011, 22, 329-337].
  • the chloro acetamide derivative of formula (5) undergoes intramolecular cychzation in the presence of a suitable base such as sodium hydride or potassium teri-butoxide in a suitable solvent to afford 5-phenylmorpholin-3-one derivative of formula (6).
  • the suitable solvent for the reaction may be THF or teri-butanol.
  • suitable reducing agent such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride solution (RED-A1), in a suitable solvent such as THF or toluene, yields the corresponding 3-phenylmorpholine derivative of formula (7).
  • the solvent used in the reaction may be IPA.
  • the ester derivative of formula (9) on hydrolysis in the presence of a suitable base and solvent furnishes the desired aryl carboxylic acid derivative of formula (la).
  • the suitable base used in the reaction may be lithium or sodium hydroxide and solvent may be selected from ethanol, methanol, THF, water or combination thereof.
  • the base used for the reaction may be potassium hydroxide and the solvent can be selected from 1,4-dioxane, toluene, DMF, water or combination thereof.
  • the suitable solvent for the reaction may be ethanol, water or combination thereof.
  • Alkylation of the thiol (14) with ethyl bromide in the presence of a suitable base and solvent affords the thio-ether (15).
  • the suitable base for the reaction may be potassium carbonate or cesium carbonate and solvent may be selected from THF, DMF, DMSO, etc.
  • the compound (15) on oxidation in the presence of 3-chloroperbenzoic acid (MCPBA) yields the sulfonyl derivative (16).
  • the oxidation reaction can be carried out in a suitable solvent such as dichloromethane.
  • the reductive amination of the cyano group of compound (16) using ammonia under hydrogen pressure in the presence of a suitable catalyst such as Raney nickel, in a suitable solvent followed by salt formation with hydrochloric acid (gas) affords the 4- (ethylsulfonyl)phenyl)methanamine hydrochloride of formula (2).
  • the suitable solvent for the reductive amination reaction may be ethanol or methanol.
  • the reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was dried well to yield 9.2 g of the titled product. The compound was as such forwarded to the next step without characterization.
  • Step 1 intermediate O-ethyl 2-((4-cyanophenyl)thio)ethanethioate (Step 1 intermediate) (18.2 g, 76.8 mmol) in ethanol (20 mL) was added a solution of potassium hydroxide (9.0 g, 161 mmol) in water (10 mL) at RT and the mixture was refluxed overnight.
  • the reaction mixture was diluted with water and acidified with dilute hydrochloric acid till pH 3-4.
  • the aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine.
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 9.7 g of the desired product.
  • the compound was as such forwarded to the next step without characterization.
  • Step 2 intermediate 4-mercaptobenzonitrile (Step 2 intermediate) (9.7 g, 72.4 mmol) in DMF (20 mL) were added potassium carbonate (20 g, 145 mmol) and ethyl bromide (8.15 mL,109 mmol) at RT under nitrogen atmosphere. The reaction mixture was stirred for 4 h at RT. The reaction mixture was diluted with water extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 8.5 g of the desired product.
  • Step 3 intermediate 4-(ethylthio)benzonitrile (Step 3 intermediate) (8.5 g, 52.14 mmol) in dichloromethane (70 mL) was added 3-chloroperbenzoic acid (55-75% w/w, 41.5 g, 156 mmol) in small portions at RT under nitrogen atmosphere. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with water extracted twice with ethyl acetate and the combined organic layers were washed twice with 5% sodium hydroxide solution followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 intermediate 4-(ethylsulfonyl)benzonitrile (Step 4 intermediate) (1.0 g, 5.12 mmol) in methanol (30 mL) was added Raney nickel (500 mg) and aqueous ammonia (2.0 mL) at RT. The mixture was subjected to hydrogenation in a Parr apparatus under 60 psi hydrogen pressure for 1 h. The reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography. The free base was stirred with hydrochloric acid in ethyl acetate to yield 513 mg of the desired product as HC1 salt.
  • Step 1 (5)-2-Chloro-N-(2-hydroxy- l-phenylethyl)acetamide
  • Step 1 intermediate To a stirred solution of (5)-2-chloro-N-(2-hydroxy-l-phenylethyl)acetamide (Step 1 intermediate) (8.7 g, 40.7 mmol) in anhydrous THF (50 mL) was added sodium hydride (60% w/w, 1.96 g, 48.9 mmol) in small portions at 20 °C under nitrogen atmosphere. The mixture was stirred for 30 min at RT. The mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate.
  • Step 2 intermediate To a stirred solution of (5)-5-phenylmorpholin-3-one (Step 2 intermediate) (3.0 g, 19.9 mmol) in anhydrous THF (40 mL) was added lithium aluminum hydride (2.57 g, 67.8 mmol) in small portions at 0 °C under nitrogen atmosphere. The mixture was warmed to 45 °C and stirred for 5 h at the same temperature. The mixture was quenched with saturated aqueous sodium sulfate solution. Ethyl acetate was added to the aqueous mixture and stirred for 10 min. The suspension was filtered through celite and the filtrate was dried over anhydrous sodium sulfate.
  • Step 4 (S)-Methyl 2-(3-phenylmorpholi oxylate
  • Step 3 intermediate To a stirred solution of (5)-3-phenylmorpholine (Step 3 intermediate) (200 mg, 1.24 mmol) in IPA ( 10 mL) was added methyl 2-bromothiazole-5-carboxylate (274 mg, 1.24 mmol) at RT under nitrogen atmosphere. The reaction mixture was heated at 95 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 109 mg of the titled product.
  • Step 4 intermediate To a stirred solution of (S)-ethyl 2-(3-phenylmorpholino)thiazole-5-carboxylate (Step 4 intermediate) (100 mg, 0.33 mmol) in ethanol (5.0 mL) was added a solution of sodium hydroxide (52 mg, 1.30 mmol) in water (2.0 mL) at RT and the mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid till pH 3- 4. The aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine.
  • Step 1 intermediate To a stirred solution of (i?)-2-chloro-N-(2-hydroxy-l-phenylethyl)acetamide (Step 1 intermediate) (3.6 g, 16.8 mmol) in anhydrous THF (30 mL) was added sodium hydride (60% w/w, 741 mg, 18.5 mmol) in small portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min at RT. The mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dried well to obtain 1.55 g of the desired product.
  • Step 2 intermediate To a stirred solution of (i?)-5-phenylmorpholin-3-one (Step 2 intermediate) (4.15 g, 23.4 mmol) in anhydrous THF (30 mL) was added lithium aluminium hydride (3.55 g, 93.8 mmol) in small portions at 0 °C under nitrogen atmosphere. The mixture was warmed to 45 °C and stirred for 5 h at the same temperature. The mixture was quenched with saturated aqueous sodium sulfate solution. Ethyl acetate was added to the aqueous mixture and stirred for 10 min. The suspension was filtered through celite and the filtrate was dried over anhydrous sodium sulfate.
  • Step 1 2-Chloro-N-((i?)-2-hydroxy- 1 -phenylethyl)propanamide
  • step 1 intermediate 2-chloro-N-((i?)-2-hydroxy- l -pheny lethyl)propanamide (step 1 intermediate) (2.5 g, 10.9 mmol) in feri-butanol (30 mL) was added potassium feri-butoxide (2.46 g, 21.9 mmol) at RT and the mixture was stirred for 1.5 h at RT. The mixture was quenched with dilute hydrochloric acid and concentrated under reduced pressure to obtain a sticky solid. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to yield 1.2 g of the desired compound.
  • step 2 intermediate To a stirred solution of (2i?,5i?)-2-methyl-5-phenylmorpholin-3-one (step 2 intermediate) (1.1 g, 5.75 mmol) in anhydrous toluene (15 mL) was added sodium bis(2-methoxyethoxy)aluminum hydride solution (Red-Al) (60% in toluene, 1 1.6 mL, 34.5 mmol) at 0 °C under nitrogen atmosphere and the mixture was stirred overnight at RT. The reaction mixture was quenched with 2M sodium hydroxide solution, diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.
  • Red-Al sodium bis(2-methoxyethoxy)aluminum hydride solution
  • the titled compound was prepared by the reaction of (2i?,5i?)-2-methyl-5-phenylmorpholine (step 3 intermediate) (250 mg, 1.41 mmol) with ethyl 6-chloronicotinate (0.32 mL, 2.11 mmol) as per the procedure described in step 4 of Intermediate 4 to yield 157 mg of the compound.
  • ESI-MS m/z 327 (M+H) + .
  • Step 5 6-((2i?,5i?)-2-Methyl-5-phenylmorpholino)nicotinic acid
  • the titled compound was prepared by the reaction of ethyl 6-((2i?,5i?)-2-methyl-5- phenylmorpholino)nicotinate (145 mg, 0.44 mmol) with sodium hydroxide ( 177 mg, 4.44 mmol) in a mixture of ethanol and water (2: 1, 15 mL) as per the procedure described in step 5 of Intermediate 4 to yield 109 mg of the compound.
  • Step 1 (R) -3 -Fluoro-4- (3 -phenylmorpholino)benzonitrile
  • IPA 2.0 mL
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue thus obtained was purified by silica gel column chromatography to yield 82 mg of the titled product.
  • Step 1 intermediate To a stirred solution of (i?)-3-fluoro-4-(3-phenylmorpholino)benzonitrile (Step 1 intermediate) (75 mg, 0.27 mmol) in 1 ,4-dioxane (3.0 mL) was added a solution of potassium hydroxide ( 149 mg, 2.65 mmol) in water (3.0 mL) at RT and the mixture was stirred at 120 °C for 2 days. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid till pH 3-4. The aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine.
  • Test compounds or reference compounds such as T0901317 were dissolved in dimethyl sulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration.
  • DMSO dimethyl sulfoxide
  • the final concentration of DMSO in the reaction was 4% (v/v).
  • the assay mixture was prepared by mixing ⁇ of the GST- tagged ROR gamma ligand binding domain (LBD) in the assay buffer containing 25 mM HEPES, 100 mM NaCl, 5mM DTT and 0.01 % BSA and 10% Glycerol with or without the desired concentration of the compound.
  • LBD GST- tagged ROR gamma ligand binding domain

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Abstract

La présente invention concerne des composés de formule (I) et leurs sels pharmaceutiquement acceptables, le noyau A, R1, R2, R3, X1, X2, m et n étant tels que définis dans la description, qui sont actifs en tant que modulateurs du récepteur orphelin lié au rétinoïde gamma t (RORγt). Les composés de la présente invention empêchent, inhibent ou suppriment l'action du RORγt et sont donc utiles pour traiter des maladies, des troubles, des syndromes ou des états pathologiques à médiation par le RORγt tels que, par exemple, la douleur, l'inflammation, la BPCO, l'asthme, la polyarthrite rhumatoïde, la colite, la sclérose en plaques, le psoriasis, les maladies neurodégénératives et le cancer. (I)
PCT/IB2017/058391 2016-12-23 2017-12-23 Dérivés de morpholine substitués en tant que modulateurs de ror gamma Ceased WO2018116285A1 (fr)

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WO2020035557A1 (fr) 2018-08-17 2020-02-20 Leo Pharma A/S Nouveaux modulateurs hétéroaromatiques du récepteur gamma orphelin associé au rétinoïde
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CN113072538A (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
CN113072546A (zh) * 2020-01-06 2021-07-06 广东东阳光药业有限公司 五元杂芳衍生物及其制备方法和用途
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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
CN115043828A (zh) * 2022-07-27 2022-09-13 黑龙江中医药大学 一种用于治疗鼻窦炎的药物及其制备方法

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WO2020011147A1 (fr) * 2018-07-10 2020-01-16 Sunshine Lake Pharma Co., Ltd. ANTAGONISTE DE RORγ ET SON UTILISATION EN MÉDECINE
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WO2020035557A1 (fr) 2018-08-17 2020-02-20 Leo Pharma A/S Nouveaux modulateurs hétéroaromatiques du récepteur gamma orphelin associé au rétinoïde
CN113166061A (zh) * 2018-11-27 2021-07-23 正大天晴药业集团股份有限公司 含有磺酰基结构的RORγ抑制剂
WO2020108538A1 (fr) * 2018-11-27 2020-06-04 正大天晴药业集团股份有限公司 INHIBITEUR DE RORγ À STRUCTURE SULFONYLE
CN113166061B (zh) * 2018-11-27 2023-11-21 正大天晴药业集团股份有限公司 含有磺酰基结构的RORγ抑制剂
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EP4089079A4 (fr) * 2020-01-06 2024-03-13 Sunshine Lake Pharma Co., Ltd. Inhibiteur de ror gamma t, son procédé de préparation et son utilisation
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WO2021139595A1 (fr) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 INHIBITEUR DE RORγT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
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US20230121086A1 (en) * 2020-01-06 2023-04-20 Sunshine Lake Pharma Co., Ltd. RORgT INHIBITOR, PREPARATION METHOD THEREOF AND USE THEREOF
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